ASH 2010: Payers' Perspectives by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

ASH 2010: PAYERS’ PERSPECTIVES AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS

Photo by Curtis Compton, courtesy of the American Society of Hematology.

February 2011 I Vol 4, No 1 I SPECIAL ISSUE

Pharmacoeconomics: Hematologists Should Prepare for the Coming Debate on Costs versus Benefits By Neil Canavan

A Hal E. Broxmeyer, PhD, Distinguished Professor of Microbiology and Immunology, Indiana University School of Medicine, addressing attendees at the ASH 2010 Annual Meeting in Orlando.

European or Canadian approach to making formulary decisions is the inevitable future. In other words, costs must be weighed against benefits, according to Joseph Mikhael, MD, of the Mayo Clinic, AZ, a self-described “healthcare economics wonk,” who spoke at a session at the 2010 American Society of Hematology’s annual meeting on the new pharmacoeconomics in cancer care.

Dr Mikhael suggested that the audience consider that “US medical insurance costs are rising faster than earnings and general inflation.” Bevacizumab, approved for lung and colon cancers, costs $4000 to $9000 per month. Cetuximab, which is approved for colon and head and neck cancers, costs $17,000 per month. Many physicians are uncomfortable with discussing drug price; they are supposed to be their patients’ ultimate Continued on page 6

Hematology Drug Pipeline Is Robust

Healthcare Reform Addresses Quality of Care for Americans

Novel Therapies with Promising Options

Oncologist and Policy Expert Dispels Many Myths

By Caroline Helwick

tudies presented at the 2010 annual meeting of the American Society of Hematology suggest that patients with multiple myeloma (MM), lymphoma, and chronic myelogenous leukemia (CML) may have new treatment options in the future that offer outcomes superior to current therapies when used individually or in combination with current therapies. Some of the products described in this article are supported by pivotal or phase 2b data, whereas others are only in early-phase testing and are included because experts consider them so

promising, as was emphasized at the meeting. Multiple Myeloma Current treatment for MM is very effective but not curative. Two drugs in preliminary testing that have shown impressive survival rates and attracted much attention at the meeting are elotuzumab and pomalidomide. Elotuzumab, a humanized monoclonal antibody directed against the CS1 antigen, combined with lenalidomide and dexamethasone, achieved a very high response rate (81%) in the Continued on page 26

Ezekiel J. Emanuel, MD, PhD

he richer the nation, the more it spends on healthcare, “but the US is phenomenally off the chart,” spending a total of $2.4 trillion annually, or $7300 per person in 2007. By contrast, the next biggest spenders are Switzerland and Norway, and

Continued on page 7

IN TH IS ISSUE HEALTH ECONOMICS . . . . . . . . . . .6 Healthcare survival depends on innovation Thrombotic microangiopathies total $227.4 million annually New outpatient treatment criteria for PE can cut costs NON-HODGKIN LYMPHOMA . .13 Rituximab effective in several combinations and in asymptomatic patients HODGKIN LYMPHOMA . . . . . . .15 Brentuximab promising Rx for refractory disease

they spend 40% less, said Ezekiel J. Emanuel, MD, PhD, then-Special Advisor for Health Policy in the Office of Management and Budget, and Chair of the Department of Bioethics at the National Institutes of Health.

LEUKEMIA . . . . . . . . . . . . . . . . .16 Imatinib enhances overall survival in ALL Excellent outcomes with nilotinib Ponatinib makes a splash MULTIPLE MYELOMA . . . . . . . . Bortezomib-based induction emerging as new standard Promising drugs in the pipeline

MYELODYSPLASTIC SYNDROMES . . . . . . . . . . . . . . . 25 First population-based MDS drug comparison OTHER HIGHLIGHTS . . . . . . . . 26 Incorporating genomic research into personalized medicine

in su 3 y pr rviv ea M evi al r o ul ou ad ve tip s v ra le ly u an ll M nt tag ye re e lo at m ed a

If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT IMPORTANT 3-YEAR 3-YEAR UPDATEUPDATE- S SUSTAINED USTAINED B BENEFIT ENEFIT UPDATED VISTA* ISTA* O OVERALL SURVIVAL OS) A ANALYSIS: NALYSIS: V VcMP vs M MP P U PDATED V VERALL S URVIVAL ((OS) cMPâ&#x20AC; vs (36.7-month (36.7-month median median follow-up) follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% PPatients atients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Months Kaplan-Meier K aplan-Meier estimate. estimate.

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

Please see Brief Summary for VELCADE on the next page of this advertisement.

www.VELCADE.com

Brief Summary INDICATIONS: VELCADE (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. ®

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. MA 02139Company. Cambridge, MA 02139 Millennium Pharmaceuticals, Inc., Cambridge, The Takeda Oncology 10 Millennium Pharmaceuticals, Inc. Copyright ©2009, V-10-0204 10 All rights reserved. Printed in USA V1215 12/09

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HEALTH OUTCOMES RESEARCH

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Health Economics

Pharmacoeconomics: Hematologists Should Prepare... advocate, not bean counters, he said. Yet Dr Mikhael insists that to be completely oblivious to drug cost is to do a disservice to other patients and to society at large. “It’s not about saying that a cancer drug is too expensive, therefore, it is not cost-effective. That’s not the point,” Dr Mikhael pointed out. Rather, the price has to be considered within the context. He explained pharmacoeconomics as defining the context, quantifying the spectrum of effects experienced by an average patient with a given drug, and putting a dollar amount to the overall outcome. How to derive this figure is the focus of many of Dr Mikhael’s considerations when thinking about limited healthcare budgets. The key is to use a method that accounts for the quantity of a therapeutic response (eg, delayed disease progression), the patient’s quality of life (QOL) during treatment, and, of course, the financial cost. Furthermore, this calculation must be applicable across all disease states. “The goal of health economics is to provide infor-

To this end, there is the determinant of quality-adjusted life-year (QALY). In brief, a QALY is a single unit measure that factors in life expectancy and the quality of those remaining years. Derived with already validated QOL instruments, a QALY is then expressed as a single number (1 = a year of perfect health; 0 = death). Differing numeric weights are assigned to differing health states, thereby accounting for pain and suffering. For example, with intervention A, the patient has 4 years of life in a health state of 0.75, or 3 QALYs; with intervention B, 4 years in a health state of 0.5 is equal to 2 QALYs. At this point, cost is not related to this expression of efficacy, and “what most people want to hear is the ICER [incremental cost-effectiveness ratio],” he said. The ICER is the ratio of change in cost to the change in effect. Expressed as a dollar amount, and historically set as the cost of treating a patient with dialysis for 1 year, it is how, combined with QALY, the “worth” of a given intervention is perceived. Of

“The goal of health economics is to provide information to key stakeholders so they can make decisions in the context of evidence-based medicine and policy.” —Joseph Mikhael, MD mation to key stakeholders so they can make decisions in the context of evidence-based medicine and policy,” said Dr Mikhael.

Continued from page 1

note, this value is not comparative across nations; the threshold of “worth” in the United Kingdom is approximately $35,000 per QALY; in the United States, it is roughly $100,000 per QALY. “QALY is an expression of what we as a society are willing to pay for, given the result,” he said. As yet, payers in the US healthcare system cannot refuse reimbursement based on the above calculation. It is primarily used now as a marketing tool, illustrating “bang for the buck.” But as stated by Dr Mikhael, “This is real science, and like it or not, it’s coming to a theater near you.” It is critical that healthcare providers, who often do not even feel equipped to have such discussions, familiarize themselves with the terms of the coming debate, Dr Mikhael emphasized. Future therapies will likely have to prove themselves—to governments, to payers, and to patients—to be cost-effective. “If we as clinicians bury our heads in the sand, someone else is going to determine how we practice.” ■

Labor Costs Reduced with Pegfilgrastim versus Comparator By Caroline Helwick

he prophylactic use of recombinant human granulocyte colony-stimulating factor (GCSF)—including filgrastim daily for up to 2 weeks per chemotherapy cycle and pegfilgrastim once per cycle— decreases the incidence of febrile neutropenia and is a well-established strategy. Cancer delivery models, however, are under pressure to become more efficient in an increasingly cost-restrictive environment, said Douglas Taylor, of i3 Innovus, Medford, MA. “Little is known regarding the use of practice resources necessary to deliver

therapy. We constructed an empirical model to calculate the human resource time and cost associated with the delivery of filgrastim and pegfilgrastim,” Mr Taylor said. The study team used a practicelevel model to detail staff tasks required during 1 month in administering G-CSF. Specific clinic characteristics were included (eg, number of patients receiving G-CSF, number of filgrastim injections per cycle, hourly pay rates for staff). The study team interviewed 400 medical professionals at 20 US community oncology practices to provide

data for the time and personnel required for tasks, such as scheduling, front desk, phlebotomy, laboratory, triage, injection, and billing.

“Future medical care delivery models should consider practice resource requirements as a means of increasing efficiency.” —Douglas Taylor The costs of the drugs were not included in the model. The case-based

Table Monthly Time and Cost-Savings of Using Pegfilgrastim Compared with Filgrastim Prophylaxis strategy Filgrastim injections/cycle, N

Filgrastim, treating 1 patient/mo 6

Nurse hrs, N

9.4

17.3

Clerk hrs, N

5.7

Total hrs, N

Once-per-cycle pegfilgrastim injection

Filgrastim, treating 30 patients/mo

Once-per-cycle pegfilgrastim injection

1.5

283

519

10.4

0.9

170

311

15.1

27.7

2.5

453

830

Opportunity cost with pegfilgrastim,a hrs

12.6

25.2

378

756

Cost, $

365

668

10,945

20,066

Opportunity cost with pegfilgrastim,a $

305

609

9151

18,271

Filgrastim minus pegfilgrastim.

AMERICAN HEALTH & DRUG BENEFITS

February 2011

1795

scenarios contrasted 1 patient versus 30 patients per month. The use of pegfilgrastim resulted in substantial savings in a comparison with filgrastim given as either 6 or 11 injections per cycle and in scenarios based on 1 or 30 patients per month (Table). The 30-patient model predicted that monthly costs were more favorable with pegfilgrastim than with 6 and 11 days of filgrastim, respectively: • Staff hours were reduced from 756 to 378 • Staff costs were reduced from $18,000 to $9000. On a per-patient basis, the monthly opportunity costs were more favorable for pegfilgrastim than for filgrastim, respectively: • Staff hours were reduced from 25 to 13 hours • Staff costs were reduced from $600 to $300. “The use of pegfilgrastim as compared with filgrastim was associated with substantial savings in time and labor costs,” Mr Taylor said, acknowledging that the model did not include the cost of purchasing the drugs. “We think that future medical care delivery models should consider practice resource requirements as a means of increasing efficiency and costeffectiveness.” ■

VOL. 4

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Health Economics

Healthcare Reform Addresses... Most spending goes toward hospital care and physician services, which comprise about 10% of the total healthcare cost. “We are not getting tremendous healthcare outcomes for all this money,” said Dr Emanuel, himself an oncologist, who was the invited speaker on healthcare reform at ASH 2010. “Despite much higher spending, the US ranks 12th [worldwide] for males and 16th for females in life expectancy at age 65.” Quality of Care Is an Issue in America, Except in Cancer In terms of overall quality, cancer care is an example of where quality in the United States is high, Dr Emanuel acknowledged. The CONCORD study (Coleman MP, et al. Lancet Oncol. 2008;9:730-756) looked at the quality of cancer care in 31 countries, measured by 5-year survival rates, and ranked the United States second in breast cancer, first in prostate cancer (but this may reflect lead time bias), and third in colorectal cancer. Within the United States, there is substantial variation in cancer outcomes. But guideline-defined care is frequently not delivered, he said. The RAND Corporation has found that Americans receive only 55% of recommended care. Good disease control has been noted for just 65% of patients with hypertension, 54% with asthma, and 39% with communityacquired pneumonia. “Quality of care is an issue for all Americans,” Dr Emanuel said. New Act Addresses Many Serious Problems The Patient Protection and Affordable Care Act (ACA) aims to make this situation better. Passage of the ACA was a “world historical event,” having been attempted by 5 previous presidents over 100 years before being accomplished by the Obama administration. But despite its promise to increase coverage to approximately 94% of the American populace (resulting in 32 million fewer uninsured persons), criticism has been abundant and the repeal efforts continue, he maintained. Some of this rancor may stem from misinterpretations and myths about the act, which Dr Emanuel set straight in his presentation.

Myth 1: The Reform Is 90% Coverage and Only 10% Cost Control “Healthcare reform will try almost every major idea to reduce healthcare costs....Many provisions will reduce

the amount of spending on healthcare,” Dr Emanuel pointed out. The greatest reductions will come from the following reductions in spending: • Reduction of payment update factor ($196 billion) • Cutting overpayment to Medicare Advantage ($136 billion) • Administrative simplification ($20 billion) • Use of generic biologics ($7 billion) • Enforcement of fraud and abuse ($3 billion) • Payment change for complex imaging procedures ($1.2 billion). In addition, other provisions will slow the growth rate in spending, including the “Cadillac tax”; patientcentered outcomes research; hospital 30-day admission policy (ie, penalties imposed when patients are readmitted as a result of inadequate care); reduction in hospital-acquired infections and conditions; and the use of medical homes, accountable care organizations, and bundled payments.

Myth 2: Even If Passed, the Cost Control Provisions Will Never Be Implemented • Reducing payment for high-cost imaging services is in the 2011 Medicare physician fee schedule • Reducing payment updates for outpatient, hospital, and ambulatory surgical centers is in the 2011 Outpatient Hospital Prospective Payment Rules • Pay as you go compels Congress not to add to the federal deficit when instituting new spending or tax changes. Myth 3: Healthcare Reform Will Cost Americans “Reform will not add to the budget or budget deficit,” he emphasized, predicting more than $100 billion in savings by 2020. He noted that unlike Medicare Part D, healthcare reform is “completely, totally paid for” with new resources and offsets. “Healthcare reform is likely to be even cheaper than anticipated if cost controls work and healthcare inflation is lower, reducing Medicare and Medicaid outlays and subsidies,” Dr Emanuel added. “I think these reforms will have a synergistic effect.” Myth 4: All the Important Parts of Reform Don’t Happen until 2014 or Later “This is partly true,” he acknowledged. “But if hospitals, physicians, insurers, and others behave like my Harvard undergraduates, and wait until the night before the due date and

Continued from page 1

“We are not getting tremendous healthcare outcomes for all this money….Despite much higher spending, the US ranks 12th [worldwide] for males and 16th for females in life expectancy at age 65.” —Ezekiel J. Emanuel, MD, PhD

pull an all nighter, they will fail and fail miserably.” Changes, therefore, were gradually initiated even before the ACA’s passage. What Reform Will Mean for Cancer Care Changes in the healthcare delivery system, including the field of oncology, will occur in 3 main areas: information (using new technologies, primarily financial incentives for installing electronic health records, and comparative effectiveness research), infrastructure (using medical homes and accountable care organizations), and incentives (using bundled payments and other financial and quality instruments). The ACA creates and funds the Patient-Centered Outcomes Research Institute to generate comparative effectiveness data. Up to $600 million per year will be directed toward this effort, based on $2 per insured person per year. The institute has broad representation from researchers, physicians, nurses, drug and device companies, and insurers. “Initial research will be very important to prevent politicization and charges of rationing,” Dr Emanuel noted. “The results will be a ‘public good.’ Get ready for a flood of data,” he told attendees. All these policies

aim to transform the delivery system to produce more coordinated care, better tertiary prevention, reduced specialty services and procedures, and reduced hospitalizations. Bundled payments may be the most striking change oncologists will experience, but Dr Emanuel put this in positive terms. “We have lots of guidelines, which will be used to determine bundled payments. This gives you flexibility in managing patients as you see fit to provide optimal care,” he said. Oncologists will benefit through improved health information technology. They will have financial incentives to install interoperable electronic health records that will enhance patient care through meaningful use. Administrative tasks should be simplified, and the burden and cost of billing should decrease, Dr Emanuel said. “For your patients, healthcare reform means better efforts at prevention,” he pointed out. This includes better coverage of breast, colon, and cervical cancer screening tests with no copays and the reduction and eventual elimination of the Medicare Part D doughnut hole. It will include a campaign for positive lifestyle changes. Patients with cancer will particularly benefit through the elimination of preexisting conditions exclusions, and the elimination of rescissions and Continued on page 8

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Health Economics

Healthcare Practice Forum: Survival Depends on Innovation By Neil Canavan

ffering a range of advice for survival in the challenging environment of recent and ongoing healthcare reform, a panel of physicians and businessmen described the innovative means by which they have adapted their hospital-based practices, multispecialty group practices, and single-specialty group practices. William C. Rupp, MD, Chief Executive Officer of the Mayo Clinic, Jacksonville, FL, shared his experience with hospitals. “There is not going to be more money in the system,” he said. “We’re going to have to figure out how to do what we do with the money that’s out there.” And the money that is out there must not be squandered; Dr Rupp estimates that 30% to 40% of operational cost results from waste. Recapturing those dollars means delivering healthcare in new and innovative ways, and to do that, the successful leader must foster a culture that is receptive to change. “The first thing you can do is give up on the idea that you’re the smartest person in the room,” he suggested. In Dr Rupp’s experience, the vast majority of viable, practicechanging ideas come from the frontline staff; they do the work, and they often know how best it can be done, he pointed out. Receiving a new idea may also require listening to an unfamiliar voice. Dr Rupp actively seeks out

diverse opinions. “I know when I surround myself with people who think the way I do, I’m heading for financial disaster.”

“There is not going to be more money in the system. We’re going to have to figure out how to do what we do with the money that’s out there.” —William C. Rupp, MD

Implementing change requires a measure of faith. For example, frequent monitoring of a task that has

Healthcare Reform... Continued from page 7 the annual and lifetime limits. The act also mandates coverage of routine costs of clinical trials. Oncologists Can Participate in Lowering Costs The oncology community has a big role to play to enhance reform and to personally benefit by it, he told attendees. “Oncologists should get their offices wired and use the financing that is available for installing electronic medical records,” he said. “You must develop quality indicators that go beyond screening percentages, and that extend to surgery, the delivery of radiotherapy, and the delivery of chemotherapy. We must also make sure these quality indicators can be collected electronically.” Physicians should also develop treatment guidelines and protocols that incorporate criteria for lower cost for the same or better quality out-

comes, he added. “Where there are diagnostic and therapeutic options that are equivalent, we should prioritize by total cost and ease of use,” he said. “For palliative radiation therapy, we should use shorter courses of treatment that are equivalent from the perspective of pain relief, less inconvenience for patients, and lower cost.” Bundled payments should also be guideline-driven with physician input. These will be used by payers to determine reimbursement for common hematologic conditions such as lymphomas, sickle-cell disease, anticoagulation therapy, and leukemias. In moving forward, the healthcare community will be “fostering innovation, rethinking and modernizing how we provide cancer care,” Dr Emanuel said. “For 50 years, most care has been hospital-focused. We are rethinking this: continuity of care should become the standard.” ■

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February 2011

been officially handed off is not delegating, it is micromanaging, he said. Dr Rupp also suggests that the failure of new processes should be “celebrated.” “Go to your staff tomorrow and ask them for a list of things they’ve tried in the last month that have not worked,” he said. “If they can’t give you a list, you’re not trying hard enough to innovate.” He added that change does not always necessitate new software, but is often implemented with a pencil and paper. Nor should the testing of innovations be time-consuming. “I’ve seen situations where a change was repeatedly tested over a period of 3 months,” he said. “So I asked, ‘Were the results any different at 3 months than they were at 1 week?’ Usually not.” Large Single-Specialty Practice Thomas Marsland, MD, of Orange Park, FL, shared specific measures implemented in his large, single-specialty practice, many of which can be described as pay attention to detail, he said. First, establish charge capture via an audit. “If you miss billing for 1 dose of Procrit, it will take 9 or 10 more administrations to make up the difference in what you lost,” Dr Marsland pointed out. “Did you collect the copay? Did you collect the coinsurance? That’s money left on the table. In one audit we found $100,000, and it was in things that were easy to miss, like putting down 1 unit when it was really 10—simple stuff.” Cost control begins at the first patient encounter. “We’ve instituted a policy where every new patient meets with a financial counselor before he receives any treatment, so the patient knows what the copay will be,” he said, adding that his staff makes the patient’s responsibilities clear and treats responsibly. “Our business office must sign off on a treatment program before it goes to the nurse. This minimizes off-label denials, which are increasingly common.” For the larger picture, Dr Marsland summarized his strategy with the famous line from the movie Jaws: “We’re going to need a bigger boat.” In today’s environment, he said, size matters. To that end, Dr Marsland and colleagues expanded services, bringing on board radiation oncologists, imaging equipment and staff, laboratory services, and so on. “Going forward we have to get

paid for what we do,” he emphasized. “Profits from drugs are gone. We have to be reimbursed for managing and taking care of patients.”

“Profits from drugs are gone. We have to be reimbursed for managing and taking care of patients.” —Thomas Marsland, MD

Multispecialty Group Practice Stuart Feldman, MD, of White Plains, NY, represented the multispecialty group practice. Having formed a group of 16 physicians in 1996, Dr Feldman’s physician-owned organization now employs 180 physicians from 20 different specialties, who are housed in 160,000 square feet of space that includes an ambulatory surgical center, 2 urgent care centers, imaging facilities, and a pathology laboratory —in other words, “a big boat.” “One-stop total healthcare keeps patients coming through the door,” Dr Feldman told attendees. The size of the organization provides leverage when negotiating fees with carriers, and its structure is leveraged for synergy (eg, radiation oncologists use inhouse facilities); referrals to other physicians can all be retained within the organization. “These are profit centers,” Dr Feldman stressed, “and the profits are then distributed among the shareholders in the form of bonuses. This is a relatively new concept in physician compensation.” Of note, and as indicated by the first question in the question and answer session, there was an 800-pound hematologist in the room: “Am I to understand from these presentations that private practice is dead?” The subject of the question and its frustrated tone occupied the remaining minutes of the forum. The moderator, Lawrence A. Solberg Jr, MD, PhD, of the Mayo Clinic, Jacksonville, FL, fervently stated that it was not the American Society of Hematology’s official position that private practice should be abandoned, but rather that solutions for private practice were not so obvious. He did advise that alliances with state and/or regional professional societies would be a good first step. ■

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Health Economics CMS Policy on VTE Prophylaxis Places New Burden on Hospitals By Caroline Helwick

he Centers for Medicare & Medicaid Services (CMS) denies reimbursement for preventable hospital-acquired conditions, including venous thromboembolism (VTE) in patients undergoing a total knee replacement or hip replacement/ revision. In cases where the VTE is secondary to hospital procedures, CMS reimburses the hospital only for the surgical procedure. A study presented at ASH 2010 suggests that this policy may not be cost-saving and, in fact, may cost hospitals about $8500 annually in lost revenue per VTE diagnosis. The study used patient discharge data from the Thomson Reuters MarketScan Hospital Drug Database, which contains hospital administrative data from more than 580 acute-care hospitals in the United States. Frequency of CMS-defined symptomatic VTE was assessed among patients undergoing total knee replacement or hip replacement/revision. This included deep-vein thrombosis (DVT) and pulmonary embolism (PE).

“When a VTE event occurs, it is associated with high incremental hospital costs.” —Steven Deitelzweig, MD The analysis included 109 mediumto-large nonteaching hospitals in urban areas. The total number of surgical knee or hip discharges was 26,144, with an average of 244 discharges per hospital. VTE occurred on average in 4.3 patient discharges per hospital. These included DVT in 2.4 discharges and PE in 1.8 discharges. Cost to the Hospital The costs to the hospital accrue from several areas. The mean length of hospital stay was 7.6 days for surgical knee or hip discharges in which a VTE occurred compared with 4.1 days in discharges without a VTE. In patient discharges where DVT and PE had occurred, anticoagulant use was recorded in 94.7% and 89.1% of patients, respectively. The mean number of days of anticoagulation was 5.1 for DVT and 6.1 for PE, reported Steven Deitelzweig, MD, of Ochsner Clinic Foundation, New Orleans. The cost per discharge without a DVT event was approximately $15,000, rising to nearly $18,000 when a DVT occurred. All factors considered, the incremental (additional) cost of the DVT per discharge was $6751. For PE, the costs were much greater, approaching $25,000, and resulting in an incre-

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mental cost of $8092 when not prevented, Dr Deitelzweig reported. “The CMS HAC [hospital-acquired conditions] policy for VTE in patients undergoing total knee replacement or hip replacement or revision, on average, caused a loss of hospital revenue,” Dr Deitelzweig said. “When a VTE

event occurs, it is associated with high incremental hospital costs. Under the new CMS HAC policy, these significant costs will no longer be reimbursed. Subsequently, hospitals will be responsible for covering them.” “Therefore, reducing the incidence of VTE through appropriate prophy-

laxis of at-risk patients is vital in order for hospitals to lessen the economic burden associated with treating VTE events,” Dr Deitelzweig suggested. “The drive to encourage hospitals to provide more efficient and effective healthcare is becoming particularly relevant now.” ■

ARZERRA HCPCS Code J9302 Announcing a NEW J-Code for ARZERRA ARZERRA will have a permanent HCPCS code effective January 1, 2011 The new J9302 Code replaces miscellaneous HCPCS Codes J9999, J3590, J3490, and C9260 that most providers have used to bill for ARZERRA to date

HCPCS code

Description

Effective

J9302

Injection, ofatumumab, 10mg

January 1, 2011

Contact your GSK representative for additional information or visit www.ARZERRA.com.

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Health Economics

Economic Analysis of Pleural Effusions in CML

SEE ALSO Leukemias, pages 16-18.

By Caroline Helwick

n patients with chronic myeloid leukemia (CML), the development of pleural effusions escalates cost beyond the direct expense of treating the effusion, according to the Analysis Group, in association with researchers from the University of Texas M. D. Anderson Cancer Center. Patients with CML plus pleural effusions incurred significantly higher resource utilization and total healthcare costs compared with those free of pleural effusions, as a result of not only the management of the effusion but also a higher use of medical services associated with complicated CML. The substantial economic burden of pleural effusion indicates a need for vigilant monitoring for its signs and symptoms, the investigators suggested. Especially, patients with CML treated with tyrosine kinase inhibitors (TKIs) (ie, imatinib, nilotinib, or dasatinib) who have cardiovascular disease or hypertension would benefit from being closely monitored, because these conditions have been shown to

increase the risk of pleural effusions. “For CML, the standard of care is oral TKIs, but pleural effusions can be an adverse event related to this treatment. This requires medical care, may

is necessary. But these costs are probably underestimates, Ms Guerin said, because they do not take into account the impact of CML on TKI treatment. The current study aimed to consider

“Patients with pleural effusions had about 3 times more inpatient admissions, and 6 times more inpatient days….[They] had an adjusted incremental cost difference of $43,668 over 6 months.” —Annie Guerin, MSc

compromise the course of CML treatment, and has economic consequences….Much of the costs relates to the need to interrupt TKI treatment,” said Annie Guerin, MSc, who presented the data at the meeting. The cost of managing TKI-associated pleural effusions has been estimated to be $2062 to $2700 and from $6400 to $9000 when an invasive procedure

the full economic burden. The study was based on the Ingenix Impact and Medstat MarketScan administrative claims databases, which together represent 85 million individuals in 176 health plans. Investigators matched characteristics between patients with CML treated with a TKI who developed pleural effusions (n = 186) and those who did not (n = 186).

The propensity score was calculated on all relevant available demographic and disease information. The patients with effusions used significantly more resources and incurred significantly more costs. After adjusting for confounding factors, patients with effusions had more allcause CML-related inpatient days and admissions, outpatient visits, other medical services, and emergency care visits. “Patients with pleural effusions had about 3 times more inpatient admissions, and 6 times more inpatient days,” she said. This led to significantly greater healthcare costs; over 6 months, the total healthcare cost was $105,715 for a patient with pleural effusions versus $49,621 for one without. Total CMLrelated costs were $67,879 versus $32,892, respectively. “Patients with pleural effusions had an adjusted incremental cost difference of $43,668 over 6 months,” Ms Guerin noted. ■

Thrombotic Microangiopathies Total $227.4 Million Annually First Ever In-Hospital Utilization Data for This Disease

n the first national examination of the burden of in-hospital care for thrombotic microangiopathies, investigators from the Children’s Hospital of Pittsburgh concluded that the disease costs the healthcare system $227.4 million annually. Although hospitalization rates have fallen over time, costs have increased significantly, reported Ashish Gupta, MD. Thrombotic microangiopathies are a category of pathologies that result in thrombosis in capillaries and arterioles. This process leads to thrombocytopenia and a variety of other symptoms. Data were used from the Nationwide Inpatient Sample (NIS), a part of the Healthcare Cost and Utilization Project. The NIS is the largest allpayer inpatient database in the United States and gives a stratified probability sample of 20% of all hospital discharges among community hospitals, Dr Gupta said. In 1997, estimated thrombotic microangiopathy–related visits totaled 1.35 per 100,000 population; this number decreased to 0.79 per 100,000 visits in 2006. However, there was a steady increase in hospitalizations from 1997

“These data suggest that there has been a significant increase in the cost of in-hospital healthcare utilization between 1997 and 2006, representing a significant length of stay and mortality.” —Ashish Gupta, MD to 2002, followed by a decreasing trend from 2004 to 2006. The mortality rate resulting from

AMERICAN HEALTH & DRUG BENEFITS

February 2011

thrombotic microangiopathy was reported to be 9.4% of total hospitalizations in 2006 compared with 8.8%

in 2003. Women were significantly more affected than men across all agegroups and had a significantly higher rate of hospitalization (P <.01) in 2006 compared with 1997. The mean duration of hospitalization was 13.4 days in 2006, with an average hospital charge of $106,512 per patient, which was a significant increase from $88,079 in 2003 and $54,083 in 1997, Dr Gupta reported. The disease contributed to an aggregate charge of $227.4 million to the national healthcare cost in 2008 compared with $210.3 million in 2003 and $93.7 million in 1997. Hospital charges for therapeutic plasmapheresis for thrombotic microangiopathy increased from $72.8 million in 2003 to $88.15 million in 2006. “We are presenting the first national data of the burden of inhospital healthcare utilization of thrombotic microangiopathies in the United States. These data suggest that there has been a significant increase in the cost of in-hospital healthcare utilization between 1997 and 2006, representing a significant length of stay and mortality,” Dr Gupta concluded.—CH ■

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Health Economics

Stem-Cell Transplantation: Safety, Economic Concerns By Neil Canavan

ighlighted during a press conference at ASH 2010, 2 studies addressed long-standing questions regarding stem-cell transplantation. In the first study—presented by Alexander Schmidt, MD, PhD, of the DKMS German Bone Marrow Donor Center, Tubingen, Germany—an attempt was made to settle the recently raised issue regarding the longterm safety of hematopoietic stem-cell donation by individuals who are unrelated to the patient. “This is a somewhat unusual circumstance in that it is an altruistic act by donors; therefore, donor safety is of the highest importance,” Dr Schmidt said. To evaluate the long-term safety of such transplantation, Dr Schmidt and colleagues surveyed 15,456 individuals who had donated peripheral blood

tional years after transplantation, making it the largest-ever donor follow-up study. Overall, the donors were found to be in excellent health, the donor groups were generally equally healthy, and the rate of malignancies was no higher than expected in the general population. Dr Schmidt emphasized the low risk for malignancy. This issue was first mentioned in the British Journal of Haematology (Bennett CL, et al. 2006; 135:642-650), which expressed concern that the use of granulocyte colony-stimulating factor for stemcell mobilization might increase the risk for developing hematologic malignancies. As the story circulated and anxiety grew in the community, the need to respond to the article became clear.

“All transplantation is expensive, but cord blood is much more so because of the cost recovery that’s required from the cord banks.” —Joseph Antin, MD stem cells or bone marrow before January 2010. The rate of return for the questionnaire exceeded all expectations, with more than 12,000 (81%) individuals responding. The results reflected 55,299 observa-

Dr Schmidt said that these unfounded concerns have been put to rest by these new findings. The survey also documented that 95% of respondents indicated their willingness to donate again.

Double Up on Cord Blood, but at What Cost? A second study, presented by Vanderson Rocha, MD, PhD, focused on the amount of cord blood required in the setting of acute leukemia. “Cord blood transplantation is an important option, and one that is being actively pursued in the United States because of the need for racially diverse donors,” Dr Rocha said. Approximately 30% of patients in need of transplantation lack a wellmatched, unrelated adult peripheral blood stem-cell donor. Experience has suggested that with cord blood, match criteria need not be as stringent. Once cord blood is obtained, however, the question arises, “What works better, 1 or 2 units?” “A favorable outcome depends on the number of cells transplanted,” he said. The minimum threshold is 2.5 ¥ 107 cells/kg; below this number, mortality risk is very high. “Early efforts demonstrated higher graft-versushost disease,” said Dr Rocha, “but lower relapse rates were the result.” Dr Rocha retrospectively assessed the outcomes of 377 single-unit and 270 double-unit cord blood recipients. Although there was a significant increase in acute graft-versus-host disease in the double-unit cohort, rates for 2-year incidence of relapse in patients in their first complete remission favored the use of 2 units. The results of the study clearly

Alexander Schmidt, MD, PhD

demonstrated the use of 2 units, but the utility of the observation is problematic: a single unit of cord blood costs upward of $35,000, Dr Rocha said. Commenting on the issue at a press conference, Joseph Antin, MD, Chief, Stem Cell Transplantation Program, Harvard Medical School, said, “All transplantation is expensive, but cord blood is much more so because of the cost recovery that’s required from the cord banks.” Typing cord blood is expensive, as are storage and the related administration aspects. Because transplantations are relatively rare, cord blood banks must keep a large inventory to sell just a few units. “We were thinking about putting up a cord blood bank in Massachusetts, but it was estimated to take 10 years to break even at the current costs,” Dr Antin said. ■

New Outpatient Treatment Criteria for Pulmonary Embolism Can Cut Expenses

he current standard therapy for patients with pulmonary embolism (PE) is initial inpatient treatment with low-molecularweight heparin (LMWH). However, several 2008 case studies highlighted in the American College of Chest Physicians Antithrombotic Therapy Guidelines suggest that outpatient treatment for PE is potentially safe and effective. The guidelines, however, lack easy-to-use criteria for selecting candidates for outpatient treatment. Reporting their findings at the late-breaking trials session, the Hestia study investigators proposed just such criteria (Table). In an investigation that involved multiple treatment centers in the Netherlands, 338 patients with acute PE were triaged with the predefined Hestia criteria for eligibility

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for outpatient treatment starting with therapeutic weight-adjusted doses of LMWH. Individuals selected for outpatient care (n = 297) were sent home either immediately or within 24 hours after the diagnosis of PE. At 6 weeks, patients were rescreened with the Hestia criteria and monitored for recurrent venous thromboembolism (VTE) or major bleeding at 3 months. Only 2% of the evaluable patients had a recurrence of VTE, and only 0.7% had a major bleed. These results compared favorably to historical rates for outpatients, estimated at up to 6.2% for VTE and as much as 1.2% for major bleeding, noted Wendy Zondag, MD, of Leiden University Medical Centre in the Netherlands. “Outpatient treatment was at

Table Hestia Study Criteria Question

Responsea

Patient hemodynamically unstable

Yes/No

Thrombolysis or embolectomy necessary

Yes/No

Active bleeding or high risk for bleeding

Yes/No

>24 hours of oxygen supply to maintain oxygen saturation >90%

Yes/No

Pulmonary embolism diagnosed during anticoagulant treatment

Yes/No

Severe pain needing intravenous pain medication >24 hours

Yes/No

Treatment in the hospital >24 hours

Yes/No

Creatinine clearance <30 mL/min

Yes/No

Severe liver impairment

Yes/No

Currently pregnant

Yes/No

Documented history of heparin-induced thrombocytopenia

Yes/No

If one of the questions is answered with YES, the patient cannot be treated at home in the Hestia study.

least as effective as treatment of patients in the hospital,” Dr Zondag said. Although she did not state it out-

right, the potential savings by avoiding hospitalization costs are clearly implied for this strategy.—NC ■

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Health Economics

Economic Benefits of Novel Dosing for Rasburicase By Caroline Helwick

asburicase is a recombinant urate oxidase approved for the prevention of tumor lysis syndrome, an oncologic emergency that leads to a host of metabolic disturbances that can result in acute renal failure and death. Currently, rasburicase is US Food and Drug Administration (FDA)-approved for the management of hyperuricemia in patients with malignancies and can prevent tumor lysis syndrome. In adults, the recommended dose is 0.2 mg/kg intravenously daily for up to 5 days, which translates into >$5100 for treatment of a 75-kg person. At ASH 2010, several studies suggested that lower doses can be just as effective, and the cost saved would be substantial.

Low Dose versus Standard Dose Investigators from the Mayo Clinic, Rochester, MN, evaluated the effectiveness of the 0.1-mg/kg dose compared with the recommended dose in the prevention of tumor lysis syndrome. The population included all patients with a hematologic or oncologic diagnosis (N = 125) between 2003 and 2009 who received rasburicase on the first day of chemotherapy. The drug was dosed at either 0.1 mg/kg (low dose) or 0.2 mg/kg (standard

ysis, because dialysis was often precipitated for hyperkalemia and hyperphosphatemia, which rasburicase does not affect,” Dr Eirin said. “Despite bias, our results suggest low-dose rasburicase may be a viable alternative and the potential savings could be enormous.”

“The cost of rasburicase is a problem for us. We found that using a single dose could save our hospital a lot of money.” —Barbara Yim, PharmD, BCOP dose) because of variations in practice. Rasburicase was repeated as necessary. Additional doses were required in 14.6% of the low-dose patients and 21.4% of the standard-dose patients, which was not a significant difference. Although reduction in uric acid was higher with the standard dose (97.1% vs 88.7%; P = .002), renal outcomes were similar.

Table Costa of Single-Dose versus Weight-Based Rasburicase Cost per patient, $ Total cost (30 events), $ Total savings, $

Dosing Single 4.5-mg dose regimen

1919

53,549

FDA-approved 5-day regimen

31,988

959,655

906,106

a Cost is calculated using August 2010 AmeriSource Bergen Bluebook average wholesale price. One 1.5-mg vial of rasburicase costs $639.77. For a 75-kg patient dosed at 0.2 mg/kg, the costs would be approximately $6397 and $31,988 for a 1-dose and 5-day therapy, respectively. FDA indicates US Food and Drug Administration.

“The low-dose patients received an average of 6 mg per dose versus 12 mg in the standard group. This represents a savings of $2601 per patient,” said Aflonso Eirin, MD. For a 75-kg patient, treatment with the standard dose costs $6504, whereas the reduced dose costs only $3252 per treatment. Renal insufficiency was noted only in the standard-dose patients: 7.4% versus 0% (P = .05). Rates of dialysis were similar between the low-dose (7.3%) and standard-dose (18.6%) groups (P = .07). Dialysis was often initiated for hyperkalemia and hyperphosphatemia. Only 12.5% of doses were started for elevations in serum creatinine. “Our results suggest that low-dose rasburicase may be as effective as 0.2 mg/kg. Although high-dose rasburicase was more effective at reducing uric acid, it did not reduce the need for dial-

Single-Dose Approach Effective and Less Expensive Since rasburicase came to market, various studies have examined single doses (3 mg and 6 mg) in the adult population in an effort to find a dosing regimen that is as effective as the FDAapproved dose but is less expensive. A single-center study evaluated a 4.5-mg dose for its ability to lower uric acid levels versus the conventional weight-based approach and to determine its cost-effectiveness (Table). The results were reported by Barbara Yim, PharmD, BCOP, of the John H. Stroger, Jr. Hospital of Cook County, Chicago. “The cost of rasburicase is a problem for us. We found that using a single dose could save our hospital a lot of money,” Dr Yim commented. The retrospective study included 25 patients with hematologic malignancies receiving chemotherapy or planning to initiate chemotherapy within 24 hours of rasburicase administration. Patients at low risk for tumor lysis syndrome were excluded. A total of 30 hyperuricemic events occurred, and 93% of these were successfully managed with the single dose of rasburicase. Three patients required a second dose to achieve response. Responders were defined as patients achieving >50% reduction in the uric acid level at 24, 48, or 96 hours. ■

Are Cost Analyses Presented at ASH Shortchanged? By Neil Canavan

ublications of cost-effectiveness analyses (CEAs) presented at annual meetings of the American Society of Hematology (ASH) were found to be few, of suboptimal quality, and largely industry-sponsored, according to a study presented at ASH 2010 by Lee Mozessohn, MD, of the University of Toronto. Dr Mozessohn and colleagues examined ASH abstracts from 1997 to 2007 that focused on malignancies and reported outcomes in either incremental cost-effectiveness ratios (ICERs) or quality-adjusted life-years (QALYs), both adjusted to US dollars. To assess the quality of reporting,

indicators associated with well-performed CEAs were derived from literature standards. The subsequent publication of an abstract was established with a MEDLINE search, and time to publication was determined using Kaplan-Meier analysis. (Author affiliation was also extracted.) A total of 29 abstracts met inclusion criteria. Of those, only 13 were subsequently published (44.8%), of which all but 1 had determined an ICER below the accepted cost-effectiveness threshold of $100,000/QALY for the study regimen (median $33,000/QALY). “Most of the studies we looked at from ASH over the 10-year period were

AMERICAN HEALTH & DRUG BENEFITS

February 2011

quite favorable in terms of the costeffectiveness ratio,” Dr Mozessohn said in an interview. Overall, 55.2% of abstracts indicated industry sponsorship, and for the years after 2001, when ASH instituted a policy of disclosure reporting, the rate was 72.7%. The indicators of reporting a societal perspective, lifetime horizon, or sensitivity analysis were noted in only 37.9%, 24.1%, and 62.1% of abstracts, respectively. No quality indicator predicted time to publication; however, abstracts reporting favorable ICERs had a more timely publication, although this trend was not significant.

Dr Mozessohn concluded that, although there was no direct evidence of bias in ASH abstracts selected for publication, most reported very favorable ICERs, and the authors were consistently affiliated with the pharmaceutical industry. Cost-analyses are clearly needed, especially in these days of comparative effectiveness research. However, with the current economic situation, it is unlikely to get funding for such analyses from independent or public groups. Complete transparency of financial support or potential conflict of interest is therefore key to ensuring the quality of such research. ■

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Non-Hodgkin Lymphoma

Rituximab Effective in Several Treatment Combinations for Patients with Lymphoma By Neil Canavan

ituximab has become an indispensable agent in the treatment of non-Hodgkin lymphoma (NHL). At ASH 2010, several investigative groups reported data on various combinations using this very effective agent. The Groupe d’Etude des Lymphomes de l’Adulte (GELA) study looked at the use of rituximab in combination with a reduced-dose version of CHOP (cyclophosphamide, Adriamycin [doxorubicin], vincristine, and prednisolone; R-mini-CHOP) for patients with lymphoma who were aged ≥80 years. This age-group represents a growing number of patients with NHL. “In Western Europe, an 80-year-old man presently has a remaining 9.5 years of life expectancy,” said Frederic Peyrade, MD, of the Centre Antoine Lacassagne, Nice, France. “That means that by 2050, there will be twice as many individuals in this age bracket as there are now—and that will represent greater than 15% of the overall population.”

Rituximab/Bendamustine versus Rituximab/Fludarabine Under the guidance of Mathias J. Rummel, MD, PhD, of Klinikum der Justus-Liebig Universität, Giessen,

Germany, the Study Group of Indolent Lymphomas (StiL) reported final results for NHL 2-2003, which examined the use of rituximab in combination with bendamustine (R-Bd), an

alkylating agent available for many years in Europe but not approved in the United States until 2008. NHL 2-2003 compared this combination (R-Bd) with a standard regimen Continued on page 14

“Even with these very old patients [≥80 years], obtaining the best response possible remains crucial in terms of overall survival.” —Frederic Peyrade, MD

GELA enrolled 149 patients with treatment-naïve, diffuse large B-cell lymphoma. The scheduled treatment for GELA was R-mini-CHOP every 21 days for 6 cycles. After a median follow-up of 20 months, the overall response rate was an impressive 74%, with 40% of patients having a complete response; this success translated into a 2-year survival rate of 59%. Despite the observed discontinuation rate (n = 41) for various reasons, serious life-threatening toxicities (grade 3-4) were not common and generally occurred within the first treatment cycle. Commenting on these robust responses, Dr Peyrade stated, “It means that even with these very old patients, obtaining the best response possible remains crucial in terms of overall survival.” In general, he said, these results indicate that even elderly patients (≥80 years) should be considered for treatment.

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Non-Hodgkin Lymphoma

Rituximab Shows Benefit in Asymptomatic Follicular Lymphoma Early Treatment Can Delay Chemotherapy By Caroline Helwick

esearch has shown little benefit for treating patients with follicular lymphoma who have not developed symptoms, but a key study at ASH 2010 found that an early course of rituximab can help defer chemotherapy for nearly 3 years. “Follicular lymphoma is a slowgrowing cancer that is usually widespread when it is diagnosed. It is generally considered to be incurable, and patients have an average life expectancy of 10 to 12 years. Many people feel very well when they are first diagnosed and do not have any symptoms. We know from previous studies that there is no benefit in starting treatment early when patients have no symptoms compared to waiting until symptoms develop,” said Kirit M. Ardeshna, MD, of University College London Hospitals. As a result, most physicians normally defer treatment and monitor patients closely until the disease progresses, usually at around 2.5 years, although a growing number of clinicians in the United States have already begun treating patients early with rituximab. This new study supports that practice, Dr Ardeshna said.

“Our study has shown that we can defer chemotherapy by a long time in patients who have asymptomatic follicular lymphoma….I imagine this will become the standard of care.” —Kirit M. Ardeshna, MD He added that while watchful waiting delays the side effects of treatment, it creates anxiety in many patients. Study Details The study randomized 462 patients into 3 treatment arms: • Watch and wait (n = 186)

• Rituximab (375 mg/m2) weekly for 4 weeks (rituximab induction) (n = 84). This arm was closed midway through the trial because of slow recruitment and because several other studies were showing a benefit to rituximab maintenance • Rituximab induction followed by rituximab maintenance (n = 192). The latter consisted of 1 dose of rituximab given every 2 months for 2 years, starting at month 3 until month 25. After a median follow-up of 3 years, there was a very significant difference in the time to initiation of new therapy between the 2 rituximab groups and the watch-and-wait group. Only 48% of patients in the watch-and-wait arm had not started chemotherapy or radiotherapy, whereas 80% of patients in the rituximab induction arm and 91% of patients in the rituximab maintenance arm were free of treatment. Median time to initiation of chemotherapy was not reached at 4 years, Dr Ardeshna reported at the plenary session. “Our study has shown that we can defer chemotherapy by a long time in patients who have asymptomatic follicular lymphoma,” Dr Ardeshna com-

On January 28, 2011, the FDA approved rituximab as a maintenance treatment for patients with advanced follicular lymphoma who responded to initial therapy with this drug plus chemotherapy. The European Commission approved rituximab for this indication in October 2010.

mented. He predicted that such an approach will prove attractive to patients, “because they can defer chemotherapy and avoid the side effects for a longer time. I imagine this will become the standard of care.” The new data come from “a very high-quality study” and show there is a clear advantage to starting rituximab therapy early, even before symptoms arise, said Charles Abrams, MD, of the University of Pennsylvania. The study did not, however, show an improvement in overall survival for those receiving early rituximab therapy. At 3 years, 96% of patients in both arms were still alive. Quality-of-life issues also were not addressed. These 2 factors will be examined in future research as well as whether patients treated early with rituximab will respond well to chemotherapy once they need it, although Dr Ardeshna believes that early treatment will not compromise outcomes later on. “We are going to be following these patients, and the study will be ongoing for several years. We are in this for the long-term,” he said. ■

Rituximab Effective in Several... Continued from page 13 of rituximab/fludarabine (R-F). The purpose of the study was a so-called noninferiority determination between the 2 therapeutic approaches, with secondary considerations being those of response rate, event-free survival, overall survival, and toxicity. A total of 219 patients with a variety of lymphomas were enrolled in the trial, with the most common conditions being follicular (47%), mantle cell (21%), and Waldenström’s macroglobulinemia (12%). The majority of the population started treatment while already experiencing advanced disease, and two thirds had received at least 1 previous treatment. Results for the R-Bd combination were favorable compared with R-F, with an overall response rate of 82% and 49%, respectively. Complete responses were observed in 39% of patients with R-Bd versus 16% with R-F; and the partial response rate also skewed toward the R-Bd combination—43% versus 33%. In addition,

event-free survival was 30.4% for RBd and 11.2% for the standard R-F comparator. The most robust response was observed in patients with follicular lymphoma.

“This is important for me that the patients with the higher risk to progress still do better with the combination.” —Bertrand Coiffier, MD, PhD

Commenting on the observed side effects for R-Bd, Dr Rummel noted that grade 3-4 events were uncommon, and the primary complaints were nausea and fatigue. There were a few more instances of infectious complications in the R-Bd treatment arm, but the difference was not significant, and no dose reductions were required to fulfill study treatment protocol.

AMERICAN HEALTH & DRUG BENEFITS

February 2011

There was no difference in overall survival between the 2 combinations; however, the NHL 2-2003 protocol was amended mid-study to implement the newly established paradigm of 2 years of rituximab maintenance after initial treatment. It is uncertain what effect, if any, this had on the comparisons of eventual outcome for study patients. Rituximab/Bortezomib Bortezomib, which is currently indicated for use in multiple myeloma and advanced mantle-cell lymphoma, was combined with rituximab (R-Bt) in a large, phase 3 trial that enrolled patients with relapsed, rituximab-naïve, or rituximab-sensitive follicular lymphoma. Results for the R-Bt combination versus rituximab alone were reported by Bertrand Coiffier, MD, PhD, of the Hospices Civils de Lyon, France. The study randomized 676 patients with advanced follicular lymphoma to either rituximab alone or to the R-

Bt combination. Patients were treated for 25 weeks and followed for a median of 33.9 months. As expected, as a result of advanced disease, discontinuation rates in this study were high (29%); however, the response was good in light of considerable pretreatment—63% for the combination versus 49% for rituximab alone. Differences in progression-free survival, however, were slight—12.8% for R-Bt versus 11% for rituximab alone. Significant difference was found in patients with the worst baseline prognosis. “This is important for me that the patients with the higher risk to progress still do better with the combination,” said Dr Coiffier. Toxicity for R-Bt was higher than for rituximab alone, but symptoms were transient and not life-threatening. Based on these results, Dr Coiffier hopes that future efficacy could be boosted with a combination of R-Bt-CHOP. ■

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Hodgkin Lymphoma

Brentuximab on the Horizon for Relapsed/Refractory Hodgkin Lymphoma May Lead to Treatment Paradigm Change By Caroline Helwick

ased on very encouraging phase 2 trial results, the investigational monoclonal antibody conjugate brentuximab vedotin seems headed for the marketplace for the treatment of relapsed or refractory Hodgkin lymphoma. In a study presented at the meeting, brentuximab vedotin achieved dramatic responses in patients who have virtually no treatment options. The drug manufacturers plan to seek regulatory approval for this product in early 2011 for the treatment of Hodgkin lymphoma and anaplastic large-cell lymphoma. Of the 102 patients with high-risk refractory or relapsed Hodgkin lymphoma, 75% achieved an objective response and 34% achieved complete remission. A majority of the patients (94%) had some degree of tumor reduction, according to lead investigator, Robert Chen, MD, of City of Hope National Medical Center, Duarte, CA. “Despite responding to front-line combination chemotherapy, up to 30% of all Hodgkin lymphoma patients will relapse. These patients have limited treatment options beyond autologous stem-cell trans-

plantation [ASCT],” Dr Chen noted. “Based on these data, brentuximab vedotin has the potential to change the treatment paradigm for patients with relapsed or refractory Hodgkin lymphoma, and could be the first treatment approved for these patients in more than 20 years,” he said.

several patients with this drug, and it is well tolerated,” Dr Laport said. Study Details Brentuximab is an antibody drug conjugate that targets CD30-expressing cells, prompting apoptosis and sparing other cells from toxicity.

“Brentuximab vedotin has the potential to change the treatment paradigm for patients with relapsed or refractory Hodgkin lymphoma, and could be the first treatment approved for these patients in more than 20 years.” —Robert Chen, MD Ginna G. Laport, MD, of Stanford University Medical Center, CA, commented on this study at ASH 2010. “This promising drug offers a new treatment option for patients with relapsed/refractory Hodgkin lymphoma who have no other options. The results are very exciting, with a 34% complete remission rate and 75% objective response rate. Peripheral neuropathy is an issue, but I’ve treated

This phase 2 study included 102 patients with relapsed/refractory Hodgkin lymphoma who had received an average of 4 previous treatments and had undergone ASCT. More than 70% had failed to achieve a complete remission to initial therapy or had progressed within 3 months, and 39% were refractory to the most recent salvage therapy (excluding ASCT). Patients were treated with an outpa-

tient infusion of brentuximab 1.8 mg/kg every 3 weeks for up to 16 total doses. Progression-free survival for the whole population was 25 weeks by independent review and 39 weeks by investigator assessment, and had not been reached in patients who achieved a complete remission. Only 3% progressed during treatment with the drug. Side effects with the investigational drug were manageable. The most common grade 3 or higher adverse events included neutropenia (20%), peripheral sensory neuropathy (8%), thrombocytopenia (8%), and anemia (6%). Peripheral neuropathy occurred to some degree in approximately 50% of the patients. Dr Chen acknowledged that this side effect is an issue with brentuximab but noted that few cases are severe. “Overall, two thirds of the neuropathy resolved over treatment,” he said. “Brentuximab vedotin achieves high response rates, has low toxicity, and because of these qualities, outpatient treatment allows patients to continue their daily routine. It has few side effects, and many are reversible,” Dr Chen said. ■

Escalated BEACOPP Prevents Treatment Failures Regimen Now New Standard of Care in Some Centers

n escalated protocol of the BEACOPP regimen has become the standard of care for the treatment of early unfavorable Hodgkin lymphoma in some German centers, because a study showed that it improved tumor control compared with standard BEACOPP. The final results of the German Hodgkin Study Group HD14 trial were presented by Andreas Engert, MD, of the University Hospital Cologne, Germany. “We achieved overall better tumor control with more aggressive treatment. The toxicity was a little higher hematologically, but this did not result in more treatment-related deaths. This is now our standard of care,” Dr Engert said. There is currently no improvement in overall survival, but Dr Engert noted this may emerge with longer follow-up. Combined modality treatment consisting of 4 cycles of chemotherapy

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and involved-field radiotherapy is the standard treatment for early unfavorable Hodgkin lymphoma. In the previous HD8 study by the same investigators, this regimen was associated with a 91% rate for 5-year overall survival and an 83% rate for freedom from treatment failure. “The rationale for HD14 was to improve on these results by increasing the dose intensity using BEACOPP escalated,” Dr Engert said. The study included 1655 patients with unfavorable risk factors. The escalated regimen included bleomycin 10 mg/m2, etoposide 200 mg/m2, Adriamycin (doxorubicin) 35 mg/m2, and cyclophosphamide 1250 mg/m2, plus vincristine, procarbazine, and prednisone. Patients received 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), followed by radiotherapy 30 Gy IF. The control arm received 4 cycles of ABVD followed by the same radiotherapy.

The study included 1655 patients who were followed a median of 42 months. At 5 years, freedom from treatment failure (relapses and deaths) was 87.6% among patients receiving stan-

“We achieved overall better tumor control with more aggressive treatment. This is now our standard of care.” —Andreas Engert, MD dard treatment and 94.3% among those receiving escalated BEACOPP (P <.001). The differences were seen in terms of progressive disease, early relapse, and late relapse. “This absolute improvement of

about 7% met our predefined criteria for stopping the trial and resulted in a new standard of care for us,” Dr Engert said. “There were stunning differences in tumor control.” Dr Engert pointed out that this trial was not only a German trial, but that it also involved 4 European countries and 350 centers. “This represented a very broad experience, with even small oncology centers taking part,” he said. Moderator of the press briefing, Ginna G. Laport, MD, of Stanford University Medical Center, said she reserves the standard BEACOPP regimen for patients with more advanced disease. “I can’t say I would change practice based on this, although the results are titillating. This is a very large and well-conducted trial, and although the toxicity is concerning, there was no difference in treatmentrelated mortality. If some physicians do switch to this regimen, I would say it’s warranted.”—CH ■

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Leukemia

Much Progress, One Setback for CML Treatments By Neil Canavan

or the treatment of chronic myeloid leukemia (CML), data showing superior first-line efficacy continue to accrue for relative newcomers, dasatinib and nilotinib, compared with the current gold-standard treatment with imatinib. Meanwhile, the investigational agent, bosutinib, is still trying to find its niche, having failed in 1 of 2 trials presented at the 2010 American Society of Hematology (ASH) meeting. Making up for the lackluster bosutinib showing, a phase 1 study for the newest tyrosine kinase inhibitor, ponatinib, was impressive enough to warrant being included among studies highlighted at a press conference at ASH.

Ponatinib Makes a Splash Phase 1 data for the investigational compound ponatinib showed intriguing activity in patients with refractory CML, according to Jorge E. Cortes,

Comparative Effectiveness: Dasatinib versus Imatinib In the S0325 Intergroup Trial, a phase 2 study, investigators compared 100 mg/day of dasatinib to the standard of 400 mg/day of imatinib in 240 newly diagnosed patients with chronic-phase CML. Results for toxicity showed that dasatinib required more dose reductions to prevent serious treatmentrelated complications, whereas more patients opted to discontinue treatment altogether in the imatinib arm. Overall, rates for adverse events were similar for the 2 agents, although dasatinib was reported to cause more serious cases of diarrhea, and imatinib, more cases of nausea. Differences in efficacy were striking. Complete cytogenetic response rate, the main indicator of efficacy in CML, was 69% for imatinib versus 82% for dasatinib, and this led to far less risk of relapse with dasatinib—

0.8% versus 4.3%, respectively. Study investigator Jerald P. Radich, MD, Seattle Cancer Care Alliance, WA, stated that these data “are further evidence that dasatinib is more efficacious than imatinib in the newly diagnosed, chronic-phase CML patient.” He further maintained that this more potent therapy may help to stave off the emergence of treatment resistance in the long-term.

These data “are further evidence that dasatinib is more efficacious than imatinib in the newly diagnosed, chronic-phase CML patient.” —Jerald P. Radich, MD

Excellent Outcomes for Nilotinib By any measure, the anticancer drug imatinib has been a tremendous success. In patients with CML, a once-deadly disease, there is now an 80% disease-free survival rate with imatinib at 8 years, yet there is always room for improvement. “Nilotinib, as compared to imatinib, is simply more potent and more selective,” said Gianantonio Rosti, MD, lead investigator of the Gruppo Italiano Malattie e Matologiche dell’Adulto (GIMEMA) trial that investigated front-line nilotinib. “In fact, when used in imatinib-resistant patients, 50% are rescued with a stable response.” In GIMEMA, a small phase 2 trial, 73 patients were treated with 400 mg/day of nilotinib and followed for more than 3 years. This chosen time point is critical because this is the time period when most treatment failures emerge, Dr Rosti noted. At 3, 6, and 12 months, complete cytogenetic response rates were 78%, 96%, and 100%, respectively. “This means that all patients achieved a complete cytogenetic response at

least once,” he said. At a median follow-up of 36 months, 99% of patients were progression-free.

“Nilotinib, as compared to imatinib, is simply more potent and more selective.” —Gianantonio Rosti, MD Dr Rosti admitted that GIMEMA was a small trial, “but what is relevant is to show that even after 3 years from the beginning of therapy, the number of [treatment] failures is only 1 out of 73.”

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February 2011

An impressive “90% of patients achieved a major cytogenetic response by 6 months.” —Jorge E. Cortes, MD

MD, University of Texas M. D. Anderson Cancer Center, Houston. In a cohort of 55 patients who had failed 2 or even 3 previous treatments, ponatinib produced a 53% complete cytogenetic response rate. An even more robust response was observed for a subset of patients who exhibited the T3151 genetic mutation—a genetic change that renders all standard CML treatments ineffective. An impressive “90% of patients achieved a major cytogenetic response by 6 months,” Dr Cortes said. The cytogenetic response in these individuals was a remarkable 89%. “These are very exciting responses in this patient population.” Dr Cortes noted that these patients currently have no treatment options. Some 20% to 30% of patients failing multiple agents may have the T3251 mutation, he added. The encouraging results for T3251 patients have led to the initiation of a large multinational phase 2 study.

Bosutinib Fails for First-Line but Shows Promise as Third-Line Therapy In a phase 3 trial of 502 treatmentnaïve patients with CML, the investigational compound bosutinib failed to meet the primary study end point— complete cytogenetic response at 1 year—compared with the treatment standard, imatinib. Complete cytogenetic response rates were 70% for imatinib versus 68% for bosutinib in the Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia (BELA) trial. A secondary end point, however, was successful. Major molecular response—where cancer cells have been reduced but are still detected— was observed in 39% of patients treated with bosutinib versus 26% receiving standard therapy with imatinib. Carlo Gambacorti-Passerini, MD, BELA lead investigator, was circumspect about the mixed results. “We are encouraged by these data….Given the length of time these patients are treated for CML, we need more therapeutic options to choose from since each patient is different and has different needs,” he said. The different needs observed in the continuum of CML treatment suggest a place for bosutinib in the third-line setting, because this agent has previously demonstrated activity in patients resistant or intolerant to imatinib. H. Jean Khoury, MD, of the Emory University School of Medicine,

presented results of a small phase 1/2 study looking at the efficacy of bosutinib in patients who had previously failed imatinib and were also resistant to dasatinib or nilotinib. In this heavily pretreated population of 114 patients, complete cytogenetic response ranged as high as 37%,

“We are encouraged by these data….Given the length of time these patients are treated for CML, we need more therapeutic options to choose from since each patient is different and has different needs.” —Carlo Gambacorti-Passerini, MD

depending on the patient’s treatment history; rates were highest for those who were intolerant, rather than resistant, to imatinib, and 2-year overall survival was also best in this group. Patients resistant to imatinib and dasatinib demonstrated the least response to bosutinib; however, even in this group, for which no obvious treatment options exist, overall survival was still 66%. ■

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CALL FOR PAPERS AL INIC CL

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offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Evaluators, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being, the health of communities and patient populations, as well as other topics with specific implications to policymakers, payers, and employers.

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Leukemia

Imatinib Enhances Overall Survival in Patients with ALL By Neil Canavan

n the largest study of its kind, investigators in the UKALL12/ ECOG2993 trial demonstrated a marked improvement in all major outcomes for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by using imatinib before therapeutic stem-cell transplantation. The UKALL12/ECOG2993 investigation had been an effort of long standing, with the first of a total of 441 patients with Ph+ enrolled in 1993, before the availability of imatinib. (The Ph+ genetic abnormality is found in several forms of leukemia and is the key indicator for sensitivity to imatinib.) The first treatment cohort, preimatinib, evaluated standard induction chemotherapy before transplant with allogeneic (unrelated donor) bone marrow stem cells.

“It takes results from a comparative study of this size to justify the expense of this drug to the officials who make the final determination of whether or not the treatment will be covered.” —Adele Fielding, MD, PhD

Once imatinib became available, additional cohorts were recruited to receive the same therapy plus imatinib, either concurrent with or after induction treatment. Patients with adequate treatment response proceeded to transplant.

Although a number of studies have detailed the value of imatinib in this disease, the size of this patient cohort and the nature of the contrasted treatment arms allowed for conclusions to be made with far greater confidence, said Adele Fielding, MD, PhD, Uni-

versity College London. The use of imatinib significantly improved event-free, relapse-free, and overall survival in patients with Ph+ ALL; the earlier imatinib was used, the better the response. The investigators concluded that imatinib per se did not extend survival, but it enabled greater numbers of patients to achieve eligibility criteria for a lifesaving transplantation. Commenting on the ramifications of the study, Dr Fielding said that although the use of imatinib for ALL is common in the United States, she is not able to prescribe it in the United Kingdom. “It takes results from a comparative study of this size to justify the expense of this drug to the officials who make the final determination of whether or not the treatment will be covered,” she noted. ■

Hospitalization Rates for CML Lower with Nilotinib than Imatinib By Caroline Helwick

atients with newly diagnosed chronic myelogenous leukemia (CML) have less hospitalization time when treated with nilotinib than with imatinib. “Although this difference did not reach statistical significance, the reduction in hospitalization rate is compelling,” said Jennifer L. Beaumont, MS, of the Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago. Imatinib is the standard of care for CML, but nilotinib is a newer, very potent, and selective agent. A previous phase 3, open-label randomized study comparing these 2 agents in patients with chronic-phase CML showed that major molecular responses were significantly greater with nilotinib (44%) than with imatinib (22%). Discontinuations because of adverse events

were also lower with nilotinib. Based on these results, twice-daily nilotinib 300 mg was approved for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronicphase CML. The study population included 846 patients with CML who received twice-daily nilotinib 300 mg (n = 282), twice-daily nilotinib 400 mg (n = 281), or imatinib 40 mg daily (n = 283). Hospitalization was defined as a visit to the hospital requiring an overnight stay, excluding any preplanned or elective surgery. Median follow-up time was 18.5 months. Patients were also asked to report time off, defined as the average number of hours per week taken away from all usual activities as a result of CML and treatment side effects over the past 4 weeks, at baseline, and at the end of months 3 and 12.

Table Hospitalizations and Time Off from Usual Activities: Imatinib vs Nilotinib Hospital events

Imatinib 400 mg/day

Nilotinib 300 mg Nilotinib 400 mg twice dailya twice dailyb

Hospitalizations, N

Total hospital days, N

642

434

591

Hospital days/1000 patient-daysc

3.99

2.72

3.69

P = .057 compared with imatinib. P = .681 compared with imatinib. Total patient-days calculated as the sum of days from randomization to date of last contact. Adapted with permission from Beaumont J. Abstract presented at the 2010 American Society of Hematology meeting. December 6, 2010; Orlando, FL. Abstract 3826.

b c

AMERICAN HEALTH & DRUG BENEFITS

February 2011

There were 57 hospitalizations in the imatinib arm, 48 in the twice-daily nilotinib 300-mg arm, and 74 in the twice-daily nilotinib 400-mg arm (Table), which resulted in a 47% higher hospitalization rate in the imatinib arm compared with the twice-daily nilotinib 300-mg arm and 8% higher compared with the nilotinib twicedaily 400-mg arm. Patients in the nilotinib twice-daily 300-mg arm had fewer hospital stays and shorter

lengths of stay than the imatinib arm. In the nilotinib twice-daily 400-mg arm, patients had more stays than with imatinib but shorter lengths of stay on average, resulting in fewer total hospital days. The majority of hospitalizations (56%) occurred within the first 9 months in all arms. “Patients in all 3 treatment groups reported significant improvements from baseline in time off from their usual activities,” Ms Beaumont said. ■

Comparing Patient Adherence: Nilotinib versus Dasatinib

atients with chronic myeloid leukemia (CML) receiving dasatinib were less likely to adhere to treatment than those treated with nilotinib, in a comparison of second-line therapies of these tyrosine kinase inhibitors, presented by Annie Guerin, MSc, Senior Economist with the Analysis Group, Boston. The study evaluated treatment adherence associated with dasatinib and nilotinib in their approved second-line indication for patients with CML who are resistant to or intolerant of imatinib. Two administrative claims databases were combined (MarketScan and Ingenix Impact) to identify patients with CML who received at least 1 treatment. Patients were followed for up to 6 months. Treatment

adherence was measured by proportion of days covered (PDC), which was calculated as the sum of the number of days with dasatinib or nilotinib on hand, divided by the number of days in the study period. The analysis included 521 patients with CML receiving second-line therapy between 2003 and 2009 with nilotinib (n = 69) or dasatinib (n = 452). Patients in the dasatinib cohort were significantly less adherent to their therapy compared with patients taking nilotinib. After adjusting for potential confounding factors, patients taking dasatinib were estimated to have a 0.096 (13%) lower PDC value, an equivalent difference of 17.1 days of coverage over a 6-month period compared with nilotinib (P = .009). ■

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Multiple Myeloma

Bortezomib-Based Induction and Consolidation Emerging as a New Standard for Multiple Myeloma By Caroline Helwick

n patients with newly diagnosed multiple myeloma (MM), the use of bortezomib before (ie, induction) and after (ie, consolidation) autologous stem-cell transplantation (ASCT) is emerging as a new standard of care. “Novel agents have shifted the treatment paradigm for younger transplant-eligible patients with myeloma. Thalidomide/dexamethasone was the first newer induction regimen to show superior activity versus conventional chemotherapy before ASCT but the rate of complete response [CR] is 10% or less, which is unsatisfactory,” said Michele Cavo, MD, Seragnoli Institute of Hematology and Medical Oncology, Bologna University School of Medicine, Italy, who spearheaded a phase 3 trial. “More effective induction regimens are needed to increase the rate of high-quality responses and improve outcomes.” In this study, investigators added bortezomib to thalidomide/ dexamethasone (VTD) and maximized the speed of tumor reduction in preparation for ASCT. “VTD consolidation led to significantly higher rates of upgraded responses, including complete responses and molecular remissions,” Dr Cavo said. In addition, double ASCT, incorporating VTD as induction and consolidation therapy, resulted in significantly longer progression-free survival (PFS), a benefit that was maintained in the subgroup with adverse cytogenetic abnormalities. The randomized study prospectively compared thalidomide/dexamethasone (TD) with VTD as induction therapy before, and consolidation after, double ASCT in 474 patients with newly diagnosed MM.

“VTD consolidation led to significantly higher rates of upgraded responses, including complete responses and molecular remissions.” —Michele Cavo, MD

Three 21-day cycles of either VTD or TD were given as induction therapy. Consolidation therapy comprised 2 35-day cycles of VTD or TD. The CR plus near-CR (nCR) rate was significantly higher in the VTD arm compared with the TD arm after all treatment phases, including induction (31% vs 11%), after the first ASCT

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(52% vs 31%), after the second ASCT (55% vs 41%), and after consolidation therapy (62% vs 45%). In a subset of patients evaluated for the effect of the consolidation regimens, the bortezomib arm substantially improved on the preconsolidation responses, upgrading many responses from less than nCR to CR/nCR, and resulted in an absolute CR upgrade that was twice as high as that seen with TD. At a median follow-up of 36 months, disease progression was reduced by 39% with VTD compared with TD. Three-year PFS was 68% with VTD and 56% with TD. “The superior PFS in the VTD arm was retained across patient subgroups with poor prognosis, including those with [chromosomal translocation] t(4;14) and/or [chromosome deletion] del(17p),” Dr Cavo added. “Randomization to VTD completely overcame the adverse influence of t(4;14), while TD plus double ASCT did not.” The probability of being alive at 3 years was 87% for VTD and 84% for TD. “VTD as consolidation therapy was associated with negligible toxicity, and it significantly improved the probability of achieving CR and CR/nCR, an objective that failed with TD consolidation,” Dr Cavo concluded.

Superior Induction with VTD in Spanish Trial In the final analysis of a phase 3 study of 386 patients conducted by the Spanish Myeloma Group (PETHEMA/GEM), induction with VTD before ASCT also resulted in significantly higher CR rates and significantly longer PFS than was achieved with 2 comparative regimens. “We found that induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics,” reported Laura Rosiñol, MD, of the Hospital Clinic, Barcelona, Spain. “The posttransplant CR rate was also significantly higher with VTD, and PFS was significantly longer,” she said. Response to induction therapy was high (35%) with VTD, and only 7% of patients progressed. VTD induction was particularly effective in patients with extramedullary plasmacytomas, which generally are prognostic for worse outcomes. The same response pattern held for patients with highrisk cytogenetics, with CR rates of 35% in these patients, as well.

The CR rate to VTD in patients with del(17p) was 58%; none of these patients responded to other induction regimens. Patients with t(11;14) did not respond well to any regimen.

“Up to 50% of patients with the bortezomib-containing regimens continue to respond at 2 to 4 years.” —Laura Rosiñol, MD

“Up to 50% of patients with the bortezomib-containing regimens continue to respond at 2 to 4 years,” Dr Rosiñol noted.

Bortezomib-Based Induction and Maintenance Overcome Chromosomal Aberrations Chromosomal aberrations are important prognostic parameters in MM. In a large German study, newly diagnosed patients with certain chromosomal alterations had worse outcomes in general (Table), but a bortezomib-based regimen often overcame the associated risks, especially for the t(4;14) abnormality. The study was presented by Kai Neben, MD, University Hospital, Heidelberg, Germany.

lowed by maintenance therapy with thalidomide (VAD group) or bortezomib (PAD group) for up to 2 years. Investigators reported data on the first 258 patients who had been followed for an average of 40.3 months. The most pronounced impact on prognosis was seen for t(4;14), del(17p13), and chromosome gain 1q21, each significantly associated with poor prognosis with respect to PFS and overall survival (OS). A total of 14.8% of patients showed t(4;14), and gain 1q21 was found in 33.7%. Bortezomib-based induction and maintenance therapy overcame the adverse outcomes associated with several high-risk aberrations. Patients with t(4;14) receiving VAD/ thalidomide had a very poor prognosis, with a median PFS only half as long as patients lacking the translocation. But that negative effect was virtually ameliorated when patients received PAD/bortezomib, which resulted in approximately 40 months of PFS, and the 3-year OS was 76% compared with 39% for the VAD/ thalidomide arm. Similarly, bortezomib significantly prolonged OS in patients with gain 1q21 but only partially overcame the adverse effect of this aberration on disease progression. Del(17p13) was significantly associated with poor OS and PFS in both arms.

Table Prognostic Impact of Chromosomal Abnormalities on Outcome Chromosome

3-year PFS Present, % Absent, %

3-year OS Present, % Absent, %

Del(8p21)

.005

Del(13q14)

.010

.006

Del(17p13)

<.001

+1q21

.002

.010

t(4;14)

.020

<.001

NS indicates nonsignificant; OS, overall survival; PFS, progression-free survival.

The study included a subgroup of 833 patients within the HOVON65/GMMG-HD 4 trial, a prospective, randomized phase 3 study in newly diagnosed patients aged ≤65 years with stage II or III MM. Patients were randomized to receive 3 cycles of vincristine/Adriamycin/ dexamethasone (VAD) or bortezomib/ Adriamycin/dexamethasone (PAD). All patients received high-dose melphalan (200 mg/m²) with ASCT fol-

“Our analysis confirms the significant negative prognostic impact of del(17p13) and gain 1q21 on PFS and OS for patients with newly diagnosed myeloma, but the negative impact of t(4;14) on PFS could almost completely be overcome by the bortezomib-based treatment,” Dr Neben said. In contrast, the bortezomib effect was more modest for patients with del(17p), with a 3-year OS of only 62%. ■

www.AHDBonline.com

AVBCC Conference

Conference Promises Valuable Perspectives

he Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will be held in Philadelphia on March 2930, 2011 (see full agenda below). To help set the stage for this meeting, ValueBased Cancer Care (VBCC) interviewed Gary Owens, MD, one of the cochairs of the meeting. Dr Owens is president of Gary Owens Associates, a medical management and pharmaceutical consulting firm in the Philadelphia area. Dr Owens is a primary care physician who has spent 20 years in health plans, and one of his major areas of focus during that time has been oncology.

In the future, I suspect that drugs will come to market with companion diagnostics attached to them. I’m not sure that health plans, providers, or anyone else is tuned in as to how to manage these situations effectively. Other areas to be covered will

VBCC: Why this meeting now? Gary Owens, MD: A number of reasons, the first being the obvious rapid growth of spending that the players in the oncology world—including the federal government, health plans, and the public—is seeing. As Peter Bach noted several years ago in the New England Journal of Medicine (2009;360:626-633), the cost of cancer care agents has risen dramatically over the years, and the ability to control those costs has been limited. Baby boomers are aging, and people are living longer with cancer. It is an almost-perfect storm (see Sidebar). Ultimately, the goal is to provide the best care possible for patients with malignant disorders but to spend those care resources wisely. We don’t want to withhold treatment from those who need it, but we don’t want to waste treatment in those for whom it is ineffective or unproven. This meeting will examine all these topics. VBCC: Who will be presenting at this meeting, and what topics can we expect to be covered? Dr Owens: We have some key thought leaders. On the clinical side, Al Benson, MD, the current president of the Association of Community Cancer Centers, and A. Mark Fendrick, MD, from the University of Michigan, will both present. Dr Fendrick is a driving force behind the value-based benefit movement, and it will be interesting to hear his perspective. Along the lines of targeted therapy, we have a session on the age of personalized oncology therapy that promises to be a very cogent topic. Right now, these offer more promise than reality. Although there are a few successful examples of this so far— KRAS testing and colorectal cancer, HER2/neu testing and breast cancer, and ABR-BCL mutations in chronic myelogenous leukemia—this is an area that will continue to grow, so it was essential that we cover this.

AMERICAN HEALTH & DRUG BENEFITS

include clinical treatment of cancer patients, the use of guidelines, and patient navigators and patient-assistance programs. With the growing number of uninsured and underinsured patients, we can’t forget about the difficulties these individuals face

in accessing treatment, so these latter sessions will be important. VBCC: What’s different about this meeting? Dr Owens: A big plus is that it brings together different viewpoints

March 29-30, 2011 Philadelphia, PA Loews Philadelphia Hotel

First Annual Stakeholder Integration Conference Integrating Payers, Providers, and the Entire Oncology Team PROGRAM OVERVIEW

PRIMARY CONFERENCE LOCATION

This is the first national stakeholder integration meeting dedicated to advancing the understanding of value in cancer care. Guided by the expertise of leaders in these fields, attendees will receive a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

WHO SHOULD ATTEND All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Surgical Oncologists • Medical Directors • Nurses • Practice Managers/Administrators • Pharmacists • Pharmacy Benefit Managers (PBMs)

CONTINUING EDUCATION INFORMATION Goal The Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care. Objectives • Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer • Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics • Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients • Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management • Analyze trends in the delivery of care in the management of cancer patients Co-Chairs

Gary Owens, MD

Burt Zweigenhaft, BS

President, Gary Owens Associates

President, CEO, OncoMed

Loews Philadelphia Hotel 1200 Market Street, Philadelphia, PA 19107-3615 Phone: 215-627-1200 http://www.loewshotels.com/en/Philadelphia-Hotel

ACCREDITATION INFORMATION PHYSICIAN ACCREDITATION Science Care designates this activity for a maximum of 6.0 AMA PRA Category 1 Credit(s)™. Science Care is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 6.0 contact hours. REGISTERED PHARMACY DESIGNATION Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 7.50 contact hours (0.750 CEUs) of continuing education credit. The Universal Activity Number for General Sessions is: 0468-9999-11-072-L01-P. The Universal Activity Number for the lunch symposium is: 0468-9999-11-071-L01-P.

CONFERENCE REGISTRATION Register Online at

www.regonline.com/avbcc-2011 $250 Includes 1-year association membership $355 Includes 3-year association membership

CONTACT/SUPPORT If you have any questions please contact: Association for Value-Based Cancer Care™ 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831 Phone: 732-992-1040 association@valuebasedcancer.com

www.regonline.com/avbcc-2011 February 2011

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AVBCC Conference from various stakeholders, including health plans, pharmacy benefit managers, providers, patients, government, manufacturers, and the National Comprehensive Cancer Network. We’re attempting to bring together a group that owns different

pieces of the cancer care equation, and to hear about the world of oncology through their eyes. We hope to identify common issues and understand how we might integrate these. The current situation with Avastin provides an excellent example of the

Tuesday, March 29 1:30 – 3:30 pm PAYER PRE-CONFERENCE (Off-site) Ritz-Carlton Philadelphia 10 Avenue of the Arts, Philadelphia, PA 19102 Payer Trends in Oncology - Panel Discussion MODERATOR Burt Zweigenhaft, BS PANEL Scott Breidbart, MD — CMO, Empire BCBS Nick J. Calla, RPh — VP, Trade Relations, Walgreens Specialty Pharmacy Maria Lopes, MD — CMO, AMC Health Mona Chitre, PharmD — Director, Clinical Strategy, Policy, and Services, Excellus GENERAL PRE-CONFERENCE SESSIONS Loews Philadelphia Hotel 1200 Market Street, Philadelphia, PA 19107-3615 Value-Based Insurance Design in Oncology CHAIR A. Mark Fendrick, MD – Co-Director, University of Michigan Center for Value-Based Insurance Design Cancer Care from a Large Insurer’s Perspective Donald Liss, MD – Senior Medical Director, Independence Blue Cross of Philadelphia The Role of Diagnostics from a PBM’s Standpoint Jane F. Barlow, MD, MPH, MBA – VP, Clinical Innovation, MEDCO Health Solutions Panel Discussion Welcome/Networking Reception

Wednesday, March 30 Corporate-Sponsored Breakfast Symposium Havalen™ (eribulin mesylate) Injection: A New FDA-approved Treatment Funded by Eisai Inc. Stephen C. Malamud, MD – Beth Israel Medical Center Intro/Opening NCCN Guidelines Acceptance and Compliance Al Benson, MD – President, ACCC The Impact of Personalized Oncology Therapies MODERATOR Gary Owens, MD PANEL Perry Dimas – VP, Premier Source Diagnostics Richard Bender, MD – CMO, Agendia Beth Davis – Senior Director, Managed Care, Agendia Gene Morse, PharmD – University of Buffalo Morning Break in the Exhibit Hall BREAKOUT SESSIONS PROVIDER TRACK Community Oncology: Trends Ted Okon – Executive Director, Community Oncology Alliance Patient Navigation/Patient Assistance Steven Patierno, PhD – Executive Director, George Washington University Cancer Institute Dawn Holcombe, MBA, FACMPE, ACHE – President, DGH Consulting Monica Knoll – Executive Director/Founder, CANCER101

interconnected nature of cancer care today. The US Food and Drug Administration (FDA)’s accelerated approval was based on the requirement of further data on patients with metastatic breast cancer. Compendia, however, continue to advocate coverage for this

Oncology Practices—Issues with Managed Care Craig Deligdish, MD – Medical Director, Florida Comprehensive Care Network Yu-Ning Wong, MD – Fox Chase Cancer Center Winston Wong, PharmD – Associate VP, Pharmacy Management, CareFirst BCBS PAYER TRACK Medicare and Reimbursement Issues Kip Piper, MA, FACHE – President, Health Results Group Jayson Slotnik, JD – Counsel, Foley Hoag Oncology Drug Reimbursement and Administration Issues John Aforismo, BSc Pharm, RPh, FASCP – President & CEO, RJ Health Systems Peyton Howell, MBA – AmerisourceBergen Scott Breidbart, MD – CMO, Empire BCBS Evolutions in Oncology Pharmacy Management MODERATOR Burt Zweigenhaft, BS ROUNDTABLE Alan Lotvin, MD – President, ICORE Kristen M. Reimers, RPh – Clinical Pharmacy Operations Manager, Excellus Jeff Ulanet – VP, Oncology, MEDCO LUNCH SYMPOSIUM Best Practices for Management of CINV: A Value-Based Approach Supported by an educational grant from Eisai Inc. Shawna Kraft, PharmD, BCOP – Hematology/Oncology Clinical Pharmacist, University of Michigan Health System Beth Faiman, RN, MSN, CNP, AOCN – Nurse Practioner, Cleveland Clinic Taussig Cancer Center Cancer Care and the New Healthcare Legislation: What to Expect Next MODERATOR Jayson Slotnik, JD PANEL Scott Gottlieb, MD – Resident Fellow, American Enterprise Institute Joseph Bailes, MD – Texas Oncology Strategies for Improving Oncology Pharmacy and Care Management Models MODERATOR Burt Zweigenhaft, BS PANEL Ira M. Klein, MD – Medical Director, Aetna Oncology Strategy Dan McCrone, MD – CMO, New Century Health Jeffery Scott, MD – SVP/CMO, P4 Healthcare, Cardinal Health Winston Wong, PharmD Afternoon Break in the Exhibit Hall Clinical Fragmentation: Impact of Oral, Injected, and Infused Therapies MODERATOR Gary Owens, MD ROUNDTABLE Atheer Kaddis, RPh – VP, Managed Markets, Diplomat Pharmacy Services Kirby Eng, RPh – Director, Oncology Management Services, CVS Caremark Ellen Scharaga, BS – SVP, Pharmacy Operations, OncoMed Cocktails/Networking in the Exhibit Hall

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condition as do some patient groups. So we have a situation where the FDA is taking one action and the real world another. Some patients are benefiting but many are probably not. Conferences such as these can be helpful in shedding light on the issues behind these situations. We’re trying to open up the lines of communication between these various groups. Currently, stakeholders may not have a chance to “cross-pollinate,” as we’re hoping to do here. I may have seen only 1 or 2 other meetings that have even tried to bring together this many stakeholders. We tend to live in our own world and often only see our own points of view, so it can be eye-opening to see those other viewpoints. We will feature multiple presenters, with interactivity not only among presenters but with members of the audience. We believe that this audience is going to have as much expertise as the people behind the podium, which should make for excellent interactions. ■

Cancer Costs Projection: Population Booming, Costs Zooming The estimated total cost of cancer care in the United States is projected to be $158 billion by 2020 if current patterns of incidence, survival, and cost remain the same. If care costs increase 2% in the initial and last phases of treatment above the base estimates, however, total costs of care could reach $173 billion by 2020, an increase of 39% from 2010. This analysis appears in the Journal of the National Cancer Institute (Mariotto AB, et al. 2011; 103:117-128). By 2020, the authors estimate there will be 18.1 million cancer survivors in the United States, whose care will cost $157.7 billion, a 27% increase from 2010’s amount of $124.5 billion. Despite this profound possible increase, the authors are hopeful. “Expanding costs of cancer care due to increases in an aging population are inevitable,” they note, “but the costs of new treatments and diagnostic technologies could potentially be managed to ensure access to quality care for all patients.”

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Multiple Myeloma

Advances in Multiple Myeloma Likely to Expand with Current Drugs in Development By Caroline Helwick

dvances in treatment have helped to achieve levels of response and durations of remission in multiple myeloma (MM) that were previously not achievable with standard approaches. As a result, patients with MM are living significantly longer than a decade ago. Drugs that have made such a difference include thalidomide, bortezomib, and lenalidomide, which are used in various combinations together and with other conventional agents, such as dexamethasone. Now, next-generation agents are in development, and new targets are being refined. Sagar Lonial, MD, Director of the Translational Research B-cell Malignancy Program, Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, discussed the current approach to remission in MM. Remissions are becoming longer, although eventually all patients with MM relapse. Patients with remission durations of <6 months and those with signs of aggressive relapse are different from patients with indolent, slowly progressing disease. The physician

“remains a strategy with limited clinical benefit,” according to Dr Lonial, “since long-term disease-free survival is seen in only 10% to 20% of patients, with a significant fraction developing debilitating chronic graft-versus-host disease or relapse. The use of allogeneic transplant for managing relapsed myeloma should be discouraged.”

“The wealth of secondgeneration and newer agents currently suggests that this improvement will continue.” —Sagar Lonial, MD must consider which agents the patient has been given and the duration of response to each. Some patients are good candidates for single-agent approaches and some need combination treatment. In addition, patients with a high-risk cytogenetic feature usually warrant combinations, Dr Lonial said. For relapse, allogeneic transplant

Second-Generation Agents and New Versions of Active Agents A promising investigative approach is to combine the proteasome inhibitor bortezomib with agents targeting new pathways (Table).

Table New Agents in Phase 3 Trials

Bortezomib ± vorinostat (HDAC inhibitor) Bortezomib/dexamethasone ± perifosine (AKT inhibitor) Bortezomib/dexamethasone ± panobinostat (HDAC inhibitor) Lenalidomide/dexamethasone ± carfilzomib HDAC indicates histone deacetylase.

These include heat shock protein inhibitors (eg, 17AAG), histone deacetylase inhibitors (eg, vorinostat, panobinostat), and drugs that target the PI2K/AKT/mTOR pathways (eg, perifosine), which appear to be activated after exposure to bortezomib. A number of novel approaches made news at ASH 2010. Especially promising was the monoclonal antibody elotuzumab, which looks active in combination with the immunomodulatory agent lenalidomide. High responses were also seen with carfilzomib, a second-generation proteasome inhibitor, and with pomalidomide, a new immunomodulatory agent. “It is clear that the availability of new classes of agents and new proteasome inhibitors and immunomodulatory agents have changed the natural history of MM over the past 10 years,” Dr Lonial said. “Their use both in the induction setting and relapsed disease setting, either alone or in combinations, has resulted in significant improvements in overall survival. The wealth of second-generation and newer agents currently suggests that this improvement will continue.” ■

Is Thromboprophylaxis Necessary in Patients with Multiple Myeloma?

atients with newly diagnosed or previously treated multiple myeloma (MM) administered thalidomide- or lenalidomide-based regimens are at high risk for venous thromboembolism (VTE), but the necessity of thromboprophylaxis and the choice of agent are not clear. Recent observational studies have suggested that thromboprophylaxis may be efficacious in decreasing risk, and consensus guidelines recommend routine thromboprophylaxis, but reliable data from randomized, controlled trials are lacking. Two studies at ASH provided some information on this issue. In a meta-analysis by Canadian investigators, clear benefit for thromboprophylaxis was not found, especially for patients receiving lenalidomide and for previously treated patients, whose risk appears low. Marc Carrier, MD, MSc, FRCPC, Division of Hematology, University of Ottawa, Ontario, Canada, and colleagues investigated the absolute rates of VTE with/without thromboprophylactic agents—aspirin, warfarin, low-

molecular-weight heparin (LMWH)— in patients with newly diagnosed or previously treated MM. Their systematic literature review included 66 studies: 61 studies (with 4264 patients) evaluated thalidomidebased regimens, and 5 studies (involving 1119 patients) assessed lenalidomide-based strategies.

“LMWH and aspirin are likely to be effective thromboprophylactic regimens in lenalidomidetreated patients with newly diagnosed myeloma.” —Federica Cavallo, PhD

Thalidomide-Based Regimens For the 444 newly diagnosed patients with MM who were treated with thalidomide only, the rates of VTE (per 100 patient-cycles) were 1.3 for the patients (n = 380) who did not receive VTE prophylaxis and 0.5 for

those receiving LMWH prophylaxis. For newly diagnosed patients who received the combination of thalidomide plus dexamethasone, the rates of VTE (per 100 patient-cycles) were: • 4.1 (n = 628) without prophylaxis • 2.3 (n = 80) with aspirin • 2.8 (n = 87) with warfarin • 2.1 (n = 446) with LMWH. The rates of VTE (per 100 patientmonths) in patients with previously treated MM managed with thalidomide-based regimens who did not receive prophylaxis VTE were: • 0.4 (n = 706) with thalidomide alone • 0.6 (n = 258) with thalidomide plus prednisone • 0.4 (n = 38) with thalidomide plus chemotherapy • 0.9 (n = 321) with thalidomide plus dexamethasone plus chemotherapy • 6.7 (n = 331) with thalidomide plus dexamethasone plus chemotherapy, including doxorubicin. Lenalidomide-Based Regimens The rates of VTE (per 100 patientcycles) in patients with newly diagnosed MM treated with lenalidomide

and dexamethasone were: • Any prophylaxis: 0.7 (n = 349) • Aspirin: 0.9 (n = 172) • No prophylaxis: 0.8 (n = 278). The rates of VTE (per 100 patientmonths) in patients with previously treated MM managed with lenalidomide-based regimens were: • No prophylaxis: lenalidomide + dexamethasone, 0.7 (n = 361) • Aspirin: lenalidomide + dexamethasone + chemotherapy, including doxorubicin, 0.6 (n = 131). None of the studies reported major bleeding events. Of note, the definition for VTE varied across studies and/or was unclear, and data are not available for all prophylaxis regimens. Low Thromboembolism Rates with Either Agent An Italian study evaluated newly diagnosed patients with MM receiving lenalidomide and dexamethasone and showed the overall incidence of thrombotic events to be less than 5% in all groups, “confirming the safety of low-dose dexamethasone in association with lenalidomide,” according to Continued on page 23

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Multiple Myeloma

Cost-Effectiveness Analysis: Zoledronic Acid versus Clodronate By Caroline Helwick

ccording to 2 studies presented at ASH 2010, the use of zoledronic acid (ZA) in patients with multiple myeloma (MM) to prevent bone complications was superior to some, but not all, bisphosphonates in improving overall survival (OS), and the drug was costeffective compared with clodronate. In the meta-analysis, ZA had a beneficial effect on OS compared with clodronate, and etidronate was superior to clodronate in improving progression-free survival (PFS). In preventing skeletal-related events (SREs), ZA was superior to clodronate, pamidronate, ibandronate, reported Rahul Mhaskar, MD, MPH, Center for Evidence-Based Medicine and Health Outcomes Re-

Is Thromboprophylaxis... Continued from page 22 Federica Cavallo, PhD, Associate Professor of Immunology, University of Torino, Italy. Preliminary studies of patients with MM receiving lenalidomide plus dexamethasone had shown an odds ratio of about 3.5 for the development of thrombosis. In a comparison of agents, no significant benefit was seen for LMWH over aspirin in this patient population. “LMWH and aspirin are likely to be effective thromboprophylactic regimens in lenalidomide-treated patients with newly diagnosed myeloma,” she said. The data came from a substudy of a prospective, multicenter phase 3 trial of 402 newly diagnosed patients with MM treated with lenalidomide and low-dose dexamethasone induction and subsequently randomized to consolidation with lenalidomide plus melphalan and prednisone or high-dose melphalan. Patients were randomly assigned to receive LMWH or aspirin during induction therapy and consolidation therapy. During induction, the overall incidence of grade 3 to grade 4 thrombotic events was 1% in the LMWH group and 2.4% in the aspirin group. VTEs, mostly of the lower limbs, were equally distributed in the 2 groups, whereas pulmonary embolism was observed only in the aspirin group. Only minor bleeding was detected in the LMWH group (1%), and no thrombotic events were observed during consolidation.—CH ■

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search, at the H. Lee Moffitt Cancer Center, Tampa, FL. “In the context of a mixed treatment comparison uncertainty analysis, ZA ranked as the best treatment, followed

by clodronate and pamidronate,” Dr Mhaskar said. The analysis was based on 18 randomized controlled trials that enrolled 4970 patients. Superiority of bisphosphonates was assessed by the

mixed treatment comparison. The pooled analysis demonstrated an OS benefit with ZA compared with clodronate and etidronate, but there was no evidence that zoleContinued on page 24

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Multiple Myeloma

Maintenance Therapy with Lenalidomide Doubled Remission Time By Caroline Helwick

oung patients with multiple myeloma (MM) often receive high-dose therapy with autologous stem-cell transplantation (ASCT). Residual disease inevitably leads to relapse, and a research aim has been to determine ways to prevent this. In 2 phase 3 studies, maintenance therapy with lenalidomide resulted in a doubling of the time to disease progression.

CALGB 100104 Updated results of the CALGB 100104 trial, now with 18 months’ follow-up on 460 patients, were presented by Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, NY. The study team randomized 570 patients to lenalidomide (10 mg/day, with dose reduction or titration allowed) or placebo after ASCT (and a variety of induction regimens). Time to disease progression (or death) was significantly better in the maintenance arm (42.3 months) compared with placebo (21.8 months), although overall survival (OS) remained similar. The lack of difference may be because most placebo recipients were allowed to receive lenalidomide when the study was unblinded. Of 100 placebo-treated patients, 86 started treatment with lenalidomide

when the trial was unblinded. Of 211 lenalidomide-treated patients, 46 had disease progression or died compared with 95 of the 229 placebo

In the CALGB 100104 study, of 211 lenalidomide-treated patients, 46 had disease progression or died compared with 95 of the 229 placebo recipients. This yielded a 60% reduction in the risk of progression with lenalidomide maintenance.

recipients (P <.001). This yielded a 60% reduction in the risk of progression with lenalidomide maintenance, Dr McCarthy reported. Lenalidomide prolonged time to progression or death in patients with high and low beta 2-microglobulin levels (indicating disease risk) and in patients with previous thalidomide or lenalidomide induction therapy. No significant OS advantage has

Cost-Effectiveness Analysis... Continued from page 23 dronate was superior to pamidronate or ibandronate. ZA was superior to clodronate in PFS. The Medical Research Council Myeloma IX study compared ZA, given intravenously monthly, with the daily oral bisphosphonate clodronate among 1970 patients with newly diagnosed MM. After a median follow-up of 3.7 years, ZA prolonged OS from 44.5 to 50.0 months, PFS from 17.5 to 19.5 months, and reduced the incidence of SREs from 35.3% to 27.0% compared with clodronate, all significant differences. Cost-effectiveness was expressed in terms of the incremental cost per quality-adjusted life-year (QALY) gained with ZA versus clodronate. Costs were in 2009/2010 Canadian dollars, discounted at 5% annually. The cost per QALY gained with ZA versus clodronate in patients with newly diagnosed MM fell below the standard threshold of

$50,000 per QALY gained. The expected lifetime costs (in cluding administration and monitoring costs) of bisphosphonate therapy were $11,967 greater with ZA than with clodronate ($14,267 vs $2301), but the expected costs of SREs were reduced by $720 with ZA ($4152 vs $4872). The expected costs of adverse events were increased by $663 with ZA ($3225 vs $2562), and the expected total lifetime costs were increased by $11,878 ($30,103 vs $18,225). On an undiscounted basis, the life expectancy with ZA increased by 0.83 years (6.43 vs 5.60), QALYs increased by 0.56 (from PFS and OS), and 0.02 QALYs were lost as a result of adverse events (predominantly jaw osteonecrosis). The total QALYs gained with ZA (undiscounted), therefore, were 0.56 (4.43 vs 3.87). On a discounted basis, total QALYs gained were 0.37 (3.51 vs 3.14). ■

AMERICAN HEALTH & DRUG BENEFITS

February 2011

been observed, although a trend favored maintenance, with 13 deaths in the lenalidomide arm and 24 in the placebo arm (P <.052). “Some hematologic toxicity was observed, but it was not severe,” he noted. In the lenalidomide arm, grade 3 hematologic events were observed in 31% of patients versus 7% with placebo, and grade 4 events occurred in 14% versus 4%, respectively (P <.001). IFM 2005-02 Supports Maintenance Lenalidomide Updated analysis of the IFM 2005-02 trial, reported by Michel Attal, MD, Hospital Purpan, Toulouse, France, also supported lenalidomide maintenance in patients with MM. The study included 614 patients aged ≤65 years who were randomized post-ASCT to receive consolidation with lenalidomide (25 mg/d, 21 days/ month, for 2 months) followed by maintenance with either lenalidomide (10-15 mg/d) or placebo until relapse. After the first preplanned interim analysis, with a median follow-up of 24 months, the study was unblinded because of the superiority of the lenalidomide arm. The final analysis was performed with a median followup of 34 months from randomization.

“There was about a 50% reduction in the risk of progression in all subgroups….The 5-year postdiagnosis overall survival remains extremely high (81%) and similar in the 2 treatment groups.” —Michel Attal, MD

Consolidation with lenalidomide improved the very good partial response rate, and maintenance with the drug improved progression-free survival (PFS). Median PFS was 24 months with placebo and 42 months with lenalidomide, for a very significant 50% reduction in risk of disease progression. “There was about a 50% reduction in the risk of progression in all subgroups,” he said. “Today, deaths have only been observed in the high-risk patients. Maintenance treatment with lenalidomide was not associated with

resistance of the disease at time of progression. The median interval between progression and death was similar in both arms at 12 months,” Dr Attal said. “With the current follow-up, the 5-year postdiagnosis overall survival remains extremely high (81%) and similar in the 2 treatment groups.” Maintenance treatment with lenalidomide was well tolerated, with treatment interruptions no higher in the active arm. Concerns Over Second Malignancies Attendees at ASH 2010 welcomed the findings of prolonged remission with lenalidomide maintenance, but some specialists expressed concern over the finding of an excess number of new malignancies in the lenalidomide arms of the CALGB and IFM trials. In the CALGB study, 25 new malignancies were reported—3 in the lenalidomide group (1 in a patient treated for breast cancer) and 2 in the placebo arm. A total of 15 malignancies occurred among the 231 patients receiving lenalidomide and 6 among the 229 receiving placebo. The exact types of cancers were not detailed, except for cases of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). In the IFM trial, hematologic malignancies have been diagnosed in 10 patients receiving lenalidomide versus 2 receiving placebo; nonhematologic cancers have been diagnosed in 6 patients versus 1 patient, respectively. Remarking on the CALGB results, Dr McCarthy said, “We don’t know how these patients were treated. We know they all got a big dose of the alkylating agent, but we cannot say anything specific. We will have to see if this holds up as something significant.” Thierry Facon, MD, of the Hospital C. Huriez, Lille, France, pointed out that the numbers of malignancies are very small and that AML/MDS has long been observed in MM. In a December 6, 2010, report on this topic (www.reuters.com/article/2010/ 12/06/celgene-idUSN062081432010 1206), Brian Gill, a spokesman for Celgene (lenalidomide maker) said it is known that about 8% of patients with MM who are alive after 2 years are at risk for developing a second cancer, and induction therapy greatly increases this risk. He maintained that the occurrence seen in these studies falls within the expected range. ■

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Myelodysplastic Syndromes

First Population-Based Comparisons of Azacitidine and Decitabine for MDS Similar Effectiveness, Varied Response Rate By Caroline Helwick

t ASH 2010, 2 population-based studies investigated current treatment options for myelodysplastic syndromes (MDS).

Efficacy Confirmed but Head-toHead Comparison Needed A retrospective, population-based study assessing the effectiveness of current treatments for MDS showed that azacitidine and decitabine are equally effective, but azacitidine produces higher response rates. The study was from the University of South Florida Center for Evidence-Based Medicine, Tampa. Although studies have shown both drugs to be more effective than supportive care, no studies have compared the 2 hypomethylating agents head to head. “Our study is the first population-based direct comparison of azacitidine versus decitabine,” said Tea Reljic, University of South Florida Clinical and Translational Science Institute Center for Evidence-Based Medicine and Health Outcomes Research, Tampa. Investigators analyzed outcomes for 174 patients with MDS, who were all treated at the H. Lee Moffitt Cancer Center, Tampa, between 1999 and 2009; 121 received azacitidine and 53 received decitabine. The unadjusted results for overall survival and progression-free survival showed significant benefits for azacitidine, which improved these outcomes by about 50%. In the multivariate

analysis, however, these gains lost statistical significance, Ms Reljic reported. Treatment with azacitidine compared with decitabine, however, was associated with significant benefits in overall response rates (20% vs 6%, respectively) and hematologic response rates (24% vs 6%, respectively), she added. Toxicities were also similar between the 2 groups. “These results warrant a prospective direct comparison of the drugs in a randomized, controlled trial,” she said. Cost and Utilization of Azacitidine The cost and utilization of azacitidine was investigated by a populationbased study from Canada. “Based on the published treatment regimen [Fenaux P, et al. Lancet Oncol. 2009;10:223-232], the average cost of azacitidine is estimated to be $10,000 [Canadian dollars] per month,” said Pamela Skrabek, MD, FRCPC, CancerCare Manitoba. “With a median of 9 full-dose cycles of the drug, the cost per patient is anticipated to be $90,000, which translates into a financial constraint that prevents many healthcare systems from using this drug. We thought a population-based study would provide a more realistic estimate of its use and cost and help our center budget for it.” Azacitidine was provided by the manufacturer on a compassionate (from April 2009 to March 2010) basis for any patient who met the approved criteria. The analysis included 11

“We think that decisions to fund or deny expensive drugs should include data from population-based studies.” —Pamela Skrabek, MD, FRCPC patients who were followed up to July 2010 and received 42 cycles (median of 3 cycles per patient). Dose reductions were required in 9 of 42 cycles as a result of cytopenias. Eleven of 42 cycles were complicated by febrile neutropenia, with 7 of these episodes requiring hospital admission. Despite receiving dose reductions and fewer total cycles, 45% of the patients still had an objective response, Dr Skrabek said. Reasons for discontinuing the drug were progressive cytopenia or transformation to leukemia, ability to undergo stem-cell transplantation, occurrence of severe sepsis, and lack of response. “In this population-based study, we demonstrate that many MDS

patients are withdrawn from further treatment due to adverse effects or lack of early response, in contrast to patients participating in clinical trials,” she explained. “Many patients are older, sicker, and frailer, and would have been excluded from a trial. Ours is a more typical population. In the real world, patients cannot tolerate 9 cycles.” The approximate cost of azacitidine in this cohort was $34,090 per patient, which was substantially lower than the anticipated cost. “We believe that people overestimate what it will cost to use this drug,” she said in an interview. “We think that decisions to fund or deny expensive drugs should include data from population-based studies.” ■

Therapies for Myelodysplastic Syndromes Improving but Still Fall Short

yelodysplastic syndromes (MDS) are a group of disorders caused by poorly formed or dysfunctional blood cells. Currently, 3 drugs are approved by the US Food and Drug Administration for treatment of MDS—azacitidine, decitabine, and lenalidomide. Although each drug has helped to improve the care of patients with MDS, “MDS treatment in 2010 ultimately failed in most patients,” said William Blum, MD, Ohio State University Comprehensive Care Center, Columbus. Current Therapies But current therapies provide a

foundation on which to build, he added. The best available evidence for this is that patients benefiting from therapy with azacitidine or decitabine should continue treatment until progression or unacceptable toxicity, Dr Blum said, but the question of which agent is superior is hard to answer. A comparative trial recently opened, but overall survival (OS), “the more relevant question,” is not a primary end point. Lenalidomide is approved for lowerrisk MDS patients with transfusiondependent anemia and the chromosomal deletion (del)5q. Lenalidomide catapulted onto the MDS treatment scene when it showed robust activity

(83% response rate) in patients who fit this profile. Subsequent studies have determined that dose reductions are often needed, and blood counts should

“With both azacitidine and decitabine, maintenance of response with continued therapy is clearly important.”—William Blum, MD

be followed weekly during the first 8 weeks of therapy.

Prophylactic granulocyte colonystimulating factor (G-CSF) is not necessary for safe administration of lenalidomide. The drug is being studied in high-risk patients with del(5q) and in lower-risk patients without del(5q). Dr Blum pointed out that higherrisk MDS patients who are otherwise healthy are excellent candidates for treatment. The drug used must be applied in repetitive cycles and administered to appropriate patients who are able to undergo prolonged therapy, he emphasized. “With both azacitidine and decitabine, maintenance of response with continued therapy is clearly important,” he said, “thus, in the absence of unacceptable Continued on page 26

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Other Highlights

Hematology Drug Pipeline... setting of relapsed/refractory disease; the rate of very good partial responses or better was 37%. The combination appears to be synergistic, said Paul G. Richardson, MD, Harvard Medical School. Pomalidomide, a novel immunomodulatory agent, was very active in combination with dexamethasone in 92 patients with advanced MM refractory to bortezomib and lenalidomide. Xavier Leleu, MD, Hopital Huriez, Lille, France, said that overall survival was >85% at 6 months, and at a median follow-up of about 7 months, median progression-free survival (PFS) ranged from 7 to 10 months, depending on the regimen. Results suggest that pomalidomide has no cross-resistance with lenalidomide (see page 22). Carfilzomib, a novel highly selective next-generation protease inhibitor, achieved durable responses in a phase 2b study of 266 patients with relapsed/refractory MM previously treated with all available therapies. Among 257 patients, responses were observed in 24.1%, and median duration of response was 8.3 months. The clinical response rate (complete

or partial remission or stable disease) was 34.2%. Median overall survival was 15 months. The most common grade 3 or 4 toxicities were thrombocytopenia (27%), anemia (22%), lymphopenia (18%), and neutropenia (10%). Carfilzomib may be of clinical benefit to patients who have relapsed or are refractory to other therapies, said David Siegel, MD, St. John Theuer Cancer Center, Hackensack, NJ (see page 22). Chronic Myelogenous Leukemia Bosutinib, a new tyrosine kinase inhibitor with a dual mechanism of action, may turn out to be a new option for first-line therapy for CML, to be added to the current agents approved by the US Food and Drug Administration as first-line therapy for this condition—imatinib, dasatinib, and nilotinib. Promising results of a randomized, phase 3, open-label trial of bosutinib were reported at the meeting. In 502 newly diagnosed patients with CML evaluated at 1 year, the major molecular response rate was 39% with bosutinib versus 26% with imatinib (P = .002). According to Carlo Gambacorti-

Therapies for Myelodysplastic... Continued from page 25 toxicity or evidence of disease progression, therapy should be continued indefinitely.” When properly administered, even elderly patients (>75 years) can have a survival benefit (2-year OS is 55%) with good tolerability, he said. Toxicity Adverse events are inevitably encountered in treating patients with MDS with these drugs. Hematologic toxicity is common, and concern for infection in the setting of disease- or drug-related neutropenia has led to frequent prophylactic use of myeloid growth factors. However, there is little evidence that this improves outcomes, according to Dr Blum. “Growth factors can add considerable cost and patient inconvenience to the regimen…. Judicious use of G-CSF in the setting of ongoing neutropenic infection, particularly for patients with predominantly drug-associated neutropenia, is quite reasonable but not necessarily mandated. I typically use G-CSF only in the setting of serious neutropenic infection, when it is clearly drug-related.”

The role of immunosuppressive therapy with antithymocyte globulin and cyclosporine “remains enigmatic” in MDS. “The serious toxicities that can be encountered with its infusion and long-term immunosuppressive effects have properly led to hesitation over its use in practice…although appropriate selection of patients affords some opportunity for prolonged responses without the requirement for repeated maintenance chemotherapy,” Dr Blum said. He added that immunosuppressive therapy could be considered in lieu of a hypomethylating agent (ie, azacitidine, decitabine) for a select group of previously untreated, younger patients in accordance with clinical guidelines. Looking ahead, he said “the greatest benefit from each of the current agents will be in providing momentum for the next decade of research. Future advances will come from the discovery of new molecular targets and development of prognostic and predictive markers, as well as development of novel therapeutic approaches, including allogeneic transplantation.”—CH ■

Continued from page 1 Passerini, MD, University of Milano Bicocca, Italy, bosutinib’s effect on treatment failure is the main message of this study. At 1 year, treatment failures occurred in 3% of patients treated with bosutinib versus 10% of those who received standard imatinib. The overall net benefit of 7% would translate to about 500 newly diagnosed patients with CML in the United States each year, he said (see page 16). A very preliminary but very positive, dose-escalation phase 1 study of 74 patients suggests that ponatinib—a novel tyrosine kinase inhibitor—will be the first drug to inhibit the entire spectrum of mutations responsible for resistance to tyrosine kinase inhibitors, including the T315I mutation, which has so far eluded drug treatment. Responses were most robust in chronicphase patients with T315I mutations, but were less robust in accelerated and blast-phase CML. Jorge Cortes, MD, of M. D. Anderson Cancer Center, Houston, called the results of this study “very exciting,” and said that ponatinib may turn out to be the first drug that can prevent the emergence of resistance resulting from mutations in this patient population (see page 16). Non-Hodgkin Lymphoma Pixantrone, a novel aza-anthracenedione structurally related to mitoxantrone and anthracyclines, achieved superior rates of complete response/complete response unconfirmed, a superior overall response

rate, and superior PFS versus comparator agents in the randomized phase 3 EXTEND trial of 140 heavily pretreated patients with non-Hodgkin lymphoma who have poor prognosis. Ruth Pettengell, MD, of St. George’s Hospital in London, United Kingdom, reported the results of the study. At 18 months of follow-up, the rates for pixantrone versus comparators, respectively, were: • Complete response/complete response unconfirmed—20% versus 5.7% • Overall response—37.1% versus 14.3% • Median PFS—5.3 months versus 2.6 months • Median overall survival 10.2 months versus 7.6 months. Hodgkin Lymphoma Brentuximab vedotin, an antibody-drug conjugate of an anti-CD30 monoclonal antibody and a potent antitubulin agent called monomethyl auristatin E, showed encouraging results in patients with relapsed/ refractory Hodgkin lymphoma in a pivotal phase 2, single-arm study reported by Robert Chen, MD, assistant professor, City of Hope, Duarte, CA (see page 15). Dr Chen called these results “dramatic” for patients with Hodgkin lymphoma who have limited or no treatment options. Of 102 high-risk patients with refractory or relapsed disease, 75% had an objective response (≥50% tumor shrinkage), and 94% had some degree of tumor shrinkage. ■

Long-Term Complications of Stem-Cell Transplant By Caroline Helwick

or too many patients with hematologic malignancies, the hope that comes with potentially being cured through an allogeneic (donor) stem-cell transplant is often tempered by the devastating cost of transplant-related complications. Improving pretransplant prediction of complications and posttransplant recognition and treatment should improve outcomes for patients, but the pace has been slow. Mohamed L. Sorror, MD, MSc, of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, described the general lack of standardization in how transplant physicians use pre-

transplant comorbidities to predict the risk of toxicity after allogeneic stem-cell transplant. He showed compelling evidence that the use of a hematopoietic-cell transplantation comorbidity index— which compiles objective organ comorbidities into a single risk factor—is a more standard and effective way to predict transplant-related toxicities. Dr Sorror gave examples of how this index may be used, for example, in considering a reducedintensity conditioning regimen in patients with increased hematopoietic-cell transplantation comorbidity index scores and myeloablative conditioning regimens in older patients Continued on page 27

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Other Highlights

Looking Ahead: Incorporating Genomic Research into Personalized Medicine By Caroline Helwick

ey advances in understanding the human genome, and the development of high-throughput methods of defining genetic loci, are accelerating the pace of discovery in all cancer, especially hematology, it seems. At ASH 2010, a number of sessions were aimed at drilling down to the level of the chromosome. Although chromosomal alterations have, for some time now, defined subsets of patients with leukemia and led to amazing treatments, such as imatinib, the search for key genes is under way in virtually all categories of hematologic disorders and malignancies. Genomic studies were the focus of many abstracts and entire sessions at the meeting. Mark D. Fleming, MD, DPhil, of Harvard Medical School, who moderated one of the sessions, suggested that attendees should begin

to understand “the principles of genome-wide association studies and how the results may be translated to clinical medicine.”

Hematologists should begin to understand “the principles of genome-wide association studies and how the results may be translated to clinical medicine.” —Mark D. Fleming, MD, DPhil

For example, European populationbased studies have identified 70 single nucleotide polymorphisms that are

associated only with platelet count and volume. And genome-wide interrogations are now addressing the etiology and responsiveness to therapy for childhood acute lymphoblastic leukemia (ALL). A collaborative study has identified single nucleotide polymorphisms that are significantly associated with ALL, some of which distinguish among subtypes and others that are associated with methotrexate pharmacokinetics, known to be important in ALL treatment response. Genes have been identified in association with a virulent subtype of pediatric leukemias that occurs in infants and in secondary leukemias after certain therapies. Other investigators are pinning down genes that may help in donor selection for hematopoietic stem-cell transplantation, and one

gene deletion is now known to be associated with the occurrence of graft-versus-host disease afterward. The hemophilias are now considered prototypic models of genetic disease and new therapies. Cloning of these genes led to the development of recombinant clotting factor concentrates that revolutionized treatment for this disease. Bioengineering is now focused on developing new second- and latergeneration concentrates that persist longer in the body and may result in reduced immunogenicity. Gene therapy approaches are advancing in this area. These are only a few examples of the genome-based research exploding in hematology that will ultimately lead to finely tuned, individualized therapy—but at what cost? ■

Long-Term Complications... Continued from page 26 with lower scores. But questions will need to be answered, he added, before this approach could be put into routine practice: • Will mitigation of toxicity affect clinical outcomes? • Should allogeneic stem-cell transplant even be offered to patients with a hematopoietic-cell transplantation comorbidity index above a certain score? Long-Term Complications Mohamad Mohty, MD, PhD, of the CHU de Nantes in France, noted that although more allogeneic stem-cell

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transplant recipients are surviving the early transplant period, they often experience long-term medical complications and increased risk of mortality down the road. These complications include: • Endocrine disorders • Secondary malignancies • Chronic graft-versus-host disease. Increased awareness and monitoring for these conditions; appropriate management strategies; and close partnering among transplant centers, organ-specific specialists, and local primary care providers will help to ameliorate these problems, Dr Mohty said. Good quality of life after allogeneic

Multiple dimensions affect health-related quality of life in patients with allogeneic stem-cell transplant—physical, psychosocial, and emotional issues surface for patients— and there can be great caregiver distress.

stem-cell transplant, therefore, is never assured, said Margaret F.

Bevans, RN, PhD, of the National Institutes of Health. She emphasized the multiple dimensions that affect health-related quality of life in patients with allogeneic stem-cell transplant—physical, psychosocial, and emotional issues surface for patients—and there can be great caregiver distress. Her group is developing formal guidelines to assist transplant centers in assessing these domains. The speakers agreed that cure is no longer enough in patients with hematologic malignancies; healthcare providers must also ensure that life after transplant is worth living. ■

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Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

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