ASH Abstracts Luspatercept

851 Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia Thalassemia and Globin Gene Regulation Program: Oral and Poster Abstracts Type: Oral Session: 112. Thalassemia and Globin Gene Regulation: Clinical Advances in Thalassemia Monday, December 5, 2016: 3:45 PM Room 7AB (San Diego Convention Center)

Antonio G. Piga, MD1, Immacolata Tartaglione, MD2*, Rita Gamberini, MD3*, Ersi Voskaridou, MD4*, Angela Melpignano, MD5*, Paolo Ricchi, MD6*, Vincenzo Caruso, MD7*, Antonello Pietrangelo, MD8*, Xiaosha Zhang9*, Dawn M. Wilson9*, Ashley Leneus9*, Abderrahmane Laadem, MD10, Matthew L. Sherman, MD9 and Kenneth M. Attie, MD9 Turin University, Turin, Italy

1

Second University of Naples, Naples, Italy

2

Arcispedale S. Anna, Cona, Ferrara, Italy

3

Laiko General Hospital, Athens, Greece

4

Ospedale "A. Perrino", Brindisi, Italy

5

AORN "A. Cardarelli", Naples, Italy

6

ARNAS Garibaldi, Catania, Italy

7

CEMEF, Medicina 2, Modena, Italy

8

Acceleron Pharma, Cambridge, MA

9

Celgene Corporation, Summit, NJ

10

Background.Luspatercept (ACE-536) is a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors causes ineffective erythropoiesis (IE) leading to anemia and dysregulated iron homeostasis. In a mouse model of beta-thalassemia, luspatercept corrected the effects of ineffective erythropoiesis and in a phase 1 clinical study with healthy volunteers, was well tolerated and increased hemoglobin (Suragani R, Nat Med, 2014; Suragani R, Blood, 2014; Attie K, Am J Hematol, 2014).

Aims.This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a longterm extension study to evaluate the effects of luspatercept in patients (pts) with either transfusiondependent (TD) or non-transfusion dependent (NTD) beta-thalassemia with the following key

endpoints: erythroid response (including Hgb increase) and patient-reported quality-of-life (QoL) measures in NTD patients, and reductions in RBC transfusion burden in TD patients.

Methods.Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥ 4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as < 4 RBC units transfused in the 8 weeks prior to first dose with baseline Hgb < 10.0 g/dL). Luspatercept was administered subcutaneously every 3 weeks for up to 5 doses over 12 weeks with an 8 week followup (20 weeks total). Six cohorts (n=35) were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort (n=29) and all pts who rolled over to the extension study (n=51) were treated at ≥ 0.8 mg/kg with escalation up to 1.25 mg/kg.

Results. A total of 30 TD pts enrolled in the base study and, of those, 24 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 38 yr (range 22-55 yr), 67% had prior splenectomy. At baseline, median transfusion burden was 8 units/12 weeks (range 4-15 units) and mean (SD) liver iron concentration (LIC) was 5.1 (5.3) mg/g dw. A total of 20/24 (83%) and 16/24 (67%) TD pts achieved a ≥ 33% and ≥ 50% decrease in transfusion burden over any 12-week period compared to baseline, respectively. Duration of response ranged from 12 to 48+ weeks.

A total of 34 NTD pts enrolled in the base study and, of those, 27 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 37 yr (range 23-62 yr); 67% had prior splenectomy. At baseline, median Hgb was 8.7 g/dL (range 7.6-9.8 g/dL) and mean (SD) LIC was 4.9 (3.4) mg/g dw. A total of 21/27 (78%) and 15/27 (56%) NTD pts achieved ≥ 1.0 g/dL and ≥ 1.5 g/dL increases, respectively, in mean Hgb over any 12-week period compared to baseline. Duration of response ranged from 16 to 72+ weeks, with no trend for lower Hgb response over time. Increases in mean hemoglobin over a 12-week period correlated with increases in a pt-reported QoL questionnaire, FACIT-F (r=0.67, p=0.001). 3/5 (60%) pts with baseline LIC ≥ 5 mg/g dw had a decrease in LIC ≥ 2 mg/g dw after at least 6 months of treatment; 8/9 (89%) patients with baseline LIC < 5 mg/g dw maintained LIC < 5 mg/g dw.

Luspatercept was generally well tolerated, with no related SAEs. AEs were mostly mild-moderate. The most frequent related AEs (≥ 10% in base + extension studies) in TD pts were bone pain, myalgia, arthralgia, headache, asthenia, and musculoskeletal pain. The most frequent related AEs (≥ 10% in base + extension studies) in NTD pts were bone pain, headache, musculoskeletal pain, and arthralgia.

Conclusions: Luspatercept treatment in pts with beta-thalassemia had a favorable safety profile.

Efficacy was clinically relevant in both NTD pts (increased Hgb levels, decreased LIC, and improved quality of life) and TD pts (decreased RBC transfusions). A Phase 3, double-blind, placebo-controlled

study of luspatercept in regularly transfused adults with beta-thalassemia is ongoing (NCT02604433).

1175 Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia: Update from the Northstar Hgb-204 Phase 1/2 Clinical Study Gene Therapy and Transfer Program: Oral and Poster Abstracts Type: Oral Session: 801. Gene Therapy and Transfer: Gene Therapy for Benign Hematologic Diseases Monday, December 5, 2016: 5:30 PM Room 24 (San Diego Convention Center)

Alexis A. Thompson, MD, MPH1, Janet Kwiatkowski, MD2, John Rasko, MBBS, PhD3, Suradej Hongeng, MD4*, Gary J. Schiller, MD5, Usanarat Anurathapan, MD4*, Marina Cavazzana, MD, PhD6, P. Joy Ho3, Christof von Kalle, MD7*, Morris Kletzel, MD, FAAP, MBA8, Philippe Leboulch, MD4,9,10*, Elliott Vichinsky, MD11, Alexandria Petrusich12*, Mohammed Asmal, MD, PhD12* and Mark C. Walters, MD13 Division of Hematology, Oncology & Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital

1

of Chicago, Chicago, IL Division of Hematology, Children's Hospital Philadelphia, Philadelphia, PA

2

Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia

3

Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

4

University of California Los Angeles, Los Angeles, CA

5

Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM,

6

Paris, France National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg,

7

Germany Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL

8

CEA and University of Paris-Sud, Institute of Emerging Diseases and Innovative Therapies, Fontenay-

9

Aux-Roses, France Harvard Medical School and Brigham & Women’s Hospital, Boston, MA

10

Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, CA

11

bluebird bio, Cambridge, MA

12

UCSF Benioff Children's Hospital Oakland, Oakland, CA

13

BACKGROUND Allogeneic hematopoietic stem cell (HSC) transplant is potentially curative for patients with βthalassemia major or, as more broadly defined, transfusion dependent β-thalassemia (TDT).

However, HSC transplant is generally restricted to younger patients with matched sibling donors.

Gene therapy could provide a transformative treatment for a broader population of patients with TDT, including those who are older or lack an appropriate donor.

HGB-204 is an international, multi-center Phase 1/2 clinical study investigating the safety and efficacy of LentiGlobin Drug Product (DP), a gene therapy product containing autologous HSCs transduced ex vivowith the BB305 lentiviral vector, in patients with TDT. We previously reported initial data in 13 treated patients with 0 to 19 months follow-up. Study enrollment is complete, and all 18 patients have undergone DP infusion. Here, we report new results on the study’s full cohort of 18 patients, 14 of whom have ≥ 6 months of follow-up, including 1 who has completed the primary 24-month analysis period.

METHODS Patients (12 to 35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. HSC mobilization was accomplished with granulocyte colony stimulating factor (G-CSF) and plerixafor, and HSCs were harvested by apheresis. In a centralized manufacturing facility, CD34+-selected stem cells were transduced with the BB305 lentiviral vector, which encodes the human β-globin gene engineered to contain a single point mutation (AT87Q) and is regulated by the βglobin locus control region. Patients underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells (LentiGlobin DP). Patients were monitored for hematologic engraftment, vector copy number (VCN), hemoglobin AT87Q (HbAT87Q) expression, and transfusion requirements. Safety assessments including adverse clinical events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL) were evaluated post-infusion.

RESULTS Eighteen patients with TDT (β0/β0 [n=8], β0/βE [n=6], β0/β+ [n=1], β0/βx [n=1] and β+/β+ [n=2] genotypes) have received LentiGlobin DP. The median age of the 13 female and 5 male patients treated was 20 years (range: 12–35 years). The median DP VCN was 0.7 (range: 0.3–1.5 copies/diploid genome) and the median cell dose was 8.1 x 106 CD34+ cells/kg (range: 5.2–18.1 x 106 cells/kg). Patients engrafted with a median time of 18.5 days (range: 14–30 days) to neutrophil recovery. The toxicity profile observed was typical of myeloablative conditioning with single agent busulfan. There have been no ≥ Grade 3 DP-related AEs and no evidence of clonal dominance or RCL during a median follow-up of 14.4 months post-infusion (range: 3.7–27.0 months; cut-off date: 27 June 2016). To date, patients with at least 6 months of follow-up achieved a median HbAT87Q level of 4.7 g/dL at 6 months (range: 1.8–8.9 g/dL; n=14), with a median VCN in peripheral blood of 0.4 (range: 0.2−1.0; n=13). Of these, all patients with non-β0/β0 genotypes and ≥12 months of followup (n=5) have remained free of transfusions (median 19.4 months without transfusion; range: 15.3 to 24.0 months) with a median total Hb of 11.6g/dL (range: 9.0–11.9 g/dL) at the most recent

follow-up visit. While patients with β0/β0genotypes and ≥12 months of follow-up (n=5) have continued to require transfusions, annual median transfusion volumes have decreased 60% (from median 171.9 ml/kg/year at baseline [range: 168.1–223.2ml/kg/year] to 67.8 ml/kg/year posttreatment [range: 14.8–123.7 ml/kg/year]).

CONCLUSIONS In the largest TDT gene therapy trial to date, all patients have demonstrated therapeutic Hb expression without ≥ Grade 3 DP-related AEs. The levels of HbAT87Q in patients with at least 6 months of follow-up have exceeded the study primary endpoint (≥ 2g/dL) in 13/14 (93%) patients and are sustained in the 10 patients with ≥12 months of follow up. Compared to their baseline, all patients with β0/β0 genotypes have considerably reduced transfusion requirements. Notably, following a single infusion of LentiGlobin DP, patients with genotypes other than β0/β0 have discontinued transfusions and remain free of transfusions to date. These early results support the continued development of LentiGlobin DP as a treatment for TDT.

2311 Update from the Hgb-205 Phase 1/2 Clinical Study of Lentiglobin Gene Therapy: Sustained Clinical Benefit in Severe Hemoglobinopathies Gene Therapy and Transfer Program: Oral and Poster Abstracts Session: 801. Gene Therapy and Transfer: Poster I Saturday, December 3, 2016, 5:30 PM-7:30 PM Hall GH (San Diego Convention Center)

Jean-Antoine Ribeil, MD, PhD1*, Salima Hacein-Bey-Abina, Pharm.D., Ph.D.2,3*, Emmanuel Payen, PhD4*, Michaela Semeraro, PhD5*, Magrin Elisa, PhD1*, Laure Caccavelli, PhD1*, Fabien Touzot, MD, PhD1*, Francois Lefrere, MD1*, Felipe Suarez, MD, PhD1, Olivier Hermine, MD, PhD1*, Valentine Brousse, MD1,6*, Catherine Poirot, MD, PhD7*, Benedicte Neven, MD, PhD1*, Philippe Bourget, PharmD, PhD1*, Wassim El Nemer, PhD8,9*, Pablo Bartolucci, MD PhD10*, Leslie Weber, MSc5*, Hervé Puy, MD, PhD8*, Jean-François Méritet, PhD11*, David Grevent, MD12*, Yves Beuzard, MD13*, Stany Chrétien, MD4*, Thibaud Lefebvre, MD8*, Mohammed Asmal, MD, PhD14*, Marcelyne Joseney-Antoine14*, Mariane De Montalembert, MD, PhD1, Stephane Blanche, MD1*, Philippe Leboulch, MD4,15,16* and Marina Cavazzana, MD, PhD1,5,17 Hôpital Universitaire Necker-Enfants Malades, Paris, France

1

Chimie ParisTech, Université Paris Descartes, Paris, France

2

Service immunologie Biologique, Groupe Hospitalier Universitaire Paris-Sud, Paris, France

3

Institute of Emerging Diseases and Innovative Therapies (iMETI), CEA, Université Paris-Sud,

4

Fontenay-aux-Roses, France IMAGINE Institute, Paris Descartes–Sorbonne Paris Cité University, Paris, France

5

Laboratory of Excellence, GR-ex, Paris, France

6

Pierre et Marie Curie University, Paris, France

7

Université Paris Diderot, Paris, France

8

Institut National de la Transfusion Sanguine (INTS), Paris, France

9

Hopital Henri Mondor, Créteil, France

10

Laboratoire de Virologie, Hôpital Cochin, Paris, France

11

Hôpital Necker-Enfants Malades, Paris, France

12

CEA (iMETI) and University of Paris-Sud, Fontenay-aux-Roses, France

13

bluebird bio, Cambridge, MA

14

Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

15

Brigham & Women's Hospital and Harvard Medical School, Boston, MA

16

Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM,

17

Paris, France

Introduction: β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms of severe sickle cell disease (SCD) and reduce or eliminate transfusion requirements in transfusion-dependent β-thalassemia (TDT). LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector, which encodes a human βglobin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed with γ-globin. We previously reported proof of concept for LentiGlobin DP treatment in severe SCD and early data from 4 treated patients with TDT. We now report 18 months of follow-up for the patient with SCD and between 9 and 30 months of follow-up for the 4 patients with TDT. Patients (5–35 years of age) with severe SCD (e.g. ≥2 acute chest syndrome episodes or ≥2 vasoocclusive crises [VOC] in preceding year/in year prior to regular transfusions) or TDT (≥100mL/kg of packed red blood cells [RBCs] per year) were enrolled. Following mobilization and apheresis (for TDT) or bone marrow harvest (for SCD), autologous CD34+ cells were transduced with the BB305 lentiviral vector. Patients underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. After infusion, patients were monitored for hematologic engraftment, vector copy number (VCN), and HbAT87Q expression. Disease-specific assessments included transfusion requirements for TDT, or VOCs and hospitalizations for SCD. Safety assessments included adverse events (AEs) and integration site analysis.

Results: As of July 2016, 1 patient with severe SCD (male; 13 years old) and 4 patients with TDT (2 male, 2 female; 16–19 years old) have received LentiGlobin DP in Study HGB-205. The median LentiGlobin DP cell dose was 8.9 (range 5.6–13.6) x 106 CD34+ cells/kg with a DP VCN of 1.2 (range: 0.8-2.0) vector copies/diploid genome. Median post-infusion follow-up as of July 6, 2016 is 20.8 months (range 9.5–31.3). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 17 days (range 14–38 days). VCN in peripheral blood has remained generally consistent from Month 3 in all patients with a range of 0.2 to 3.4 at last measurement. The toxicity profile observed from start of conditioning to latest follow-up remains consistent with myeloablative conditioning with single-agent busulfan, with no DP-related ≥Grade 3 AEs or serious AEs and no evidence of clonal dominance reported to date.

Three patients with TDT have β0/βE genotypes and 1 is homozygous for the severe β+ mutation IVS1 nt 110 G>A. The 2 patients who have completed the 2-year primary follow-up period (both β0/βE) have not required RBC transfusions for 31 and 28 months, with total Hb of 10.9 and 13.5 g/dL, and HbAT87Q expression of 7.7 and 10.1 g/dL, respectively, at most recent study visit. Iron chelation has been discontinued and phlebotomy initiated for 1 of the patients. The remaining patient with β0/βE genotype has 9 months of follow-up and has not required transfusions since 4 days postLentiGlobin DP infusion, achieving a total Hb of 11.3 g/dL at last study visit. The patient with the

severe IVS1 genotype has 12 months of follow-up and has been free of transfusions for 9 months, with a total Hb of 8.3 g/dL at last study visit.

The patient with severe SCD, who prior to study enrollment received regular RBC transfusions, has experienced no clinical symptoms or complications of SCD in the 18 months since treatment, despite discontinuing transfusions 3 months after LentiGlobin DP infusion. Total Hb in this patient was 12.5 g/dL, with 6.6 g/dL HbAT87Q (53%) and 5.7 g/dL HbS (45%) at last study visit. Compared with values at screening, unconjugated bilirubin had dropped 78% (50 to 11 Îźmol/L), lactate dehydrogenase had dropped 54% (626 to 287 U/L), and reticulocyte count had dropped 45% (238x10 9/L to 132x109/L)

by Month 18.

Conclusions: Data from this ongoing Phase 1/2 clinical study suggest that treatment with LentiGlobin DP can result in sustained production of therapeutic HbAT87Q, which ameliorates the clinical and biochemical effects of severe SCD and TDT, with an acceptable safety profile. Gene therapy presents a potentially promising therapy for patients with severe hemoglobinopathies.

Further follow-up and additional data from patients are needed to confirm the encouraging results seen to date in this study.

852 Efficacy and Safety of Ruxolitinib in Regularly Transfused Patients with Thalassemia: Results from Single-Arm, Multicenter, Phase 2a Truth Study Thalassemia and Globin Gene Regulation Program: Oral and Poster Abstracts Type: Oral Session: 112. Thalassemia and Globin Gene Regulation: Clinical Advances in Thalassemia Monday, December 5, 2016: 4:00 PM Room 7AB (San Diego Convention Center)

Yesim Aydinok, MD1, Zeynep Karakas, MD2*, Elena Cassinerio, MD3*, Noppadol Siritanaratkul, MD4, Antonis Kattamis, MD5, Aurelio Maggio, MD6, Norbert Hollaender, PhD7*, Bruyère Mahuzier, Pharm D8*, Brian Gadbaw, MD9 and Ali T. Taher, MD, PhD10 Ege University Hospital, Izmir, Turkey

1

Department of Pediatric Hematology and Oncology, Istanbul University, Istanbul Medical Faculty,

2

Istanbul, Turkey Università di Milano, Ca Granda Foundation IRCCS, Milan, Italy

3

Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

4

First Department of Pediatrics, University of Athens, Athens, Greece

5

Campus of Haematology Franco e Piera Cutino- A.O.O.R. “Villa Sofia-V. Cervello, Palermo, Italy

6

Novartis Pharma AG, Basel, Switzerland

7

Novartis Pharma S.A.S, Rueil-Malmaison, France

8

Novartis Pharmaceuticals Corporation, East Hanover, NJ

9

American University of Beirut Medical Center, Beirut, Lebanon

10

BACKGROUND: Ruxolitinib (RUX) is approved in adult patients (pts) with myelofibrosis (MF), and in pts with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea. Splenomegaly, a key clinical feature in advanced MF/PV, is also common in pts with transfusion-dependent thalassemia (TDT). In pts with TDT, splenomegaly worsens anemia, leading to increased transfusion requirement (TR). Similar to murine models of MF (Ostojic A, 2012), JAK2 inhibition led to a decrease in spleen size in murine models of thalassemia (Musallam KM, 2013). Additionally, thalassemia-related ineffective erythropoiesis was associated with hyperactivation of JAK-STAT pathway in preclinical studies. These findings indicate that RUX treatment (Tx) might benefit pts with TDT and splenomegaly. Present exploratory study aims to evaluate the effect of RUX Tx on TR, spleen volume (SV), and pre-transfusion hemoglobin (Hgb) levels.

METHODS: TRUTH is a single-arm, multicenter, phase 2a study exploring the efficacy and safety of RUX in regularly transfused adult pts (N = 30) with thalassemia and splenomegaly, for 30 weeks (core study). Starting dose of RUX was 10 mg twice daily (maximum dose of 25 mg in 5 mg/10 mg increments). Pts were required to receive iron chelation (deferoxamine/deferasirox) for at least 4 week prior to screening and throughout the study. Primary end point was the percent change of red blood cells (RBCs) transfused between week 6 to 30 vs baseline period (BL; defined as period between 24 weeks prior to start of Tx and week 0). Change of SV from BL (by MRI/CT) at week 12 and week 30 was a secondary end point. Other secondary end points included safety (N = 30, safety set) and change of pre-transfusion Hgb level from BL. RESULTS: Of the 30 pts enrolled (median age, 24 years; 60% male), 26 completed the core phase at week 30 and 4 discontinued before week 30 (adverse event [AE], N = 2; withdrew consent, N = 1; subject/guardian decision, N = 1). Of those 26 who completed core Tx, 20 pts continue to receive RUX beyond the core study via other mechanisms. The median duration of exposure during the core phase was 30.2 weeks and median actual dose intensity of RUX was 27.2 mg/day (range, 13.3-39.0 mg/day). Mean hematocrit (HCT) adjusted volume of transfused RBC per 4 weeks was 605 mL for the BL period and 560 mL for the on-Tx period (between week 6-30; N = 27, per protocol set; 3 pts received < 18 weeks of Tx). Mean percent change of transfusion rate was −5.9 (95% CI: −14.7, 2.83). Change of HCT adjusted transfused volume per 4 weeks for on-Tx period vs BL is shown in Figure 1A. The percent change from BL in SV at week 30 is represented in Figure 1B. The mean SV reduction from BL at week 12 (N = 26) and week 30 (N = 25) was −19.7% and −26.8%, respectively.

A slight trend for improvement was observed in the median pre-transfusion Hgb levels over time (pre-Tx = 8.4 g/L; end of study [week 24-30] = 8.9 g/L). At BL, 77% (23/30) of pts had Hgb levels below LLN but ≥ 8 g/dL and 20% (6/30) of pts had Hgb levels < 8 g/dL. At BL, 20% (6/30) of pts had a platelet (PLT) count below LLN but > 50 × 109/L, while no pt had PLT counts < 50 × 109/L. Worst post-BL hematologic abnormalities were Hgb (< 8g/dL, [hypo] = 17 pts [57%]), and PLT counts (< 50 × 109/L [hypo] = 1 pt [3%]). The most common AEs (all grade [G], ≥ 5%, regardless of study drug relationship) were upper respiratory tract infection (27%), nausea (20%), and upper abdominal pain/anemia/diarrhea/weight increased [each = 17%]). Overall, 25 pts experienced AEs, 11 pts had G 3 or 4 AEs, and 6 pts had serious AEs (regardless of study drug relationship); while, 13 pts experienced AEs, 5 pts had G 3 or 4 AEs, and 3 pts had serious AEs that were suspected to be related to the study drug. No deaths were reported during the study. AEs led to dose reduction/study Tx interruption in 9 pts (regardless of study drug relationship [≥ 5%]: nausea [all G = 2 pts (7%); G 3 or 4 = 1 pt (3%)] and vomiting [all G = 2 pts (7%); G 3 or 4 = 1 pt (3%)]).

CONCLUSION: RUX Tx showed a trend for improvement in transfused red cells and a slight improvement in pre-transfusion Hgb; while, there was a noticeable reduction in SV over time. As per

investigator assessment of clinical benefit, a majority of pts continued Tx beyond the core study.

RUX was well tolerated in the study population with modest incidences of G 3 or 4 and serious AEs, with no new safety findings. Given the sustained decrease in SV, further studies could be valuable to determine if RUX Tx may be an alternative to splenectomy in pts with TDT.

3633 Factors Impacting Quality of Life in Thalassemia Patients; Results from the Intercontinenthal Collaborative Study Thalassemia and Globin Gene Regulation Program: Oral and Poster Abstracts Session: 112. Thalassemia and Globin Gene Regulation: Poster III Monday, December 5, 2016, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center)

Ali Amid, MD1, Rebecca Leroux, BScN2*, Manuela Merelles-Pulcini, MSc3*, Saeed Yassobi, MD3*, Antoine N Saliba, MD4*, Richard Ward, MSc, MRCP, FRCPath5, Mehran Karimi, MD6, Ali T. Taher, MD, PhD7, Robert J Klaassen, MD8* and Melanie Kirby-Allen, MD9* Division of Paediatric Haematology/Oncology, The Hospital for Sick Children, University of Toronto,

1

Toronto, ON, Canada Division of Medical Oncology and Hematology, Toronto General Hospital, University Health Network,

2

Toronto, ON, Canada Division of Paediatric Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada

3

Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut

4

Medical Center, Beirut, Lebanon Division of Medical Oncology and Hematology, Department of Medicine, University Health Network,

5

Toronto, ON, Canada Hematology Research Center,, Shiraz University of Medical Sciences, Shiraz, Iran

6

American University of Beirut Medical Center, Beirut, Lebanon

7

Division of Pediatric Hematology/Oncology, Children's Hospital of Eastern Ontario, University of

8

Ottawa, Ottawa, ON, Canada Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children,

9

Toronto, ON, Canada Thalassemia is one of the most common causes of inherited anemia worldwide. While significant advances has been made in clinical management of thalassemia patients over the past few decades, our knowledge on the factors affecting the quality of life of thalassemia patients is limited.

The “IntercontinThal Study” is a collaborative effort to study the quality of life (QoL) and quality of care of thalassemia patients in populations across diverse social and health care systems. Data presented here are from the three participating centers in Canada, Lebanon and Iran. We have gathered study data through: a) QoL questionnaire SF-36 completed by patients, b) a specifically designed and validated questionnaire completed by patients which addressed patient’s social status

(marriage/relationship status, education, employment status, and access to social support and health care), and c) review of the patientsâ&#x20AC;&#x2122; charts using a data collection form. This form included: patientsâ&#x20AC;&#x2122; demographics, specifics of transfusion therapy and iron chelation, thalassemia-related and other clinical complications (endocrinopathies, bone disease, cardiac disease, hemolysis-related complications, etc.), tissue iron content (liver and cardiac) and/or serum ferritin within the past three years, and splenectomy status. All study questionnaires were translated into Persian (for Iranian patients) and Arabic (for Lebanese patients). Due to the variety of the clinical complications, all clinical complications were aggregated together for statistical analysis. We used univariate and multivariate regression analysis to study the association of predictors and patientsâ&#x20AC;&#x2122; QoL Mental Component Summary (MCS) Score.

Ninety seven patients [46 female, 59 transfusion-dependent beta-thalassemia (TDT) and 38 nontransfusion-dependent beta-thalassemia (NTDT)] were included in the analysis. All patients were older than 18 years of age (Mean 32 years, SD: 7 years). In univariate analysis age, access to social support and health care, marriage status, liver iron concentration and ferritin (strongly correlated with each other), and disease-related complications were found to be predictor of QoL MCS scores.

In NTDT patients, splenectomy and lower baseline hemoglobin were also significantly associated with reduced QoL. In multivariate analysis, ferritin and age (and clinical complications in TDT patients) were found to independently be associated with reduced QoL. LIC was not found to be an independent factor likely due to the fewer number of patients who had recent LIC assessments. Of interest, patients with NTDT reported better QoL at younger age compared to TDT patients but there was a trend toward worse QoL at older age.

Our results provide a better understanding of the factors that affect the QoL of thalassemia patients and highlights the importance of management of body iron in both TDT and specially in NTDT patients. In addition, it confirms the notion that while NTDT patients may not require regular transfusions based on conventional criteria, they may experience significant reduction in QoL especially at older ages. Further efforts to address the health and QoL of NTDT patients are required to improve the outcomes of this often neglected condition. (Funded by a research grant from the Thalassemia Foundation of Canada)

3533 Beta-Thalassemia (BT) Prevalence and Treatment Patterns in Italy: A Survey of Treating Physicians Health Services Research—Non-Malignant Conditions Program: Oral and Poster Abstracts Session: 901. Health Services Research—Non-Malignant Conditions: Poster II Sunday, December 4, 2016, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center)

Emanuele Angelucci, MD1, Nigel Burrows2*, Stefano Losi2*, Chris Bartiromo3* and X. Henry Hu, MD, PhD3* IRCCS Azienda Ospedaliera Universitaria San Martino, Genoa, Italy

1

IMS Health, Milan, Italy

2

Celgene Corporation, Summit, NJ

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Background: BT is an important public-health challenge in Italy. Seminal work has begun to better characterize disease prevalence, treatment patterns, and institutional capabilities within Italy.

Objective: Evaluation of current BT prevalence and treatment in Italy was done using proprietary IMS Health hospital audit data as the basis of a targeted survey of hematologists, pediatricians, and internists treating BT. We estimated the prevalence and distribution of patients with transfusiondependent (TD) BT major (BT-M) and intermedia (BT-I), and non-transfusion-dependent BT (NTD BT), and characterized current treatment patterns.

Methods: A preliminary list of possible BT-treating centers was extracted from the IMS Health audit of hospitals and treatment centers across Italy, covering 656 public hospitals and accounting for 205,021 beds (85% of hospital capacity in Italy).The IMS Health hospital audit also included 95% of the pharmaceutical Direct Patient Distribution channel. This list was reviewed to identify centers receiving iron-chelating agents, thus identifying a total of 365 potentially BT-treating hospitals. One hematologist or pediatrician in each potential hospital ward was contacted by telephone. The physician was asked to provide details about the number of TD BT-M, TD BT-I, and NTD BT patients managed in their ward. In case of refusal to provide the required information, telephone or inperson interviews were organized with other specialists in the same facility. We identified 124 treatment centers, 114 of which were successfully surveyed (92% completed the survey).

Subsequently we used a web-based questionnaire to ask a geographically stratified sample of 60 treating physicians about general treatment patterns, with a focus on potential drivers of health-care resource utilization. Responding physicians each referenced 3–4 records for patients currently under

their care to inform their responses to our survey, and 205 records were referenced in total: 162 TD and 43 NTD patients.

Results: In the 114 treatment centers surveyed, a total of 5,748 TD BT patients under regular treatment were reported, plus 1,296 additional patients receiving occasional treatment (NTD BT).

Distribution of TD patients was heterogeneous, with the highest prevalence in Sicily, Sardinia, and Puglia. These regions each had > 500 TD patients and hosted in total 3,051 TD patients (Table).

National patient volume was highly concentrated with the 7 largest centers managing 1,766 TD patients.

Based on the information in 205 patient records, complete blood count, ferritin level, echocardiography, and T2*-weighted MRI were the tests most commonly performed in the preceding 12 months. Of 162 TD patient records reviewed, 83 patients required 1â&#x20AC;&#x201C;2 units of red blood cells per month, while 78 patients required â&#x2030;Ľ 3 units per month (this information was not captured in 1 patient record). Deferasirox was the most commonly administered chelation treatment in TD patients, prescribed to 109 of 162 patients. Most TD patients (n = 126) had previously had a change of iron chelation treatment; 72 of these switched from deferoxamine to another agent. In-patient hospitalizations were estimated at 9 days/year, 7 days/year, and 4 days/year for TD BT-M, TD BT-I, and NTD BT patients, respectively. Endocrine pathologies were the most commonly reported comorbidity in all groups; 36 patients required medical treatment. Hepatitis C virus infection and hepatic and cardiac complications were also reported.

Conclusions: Prevalence of BT is regionally focused and likely to consume significant health-care resources for management of the disease and associated comorbidities. Although the telephone and web surveys used for our project were not designed to be a clinical trial, we were able to assess practices by a number of physicians (n = 60) for patients (n = 205) that were representative of the distribution of BT across Italy. We also screened the overall BT caseload of up to 365 potentially BTtreating centers in the country. Our survey complements recent work to understand the burden of this disease in Italy.