ASH Highlights

Breakthrough for fragile patients with CLL

During ASH, the GLOW study – a phase III trial evaluating the efficacy and safety of ibrutinib-venetoclax in older patients and/or those with comorbidities with previously untreated chronic lymphocytic leukemia (CLL) was presented. In this study, the combination of ibrutinib-venetoclax (14 months) is compared with the combination of chlorambucil-obinutuzumab (6 months) for frail patients, defined as elderly patients or patients with comorbidities such as reduced kidney function.

The study is the first to document that elderly and frail patients can achieve an improved survival with a time-limited targeted treatment compared to chemo-immunotherapy. Furthermore, the study indicates that an equally deep MRD response is not necessary when treating with a BTK inhibitor (ibrutinib) combined with a BCL2 inhibitor (venetoclax) compared to chemo-immunotherapy.

Given their distinct and complementary mechanisms of action, ibrutinib and venetoclax work synergistically to eradicate CLL by eliminating both dividing and resting leukemic subpopulations. Ibrutinib effectively inhibits tumor cell proliferation and mobilises leukemic cells from protective lymphoid niches. Further, ibrutinib increases the sensitivity of CLL cells to BCL-2 inhibition, thereby accelerating apoptotic cell killing by venetoclax.

There is, thus, not the same coalition between progression-free survival with different genetics. Authors explain this by the combination of BTK inhibitor and BCL2 inhibitor to affect different compartments of the disease such as lymph nodes, blood, and bone marrow.

We met with Carsten Utoft Niemann, chair of the Nordic CLL Groupe, at ASH. He elaborated on the connection between the ibrutinib-venetoclax combination and undetectable MRD. He pointed out that infection is still considered a major risk factor for patients with CLL but that future machine learning may be able to help identify the patients with the greatest risk of infection. By this, the treatment can be more individualized in the future. We also expect better methods for dividing patients into genetic subgroups combined with the risk of infection, which he expects will impact future clinical studies' design.

Evidence to use MRD after induction therapy of AML

Dr. Jacqueline Cloos, an expert in the field of Acute Myeloid Leukemia (AML), is part of a group called The European LeukemiaNet (ELN) MRD Working Party, which aims to improve the use of Minimal Residual Disease (MRD) as a tool in AML treatment. Recently, the group published new guidelines offering more evidence-based recommendations, particularly for using MRD after induction therapy for intermediate-risk AML patients. The guidelines also emphasize the importance of using validated MRD tests. At ASH22, we spoke with Dr. Cloos, who explained that the ELN MRD Working Party is divided into four subgroups, each consisting of experts in flow cytometry, qPCR, next-generation sequencing, and clinical implementation of MRD. The group also strives to understand how MRD is used in real-world settings and in patients receiving fewer intensive treatments.

Dr. Cloos is particularly interested in standardizing MRD tests and improving their quality. The efforts of the ELN MRD Working Party should ultimately improve MRD for all AML patients and, hopefully, increase the usage of MRD as an intermediate endpoint for trials investigating novel drugs. The new guidelines and the ongoing work of the ELN MRD Working Party are promising steps towards better AML treatment and care.

The Future Treatment of Multiple Myeloma

Dr. Sagar Lonial from the Winship Cancer Institute of Emory University in Atlanta, USA, spoke with us at ASH22 about the exciting developments in BCMA-targeted immune therapies and CART-T cells therapy for patients suffering from multiple myeloma. This year's ASH showcased several T cell engager treatments targeting BCMA.

Even though continuous therapy with T cell engagers can cause concerns due to a higher risk of infectious complications and potential genetic mutations, Dr. Lonial expects a bright future for both T cell engagers and CAR-T cells in the treatment of multiple myeloma. The key question is the optimal treatment sequence, and Dr. Lonial believes that initiating treatment with CAR-T cell therapy and then using T cell engagers if relapse occurs may be the ideal approach. As more research is conducted, the future will reveal the answer.

With a wide range of sessions, events, and presentations, ASH22 provided a valuable opportunity for attendees to keep up-to-date with the latest developments in hematology and to network with like-minded professionals. Photo : BestPractice Nordic

Mezigdomide : Promising Efficacy in Triple-class Refractory R/R Multiple Myeloma

Mezigdomide, a novel cereblon E3 ligase modulator, has shown great promise in the treatment of relapsed and refractory multiple myeloma. This potent drug induces apoptosis in myeloma cells and has a powerful synergy with dexamethasone, explains Dr. Paul Richardson from the Dana Farber Cancer Institute, who presented preliminary results of a dose expansion study at ASH22. During the conference, we were fortunate to have the opportunity to discuss the study with Dr. Richardson.

The study involved younger patients receiving 40 milligrams of mezigdomide and dexamethasone weekly and older patients receiving 20 milligrams of mezigdomide weekly with the option to reduce doses. Patients were triple-class refractory and could have been BCMA exposed. Results suggest about 30% of high-risk synergetics and approximately 40% of extramedullary disease. Up to 30% of the patients had prior BCMA exposure, making them a very high-risk, vulnerable population in the study, with up to six prior lines of therapy.

Despite the challenges posed by this patient population, the study showed very positive results. The overall response rate was 41%, with a 50% overall response rate among the group who had prior BCMA exposure and a response rate of 30% in patients with active disease.

Dr. Richardson highlighted the favorable safety profile of mezigdomide. During the COVID-19 pandemic, just one COVID-related death during the entire duration of the dose expansion phase was registered. Moreover, the rates of other infections were relatively low, and there were no dose discontinuations due to side effects.

Overall, the study indicates very promising results for using mezigdomide in treating relapsed and refractory multiple myeloma. The drug's potent efficacy and favorable safety profile make it a promising new option for patients with this challenging disease.

R/R Large B-cell Lymphoma : Interesting Results for CAR-T Treatment

During ASH22, we had the opportunity to meet with Frederick L. Locke from the Moffitt Cancer Center in Tampa, Florida, who presented data from the ZUMA 7 randomized phase III trial. The study aimed to analyze the correlation between metabolic tumor volume and clinical outcomes in patients receiving axicabtagene ciloleucel as a second-line treatment versus standard of care.

Locke's team studied more than 1,000 patients treated with axicabtagene ciloleucel and conducted their outcomes based on the ‚»vein to vein time,« which is the duration between the collection of T cells to CAR-T infusion.

The study revealed that patients who experienced a longer vein-to-vein time had poorer outcomes, particularly in progression-free and overall survival. Based on this finding, Locke suggested that shortening the vein-to-vein time could enhance the therapy's effectiveness.

However, further research is necessary to determine potential underlying reasons for patients' extended wait before receiving their CAR-T cell infusion. One reason is that patients with more aggressive diseases needed bridging therapy, while another possibility is that delays in manufacturing contributed to the wait time.