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The Final Countdown

December 18, 2022
Naseema Gangat, MBBS, Editor, ASH News Daily

Dr. Naseema Gangat (@n_gangat) graduated from medical school at Aga Khan University in Karachi, Pakistan, and attended Mayo Clinic College of Medicine for her internal medicine residency and hematology/oncology fellowship. She continues to call the Mayo Clinic and Rochester, Minnesota, home and is currently a professor of medicine in the division of hematology. 2022 marks Dr. Gangat’s third serving on the ASH News Daily editorial board — she was an Author in 2018, became Editor in 2021, and clearly is really having fun with this. Outside of hematology, Dr. Gangat is also a bona fide fashionista. “I share an equal passion for keeping up with the latest fashion scene through visits to Rodeo Drive, Beverly Hills, and Sloane Street, London,” she said. Last year, she had the good fortune to explore Hollywood’s elusive “San Vincente Bungalow” during the Burberry AW21 runway experience, and more recently, she made it to the Abbey Road Crossing, which was apparently made famous by a rock band.

The #ASH22 Late-Breaking Abstracts session makes history by featuring six randomized phase III clinical trials, opening new therapeutic horizons in malignant and classical hematology. Akin to the dreamy lyrics of the song “The Final Countdown,” the session was an optimistic journey into space (Venus), leaving earth behind and literally representing the final countdown to the end of #ASH22. When we asked session chair Dr. Olatoyoso Odenike about the trials, she explained, “This set of abstracts underscores the importance of conducting well-designed phase III studies, despite the time, effort, and challenges that may be encountered in bringing them to fruition. The studies presented are all exciting practice-changing and/or practice-affirming studies, spanning both the malignant and classical hematology realms.”

Let’s now count down the six clinical trials presented on Tuesday in New Orleans:

6. ALPINE

Ibrutinib, a first-generation, Bruton tyrosine kinase (BTK) inhibitor, yields high response rates in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL); however, toxicities frequently lead to discontinuation of therapy. Accordingly, the second-generation BTK inhibitor zanubrutinib was designed to minimize toxicities and increase specificity by reducing off-target inhibition. In the phase III ALPINE trial, which compared zanubrutinib to ibrutinib in relapsed/refractory CLL/SLL, the former emerged superior in terms of overall response, including in patients with del(17p)/TP53 mutations. Zanubrutinib also resulted in fewer cardiac events and treatment discontinuations. The final analysis of the study presented by Dr. Jennifer Brown from the Dana-Farber Cancer Institute demonstrated progression-free survival superiority of zanubrutinib over ibrutinib. Based on these findings, the European Commission recently approved zanubrutinib for CLL, and U.S. Food and Drug Administration (FDA) approval is forthcoming.

5. ALIFE2

The off-label use of low-molecular-weight heparin (LMWH) for prevention of recurrent miscarriage is widely practiced despite no improvement in live birth rate with enoxaparin use in women without thrombophilia in a prior double-blind randomized trial. Similarly, the ALIFE2 study, led by Dr. Saskia Middeldorp, investigated the role of LMWH in prevention of pregnancy loss, specifically in women who inherited thrombophilia and confirmed a lack of benefit. Because of this study, we can convincingly discourage the use of LMWH in women with recurrent miscarriages. Moreover, routine thrombophilia testing is not advised given its weak association with recurrent pregnancy loss.

4. BMT CTN 1703

Post-transplant cyclophosphamide (PTCy) ushers in a new era in allogeneic hematopoietic cell transplantation (allo-HCT) and constitutes the standard of care for mismatched transplants. Conversely, traditional graft-versus-host disease (GVHD) prophylaxis for matched transplants includes tacrolimus (Tac) and methotrexate (MTX). The randomized phase III BMT CTN 1703 study presented by Dr. Shernan Holtan compared PTCy/Tac/mycophenolate mofetil (MMF) with Tac/MTX in patients undergoing reduced-intensity conditioning matched allo-HCT and found superior one-year GVHD-free survival with PTCy/Tac/MMF. Similar results were observed with PTCy/Tac/MMF use in the setting of myeloablative allo-HCT (abstract #114). Dr. Shernan Holtan (shown left) shared her gratitude for the team that collaborated on PROGRESS III: BMT CTN 1703/1801. “Despite the many hurdles that we faced over the past few years, we completed the study a year ahead of schedule. We think the results will be practice changing for reduced-intensity transplantation,” said Dr Holtan. She now awaits the patient-reported outcomes/quality-of-life data analyses from the trial and expressed her excitement for the microbiome analyses from the BMT CTN 1801 counterparts. She also elaborated on her vision for the field of allo-HCT, stating, “With a markedly lower risk of severe acute and chronic GVHD, we must now shift focus to toxicities and relapse mitigation. We are truly entering a new era!”

3. MATRix/IELSG43

The rationale for high-dose chemotherapy followed by autologous SCT (HDC-ASCT) in patients with primary central nervous system (CNS) lymphoma (PCNSL) is to facilitate delivery of high doses of chemotherapy in order to achieve therapeutic drug concentrations in the CNS and eliminate residual chemoresistant disease through incorporation of non–cross-resistant alkylating agents as part of conditioning therapy. MATRix/IELSG43, an international randomized phase III trial, sought to determine whether the same could be achieved through nonmyeloablative chemoimmunotherapy. Following induction with MATRIx (high-dose methotrexate, cytarabine, thiotepa, and rituximab), patients who achieved a partial response or better were randomized to receive R-DeVIC (rituximab, dexamethasone, etoposide, ifosfamide, and carboplatin) or conditioning chemotherapy with BCNU/thiotepa followed by ASCT. Dr. Gerald Illerhaus summarized study results demonstrating superior progression-free and overall survival in patients that underwent ASCT. These findings reaffirm the importance of ASCT as standard consolidation therapy for fit patients with PCNSL.

2. APPLY-PNH

Iptacopan, an oral targeted factor B inhibitor of the alternative complement pathway, acts upstream of the C5 terminal pathway, preventing not only intravascular but also extravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). In the randomized Apply-PNH study, PNH patients with hemoglobin less than 10 g/dL while on eculizumab/ravulizumab received iptacopan or continued anti-C5 therapy. Dr. Regis Peffault De Latour (shown left) discusses that iptacopan monotherapy resulted in a clinically meaningful rise in hemoglobin and achievement of transfusion independence, unveiling an oral treatment option for patients with PNH who are already on anti-C5 therapy. Additionally, a separate phase III trial with iptacopan in anti-C5–naïve PNH patients (APPOINT-PNH) is currently ongoing.

1. ECOG-ACRIN E1910

Blinatumomab, a bispecific T-cell engager (BiTE), is FDA-approved for patients with B-lineage acute lymphoblastic leukemia (B-ALL) in remission with measurable residual disease (MRD), as well as those with relapsed/refractory disease. In the ECOG-ACRIN E1910 trial, patients with MRD-negative B-ALL were randomized to receive a standard course of consolidation chemotherapy or chemotherapy interspersed with four cycles of blinatumomab. The results showed that patients receiving blinatumomab plus chemotherapy had significantly improved overall survival. “Patients with ALL who are MRD negative have a better prognosis than patients who are MRD positive generally, but they still relapse. We wanted to see if blinatumomab would improve the results in this already more favorable risk group, and the study showed that adding blinatumomab to chemotherapy keeps MRD-negative patients in remission longer and improves their survival. Based on the study results, adding blinatumomab to consolidation chemotherapy represents a new standard of care,” shared Dr. Mark Litzow, lead investigator of the study.

And just like that, the countdown is over. This year’s late-breaking offering is a conveyor belt of winning clinical trials to suit every taste, fueling growing optimism for making a difference one trial at a time!


Dr. Gangat indicated no relevant conflicts of interest.

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