Report from the 2022 American Society of Hematology Annual Meeting — Malignant Hematology

Presenters at the 2022 American Society of Hematology (ASH) annual meeting, held December 10–13 in New Orleans, reported the latest research in hematology. NEJM Group was on hand to cover the meeting. Here, NEJM Journal Watch Oncology and Hematology reports some of the key findings in hematologic malignancies and Associate Editor Dr. Michael E. Williams provides clinical perspective. Abstracts can be found on the ASH meeting site.

Talquetamab, an investigational bispecific antibody that binds to CD3 and GPRC5D receptors, had significant antitumor effects in patients with heavily pretreated relapsed or refractory (R/R) multiple myeloma, according to the industry-conducted, phase 1/2 MonumenTAL-1 study presented at ASH. The phase 1 findings were simultaneously published in the New England Journal of Medicine.

Based on results of the phase 1 trial, the doses recommended for phase 2 were 405 µg/kg of subcutaneous talquetamab every week (with step-up doses of 10 and 60 µg/kg) and 800 µg/kg of subcutaneous talquetamab every other week (with step-up doses of 10, 60, and 300 µg/kg).

Phase 2 enrolled patients who had received at least three prior lines of therapy. Among the 143 patients given the 405-µg/kg dose (modified to 400 µg/kg), 74% had a response. For the 145 patients given the 800-µg/kg dose, the overall response rate was 73%. Median progression-free survival was 7.5 and 11.9 months, respectively.

Common adverse events included cytokine release syndrome, skin and nail toxic effects, and dysgeusia. Grade 3 and 4 infections occurred in less than 20% of patients.

Summary by Kelly Young, Staff Writer

COMMENT — DR. MICHAEL E. WILLIAMS

Bispecific T-cell–engaging monoclonal antibodies are expanding immunotherapy approaches for heavily treated relapsed and refractory myeloma. As with B-cell lymphomas, their role in earlier lines of treatment and poor-risk disease subtypes will be of interest, as will use in place of or following CAR T-cell therapy.

Adding ibrutinib, a Bruton's tyrosine kinase inhibitor, to standard first-line immunochemotherapy is effective — with or without autologous stem-cell transplantation (ASCT) — in patients 65 and younger with previously untreated stage II–IV mantle-cell lymphoma (MCL), according to a phase 3, open-label trial.

In the multinational trial, 870 patients were randomized to one of three regimens:

• Three cycles each of alternating rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)/rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP), with ASCT for responding patients (arm A)
• The above regimen plus ibrutinib added to R-CHOP cycles and 2 years of ibrutinib maintenance therapy, with ASCT for responding patients (arm A+I)
• The above chemotherapy and ibrutinib regimen, without ASCT (arm I)

Patients in all arms could receive rituximab maintenance therapy according to practice guidelines established by the country in which treatment was administered.

Three-year failure-free survival — the primary outcome — was 72% in arm A, 86% in arm I, and 88% in arm A+I. For this outcome, regimen A was not superior to regimen I (hazard ratio, 1.77) and regimen A+I was superior to regimen A (HR, 0.52). Analysis of regimen A+I versus regimen I is not yet complete. Overall survival at 3 years was 86% in arm A, 91% in arm A+I, and 92% in arm I.

Rates of grade 3–5 adverse events did not differ substantially between the two ASCT arms or during induction between regimens with and without ibrutinib. However, toxicity rates were higher during maintenance in arm A+I compared with the other arms.

The authors conclude, “It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT.”

Summary by Cara Adler, Staff Writer

COMMENT — DR. MICHAEL E. WILLIAMS

This practice-changing study demonstrates the efficacy of ibrutinib plus induction immunochemotherapy and ibrutinib maintenance therapy in mitigating the need for consolidation with high-dose therapy plus ASCT. Additional data will be forthcoming regarding high-risk subgroups of MCL, such as patients with blastoid and pleomorphic variants or TP53 mutations. The relative benefits and optimal duration of maintenance with ibrutinib, with or without rituximab, need to be clarified regarding infection and other toxicities.

Read more about the study.

The investigational bispecific antibody glofitamab is promising in treating poor-prognosis diffuse large B-cell lymphoma (DLBCL), but serious adverse events are common, according to an industry-conducted, phase 2 trial published in the New England Journal of Medicine and presented at ASH.

Roughly 150 adults with relapsed or refractory DLBCL who had undergone at least two prior lines of therapy received obinutuzumab pretreatment followed by increasing doses of intravenous glofitamab (step-up doses of 2.5 mg and 10 mg during cycle 1, followed by 30 mg on day 1 of cycles 2 through 12).

At a median 12.6 months' follow-up, 39% of participants achieved a complete response, the primary end point. In addition, 52% had an objective (complete or partial) response. Estimated 12-month overall survival was 50%.

Some 62% of participants experienced grade 3 or higher adverse events. Cytokine release syndrome was the most common adverse event, occurring in nearly two thirds of patients and usually with the first dose, but only 4% of participants had grade 3 or higher symptoms.

Summary by Kelly Young, Staff Writer

COMMENT — DR. MICHAEL E. WILLIAMS

Relapsed or refractory DLBCL remains challenging, especially for those with early relapse following induction treatment, those with certain disease subtypes, and those ineligible for or relapsing after CAR T-cell therapy. Bispecific T-cell–engaging monoclonal antibodies such as glofitamab are thus important emerging options in DLBCL and other B-cell lymphomas.

Zanubrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, confers superior progression-free survival (PFS) compared with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to the industry-conducted, phase 3 ALPINE study published in the New England Journal of Medicine and presented at ASH.

In this multinational, open-label study, roughly 650 patients with relapsed/refractory CLL or small lymphocytic lymphoma who'd received at least one previous therapy and had measurable disease on imaging were randomized to receive zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) until disease progression or unacceptable toxicity.

At a median 30 months' follow-up, zanubrutinib conferred superior PFS, relative to ibrutinib (87 vs. 118 events; hazard ratio, 0.65). At 24 months, the proportion of patients with PFS was 78% in zanubrutinib recipients and 66% in ibrutinib recipients. Overall response was significantly higher in the zanubrutinib group than the ibrutinib group (84% vs. 74%).

Roughly 15% of zanubrutinib recipients experienced an adverse event leading to treatment discontinuation, compared with 22% of ibrutinib recipients. The zanubrutinib group also had a lower incidence of cardiac disorders (21% vs. 30%). Six cardiac deaths occurred, all in the ibrutinib group.

Summary by Kelly Young, Staff Writer

COMMENT — DR. MICHAEL E. WILLIAMS

This head-to-head comparison of first- and second-generation BTK inhibitors confirms other recent reports of more favorable toxicity profiles and fewer treatment discontinuations due to intolerable side effects with the second-generation drug. Treatment response and PFS benefits for zanubrutinib were also observed in this cohort of patients with relapsed/refractory CLL.

Watch our interview with the lead author of the ALPINE study.

Among adults with relapsed or refractory acute myeloid leukemia (AML), remission induction with intensive chemotherapy before allogeneic hematopoietic-cell transplantation does not improve rates of treatment success or survival, according to a phase 3, randomized trial.

Roughly 280 patients were assigned to remission induction (high-dose cytarabine and mitoxantrone) followed by allogeneic hematopoietic-cell transplantation, or to disease control before sequential conditioning and allogeneic hematopoietic-cell transplantation.

The primary end point — complete remission at day 56 after transplantation — was similar in the two groups (81% in the remission-induction arm, 84% in the disease-control arm). In addition, leukemia-free survival 1 year after day-56 complete remission did not differ between the groups, at roughly 70%.

In the intention-to-treat population, overall survival was similar in the two groups at 1 year (approximately 70%) and at 3 years (approximately 50%).

The researchers conclude, “These data support sequential conditioning and [allogeneic hematopoietic-cell transplantation] without prior remission induction [chemotherapy] whenever a stem cell donor is readily available.”

Summary by Amy Herman, Staff Writer

COMMENT — DR. MICHAEL E. WILLIAMS

A frequent practice has been to pursue full reinduction chemotherapy in relapsed AML prior to commencing allogeneic hematopoietic-cell transplantation, the curative treatment option for this disease. The rationale has been to reduce disease burden prior to transplant, but in some cases reinduction fails or complications develop that then preclude the transplant. These important results indicate that earlier commencement of transplant is feasible and effective.

Read more about the study.