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Report from the 63rd Annual American Society of Hematology Meeting — Malignant Hematology
Presenters at the 2021 meeting of the American Society of Hematology (ASH; December 11–14, 2021) reported the latest research in hematology. Here, NEJM Journal Watch Oncology and Hematology Associate Editor Dr. Michael E. Williams describes the key findings in hematologic malignancies.
In patients with relapsed/refractory large B-cell lymphoma (LBCL) after first-line chemoimmunotherapy, axicabtagene ciloleucel (axi-cel) offers an event-free-survival advantage over standard care, according to the industry-funded, phase 3 ZUMA-7 trial (abstract 2). The trial was published in the New England Journal of Medicine. Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved to treat relapsed/refractory LBCL after at least two prior systemic therapies.
In the ZUMA-7 trial, 359 adults with relapsed/refractory LBCL who progressed within 12 months after first-line chemoimmunotherapy were randomized to receive either axi-cel or investigator-selected standard therapy (i.e., platinum-based chemoimmunotherapy and, for responders, subsequent high-dose chemotherapy with autologous stem cell rescue).
At a median 25 months' follow-up, event-free survival — the primary outcome — was significantly longer in the axi-cel group than in the standard-care group (median, 8.3 vs. 2.0 months). In addition, the objective response rate was significantly higher with axi-cel (83% vs. 50%). Overall survival, assessed in an interim analysis, also favored axi-cel, but the difference between groups was not significant.
Grade 3 or higher adverse events occurred in 91% of the axi-cel group and 83% of the standard-care group.
Summary by Amy Herman, Staff Writer
COMMENT — DR. MICHAEL E. WILLIAMS
This practice-changing study demonstrates a benefit in complete response rate and 2-year event-free survival in patients who were primary-refractory to or had an early relapse after induction immunochemotherapy. It is known that second-line high-dose chemotherapy and consolidative autologous stem cell transplantation (ASCT) fails to achieve durable remission and cure in the majority of such patients, whereas the ASCT outcomes are improved for those with more durable response to initial therapy. Longer follow-up will be important to assess the durability of CAR T-cell responses and the ultimate impact on survival.
Watch our interview with the lead author of the ZUMA-7 trial.
Second-line therapy with tisagenlecleucel (tisa-cel) does not improve event-free survival compared with standard of care in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma, according to the industry-funded, phase 3 multinational BELINDA trial (abstract LBA-6). The study was published in the New England Journal of Medicine.
Over 300 adults whose disease did not respond to front-line immunochemotherapy or progressed within 12 months of initial induction treatment underwent leukapheresis and were then randomized to tisa-cel chimeric antigen receptor T-cell (CAR-T) therapy along with optional bridging and lymphodepleting chemotherapy or to standard of care. The tisa-cel group had a higher rate of high-grade B-cell lymphomas and worse prognosis scores.
In the tisa-cel group, 83% received one or more bridging chemotherapy cycles and 96% received tisa-cel (median dose, 2.9 x 108 cells). In the standard of care group, 96% received 2 or more chemotherapy cycles and 33% received autologous hematopoietic cell transplantation. Patients were followed for a median of 10 months.
Median event-free survival — the primary outcome — was 3 months in both groups. Overall and complete response rates at 12 weeks were also similar in the two groups.
Treatment-related grade 3 and higher adverse events occurred in 75% of the tisa-cel group and 86% of the standard care group.
Summary by Cara Adler, MS, Staff Writer
COMMENT — DR. MICHAEL E. WILLIAMS
The findings of this trial contrast with the positive results from the ZUMA-7 trial, in which the CAR-T cell agent axicabtagene ciloleucel (axi-cel) showed significantly improved outcomes versus standard of care — re-induction chemotherapy plus autologous stem cell transplantation — among patients with large B-cell lymphoma progressing within one year of initial induction therapy. Whether the disparate outcomes relate to differences between the CAR-T cell agents, the patient populations, the use of bridging therapy in the present trial, or other factors awaits further analysis.
A combination therapy known as pola-R-CHP is associated with reduced risk of disease progression, relapse, or mortality in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), compared with standard treatment with R-CHOP, according to results from the phase 3, industry-conducted POLARIX study (abstract LBA-1). The study was published in the New England Journal of Medicine. R-CHOP comprises rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, while pola-R-CHP replaces the vincristine with the antibody-drug conjugate (ADC) polatuzumab vedotin.
Roughly 900 patients with DLBCL who were at intermediate-to-high risk by the International Prognostic Index (IPI) score were randomized to receive either pola-R-CHP or R-CHOP (for six 21-day cycles), followed by two more cycles of rituximab monotherapy.
After a median 28 months' follow-up, the pola-R-CHP arm had a significantly higher rate of progression-free survival, the primary outcome, than the R-CHOP arm (77% vs. 70%; hazard ratio for progression, relapse, or mortality, 0.73). In exploratory analyses, the following subgroups did not see a clear benefit: age 60 years and younger, germinal-center B-cell–like subtype of DLBCL, bulky disease, and lower IPI risk scores.
Rates of adverse events were similar between the groups.
Summary by Kelly Young, Staff Writer
COMMENT — DR. MICHAEL E. WILLIAMS
This interesting study demonstrates an incremental improvement by incorporating the ADC polatuzumab vedotin into R-CHP as initial induction therapy. Encouraging improvements in progression-free survival and disease-free survival were identified despite a lack of improvement in post-induction PET-based complete remission. Overall survival benefit has not yet been demonstrated, although it may emerge with longer follow-up and among specific DLBCL subsets. In particular, Pola-R-CHP could be considered for initial treatment of older patients with activated B-cell subtype of DLBCL.
Oral azacitidine is associated with a long-lasting survival benefit in patients with acute myeloid leukemia (AML) who have previously received intensive chemotherapy, according to a new analysis from the phase 3, industry-supported QUAZAR AML-001 trial (abstract 871).
In the original study, nearly 500 patients with AML who achieved remission following intensive chemotherapy and were not eligible for stem cell transplant consolidation were randomized to receive either oral azacitidine or placebo for 14 days in each 28-day treatment cycle. Azacitidine was associated with improved overall survival compared with placebo (25 vs. 15 months). At that time, the trial was unblinded and azacitidine patients could continue receiving treatment.
In the updated analysis, with a median follow-up of 52 months, overall survival was unchanged. However, the overall survival curves showed greater separation with the longer follow-up. Estimated 3-year survival rates were roughly 37% and 28% in the treatment and placebo groups, respectively.
Factors linked to longer survival included intermediate-risk cytogenetics, NPM1 mutations at diagnosis, and absence of detectable minimal residual disease after intensive chemotherapy.
Summary by Kelly Young, Staff Writer
COMMENT — DR. MICHAEL E. WILLIAMS
Maintaining durable remissions in older AML patients has been a challenge due to a high frequency of adverse AML subtypes and the inability to offer allogeneic stem cell transplantation due to age or comorbidities. The placebo-controlled QUAZAR trial now verifies a clear benefit for the use of the oral hypomethylating agent azacitidine as maintenance therapy. This strategy, as well as other approaches that incorporate the BCL2-inhibitor venetoclax with initial therapy, is moving the field forward to improved outcomes and survival.
The BRAF inhibitor vemurafenib, combined with the anti-CD20 monoclonal antibody obinutuzumab, appears effective for newly diagnosed hairy cell leukemia, according to a phase 2, multicenter, open-label, single-arm trial (abstract 43).
Thirty adults with previously untreated hairy cell leukemia were assigned to receive 28 days of oral vemurafenib (960 mg twice daily), followed by 3 months of vemurafenib plus intravenous obinutuzumab (1000 mg given 3 times during the first month of combination therapy and 1 time in each of the last 2 months).
Of 27 patients who completed all 4 months of treatment, 26 had a complete response at the end of treatment. The remaining patient had a partial response at month 4 and, with no additional treatment, a complete response by month 10. After a median follow-up of 16.7 months, all 27 patients remained in remission.
The most common adverse events associated with vemurafenib were rash, arthralgia, fatigue, alopecia, and pruritus. No patient experienced febrile neutropenia or significant T-cell immunosuppression.
Summary by Amy Herman, Staff Writer
COMMENT — DR. MICHAEL E. WILLIAMS
Classical hairy cell leukemia is characterized by mutation in the BRAF gene, and patients with relapsed or refractory disease have a high response rate to the BRAF inhibitor vemurafenib. This study demonstrates complete remission in all patients completing planned therapy with vemurafenib plus obinutuzumab. The current standard-of-care is to use the cytotoxic agent cladribine as initial therapy with a 5- to 7-day course, usually in combination with rituximab. Longer follow-up will be needed to confirm the durability of responses to the new regimen, as the single cycle of cladribine offers years of ongoing remission for the majority of hairy cell leukemia patients.
First-line treatment with daily ibrutinib, an oral Bruton tyrosine kinase inhibitor (BTKi), plus venetoclax, an oral BCL2 inhibitor, leads to high and durable response rates in patients with chronic lymphocytic leukemia (CLL), according to an industry-funded, phase 2 study (abstract 68).
Roughly 160 patients with treatment-naïve CLL received 3 cycles (28 days each) of ibrutinib (420 mg daily), followed by 12 cycles of ibrutinib plus venetoclax (ramp-up to 400 mg/daily). After the combination-therapy regimen, 86 patients with undetectable minimal residual disease (uMRD) were randomized to receive double-blind treatment with ibrutinib or placebo, and 63 who did not meet uMRD criteria were randomized to receive open-label treatment with ibrutinib or continued combination therapy.
In patients with uMRD, disease-free survival rates 2 years' post-randomization were high and similar with ibrutinib and placebo, at 100% and 95%, respectively. Estimated 3-year progression-free survival rates were also 100% and 95%.
In patients without uMRD, response rates favored continued combination therapy over ibrutinib alone, but estimated 3-year progression-free survival was 97% in both groups.
Overall, the most common grade 3–4 adverse events were neutropenia, hypertension, thrombocytopenia, and diarrhea.
Summary by Amy Herman, Staff Writer
COMMENT — DR. MICHAEL E. WILLIAMS
Longer-term follow-up data confirm the study's earlier results, as well as emerging data from other BTKi/venetoclax trials, that this frontline combination therapy offers durable uMRD responses in CLL, including patients with poor-risk biomarkers such as TP53 mutation, complex karyotype, and unmutated IGHV. This approach avoids cytotoxic chemotherapy and offers the potential for time-limited therapy based on clinical and MRD responses.
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Michael E. Williams, MD, ScM