From Blinatumomab to Venetoclax: Highlights From the 66th American Society of Hematology Annual Meeting and Exposition

Key trial results that may soon shape clinical practice in hematology and oncology were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, from December 7 to 10, 2024. Below are some of the notable highlights from the conference.

AALL1731 Trial

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AALL1731 (NCT03914625) is a phase 3 randomized trial assessing whether 2 nonsequential cycles of the bispecific T-cell engager blinatumomab (Blincyto; Amgen, Inc) (15 mg/m²/day 4 continuous x 28 days) added to chemotherapy improves disease-free survival (DFS) in children with National Cancer Institute standard-risk B-cell acute lymphoblastic leukemia (B-ALL) with average or higher risk of relapse. The results of the trial, presented by Rachel E. Rau, MD, associate professor of pediatrics at the University of Washington and a board-certified pediatric hematologist-oncologist at Seattle Children’s, showed that children with B-ALL who received blinatumomab with standard chemotherapy were 61% less likely to die or experience a relapse at 3 years than children who received standard chemotherapy alone. The trial investigators noted that the trial stopped early due to the high efficacy seen in the blinatumomab arm.¹

Blinatumomab is a monoclonal antibody approved by the FDA for treating certain types of B-ALL in certain patient groups. It works by bringing healthy immune cells into the close proximity of leukemia cells, prompting the immune system to attack and kill the cancer cells. This mechanism of action makes it a more targeted treatment than chemotherapies, which eradicate both healthy and cancerous cells, usually resulting in fewer adverse effects (AEs).

Three years after randomization, 96% of participants who received blinatumomab were alive without experiencing any cancer recurrence (the study’s primary end point) compared with 87.9% for those given chemotherapy.¹ Participants with average-risk B-ALL saw 3-year DFS rates of 97.5% for those who received blinatumomab and 90.2% for those who received chemotherapy alone. Among those with high-risk B-ALL, these rates were 94.1% for participants taking blinatumomab and 84.8% for those taking chemotherapy alone.¹

Based on the findings, study investigators noted blinatumomab can be considered a new standard first-line therapy along with chemotherapy for all children with B-ALL except those with the most favorable risk profile. This new standard would apply to approximately two-thirds of children diagnosed with B-ALL each year.¹

Abstract 259

Consuming a high-fiber diet after undergoing stem cell transplantation could help to reduce the risk of graft-vs-host disease (GVHD) by cultivating a healthy gut microbiome, according to the authors of abstract 259 at ASH. In the trial conducted in collaboration with Memorial Sloan Kettering Cancer Center, the investigators used both patient data and mouse models, noted Jenny Paredes, PhD, a staff scientist at City of Hope in Los Angeles, California, in her presentation.²

GVHD is the most common complication of allogeneic hematopoietic cell transplantation (allo-HCT), a procedure in which a person’s cancerous or abnormal blood stem cells are removed and replaced with healthy cells from a donor. GVHD occurs when the donated cells attack the patient’s own tissues, and it can cause a variety of symptoms ranging from mild to life-threatening.²

Dietary fiber can modulate the intestinal microbiome and increase the production of short-chain fatty acids and bile acids, which are beneficial microbial metabolites associated with intestinal homeostasis. The findings of abstract 259 add to a growing body of evidence highlighting the benefits of a high-fiber diet for maintaining microbiome health and suggest that dietary restrictions commonly recommended after a stem cell transplant—which typically result in low fiber intake—may be counterproductive for some patients.²

To examine the potential benefits of maintaining high fiber intake during stem cell transplantation to prevent GVHD, the investigators analyzed the diets of 173 patients undergoing allo-HCT. To measure fiber intake, the investigators tracked all foods and beverages that participants consumed and used food databases from the FDA to calculate the amount of fiber and other nutrients in their diets from 10 days before their transplant until 30 days afterward.²

Paredes and her colleagues found that a low-fiber diet was linked with reduced gut microbiome diversity, which can also increase susceptibility to infection by intestinal pathogens. They conversely found that a high-fiber diet was associated with better overall survival (OS), reduced risk of acute GVHD affecting the lower gastrointestinal tract, and higher microbial diversity in the gut.²

Patients with higher fiber intake also had higher levels of butyrate—a product of dietary fiber fermentation—and more gut microbes that produce butyrate. Previous study data have demonstrated that people with more butyrate producers in their gut are less likely to die from GVHD than those with lower levels of these microbes.²

The investigators also studied the mechanisms involved in these effects through a companion study of GVHD and the dietary fiber source cellulose, a type of fiber that mammals cannot digest without the help of gut microbiota, in mouse models. Mice fed a diet high in cellulose during allo-HCT had a reduced rate of death from GVHD and other markers of reduced GVHD risk, as well as higher microbial diversity and butyrate concentrations in the gut.2

InMIND Trial

At ASH, Laurie H. Sehn, MD, MPH, a clinical professor of medicine at the BC Cancer Centre for Lymphoid Cancer and University of British Columbia in Vancouver, Canada, presented data from the phase 3 InMIND trial (NCT04680052). The data showed that patients with follicular lymphoma who did not respond to or relapsed after prior therapy experienced a 57% reduction in the risk of disease progression, relapse, or death when treated with tafasitamab (Monjuvi; MorphoSys US Inc and Incyte Corporation) plus 2 standard drugs, lenalidomide (Revlimid; Celgene Corporation) and rituximab (Rituxan; Biogen and Genentech, Inc), compared with patients who received a placebo with these same 2 drugs.³ Like rituximab, tafasitamab is a monoclonal antibody that stimulates the immune system to look for, latch onto, and kill cancer cells. Tafasitamab is currently approved by the FDA for use with lenalidomide to treat diffuse large B-cell lymphoma.³

The primary end point of the trial was to test whether adding tafasitamab to lenalidomide and rituximab would increase both the duration of remission and the number of patients achieving it. After a median follow-up of 14.1 months, the median progression-free survival (PFS) for patients in the tafasitamab group was 22.4 months compared with 13.9 months for those in the placebo group, representing a 57% improvement in PFS. Improvement in PFS was also consistent across subgroups of patients, such as those whose cancer had returned within 2 years and those who had received multiple prior therapies.³

Among patients who received tafasitamab, 83.5% responded to treatment compared with 72.4% of those who received the placebo. In the tafasitamab group, 49.4% showed no evidence of cancer on a PET scan compared with 39.8% of those in the placebo group. Rates of AEs were comparable in the 2 groups.³

EA4151 Trial

In the phase 3 EA4151 trial (NCT03267433), investigators found that patients with no detectable cancer after initial therapy for mantle cell lymphoma (MCL) did not experience any survival benefit from undergoing autologous hematopoietic cell transplantation (auto-HCT) compared with maintenance therapy alone.⁴ The trial was stopped early based on the results of an interim analysis conducted when the study had followed patients for a median of 2.7 years. According to Timothy S. Fenske, MD, a lymphoma specialist at the Medical College of Wisconsin in Wauwatosa, who presented the initial report at ASH, the findings suggest that patients who test negative for minimal residual disease (MRD) with an ultra-high sensitivity blood test do not need to undergo auto-HCT or take the high-dose chemotherapy regimen used to prepare for a transplant.⁴

The investigators also found no differences in outcomes among the randomized groups based on patients’ Mantle Cell Lymphoma International Prognostic Index-c levels (a prognostic index for MCL) or the intensity of the induction therapy patients had undergone to achieve their first remission. OS and PFS rates were also similar among participants who were MRD positive or MRD indeterminate and assigned to undergo auto-HCT.⁴

Based on the evidence from this trial, investigators said that patients who tested negative for MRD can safely avoid a stem cell transplant—and the associated AEs and risks—as they are likely to see no additional survival benefit from undergoing the procedure.⁴

AQUILA Trial

In the phase 3 AQUILA study (NCT03301220), patients at high risk for developing multiple myeloma (MM) who received daratumumab (DARA, Darzalex; Janssen Biotech, Inc) for up to 3 years saw a 51% reduction in their risk of disease progression compared with similar patients who were actively monitored but not treated.⁵ The randomized clinical trial was conducted in 24 countries and included patients who had been diagnosed with high-risk smoldering MM, a precancerous condition with features that put them at more than 50% risk of developing active cancer within 2 years.⁵ A total of 390 patients were enrolled (median age, 64 years; 48% men).

During the trial, patients were randomly assigned to receive either subcutaneous DARA every 28 days or active monitoring for up to 36 months or until their condition progressed to MM, whichever came first. ASH presenter Meletios-Athanasios Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece, and his colleagues estimated that after a median follow-up of 65.2 months (approximately 5.5 years), 63.1% of the patients assigned to DARA had not progressed to active MM at 5 years had not progressed to active MM at 5 years compared with 40.8% of those assigned to active monitoring. For patients in the active monitoring arm, the median time to an MM diagnosis was 41.5 months.⁵

The overall response rate (ORR) was 63.4% among patients receiving DARA compared with 2.0% for those actively monitored. In the DARA group, 33% of patients began treatment for active MM compared with 52% of those in the active monitoring group.⁵

AMPLIFY Trial

In the AMPLIFY trial (NCT03836261), treatment-naive patients with chronic lymphocytic leukemia (CLL) who received a combination regimen of the oral medications acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP) and venetoclax (Venclexta; AbbVie Inc) had significantly better survival without disease progression and with fewer serious AEs than patients who received 1 of 2 standard multidrug treatment regimens for CLL. Patients who received a third agent, obinutuzumab (Gazyva; Genentech, Inc), had even better survival free of disease progression but also experienced a higher rate of serious AEs.⁶

The primary end point was blinded independent central review (BICR)–assessed PFS of acalabrutinib-venetoclax (AV) vs fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR) in the intent-to-treat population (all randomly assigned patients). Secondary end points included BICR-assessed PFS (AV plus obinutuzumab [AVO] vs FCR/BR), undetectable MRD (uMRD) rate assessed in peripheral blood (AV vs FCR/BR, AVO vs FCR/BR), and OS (AV vs FCR/BR, AVO vs FCR/BR). Patients in arm A received AV; in arm B, AVO; and in arm C, the control arm dosage of FCR or BR. The randomized phase 3 clinical trial was conducted in 27 countries, and a total of 867 patients (median age, 61 years; 64.5% men) were randomly assigned.⁶

After a median follow-up period of 41 months, both the AV and AVO regimens showed a statistically significant improvement in PFS compared with the control regimen of FCR or BR. Study investigator Jennifer Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, Massachusetts, and her colleagues estimated that 76.8% of patients who received AV and 83.1% of those who received AVO were free of disease progression at 3 years compared with 66.5% of patients who received FCR or BR.⁶

EPCORE CLL-1 Trial

In early results from a nonrandomized study, the biologic agent epcoritamab (Epkinly; Genmab US, Inc and AbbVie Inc), a bispecific T-cell engager, showed promise in patients with relapsed or refractory (R/R) CLL following 2 prior treatments. Epcoritamab is approved by the FDA to treat 2 types of R/R lymphoma after at least 2 prior therapies, including a Bruton tyrosine kinase inhibitor.⁷

The ongoing EPCORE CLL-1 trial (NCT04623541) is testing the effectiveness of epcoritamab in patients with R/R CLL and other blood cancers. The trial, which is being conducted in 12 countries, will enroll a total of 184 patients.⁷

At ASH, Alexey Danilov, MD, PhD, a professor in the Division of Lymphoma and codirector of the Toni Stephenson Lymphoma Center at City of Hope and translational medicine chair of lymphoma at the SWOG Cancer Research Network in Duarte, California, presented early results for the first 40 patients (median age, 71.5 years; majority, men) enrolled in the trial. Most had CLL with features that make it more challenging to treat, such as a mutation in the TP53 gene or 17p deletion. All patients were treated with the same dose of epcoritamab, with the first group (the CLL expansion cohort [EXP], 23 patients) receiving the drug in 3 gradually increasing doses, whereas the second group (the optimization cohort, 17 patients), who were enrolled later, received epcoritamab in 4 increasing doses.⁷

The primary end point for the EXP cohort was ORR. In the EXP cohort, after a median follow-up period of 22.8 months, the ORR was 61%. Among responding patients, 39% had a complete response, meaning that signs of cancer had completely cleared. For all patients in this cohort, the median time until their cancer showed signs of worsening was 12.8 months. After approximately 15 months of follow-up, an estimated 65% of patients (n = 15) were still alive. Among 12 responding patients (52%) who underwent MRD testing, 9 (75%) had uMRD in tests based on the standard sensitivity level.⁷

REFERENCES

1. Rau RE. Blinatumomab added to chemotherapy improves disease-free survival in newly diagnosed NCI standard risk pediatric B-acute lymphoblastic leukemia: results from the randomized Children’s Oncology Group Study AALL1731. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper207450.html

2. Paredes J. Increased fiber intake results in better overall survival and lower GI-aGVHD in allo-HCT recipients and pre-clinical Gvhd models. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ ash/2024/webprogram/Paper204399.html

3. Sehn LH. Tafasitamab plus lenalidomide and rituximab for relapsed or refractory follicular lymphoma: results from a phase 3 study (inMIND). Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper212970.html

4. Fenske TS. Lack of benefit of autologous hematopoietic cell transplantation (auto-HCT) in mantle cell lymphoma (MCL) patients (pts) in first complete remission (CR) with undetectable minimal residual disease (uMRD): initial report from the ECOG-ACRIN EA4151 phase 3 randomized trial. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper212973.html

5. Dimopoulos MA. Phase 3 randomized study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: primary results of the Aquila study. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper201057.html

6. Brown JR. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper200701.html

7. Danilov A. Epcoritamab monotherapy in patients (Pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL): results from CLL expansion and optimization cohorts of Epcore CLL-1. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Accessed December 10, 2024. https://ash.confex.com/ash/2024/webprogram/Paper199708.html