ASH 2024 Press Briefing Rundown: Diagnosing and Treating Blood Cancers and "Almost Cancers"

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Phase III study of daratumumab monotherapy in high-risk SMM: primary results of the AQUILA study The AMPLIFY trial: fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab in first-line CLL Epcoritamab monotherapy in R/R CLL: results from EPCORE CLL-1 Age-related mutational patterns and elevated clonal hematopoiesis in environmentally exposed responders Impact of socioeconomic factors on access to and outcomes of alloSCT in AML

Phase III study of daratumumab monotherapy in high-risk SMM: primary results of the AQUILA study

Smoldering multiple myeloma (SMM) is a precursor to active multiple myeloma, and patients with high-risk SMM are at significant risk of progressing to symptomatic disease.¹ Recent studies have demonstrated that early intervention in high-risk SMM can significantly delay progression and improve overall survival (OS).² Daratumumab (DARA), a monoclonal antibody targeting CD38, has shown promise in various stages of myeloma treatment, including in high-risk SMM.³

The primary results of the AQUILA study (NCT03301220) were presented at ASH 2024 by Meletios Dimopoulos, MD, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. This Phase III trial randomized 390 patients to receive either DARA or active monitoring, with a median treatment duration of 38 cycles in the DARA group. At a median follow-up of 65.2 months, progression-free survival (PFS) was not reached in the DARA group compared with 41.5 months in those who received active monitoring, showing a significant improvement in the DARA group (HR, 0.49; 95% CI, 0.36-0.67; p<0.0001). The overall response rate (ORR) was 63.4% with DARA versus 2.0% with active monitoring (p<0.0001), and 33.0% of patients in the DARA group progressed to first-line myeloma treatment compared with 52.0% in the active monitoring group.⁴

Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). Despite the higher rate of TEAEs in the DARA group, these results add to the growing body of evidence supporting the early use of DARA to delay progression and improve survival outcomes in patients with high-risk SMM.⁴

The AMPLIFY trial: fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab in first-line CLL

Chronic lymphocytic leukemia (CLL) remains one of the most common leukemias in adults, with approved targeted agents including Bruton’s tyrosine kinase inhibitors (BTKis) and B-cell lymphoma-2 inhibitors (BCL2is).⁵ Previous research indicates that combining a BTKi with a BCL2i is a promising chemotherapy-free and fixed-duration frontline treatment option.⁶ Findings from the AMPLIFY trial (NCT03836261) were presented at ASH 2024 by Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute, Boston, MA. This multicenter, open-label, randomized, Phase III trial evaluated the combination of acalabrutinib, a BTKi, with venetoclax, a BCL2i, (±obinutuzumab) in patients with previously untreated CLL.⁷

This interim analysis of 867 patients showed that the combination therapy was highly effective, achieving a statistically significant improvement in PFS both with and without obinutuzumab when compared with chemoimmunotherapy. The estimated 36-month PFS rate was 76.5% without obinutuzumab and 83.1% with obinutuzumab. The combination also demonstrated an OS benefit compared with chemoimmunotherapy. The safety outcomes in the experimental arms were manageable, with the most common grade ≥3 adverse event (AE) being neutropenia. The results of the AMPLIFY trial represent a promising fixed-duration treatment option for patients with newly diagnosed CLL, offering an effective alternative to chemotherapy.⁷

Epcoritamab monotherapy in R/R CLL: results from EPCORE CLL-1

For patients with relapsed/refractory (R/R) CLL, treatment options are limited after the failure of BTKis and BLC2is. Epcoritamab, a bispecific antibody targeting CD20 and CD3, has shown promising efficacy in treating hematologic malignancies by enhancing T-cell-mediated killing of malignant B-cells.⁸ At ASH 2024, data from the EPCORE CLL-1 study (NCT04623541), presented by Alexey Danilov, MD, PhD, City of Hope, Duarte, CA, showed that epcoritamab monotherapy resulted in high response rates in this patient population. The data presented was from the fully enrolled CLL expansion cohort (EXP) and the first data from a cycle (C) 1 optimization cohort (OPT) of EPCORE CLL‑1.⁹

This multicenter, open-label trial included patients with CD20+ R/R CLL or small lymphocytic lymphoma (SLL) who all had prior BTKi exposure. In the EXP cohort, the ORR was 61% and the complete response (CR) rate was 39%. Median PFS was 12.8 months and median OS was not reached. The most frequent TEAEs in EXP were cytokine release syndrome (CRS; 96%), diarrhea (48%), and peripheral edema (48%). In EXP, there were three cases of immune effector cell-associated neurotoxicity syndrome (ICANS), and there were none in OPT. This study provides further evidence that epcoritamab could be a valuable treatment option for R/R CLL, offering an alternative to existing therapies like ibrutinib and venetoclax.⁹

Age-related mutational patterns and elevated clonal hematopoiesis in environmentally exposed responders

Clonal hematopoiesis (CH) is a condition in which specific genetic mutations give rise to hematopoietic clones that expand over time, increasing the risk of hematologic malignancies. Environmental exposures, such as smoking, have been associated with increased rates of CH.¹⁰ The relationship between CH and age-related mutations due to environmental exposures remains an area of active research.

At ASH 2024, Divij Verma, PhD, Albert Einstein College of Medicine, New York, NY, discussed a study evaluating age-related mutational patterns and their impact on CH in 988 World Trade Center (WTC) responders who were exposed to potential environmental carcinogens. There was a significantly higher prevalence of CH in WTC-exposed responders (14%) compared with non-WTC exposed cohorts (7%). DNMT3A and TET2 were the two most common mutated genes, with various other mutations being distinct in younger WTC-exposed responders. An in vivo model mimicking WTC exposure revealed increased expression of IL-1 receptor accessory protein (IL1RAP), indicating that clonal expansion is IL1RAP-dependent.¹¹

This study demonstrates age-related patterns in CH due to environmental exposures, and reveals that clonal expansion relies on IL1RAP. These findings could help identify individuals at higher risk of developing hematologic malignancies, with IL1RAP being a potential therapeutic target.

Impact of socioeconomic factors on access to and outcomes of alloSCT in AML

Previous research has shown socioeconomic disparities in the access to and outcomes of allogeneic stem cell transplantation (alloSCT) for the treatment of hematologic malignancies.¹² This multi-center observational study, presented by Natalie Wuliji, DO, Fred Hutchinson Cancer Center, Seattle, WA, investigated the impact of socioeconomic status (SES) on access to alloSCT and post-transplant outcomes for patients with acute myeloid leukemia (AML).¹³

This analysis included 695 adult patients with AML across 13 centers. It examined the following determinants of SES: median household income, high school education, poverty level, receipt of food benefits, among others. Overall, the findings revealed an association between the likelihood of being offered alloSCT and high school education. There was also a 14% decrease in the likelihood of receiving alloSCT for each 10% increase in households receiving food benefits compared with baseline levels. A modest association between poverty levels and the likelihood of receiving alloSCT was observed. There was little evidence of an association between median area income and overall mortality after alloSCT. However, there was a modest impact on mortality after alloSCT in those with less than a high school education, as well as a modest increase in mortality in households receiving food benefits.¹³

Overall, this study suggests that access to alloSCT is the main socioeconomic barrier, underscoring the need for interventions to improve access to life-saving treatments for patients from lower SES backgrounds.