A record-breaking number of abstracts were submitted for the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition, and nearly 8,000 were accepted. The ASCO Post strives to provide in-depth coverage of those with the greatest impact. Here, we offer snapshots of others of particular interest at the conference.
Anitocabtagene Autoleucel in Relapsed or Refractory Multiple Myeloma
Preliminary findings from the phase II registrational IMMagine-1 trial highlighted the potential of anitocabtagene autoleucel, an anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy, in heavily pretreated patients with relapsed or refractory multiple myeloma.1 With a median follow-up of 9.5 months, the trial showed an investigator-assessed overall response rate of 97%, with 62% of patients achieving a complete response or better.
“Anitocabtagene autoleucel, with its novel D-domain binder and enhanced CAR T-cell transduction efficiency, shows remarkable efficacy in this challenging population and is a promising, novel therapeutic option,” said lead study author Ciara Freeman, MD, PhD, of the Moffitt Cancer Center, Tampa. “There appear to be key advantages to the novel D-domain binder such as enhanced CAR T-cell transduction efficiency. Although preliminary, and more follow-up is needed, the depth of responses combined with the low incidence of challenging adverse events highlight its potential as an effective and well-tolerated treatment for relapsed and refractory multiple myeloma.”
The single-arm study enrolled 117 heavily pretreated patients with relapsed or refractory multiple myeloma, all of whom had received at least three prior lines of therapy. In addition to the high overall response rate, 93% of evaluable patients achieved measurable residual disease (MRD) negativity at a sensitivity of 10-5, with a median time to MRD negativity of 1 month.
Preliminary progression-free survival rates were also encouraging, said Dr. Freeman, with an estimated 6-month progression-free survival of 93.3% and a 12-month progression-free survival of 78.5%, but she cautioned that more follow-up would be needed for these data to mature. Median overall survival has not yet been reached, but estimates at 6 and 12 momths were identical at 96.5%.
The safety profile of anitocabtagene autoleucel showed that most patients experienced grade 1 or 2 cytokine-release syndrome (CRS). CRS occurred in 83% of patients, with severe (grade ≥ 3) cases reported in 2%. Immune effector cell–associated neurotoxicity syndrome (ICANS) was observed in 9% of patients, with all cases resolving without long-term effects. Of note, no delayed or non-ICANS neurotoxicities, such as cranial nerve palsies, Guillain-Barré syndrome, or parkinsonism, were reported.
The most common grade ≥ 3 adverse events included cytopenias, such as low white blood cell counts and anemia. Of note, three deaths occurred during the trial (one from an inflammatory storm related to rapidly progressing disease and another from an invasive fungal infection).
Enrollment is now underway for the phase III IMMagine-3 trial, which will compare anitocabtagene autoleucel with standard-of-care therapies in patients with one to three prior lines of treatment.
“These early results are very encouraging for patients and continue to build on what we know about how effective these personalized therapies can be for patients with multiple myeloma, even in those where multiple prior treatments have failed,” Dr. Freeman concluded.
Smoking Linked to Progression of MDS
In a dose-response fashion, apparently via genetic alterations, cigarette smoking increases the chance of disease progression in myelodysplastic syndrome (MDS) and overall survival in its precursor state, called clonal cytopenia of undetermined significance, researchers from Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine reported.2
“We have shown that tobacco smoking is associated with specific genetic mutations related to MDS, and when individuals smoke for a long time, they accumulate more mutations and are more likely to progress to MDS,” said Sangeetha Venugopal, MD, MS. “There is definitely a dose-response relationship and also an association between disease progression and overall survival.”
Dr. Venugopal explained that in the evolution of myeloid subtypes of blood cancers, the risk for cancer progressively increases with the mutation number. “There is no clonal disorder with no mutations,” she added.
The link between smoking and several solid tumors is well established, but the genetic mechanisms linking smoking with hematologic cancers have been unclear. To study this, the researchers analyzed genetic data, smoking history, and disease progression among nearly 1,900 participants in the National MDS Natural History Study. More than 50% of the participants had a history of smoking, and 18% still smoked at the time of diagnosis. Many were heavy smokers, reporting on average 16 cigarettes per day for nearly 30 years.
Adjusting for confounders, they found that smokers had significantly more genetic mutations, especially the heaviest smokers. Those in the 75th and 90th percentiles for pack-years had 1.8 and 3.5 times the number of mutations, respectively, compared with nonsmokers. People who had smoked for longer periods were also significantly more likely to experience disease progression than those with shorter exposure or nonsmokers: 27% vs 18% (P < .05). “This shows that the longer you smoke, the higher the incidence of disease progression,” Dr. Venugopal said.
Some of the genetic mutations identified, such as ASXL1, had previously been associated with smoking, but others had not. Compared with patients who did not smoke, those who did were enriched with pathways of mutations, including the chromatin modification (15.3% vs 10.9%; P = .001) and RNA splicing (25.5% vs 18.6%; P < .001). The prevalence of individual mutations between smokers and nonsmokers included, respectively, ASXL1 (12% vs 8%; P < .01), SF3B1 (9% vs 6%; P < .05), U2AF1 (6% vs 3%; P < .05), and ZRSR2 (2% vs 1%; P < .05). “They all are very-high-risk mutations in the pathogenesis of MDS,” she added.
Finally, overall survival was significantly lower in patients with clonal cytopenia of undetermined significance who smoked compared with those who did not (hazard ratio = 1.91; P = .04).
“The most important message is that we as hematologists can initiate smoking cessation counseling in our patients to help delay their disease progression,” Dr. Venugopal said. Considering that half the patients with MDS were smokers in this study, she was asked whether smoking might actually cause MDS. “That’s a fantastic question,” she answered.
Epcoritamab Monotherapy in Relapsed CLL
Single-agent subcutaneous epcoritamab-bysp, a bispecific CD20-directed CD3 T-cell engager, generated deep responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), regardless of the presence of high-risk features, in an analysis of the expansion and optimization cohorts of the phase I/II EPCORE CLL-1 study, investigators reported at the 2024 ASH Annual Meeting & Exposition.3
The response rate exceeded 60% in almost all subsets, and optimization of dosing made this treatment safer. “There was a comparable response rate between the expansion and the cycle 1 optimization cohorts…. And simple cycle 1 optimization measures of an additional step-up dose, along with dexamethasone and adequate hydration, decreased the risk and severity of adverse events of special interest,” said Alexey Danilov, MD, PhD, of City of Hope, Duarte, California.
EPCORE CLL-1 enrolled patients with CD20-positive relapsed or refractory CLL who had received two or more lines of treatment but no transplant. The expansion cohort was required to have measurable disease with at least 5 × 109/L lymphocytes. The 23 patients in the expansion cohort were treated at three dose levels within a step-up schedule, with prednisone prophylaxis for cytokine-release syndrome permitted. They were followed for a median of 22.8 months.
In the cycle 1 optimization cohort, 17 patients received step-up dosing with a fourth dose step added, starting with 0.16 mg on cycle 1, ultimately reaching 48 mg on cycle 1, day 22. Their median follow-up was 2.9 months.
The primary endpoint in the expansion cohort was objective response, but in the cycle 1 optimization cohort, the primary endpoints were incidence and severity of cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, and clinical tumor lysis.
Patients’ median time from initial diagnosis was more than 10 years; the median number of prior regimens was four (all received a Bruton’s tyrosine kinase inhibitor, and approximately 85% received a BCL2 inhibitor). The median time from last treatment was 0.7 months for the expansion cohort and 1.6 months for the optimization cohort.
Response rates were high in the expansion cohort, both overall and in high-risk subsets:
- Entire cohort: 67% overall, with 43% complete responses; 19% achieved stable disease.
- TP53-altered: 67% overall, with 33% complete responses; 13% achieved stable disease.
- IGHV-unmutated: 63% overall, with 37% complete responses; 19% achieved stable disease.
- Double-exposed: 53% overall, with 37% were complete responses; 21% achieved stable disease.
The estimated 1-year progression-free survival and overall survival rates were 52% and 70%, respectively, in the expansion group. Median progression-free survival was almost 13 months, and median overall survival was not reached. Median follow-up was less than 3 months for the cycle 1 optimization cohort; the overall response rate was 60%, of which 10% were complete responses.
For the subset of patients tested for MRD at 10-4, MRD was undetectable in 100% of complete responders and in 40% of partial responders.
Dosing optimization did reduce the rate and severity of cytokine-release syndrome and eliminated cases of immune effector cell–associated neurotoxicity syndrome and clinical tumor lysis. The overall rate of cytokine-release syndrome in this group was 82%, all grade 1 or 2.
Cytokine-release syndrome was more of a concern in the expansion cohort, where it was observed in 96% of patients and was grade 3 in 17%, though all cases resolved. Immune effector cell–associated neurotoxicity syndrome occurred in 13% of patients, all grade 1 or 2, and one patient developed clinical tumor lysis, grade 2. Almost all the expansion cohort received tocilizumab, compared with less than half the optimization cohort.
Epcoritamab is already approved for adults with relapsed or refractory follicular lymphoma following prior therapy. EPCORE CLL-1 is evaluating its benefit as a single agent and in combination for patients with CLL and Richter’s transformation.
DISCLOSURE: Dr. Freeman reported financial relationships with BMS, Roche/Genentech, Janssen, Amgen, AbbVie, Seattle Genetics, ONK Therapeutics, Celgene, Sanofi, and Incyte. Dr. Venugopal reported no conflicts of interest. Dr. Danilov has served as a consultant to AstraZeneca, AbbVie, BeiGene, Genentech, Nurix, MorphoSys, Incyte, TG Therapeutics, Bayer, ADC Therapeutics, Bristol Myers Squibb, GenMab, and Janssen; and has received research funding support from AstraZeneca, Nurix, TG Therapeutics, Bayer, Takeda, MEI Pharma, Bristol Myers Squibb, Cyclacel Pharmaceuticals, and GenMab.
REFERENCES
- Freeman CL, Dhakal B, Kaur G, et al: Phase 2 registrational study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma: Preliminary results from the IMMagine-1 trial. 2024 ASH Annual Meeting & Exposition. Abstract 1031. Presented December 9, 2024.
- Venugopal S, Otterstatter M, DeZern AE, et al: Association between smoking intensity, genetic mutations, and disease progression in myelodysplastic syndromes. 2024 ASH Annual Meeting & Exposition. Abstract 4597. Presented December 9, 2024.
- Danilov A, Fakhri B, Awan FT, et al: Epcoritamab monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): Results from CLL expansion and optimization cohorts of EPCORE CLL-1. 2024 ASH Annual Meeting & Exposition. Abstract 883. Presented December 9, 2024.
