American Society of Hematology (ASH) 2023: Annual Meeting

Olivia White, PharmD, BCOP, Lymphoma/Myeloma Pharmacist, UVA Health

Introduction:

The 65th American Society of Hematology (ASH) annual meeting took place December 9-12, 2023 in San Diego, California and virtually. This meeting is the largest annual gathering of hematology experts worldwide, where discussions include emerging data in malignant and benign hematology distributed in the form of educational sessions, oral abstracts, and research posters.

Below is a summary of select abstracts with the potential to be practice changing including the initial data involving Menin inhibition for patients with relapsed/refractory AML, the late-breaking SYMPATICO study that assessed the combination of BTK inhibition with venetoclax in relapsed MCL, the data looking at replacing Brentuximab Vedotin with Nivolumab for older patients with cHL, the PERSEUS data in multiple myeloma, looking further into quadruplet therapy for the newly diagnosed and HSCT eligible patients, and the overall survival data surrounding idacabtegene vicleucel (ide-cel) in relapsed-refractory multiple myeloma.

Highlight 1: Revumenib in Relapsed Leukemia1

Dr. Ibrahim Aldoss presented the primary results of the AUGMENT 101 study. This was a phase 2 trial assessing the use of revumenib in patients with relapsed or refractory KMT2A rearranged (KMT2Ar) acute leukemia. Based on initial phase 1 data, revumenib was given at 163mg by mouth twice daily in combination with a strong CYP3A4 inhibitor in 28-day cycles.2 This study notably involved all different classifications of leukemias; however, the primary population represented in this study was AML.

The primary endpoint of this trial was complete remission (CR)/complete remission with partial hematologic recovery (CRh) rate. Ninety-four patients were included in the initial safety analysis and 57 were involved in the efficacy portion. The most common mutation present in the baseline characteristics was a RAS mutation, seen in 13-16% of the population. The majority of patients had previously been exposed to venetoclax, and approximately 50% had a prior allogeneic transplant. At a median follow up of 6 months, the overall response rate (ORR) was estimated to be 63%, with a CR/CRh rate of 23% (12.7-35.8, p=0.0036). At time of interim analysis, the median overall survival (OS) was 8 months. The median duration of response was 6.4 months. Notably, 13% of patients required treatment discontinuation and 10% required dose reduction due to adverse events (AEs). The most common AE was febrile neutropenia. Due to the primary efficacy endpoint being met at the predefined interim analysis, this study has now been stopped and revumenib is under FDA review.

Highlight 2: SYMPATICO Trial3

Dr. Michael Wang presented the results of the phase 3, multinational, randomized, double blind, placebo-controlled SYMPATICO study. This was a trial which randomized patients with relapsed/refractory mantle cell lymphoma to receive ibrutinib 560mg daily and placebo or venetoclax 400mg daily for 24 months. Following 24 months of therapy, patients were then changed to ibrutinib monotherapy. Patients involved in this study could not have received a covalent BTK inhibitor prior to treatment and they must have received a prior anti-CD20 agent. The primary endpoint was progression free survival (PFS) (as assessed by the Lugano criteria) and secondary endpoints included CR rate, OS, ORR, and time to next treatment (TTNT).

The trial included 267 patients, approximately 30% of which were TP53 mutated. The median time on study was 51.2 months. The PFS demonstrated a benefit with combination therapy, with the result being 31.9 months versus 22.1 months (HR=0.65; 95% CI 0.47-0.88; p=0.0052). Both TTNT and ORR also benefited in the combination therapy arm. The median OS was not statistically beneficial at interim analysis; 44.9 months versus 38.6 months (HR=0.85; 95% CI 0.62–1.19; p=0.3465). Grades >3 AEs were fairly common in both arms; however, there was no statistical different between the two arms in AEs that led to discontinuation, dose reduction, or death. The authors concluded that per these data, ibrutinib and venetoclax should be considered a new standard of care for relapsed mantle cell lymphoma in countries where these agents are available.

Highlight 3: SWOG S1826 - N-AVD in cHL4

Dr. Sarah Rutherford presented on the data from the SWOG S1826 study and specifically addressed the outcomes in older patients (³60 years of age). This is a phase 3 study assessing patients with advanced stage classic Hodgkin Lymphoma (cHL). This study assessed the role of doxorubicin, vinblastine, and dacarbazine (AVD) in combination with either brentuximab vedotin (BV) or nivolumab (N). Both regimens were administered for a total of 6 cycles and G-CSF was required with the BV-AVD arm, while optional for the N-AVD arm. The primary endpoint was PFS. Notably patients had to have a LVEF ³ 50% and an estimated CrCl of > 30 mL/min.

These data included the results of 103 patients that were all ³ 60 years involved in the SWOG S1826 study. These patients were a median of 66 years old in the N-AVD arm, and a median of 67 years in the BV-AVD arm. In general, these patients more commonly presented with stage IV disease and bulky disease (> 10cm). Sixty-nine percent of patients in the N-AVD arm received G-CSF. More neutropenia was present with N-AVD; however, there was no statistical different of infection occurrence. There were higher grades of peripheral neuropathy seen with the BV-AVD arm. Notably, 33% of patients on BV-AVD discontinued treatment versus 10% on N-AVD and non-relapse mortality was higher in this population with 14% on BV-AVD versus 4%. 1-year PFS was 93% with N-AVD versus 64% (HR=0.35; 95% CI 0.12-1.02, p=0.022). There was no statistical difference between 1 year OS.

Highlight 4: PERSEUS Trial5

Dr. Pieter Sonneveld presented the PERSEUS data, which was a phase 3 trial assessing the addition of daratumumab (dara) to bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone for patients with newly diagnosed multiple myeloma and who are transplant eligible. These patients notably received Dara-VRd induction, transplantation, Dara-VRd consolidation, and then Dara-lenalidomide maintenance versus VRd induction, transplantation, VRd consolidation, and then lenalidomide maintenance. The patients received daratumumab subcutaneously and cycles were lengthened to 28 days for this phase 3 trial. The primary endpoint of this study was PFS.

The Dara-VRd arm included 355 patients and VRd included 354. The PFS at 48 months was 84.3% versus 67.5% (HR=0.42, 95% CI 0.30-0.59; p<0.0001). The overall CR or better rate also favored the daratumumab arm at 87.9% versus 70.1%. At 57 months, there was no difference in the OS rate. Notably with the daratumumab arm, there were increased risks of neutropenia and infections. Based on the authors conclusions, this phase 3 trial confirms the benefit of first line daratumumab. As discussed following the oral presentation, future studies will be comparing this data to other targeted agents (including CAR-T and BsA) and the benefit gained with the addition of daratumumab will continue to be assessed.

Highlight 5: KarMMa-3 Updated Analysis6

Dr. Paula Rodrigues Otero presented on the updated analysis of the KarMMa-3 study, which assessed the use of idecabtagene vicleucel (ide-cel) versus standard of care for patients with relapsed or refractory multiple myeloma. This phase 3 trial was initially published in NEJM in March of 2023.7 This study randomized patients in a 2:1 fashion to receive ide-cel or standard of care. The authors allowed for crossover following disease progression, thus resulting in approximately 56% of patients in the standard of care arm to eventually receive ide-cel.

This analysis was complete following 30.9 months. The original PFS seen was 13.8 months with ide-cel versus 4.4 months (HR=0.49; 95% CI 0.38-0.63, p < 0.0001). This analysis also continued to support the increased ORR with ide-cel at 41% versus 19%. Notably, the median OS data was presented reporting a OS of 41.4 months with ide-cel versus 37.9 months with standard of care (HR=1.01, 95% CI 0.73-1.40). Furthermore, when adjusting for cross over, the median overall survival was found to be 41.4 months versus 23.4 months (HR=0.72, 95% CI 0.49-1.01). The authors felt that these data were likely due to the high rate of cross over in the standard of care arm, and that more data is necessary before determining the ideal ide-cel patient.

Conclusion:

Overall, the 2023 ASH annual meeting presented incredibly exciting data that will shape the future of hematology practice. Other interesting updates included discussions surrounding Menin inhibition, CAR-T in CNS Lymphoma, the BOVEN Trial (zanubrutinib/obinutuzuab/venetoclax in treatment naïve and TP53 mutated MCL), and the implementation of MRD in multiple disease states. I encourage you to review all associated abstracts at the following link: https://www.hematology.org/meetings/annual-meeting/abstracts.

Recommended Reading/References:

1.Aldoss I, Issa GC, Thirman M, Dipersio J, et al. Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study. Presented at American Society of Hematology Annual Meeting; December 12, 2023; San Diego, CA. Available at: https://ash.confex.com/ash/2023/webprogram/Paper192042.html

2.Issa GC, Aldoss I, DiPersio JF, Cuglievan B, et al. The Menin Inhibitor SNDX-5613 (revumenib) Leads to Durable Responses in Patients (Pts) with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase (Ph) 1 Study. Presented at American Society of Hematology Annual Meeting; December 10, 2022; New Orleans, LA. Available at: https://ashpublications.org/blood/article/140/Supplement%201/150/487331/The-Menin-Inhibitor-SNDX-5613-revumenib-Leads-to

3.Wang M, Jurczak W, Trnêný M, Belada D, et al. Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study. Presented at American Society of Hematology Annual Meeting; December 12, 2023; San Diego, CA. Available at: https://ash.confex.com/ash/2023/webprogram/Paper191921.html

4.Rutherford SC, Li H, Herrera AF, Leblanc M, et al. Nivolumab-AVD Is Better Tolerated and Improves Progression-Free Survival Compared to Bv-AVD in Older Patients (Aged [Equation]) with Advanced Stage Hodgkin Lymphoma Enrolled on SWOG S1826. Presented at American Society of Hematology Annual Meeting; December 9, 2023; San Diego, CA. Available at: https://ash.confex.com/ash/2023/webprogram/Paper180114.html

5.Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

6.Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Idecabtagene Vicleucel (ide-cel) Versus Standard (std) Regimens in Patinets (pts) with Triple-Class-Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): Updated Analysis from KarMMa-3. Presented at American Society of Hematology Annual Meeting; December 11, 2023; San Diego, CA. Available at: https://ash.confex.com/ash/2023/webprogram/Paper178933.html

7.Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614