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Therapy-Related Acute Leukemia Following AHCT for MM Remains Uncommon, Outcomes Remain Poor in Retrospective Analysis

January 30, 2025

February 2025

Katie Robinson

Katie Robinson is a medical writer based in New York.

Among patients who develop therapy-related acute leukemia after autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM), long-term survival was common if they entered acute leukemia remission, with poorer outcomes in those who did not reach remission. This is according to a study published in Bone Marrow Transplantation, which also confirmed the relatively rare incidence rate of therapy-related acute leukemia development after AHCT in patients with MM.

“The development of second primary malignancies is known to be increased in patients with myeloma in general and increased further after high-dose melphalan and AHCT,” said corresponding author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia. “The survival benefits, however, continue to favor continued incorporation of AHCT into the early lines of therapy for appropriate patients with myeloma. Treatment-related acute leukemia is among the most challenging second primary malignancies, with a historically poor outcome.

“We sought to interrogate a large single institution experience to see the incidence and outcome of acute leukemia in the current era. Fortunately, we found a relatively low incidence of acute leukemia, and outcomes of therapy for those patients were perhaps better than expected, but with a relatively small number in this cohort,” Dr. Stadtmauer said.

In this retrospective study, the researchers reviewed the records of 1,770 patients with MM who underwent their first AHCT between January 2010 and January 2023. The researchers investigated the clinical characteristics and treatment outcomes of those who later developed therapy-related acute leukemia.

Of the patients, 18 (1.01%) developed therapy-​related acute leukemia at a mean interval of 60 months (±41.3 months) after undergoing AHCT. The patients with therapy-related acute leukemia were mainly female (66.7%) and white (83%). They all had an Eastern Cooperative Oncology Group performance score of 0 or 1, and 83% had IgG myeloma while 78% exhibited Kappa light chain predominance. Nine (50%) developed B-cell acute lymphoblastic leukemia, eight (44.4%) developed acute myeloid leukemia (AML), and one (5.6%) developed acute promyelocytic leukemia. Patients underwent one median line of treatment before AHCT (range = 1-3).

Of note, no patients received “bispecific antibodies and CAR [chimeric antigen receptor] T-cell therapy. Secondary malignancy is a well-recognized risk after commercial CAR-T including CD19 and BCMA [B-cell maturation antigen] subtypes,” the authors wrote.

All 18 patients received cyclophosphamide as part of their mobilization regimen, 12 (67%) received lenalidomide maintenance, and six (33%) received bortezomib maintenance. The authors highlighted prior reports of the increased incidence of therapy-related acute leukemia with alkylating agents as induction for MM along with lenalidomide as a significant risk factor for AML. The most frequently mutated genes identified at the time of therapy-related acute leukemia diagnosis included DNMT3A, TP53, ETV6, and RUNX1, with the authors noting consistency with prior reports.

The median overall survival (OS) from diagnosis of therapy-related acute leukemia stood at 19.5 months. At the last follow-up, 10 patients exhibited acute leukemia remission, and 15 patients achieved MM remission. Compared with no remission, acute leukemia remission was associated with OS (19.2 months vs. median OS not reached; p<0.001), but MM remission was not associated with OS (8.19 vs. 10.50 years from time of transplant; p=0.35).

Limitations to the study include its retrospective design, with potential for selection bias and incomplete data collection. The small number of patients who developed therapy-related acute leukemia prevented outcome analyses other than survival data and precluded direct comparisons with patients who did not develop acute leukemia. Additionally, the researchers could not directly compare treatment outcomes to those of other studies because treatments for MM and acute leukemia continually evolve.

“Further analyses of larger databases and close monitoring of recent approaches incorporating CD38 monoclonal antibodies and BCMA-directed immunotherapies into early therapy for myeloma need to be conducted,” Dr. Stadtmauer concluded.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Elghawy O, Deshpande S, Sussman J, et al. Characteristics and outcomes of therapy-related acute leukemia following autologous transplant (auto-HCT) for multiple myeloma [published online ahead of print, 2024 Oct. 24]. Bone Marrow Transplant. doi: 10.1038/s41409-024-02455-4.

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