Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma

Radivoyevitch, Tomas; Dean, Robert M.; Shaw, Bronwen E.; Brazauskas, Ruta; Tecca, Heather R.; Molenaar, Remco J.; Battiwalla, Minoo; Savani, Bipin N.; Flowers, Mary E.D.; Cooke, Kenneth R.; Hamilton, Betty K.; Kalaycio, Matt; Maciejewski, Jaroslaw P.; Ahmed, Ibrahim; Akpek, Görgün; Bajel, Ashish; Buchbinder, David; Cahn, Jean Yves; D’Souza, Anita; Daly, Andrew; DeFilipp, Zachariah; Ganguly, Siddhartha; Hamadani, Mehdi; Hayashi, Robert J.; Hematti, Peiman; Inamoto, Yoshihiro; Khera, Nandita; Kindwall‐Keller, Tamila L.; Landau, Heather; Lazarus, Hillard M.; Majhail, Navneet S.; Marks, David I.; Olsson, Richard F.; Seo, Sachiko; Steinberg, Amir; William, Basem M.; Wirk, Baldeep; Yared, Jean A.; Aljurf, Mahmoud; Abidi, Muneer H.; Allewelt, Heather; Beitinjaneh, Amer; Cook, Rachel J.; Cornell, Robert F.; Fay, Joseph W.; Hale, Gregory A.; Chakrabarty, Jennifer Holter; Jodele, Sonata; Kasow, Kimberly A.; Mahindra, Anuj; Malone, Adriana K.; Popat, Uday; Rizzo, J. Douglas; Schouten, Harry C.; Warwick, Anne B.; Wood, William A.; Sekeres, Mikkael A.; Litzow, Mark R.; Gale, Robert Peter; Hashmi, Shahrukh K.

doi:10.1016/j.leukres.2018.07.016

Cited by 47 publications

(36 citation statements)

References 22 publications

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“…8a). Future studies will reveal whether mutations induced by melphalan shape the evolution of relapsed disease or development of secondary malignancies, such as acute myeloid leukemia 44 .…”

Section: Discussionmentioning

confidence: 99%

Timing the initiation of multiple myeloma

et al. 2020

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The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2 nd -3 rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the premalignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

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Section: Discussionmentioning

confidence: 99%

Timing the initiation of multiple myeloma

et al. 2020

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“…55 years, $3 prior chemotherapy regimens, and TBI or busulfanbased conditioning. 43 These data suggest that, although secondary MDS/AML must be considered, the risk may be lowest in young less heavily pretreated patients conditioned with BEAM. Upfront risks for allo-HCT are generally related to acute GVHD and infectious complications, both of which can have a lifelong impact on quality of life.…”

Section: Novel Approaches To Allo-hctmentioning

confidence: 89%

Where does transplant fit in the age of targeted therapies?

Chow

Gopal

2019

Hematology

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The role of hematopoietic cell transplantation (HCT) for indolent lymphoma has evolved over the last 5 years with the availability of novel low-toxicity therapies and a better understanding of the prognosis of these entities. However, despite numerous treatment options for patients with follicular lymphoma, none are thought to be curative, and many require ongoing therapy with chronic toxicity. Historical trials indicate that autologous HCT as initial consolidation leads to improved progression-free survival, but not overall survival (OS) and, thus, is not typically recommended. However, autologous HCT for chemosensitive relapse can be carried out with ∼1% early mortality risk, affording disease control lasting a median of 3 to 5 years and the potential to improve OS. These results may compare favorably in efficacy, toxicity, and cost vs multiple sequential novel therapies with shorter durations of benefit. Recent data indicate that autologous HCT in follicular lymphoma patients with early initial progression will result in more than one third being alive and without relapse at 5 years, leading to improved OS when used within a year of the first recurrence. Unlike other available therapies, allogeneic HCT has the potential to cure up to one half of those transplanted with indolent B-cell non-Hodgkin lymphoma, although the risks need to be recognized and appropriate patient and donor selection is critical to ensure the best outcomes. HCT continues to remain a viable option in the current era of multiple targeted agents.

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“…This is not only due to the immediate toxicities of HDM-ASCT, but also the long-term risks such as an approximate 10-fold increase in myelodysplastic syndrome (MDS) and acute myelogenous leukaemia (AML) when compared to non-HDM-ASCT-based therapies. 4 Acknowledging geographical disparities in access to novel drugs, it is also important to note that the available therapeutic regimens for first-line treatment in many countries do not consistently deliver deep and durable treatment responses to the degree achieved by IMiD-PI combinations, and so HDM-ASCT will continue to play an important role in this regard. 5 In the USA, however, both IMiD and PI in the first-line setting are widely available and adopted by treatment guidelines and the Centres for Medicare and Medicaid Services (CMS).…”

Section: The Impact Of Novel Drug Combinationsmentioning

confidence: 99%

“…These observations may provide clues as to the biological underpinnings of the aforementioned data indicating that patients with MM previously treated with HDM-ASCT have a 50-to 100-fold higher risk of developing MDS/AML compared to the general population. 4 Moreover, as novel agents continue to increase in number and improve outcome for patients, it is possible that a higher incidence of secondary leukaemia in those exposed to HDM will be analogous to the current situation in Hodgkin lymphoma (HL), where patient survival over the past half-century has improved dramatically. As cured HL patients are now living for decades after their diagnosis, an increase in the incidence of secondary malignancies, most notably breast cancer from radiation therapy, has come to light, with breast cancer risk increasing by up to eightfold over that of the general population and persisting for 25 years.…”

Section: Hdm-asct Is a Potentially Toxic Therapymentioning

confidence: 99%

The role of high‐dose melphalan with autologous stem‐cell transplant in multiple myeloma: is it time for a paradigm shift?

Kazandjian

Landgren

et al. 2020

Br J Haematol

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Recent advances in multiple myeloma include numerous approvals of novel therapies with unprecedented efficacy, a rapid and sustained tempo of new drug development, and further refinements to prognostication to include minimal residual disease (MRD) testing and improved risk stratification. The upfront use of immunomodulatory drug and proteasome inhibitor combinations followed by maintenance has resulted in transformative clinical benefit. Four-drug regimens incorporating monoclonal antibodies are reporting unprecedented rates of complete response and MRD negativity in the absence of intensification. In the context of these advances, the added value of high-dose melphalan with autologous stem-cell transplant (HDM-ASCT) is a key question. From a safety standpoint, HDM-ASCT is associated with both acute toxicities that reduce quality of life and long-term toxicities that may limit life expectancy for some patients. The present review discusses the recent advances in induction therapy, the impact of these advances on HDM-ASCT, the evolving role of MRD testing and the shortand long-term risks of HDM-ASCT. Recognising that prospective data remains limited, we suggest that HDM-ASCT not be considered mandatory for eligible newly diagnosed patients who are treated with highly efficacious regimens and achieve deep responses, but rather be held in reserve without early exposure to the clinical and genomic toxicity inherent to this approach.

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Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma

Abstract: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Cited by 47 publications

References 22 publications

Timing the initiation of multiple myeloma

Timing the initiation of multiple myeloma

Where does transplant fit in the age of targeted therapies?

The role of high‐dose melphalan with autologous stem‐cell transplant in multiple myeloma: is it time for a paradigm shift?

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