Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study

Bejanyan, Nelli; Zhang, Mei‐Jie; Bo-Subait, Khalid; Brunstein, Claudio G.; Wang, Hailin; Warlick, Erica D.; Giralt, Sergío; Nishihori, Taiga; Martino, Rodrigo; Passweg, Jakob; Dias, Ajoy; Copelan, Edward A.; Hale, Gregory A.; Gale, Robert Peter; Solh, Melhem; Kharfan‐Dabaja, Mohamed A.; Díaz, Miguel Ángel; Ganguly, Siddhartha; Gore, Steven D.; Verdonck, Leo F.; Hossain, Nasheed; Kekre, Natasha; Savani, Bipin N.; Byrne, Michael; Kanakry, Christopher G.; Cairo, Mitchell S.; Ciurea, Stefan O.; Schouten, Harry C.; Bredeson, Christopher; Munker, Reinhold; Lazarus, Hillard M.; Cahn, Jean Yves; Poel, Marjolein van der; Rizzieri, David A.; Yared, Jean A.; Freytes, Cesar; Černý, Jan; Aljurf, Mahmoud; Palmisiano, Neil; Pawarode, Attaphol; Bacher, Vera Ulrike; Grunwald, Michael R.; Nathan, Sunita; Wirk, Baldeep; Seo, Sachiko; Olsson, Richard F.; George, Biju; Lima, Marcos de; Hourigan, Christopher S.; Sandmaier, Brenda M.; Litzow, Mark R.; Kebriaei, Partow; Saber, Wael; Weisdorf, Daniel J.

doi:10.1016/j.bbmt.2020.09.026

Cited by 20 publications

(15 citation statements)

References 36 publications

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“…In a larger, very recent CIBMTR analysis, MAC resulted in an improved survival in comparison to RIC in AML/MDS patients 40 to 65 years old with low/intermediate risk DRI, but similar clinical benefit to RIC despite higher risk of relapse in patients with high/very high risk DRI. 56 …”

Section: Factors Which May Be Helpful In the Decision Process: Balance Between The Risk Of Relapse And Non-relapse Mortalitymentioning

confidence: 99%

Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend “when and for whom” in 2021?

Gagelmann

2021

haematol

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Allogeneic hematopoietic stem-cell transplantation is a potentially curative therapy for various hematologic diseases. An essential component of this procedure is the pre-transplant conditioning regimen, which should facilitate engraftment and reduce or eliminate tumor cells. The recognition of the substantial association of a graft-versus- tumor effect and the high toxicity of the commonly used conditioning regimen led to the introduction of more differentiated intensity strategies, with the aim of making hematopoietic stem-cell transplantation less toxic and safer, and thus more applicable to broader populations such as older or unfit patients. In general, prospective and retrospective studies suggest a correlation between increasing intensity and nonrelapse mortality and an inverse correlation with relapse incidence. In this review, we will summarize traditional and updated definitions for conditioning intensity strategies and the landscape of comparative prospective and retrospective studies, which may help to find the balance between the risk of non-relapse mortality and relapse. We will try to underscore the caveats regarding these definitions and analyses, by missing complex differences between intensity and toxicity as well as the broad influences of other factors in the transplantation procedure. We will summarize evidence regarding several confounders which may influence decisions when selecting the intensity of the conditioning regimen for any given patient, according to the individual risk of relapse and non-relapse mortality.

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Section: Factors Which May Be Helpful In the Decision Process: Balance Between The Risk Of Relapse And Non-relapse Mortalitymentioning

confidence: 99%

Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend “when and for whom” in 2021?

Gagelmann

2021

haematol

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“…Additional barriers to conventional HCT approaches include the presence of active disease, older age, lacking suitable fully matched sibling donors, and unfavorable disease kinetics that make timing an unrelated donor difficult ( 4 , 34 ). In turn, RIC haplo-HCT strategies are attractive from tolerability and logistical perspectives, but the post-HCT relapse risk remains high using standard approaches ( 3 , 35 , 36 ). Augmenting RIC haplo-HCT with ML NK cell adoptive transfer and N-803 injections was feasible and well tolerated in our study.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia

et al. 2022

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Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA -haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.

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“…The discrepancy in the results may be due to the inclusion of AML patients in BMTCTN 0901, or potentially due to differences in the specific conditioning chemotherapy regimens used in the USA versus Europe. In a retrospective study by Bejanyan et al., RIC and MAC were compared in 4387 MDS/AML patients between 40 to 65 years stratified by DRI ( 77 ). They found that in patients with low or intermediate DRI, RIC was associated with lower TRM (HR 0.74, p<0.001) but led to greater risk of relapse (HR 1.54; p<0.001), resulting in worse DFS (HR 1.19; p=0.001).…”

Section: Role and Considerations For Allogeneic Transplantmentioning

confidence: 99%

BMT for Myelodysplastic Syndrome: When and Where and How

Jain

Elmariah

2022

Front. Oncol.

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Myelodysplastic syndromes (MDS) are a diverse group of hematological malignancies distinguished by a combination of dysplasia in the bone marrow, cytopenias and the risk of leukemic transformation. The hallmark of MDS is bone marrow failure which occurs due to selective growth of somatically mutated clonal hematopoietic stem cells. Multiple prognostic models have been developed to help predict survival and leukemic transformation, including the international prognostic scoring system (IPSS), revised international prognostic scoring system (IPSS-R), WHO prognostic scoring system (WPSS) and MD Anderson prognostic scoring system (MDAPSS). This risk stratification informs management as low risk (LR)-MDS treatment focuses on improving quality of life and cytopenias, while the treatment of high risk (HR)-MDS focuses on delaying disease progression and improving survival. While therapies such as erythropoiesis stimulating agents (ESAs), erythroid maturation agents (EMAs), immunomodulatory imide drugs (IMIDs), and hypomethylating agents (HMAs) may provide benefit, allogeneic blood or marrow transplant (alloBMT) is the only treatment that can offer cure for MDS. However, this therapy is marred, historically, by high rates of toxicity and transplant related mortality (TRM). Because of this, alloBMT is considered in a minority of MDS patients. With modern techniques, alloBMT has become a suitable option even for patients of advanced age or with significant comorbidities, many of whom who would not have been considered for transplant in prior years. Hence, a formal transplant evaluation to weigh the complex balance of patient and disease related factors and determine the potential benefit of transplant should be considered early in the disease course for most MDS patients. Once alloBMT is recommended, timing is a crucial consideration since delaying transplant can lead to disease progression and development of other comorbidities that may preclude transplant. Despite the success of alloBMT, relapse remains a major barrier to success and novel approaches are necessary to mitigate this risk and improve long term cure rates. This review describes various factors that should be considered when choosing patients with MDS who should pursue transplant, approaches and timing of transplant, and future directions of the field.

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Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study

Cited by 20 publications

References 36 publications

Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend “when and for whom” in 2021?

Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend “when and for whom” in 2021?

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia

BMT for Myelodysplastic Syndrome: When and Where and How

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