Characteristics and outcomes of therapy-related myeloid neoplasms following autologous stem cell transplantation for multiple myeloma

Nadiminti, Kalyan; Sidiqi, M Hasib; Meleveedu, Kapil; Alkhateeb, Hassan B.; Litzow, Mark R.; Patnaik, Mrinal M.; Kumar, Shaji; Gertz, Morie A.; Chen, Dong; Shah, Mithun Vinod

doi:10.1038/s41408-021-00454-y

Cited by 13 publications

(13 citation statements)

References 14 publications

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“…Therapy-related myeloid neoplasms (t-MN) develop as a complication of prior DNA-damaging therapies including chemotherapy, radiation, stem cell transplantation (SCT), or immunosuppressive therapies (IST) for autoimmune diseases (AID). t-MN are aggressive neoplasms with overall survival of approximately 1 year from diagnosis, regardless of the therapies employed [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

et al. 2022

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Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN (n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with <5% bone marrow blasts (124.5 vs. 16.3 months, P < 0.001) respectively. The presence of cytogenetic abnormality and the absence of variants in DNMT3A, TET2, or ASXL1 (DTA-genes) were associated with a higher likelihood of developing a subsequent t-MN and an inferior survival. We describe a putative precursor entity of t-MN with distinct features and outcomes.

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Section: Introductionmentioning

confidence: 99%

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

et al. 2022

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“…10,11,12 Similarly, while SCT remains the "gold standard" modality, <20% patients are able to undergo SCT and outcomes following SCT remain sobering. [12][13][14] As opposed to relatively homogenous entity of AML, t-MN is a clinicopathological entity encompassing t-MDS, t-MDS/MPN, and t-AML. Therefore, there is an urgent need to assess the role of novel agents.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] Finally, TP53 status is a known adverse risk factor in almost all the known malignancies, including MDS, AML, and t-MN. 1,13,21 Biallelic TP53 loss is associated with a more aggressive phenotype and an inferior survival in MDS, but not AML. 22,23 In newly diagnosed AML, the likelihood of CRc, duration of response, and survival were inferior in those with TP53 PV.…”

Section: Discussionmentioning

confidence: 99%

“…HMAs—long considered to be a cornerstone for treatment of high‐risk MDS and unfit AML patients—do not substantially improve outcomes in t‐MN 10,11,12 . Similarly, while SCT remains the “gold standard” modality, <20% patients are able to undergo SCT and outcomes following SCT remain sobering 12–14 . As opposed to relatively homogenous entity of AML, t‐MN is a clinicopathological entity encompassing t‐MDS, t‐MDS/MPN, and t‐AML.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, TP53 status is a known adverse risk factor in almost all the known malignancies, including MDS, AML, and t‐MN 1,13,21 . Biallelic TP53 loss is associated with a more aggressive phenotype and an inferior survival in MDS, but not AML 22,23 .…”

Section: Discussionmentioning

confidence: 99%

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Outcomes following venetoclax‐based treatment in therapy‐related myeloid neoplasms

et al. 2022

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Therapy-related myeloid neoplasms (t-MN) are aggressive malignancies in need of effective therapies. The BCL-2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t-MN. We retrospectively analyzed 378 t-MN patients, of which 96 (25.4%, 47 therapy-related acute myeloid leukemia, 1 therapy-related chronic myelomonocytic leukemia, 48 therapy-related myelodysplastic syndrome) received venetoclax. Median interval from t-MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7-12) months, and patients received a median of 3 (IQR 1-4) cycles. The composite complete remission (CRc) rate, median progression-free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively.The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53-status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53-mutated clone.

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Single‐agent lenalidomide maintenance after upfront autologous stem cell transplant for newly diagnosed multiple myeloma: The MD Anderson experience

et al. 2023

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The optimal duration of lenalidomide (Len) maintenance for patients with multiple myeloma (MM) after autologous stem cell transplantation (autoHCT) is unknown. We conducted a retrospective single‐center analysis of adult MM patients that received upfront autoHCT between 2005 and 2021, followed by single‐agent Len maintenance. A total of 1167 patients were included with a median age of 61.4 (range 25.4–82.3) years, and high‐risk chromosomal abnormalities in 19%. Median duration of maintenance was 22.3 (range 0.03–139.6) months. After a median follow‐up of 47.9 (range 2.9–171.7) months, median PFS and OS for the entire cohort were 56.6 (95% CI 48.2–61.4) months and 111.3 (95% CI 101.7–121.5) months, respectively. In MVA, high‐risk cytogenetics was associated with a worse PFS (HR 1.91) and OS (HR 1.73) (p < .001 for both). Use of KRD induction and achievement of MRD‐negative ≥ VGPR before autoHCT were associated with an improved PFS (HR 0.53 and HR 0.57, respectively; p < .001 for both). Longer maintenance duration, even with a 5‐year cutoff, was associated with superior PFS and OS (HR 0.17 and 0.12, respectively; p < .001 for both). A total of 106 patients (9%) developed a second primary malignancy (SPM), mostly solid tumors (39%) and myeloid malignancies (30%). Longer maintenance duration was associated with a higher risk of SPM, reaching statistical significance after >2 years (odds ratio 2.25; p < .001). In conclusion, outcomes with Len maintenance were comparable to those reported in large clinical trials. Longer duration of maintenance, even beyond 5 years, was associated with improved survival.

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Characteristics and outcomes of therapy-related myeloid neoplasms following autologous stem cell transplantation for multiple myeloma

Cited by 13 publications

References 14 publications

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

Outcomes following venetoclax‐based treatment in therapy‐related myeloid neoplasms

Single‐agent lenalidomide maintenance after upfront autologous stem cell transplant for newly diagnosed multiple myeloma: The MD Anderson experience

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