Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

Calleja, Anne; Yun, Seongseok; Moreilhon, Chimène; Karsenti, J.M.; Gastaud, Lauris; Mannone, Lionel; Komrokji, Rami; Ali, Najla Al; Dadone-Montaudie, Bérangère; Robert, Guillaume; Auberger, Patrick; Raynaud, Sophie; Sallman, David A.; Cluzeau, Thomas

doi:10.1111/ejh.13390

Cited by 9 publications

(7 citation statements)

References 53 publications

(147 reference statements)

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“…Of note, we witnessed significantly lower relapse rates and NRM for transplant from female to male donor which probably might be related to enhanced graft vs leukemia effects without GVHD (non-tolerized donor T cells) against SMCY, which might have translated into survival/PFS benefit [27,28]. We found lower relapse rates among untreated patients as compared to patients who received treatment (irrespective of response and disease status-blast count), and this might be due to inability of treatment such as azacytidine to eliminate founder precursor clones, and emergence/selection of resistant clones while on treatment [29][30][31][32].…”

Section: Discussionmentioning

confidence: 73%

Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT

Raj

Eikema²,

Sheth³

et al. 2022

Blood Cancer J.

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Myelodysplastic syndromes (MDS) are the second common indication for an Allo-HCT. We compared the outcomes of 1414 matched sibling (MSD) with 415 haplo-identical donors (HD) transplanted with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis between 2014 and 2017. The median age at transplant with MSD was 58 and 61 years for HD. The median time to neutrophil engraftment was longer for HD being 20 vs 16 days for MSD (p < 0.001). Two-year overall survival (OS) and PFS (progression free survival) with MSD were significantly better at 58% compared with 50%, p ≤ 0.001, and 51% vs 47%, p = 0.029, with a HD. Relapse at 2 years was lower with a HD 23% than with MSD 29% (p = 0.016). Non relapse mortality (NRM) was higher with HD in the first 6 months post-transplant [HR 2.59 (1.5–4.48) p < 0.001] and was also higher at 2 years being 30% for HD and 20% for MSD, p ≤ 0.001. The incidence of acute GVHD grade II-IV and III–IV at 100 days was comparable for MSD and HD, however, chronic GVHD at 2 years was significantly higher with MSD being 44% vs 32% for HD (p < 0.001). After multivariable analysis, OS and primary graft failure were significantly worse for HD particularly before 6 months [HR 1.93(1.24–3.0)], and HR [3.5(1.5–8.1)]. The median age of HD 37 (IQR 30–47) years was significantly lower than sibling donors 56 (IQR 49–62 years) p < 0.001. However, there was no effect on NRM, relapse or PFS. This data set suggests that a MSD donor remains the preferred choice in MDS over a haplo donor. Transplants with haploidentical donors result in satisfactory long-term outcome, justifying it’s use when no better donor is available.

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Section: Discussionmentioning

confidence: 73%

Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT

Raj

Eikema²,

Sheth³

et al. 2022

Blood Cancer J.

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“…Patients with TP53 mutations could benefit from AZA, which have been shown to confer better overall response rate to azacitidine than those with negative TP53 mutation in patients with higher-risk MDS (46% vs. 14%) [40,41]. Furthermore, decreased TP53-mutated clone was observed in patients with MDS/AML harboring TP53 mutation under AZA treatment [42]. VEN is a highly selective, potent BCL2 inhibitor, which induced apoptosis in malignant cells through BCL-2-mediated pathway.…”

Section: Discussionmentioning

confidence: 99%

Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review

Ma,

Lang,

Chen

et al. 2024

Anti-Cancer Drugs

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Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disease, which is prone to transform into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). TP53 mutation is a driving factor involved in the transformation of SDS into MDS/AML, and in the evolution of MDS to AML. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable approach, however, challenge remains regarding the balance between efficacy and the high risk from treatment-related toxicity and mortality to achieve temporary disease control before transplantation to gain time and opportunities for transplantation. At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case.

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“…Similar to previous SEER studies, we observed continued increase in tAML risk as stem cell transplantation and lenalidomide continue to remain a cornerstone of myeloma therapy 5 , 36 . A selective advantage of the RAS pathway gene mutations as well as TP53 clones 28 , 37 , 38 may have contributed to an increased risk for tAML after MM. It was interesting to note declining tMDS risk after MM.…”

Section: Discussionmentioning

confidence: 99%

Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States

Singh

Herr

Griffiths

et al. 2021

Sci Rep

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Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000–2005, 2006–2010 and 2011–2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006–2010 to 2011–2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

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Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

Cited by 9 publications

References 53 publications

Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT

Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT

Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review

Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States

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