Dynamic acquisition of FLT3 or RAS alterations drive a subset of patients with lower risk MDS to secondary AML

Takahashi, Koichi; Jabbour, Elias; Wang, X; Luthra, Raja; Bueso‐Ramos, Carlos E.; Patel, Keyur P.; Pierce, Sherry; Yang, Hui; Wei, Yue; Daver, Naval; Faderl, Stefan; Ravandi, Farhad; Estrov, Zeev; Cortes, Jorge; Kantarjian, Hagop M.; Garcia‐Manero, Guillermo

doi:10.1038/leu.2013.165

Cited by 54 publications

(36 citation statements)

References 14 publications

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“…Previously published data indicate that RUNX1, FLT3, RAS mutations occur infrequently in AHD/MDS suggesting that acquisition of this class of mutations plays a transformative role in disease progression. [30][31][32] 0.0 0 1 2 2 4 3 6…”

Section: Discussionmentioning

confidence: 99%

Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis

et al. 2017

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Key Points• ts-AML (arising from treated antecedent hematological disorder) is less responsive to currently applied treatment strategies.• Future trial designs should accommodate this entity as a distinct category, and patients would be best evaluated on investigational therapies.Secondary acute myeloid leukemia (s-AML) includes therapy-related AML and AML evolving from antecedent hematological disorder (AHD). s-AML arising after treating AHD likely represents a prognostically distinct, high-risk disease category. In this study, treated s-AML (ts-AML) was defined by: (1) prior diagnosis of myelodysplasia, myeloproliferative neoplasm, or aplastic anemia and (2) at least 1 therapy for that diagnosis. ts-AML was categorized by age (, or $60 years), and each cohort assessed for response rates and overall survival (OS) on various treatment regimens. Survival outcomes were compared against other high-risk prognostic subsets. Results showed that complete response and 8-week mortality rates were 32% and 27% in the younger, and 24% and 19% in the older age groups,respectively. There was a significant OS difference within s-AML based on prior treatment of AHD (ie, ts-AML vs s-AML with untreated AHD, 4.2 vs 9.2 months; P , .001). Survival in ts-AML was poor across both cohorts (younger and older, 5 and 4.7 months, respectively). In younger AML, survival was significantly inferior in ts-AML when compared with deletion 5/7, TP53, 3q abnormality, and therapy-related AML groups (median, 5 vs 7.9, 7.8, 7.9, and 11.2 months, respectively; P , .01). Additional adverse karyotype within ts-AML was associated with even worse outcomes (OS range, 1.6-2.8 months). ts-AML represents a very high-risk category, even in younger AML patients. s-AML should be further classified to describe ts-AML, an entity less responsive to currently applied treatment approaches.Future AML trial designs should accommodate ts-AML as a distinct subgroup.

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Section: Discussionmentioning

confidence: 99%

Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis

et al. 2017

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“…11,12 Takahashi et al in a retrospective review reported that subset of patients with low/intermediate risk MDS who acquire RAS mutation in disease course had shorter transformation free survival to AML and overall survival in contrast to wild type patients. 13 …”

Section: Introductionmentioning

confidence: 99%

Phase I Study of S-Trans, Trans-Farnesylthiosalicylic Acid (Salirasib), a Novel Oral RAS Inhibitor in Patients With Refractory Hematologic Malignancies

Badar

Cortes

Ravandi

et al. 2015

Clinical Lymphoma Myeloma and Leukemia

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Background RAS/RAF/MAPK activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane binding proteins. Salirasib does not inhibit farnesyl transferase enzyme. Methods We report a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1–21 of a 28 day cycle in a “3+3” dose escalation design. Results Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1–29). Three patients each were enrolled at dose level of 100, 200, 400, 600 and 800 mg twice daily and 2 pts at dose level of 900 mg twice daily. No dose limiting toxicities were encountered. Grade 1–2 diarrhea has been the only frequent non-hematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral anti-diarrheal. Eight (47%) pts (4 MDS, 2 AML, 1 CMML, and 1 CML) had hematological improvement; 1 in three lineages, 1 in two lineages, and 6 in one lineage. None of the patient achieved complete remission. The responses lasted for a median of 10 weeks (range, 5–115). Study was discontinued for financial constraints. Conclusion Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be utilized in combination therapy.

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“…FLT3 and NRAS mutations are thought to be important genetic events contributing to the pathogenesis of AML 4-6 and the expected increase in the frequencies of mutations in s-AML cases was observed, confirming previously reported data. 7,8 In an very elegant study, recently published by Lindsley et al, the three different AML subtypes -secondary, therapy-related and de novo -were genetically compared and also in a small group of 17 MDS/s-AML matched samples the authors showed that 78% of the patients gained mutations in transcription factors as well as signal transduction proteins (FLT3 and RAS pathway) during s-AML transformation. 9 These results are in line with our data showing predominantly acquired mutations in signal transduction.…”

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confidence: 99%

Karyotype evolution and acquisition of FLT3 or RAS pathway alterations drive progression of myelodysplastic syndrome to acute myeloid leukemia

Meggendorfer¹,

Albuquerque²,

Nadarajah³

et al. 2015

Haematologica

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Dynamic acquisition of FLT3 or RAS alterations drive a subset of patients with lower risk MDS to secondary AML

Cited by 54 publications

References 14 publications

Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis

Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis

Phase I Study of S-Trans, Trans-Farnesylthiosalicylic Acid (Salirasib), a Novel Oral RAS Inhibitor in Patients With Refractory Hematologic Malignancies

Karyotype evolution and acquisition of FLT3 or RAS pathway alterations drive progression of myelodysplastic syndrome to acute myeloid leukemia

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