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ACUTE MYELOID LEUKEMIA

Outcomes of patients with IDH1-mutant relapsed or refractory acute myeloid leukemia receiving ivosidenib who proceeded to hematopoietic stem cell transplant

Leukemia volume 35, pages 3278–3281 (2021)Cite this article

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For patients with relapsed/refractory (R/R) acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (HCT) following salvage therapy is a potentially curative treatment approach [1]. Unfortunately, only a minority of patients are able to obtain a complete remission (CR) in the relapsed setting with standard therapies. Outcomes of patients who transition to HCT after remission induction with mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor monotherapy have not been previously reported.

Somatic mutations in the conserved active site of the metabolic enzyme IDH1 are present in ~6−10% of patients with AML [2,3,4], and lead to the production of the oncometabolite D-2-hydroxyglutarate (2-HG) [5], leading to metabolic dysregulation, epigenetic dysregulation, and impaired cellular differentiation [6, 7]. Ivosidenib (formerly AG-120) is an oral, targeted, small-molecule inhibitor of the mIDH1 enzyme, which effectively suppresses production of 2-HG, and is approved for the treatment of AML with a susceptible IDH1 mutation as detected by a US FDA-approved test in adults with newly diagnosed AML who are aged ≥75 years or who are ineligible for intensive induction chemotherapy, and those with R/R AML. In a phase 1 dose-escalation and -expansion study enrolling patients with advanced mIDH1 hematologic malignancies, those with R/R AML receiving ivosidenib 500 mg once daily (QD) had a CR plus CR with partial hematologic recovery (CRh) rate of 30.2% [8]. CRh was defined as <5% blasts in the bone marrow and partial recovery of peripheral blood counts (platelets >50 × 109/L and absolute neutrophil count >0.5 × 109/L) [8]. Given its favorable safety profile in patients with AML and its clinical efficacy [8], ivosidenib could provide an effective nonintensive treatment strategy for remission induction prior to HCT for patients with mIDH1 R/R AML.

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Fig. 1: Treatment duration, response, and post-HCT follow-up duration in patients who underwent HCT (n = 17).

References

  1. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  2. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl J Med. 2009;361:1058–66.

    Article  CAS  Google Scholar 

  3. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.

    Article  CAS  Google Scholar 

  4. Patel KP, Ravandi F, Ma D, Paladugu A, Barkoh BA, Medeiros LJ, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011;135:35–45.

    Article  CAS  Google Scholar 

  5. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.

    Article  CAS  Google Scholar 

  6. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483:474–8.

    Article  CAS  Google Scholar 

  7. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.

    Article  CAS  Google Scholar 

  8. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl J Med. 2018;378:2386–98.

    Article  CAS  Google Scholar 

  9. Zahid MF, Malik UA, Sohail M, Hassan IN, Ali S, Shaukat MHS. Cytogenetic abnormalities in myelodysplastic syndromes: an overview. Int J Hematol Oncol Stem Cell Res. 2017;11:231–9.

    PubMed  PubMed Central  Google Scholar 

  10. Burchert A, Bug G, Finke J, Stelljes M, Rollig C, Wäsch R, et al. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicentre Sormain trial. Blood. 2018;132:661.

    Article  Google Scholar 

  11. Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H. German-Austrian AML Study Groupet al.Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133:840–51.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Medical writing assistance was provided by David Pertab, PhD, Excel Medical Affairs, Glasgow, UK, and supported by Agios Pharmaceuticals, Inc.

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Authors and Affiliations

  1. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Courtney D. DiNardo

  2. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Eytan M. Stein

  3. Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    Arnaud Pigneux

  4. Northwestern University, Chicago, IL, USA

    Jessica K. Altman

  5. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Robert Collins

  6. University of Alabama at Birmingham, Birmingham, AL, USA

    Harry P. Erba

  7. University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Justin M. Watts

  8. Washington University School of Medicine, St. Louis, MO, USA

    Geoffrey L. Uy

  9. Agios Pharmaceuticals, Inc., Cambridge, MA, USA

    Thomas Winkler, Hongfang Wang, Sung Choe, Hua Liu, Bin Wu & Stephanie M. Kapsalis

  10. Weill Cornell Medicine and The New York Presbyterian Hospital, New York, NY, USA

    Gail J. Roboz

  11. Institut Gustave Roussy, Villejuif, France

    Stéphane de Botton

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  1. Courtney D. DiNardo
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Contributions

CDD, EMS, AP, JKA, RC, HPE, JMW, GLU, GJR, and SdB participated in the recruitment and treatment of patients in the trial and the collection of data. HL performed the data analysis. All authors participated in clinical data interpretation. CDD, TW, HW, SC, HL, BW, and SMK oversaw drafting of the manuscript. All authors participated in manuscript development and final approval of the submitted version.

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Correspondence to Courtney D. DiNardo.

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Conflict of interest

CDD acted as a consultant/advisor for Agios and Celgene; received honoraria from AbbVie, Agios, Bayer, Celgene, Karyopharm, and MedImmune; and received research funding from AbbVie, Agios, Celgene, and Daiichi Sankyo. EMS holds stock/ownership interests in Auron; acted as a consultant/advisor for AbbVie, Agios, Astellas, Bayer, BioLineRx, Celgene, Daiichi Sankyo, Genentech, Novartis, Pfizer, PTC, and Syros; received research funding from Agios, Amgen, Bayer, Celgene, and Syros; and received travel expenses from AbbVie, Astellas, Celgene, Daiichi Sankyo, Novartis, and Syros. AP acted as a consultant/advisor for AbbVie, Amgen, Astellas, Daiichi Sankyo, Jazz, Pfizer, and Roche; received honoraria from Novartis; and received research travel expenses from Sanofi. JKA acted as a consultant/advisor for AbbVie, Agios, Astellas, Cancer Expert Now, Daiichi Sankyo, GlycoMimetics, Novartis, and Theradex; was on a speakers bureau for France Foundation, PeerView, and prIME Oncology; and received research funding to institution from Agios, Astellas, Boehringer Ingelheim, Celgene, FujiFilm, and Genentech. RC received research funding from Aeglea BioTherapeutics, Agios, Astellas, MedImmune, and Oregon Health & Science University; HPE acted as a consultant/advisor for Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, GlycoMimetics, ImmunoGen, Incyte, Jazz, MacroGenics, Novartis, Pfizer, and Seattle Genetics; was on a speakers bureau for Agios, Celgene, Incyte, Jazz, and Novartis; received research funding from Agios, Amgen, Daiichi Sankyo, GlycoMimetics, ImmunoGen, Janssen, Juno, Pfizer, Seattle Genetics, and Takeda; and received other fees from Celgene and GlycoMimetics. JMW acted as a consultant/advisor for Bristol Myers Squibb, Celgene, Genentech, Jazz, Rafael, and Takeda; and received research funding from Takeda. GLU acted as a consultant/advisor for Abbvie, Agios, Astellas, Genentech, GSK, and Jazz. TW, HW, SC, HL, BW, and SMK are employees of and hold stock/ownership interests in Agios. GJR acted as a consultant/advisor or Data and Safety Monitoring Committee member for AbbVie, Actinium, Agios, Amphivena, argenx, Astellas, Astex, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz, MEI Pharma, Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, and Trovagene; and received research funding from Cellectis. SdB acted as a consultant/advisor for Agios, Bayer, CarthaGenetics, Celgene, FORMA, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, and Servier; received honoraria from AbbVie, Agios, Bayer, CarthaGenetics, Celgene, FORMA, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, and Servier; received research funding from Agios; received travel expenses from Agios, CarthaGenetics, Celgene, FORMA, Novartis, Pfizer, Pierre Fabre, Seattle Genetics, and Servier; and was on a speakers bureau for AbbVie.

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DiNardo, C.D., Stein, E.M., Pigneux, A. et al. Outcomes of patients with IDH1-mutant relapsed or refractory acute myeloid leukemia receiving ivosidenib who proceeded to hematopoietic stem cell transplant. Leukemia 35, 3278–3281 (2021). https://doi.org/10.1038/s41375-021-01229-x

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