clinical topic updates

Update on Actionable Targets in the MDS and AML Disease Spectrum

by David Sallman, MD


Mutations in FLT3 and IDH1/IDH2 are among those that are currently actionable in acute myeloid leukemia (AML). Trials of novel agents and combinations promise to transform the future treatment landscape for patients with high-risk myelodysplastic syndrome (MDS), AML, and other myeloid malignancies.

Expert Commentary

David Sallman, MD

Assistant Member, Department of Malignant Hematology
H. Lee Moffitt Cancer Center & Research Institute
Assistant Professor, Department of Oncologic Sciences
University of South Florida
Tampa, FL

AML research has been the leader in terms of targeted therapies in myeloid malignancies, but it is also an exciting time right now for MDS research, with studies investigating novel targeted, immune-based, and combination therapies.” 

David Sallman, MD

Today, we can truly personalize the interrogation of a patient’s disease through next-generation sequencing. We can identify mutations in nearly 95% of patients with MDS and AML. At one time, these genomic alterations were mainly prognostic, but today they currently guide treatment. AML research has been the leader in terms of targeted therapies in myeloid malignancies, but it is also an exciting time right now for MDS research, with studies investigating novel targeted, immune-based, and combination therapies.

Some targets are mainly applicable to AML. For instance, FLT3 mutations may be targeted by midostaurin or gilteritinib and are present in approximately one-third of patients with AML, but they occur only very rarely in MDS. For patients with FLT3-mutated AML, there is a clear survival benefit with the FLT3 tyrosine kinase inhibitor midostaurin combined with 7+3 chemotherapy in the frontline setting. In the relapsed/refractory setting, gilteritinib monotherapy has demonstrated a survival advantage compared with salvage chemotherapy. Somatic mutations in IDH1/IDH2 (ie, ivosidenib and enasidenib, respectively) are also actionable. Taken together, they occur in approximately 20% of patients with AML, but these mutations are less frequent in patients with MDS.

In TP53-mutated disease, whether AML or MDS with excess blasts, the clinical and pathologic features are often shared, and overall survival is poor. In patients with TP53 mutations, the combination of hypomethylating agents (HMAs) and venetoclax has demonstrated improved response rates but has not shown survival benefit. There is some research suggesting that TP53 may alter the BCL-2 target, resulting in primary venetoclax resistance. Investigational efforts to restore p53 function are ongoing. For instance, the combination of the p53 reactivator eprenetapopt (APR-246) and azacitidine was given a breakthrough therapy designation for the treatment of patients with MDS and a susceptible TP53 mutation, and a phase 3 trial with this combination recently completed enrollment. In addition, there is an ongoing study investigating the efficacy of triplet therapy with azacitidine, eprenetapopt, and venetoclax.

So, it is an exciting time for research into novel HMA combinations as frontline therapy in high-risk MDS and AML. For example, the combination of the CD47 inhibitor magrolimab with azacitidine has had synergistic activity for higher-risk MDS and has received a breakthrough therapy designation by the US Food and Drug Administration. A randomized phase 3 trial of combination therapy vs azacitidine therapy alone has been initiated. Additionally, the TIM-3 inhibitor MBG453 in combination with an HMA has shown increased response rates, and a study of MBG453 in combination with azacitidine and venetoclax in patients with AML who are unfit for chemotherapy is ongoing. Pevonedistat is a novel NEDD8-activating enzyme inhibitor that recently received breakthrough therapy designation for higher-risk MDS. Recent phase 2 data demonstrated that approximately 50% of patients treated with pevonedistat and the HMA azacitidine achieved complete remission.

Still, it is important to note that, although there is an impact at diagnosis with such frontline treatment, AML and MDS mutations are dynamic and may change over time, and we need to better understand mechanisms of resistance. Furthermore, while we have made great strides with novel HMA combinations in the frontline setting, we need additional research to identify molecular subsets of patients who may be more likely to respond to particular novel therapies and combinations.


Ades L, Watts JM, Radinoff A, et al. Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777). J Clin Oncol. 2020;38(suppl 15):7506. doi:10.1200/JCO.2020.38.15_suppl.7506

Borate U, Esteve J, Porkka K, et al. Phase 1b study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood. 2019;134(suppl 1):570. doi:10.1182/blood-2019-128178 A study of MBG453 in combination with azacitidine and venetoclax in AML patients unfit for chemotherapy (STIMULUS-AML1). Accessed October 21, 2020.

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DiNardo CD, Jabbour E, Ravandi F, et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia. 2016;30(4):980-984. doi:10.1038/leu.2015.211

DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971

DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984

Jeay S, Ferretti S, Holzer P, et al. Dose and schedule determine distinct molecular mechanisms underlying the efficacy of the p53-MDM2 inhibitor HDM201. Cancer Res. 2018;78(21):6257-6267. doi:10.1158/0008-5472.CAN-18-0338

Lachowiez CA, Loghavi S, Kadia TM, et al. Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens. Blood Adv. 2020;4(7):1311-1320. doi:10.1182/bloodadvances.2019001267

Nechiporuk T, Kurtz SE, Nikolova O, et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 2019;9(7):910-925. doi:10.1158/2159-8290.CD-19-0125

Perl AE, Marinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688

Sallman DA, Al Malki M, Asch AS, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: phase Ib results. J Clin Oncol. 2020;38(suppl 15):7507. doi:10.1200/JCO.2020.38.15_suppl.7507

Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;134(suppl 1):676. doi:10.1182/blood-2019-131055

Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019;133(7):676-687. doi:10.1182/blood-2018-08-869008

Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359

Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131(13):1415-1424. doi:10.1182/blood-2017-09-805895

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