Hypomethylating Agents Can Produce Long Remission of MPNs but May Contribute to Morbidity, Mortality

Hypomethylating agents are a widely used treatment option in acute myeloid leukemia secondary to myeloproliferative neoplasms (MPNs), but careful monitoring of thromboembolic risk is needed for optimal outcomes.

Philadelphia-negative myeloproliferative neoplasms (MPNs) are rare but carry a risk of severe complications, including transformation into acute myeloid leukemia (AML). Hypomethylating agents (HMAs) can effectively induce remission in some patients, but a small study published in Leukemia Research suggests that reversing the course of the disease to a more chronic form may also lead to morbidity and mortality without close monitoring.

The risk of secondary AML varies between MPNs, and post-MPN AML is notably different from de novo AML. The frequent TP53 mutations, epigenetic modifiers, and complex and monosomal karyotypes seen in the accelerated phase (AP) or blast phase (BP) of MPN (MPN-BP/AP) are partially similar to de novo high-risk AML and myelodysplastic syndromes.

Post-MPN AML is difficult to treat and typically has a poor prognosis—allogeneic stem-cell transplantation is the only curative option, yet most patients are ineligible due to age and comorbidities. Patients treated with HMAs have may have favorable responses and overall survival (OS) compared with those treated with induction chemotherapy, and HMAs have better tolerability. It is rare that patients experience durable responses on HMAs, however, and MPN recurrence after AML remission on HMAs is not well characterized.

The current study included a cohort of 6 patients with MPN-BP/AP whose MPN recurred following disease response on azacytidine. All of the patients had JAK2 V617F mutations when they were diagnosed with MPN, and all had poor prognostic factors such as complex and monosomal karyotypes, TP53 mutations, and EVI-1 overexpression. Of these patients, 5 achieved complete remission (CR) on azacytidine.

For 4 of the patients, remissions lasted more than 5 years, but MPN reemerged rapidly in all patients, with a median time of 2 months. Anagrelide or ruxolitinib were given with azacytidine or hydroxyurea was given in the 7-day period between azacytidine cycles to address thrombocytosis. Three patients experienced thromboembolic events, with 1 of those events leading to death. Median OS from BP/AP diagnosis was 67 months, and patients underwent a median of 64 cycles of azacytidine.

“These findings confirm that HMA may reverse the disease course to a more chronic phase in BP/AP MPN,” study authors wrote. “An unanswered question is whether these long-lasting responses are obtained because of a higher resistance of the MPN clone that better outcompetes the blastic clone than normal hematopoietic stem cells under treatment and repopulates the bone marrow niche.”

In the study cohort, JAK2 V617F variant allele frequency (VAF) was generally stable during MPN-BP/AP, remission, and MPN reemergence. This is in line with previous research and suggests MPN clones are resistant to AML treatments.

While serial high-throughput sequencing can help predict AML relapse, the findings emphasize a need for reliable biomarkers to predict MPN-related thromboembolic risk after HMA therapy.

“AP/BP MPN patients who achieve CR may experience MPN recurrence and long survival times,” the authors concluded. “Careful evaluation of the thrombosis risk and reinstatement of MPN-specific therapy in parallel with ongoing HMA therapy is needed to optimize the clinical benefit in these rare patients.”


Chauvet P, Nibourel O, Berthon C, et al. Resurgence of myeloproliferative neoplasm in patients in remission from blast transformation after treatment with hypomethylating agents. Leuk Res. 2022;118:106871. doi:10.1016/j.leukres.2022.106871

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