Targeted Approach Considered for the Treatment of Accelerated/Blast Phase MPNs – Targeted Oncology

Standard treatment for accelerated or blast phase myeloproliferative neoplasms (MPNs) consists of hypomethylating agents (HMAs) or intensive induction chemotherapy and transplant. However, newer studies have suggested that accelerated or blast phase MPNs, such as acute myeloid leukemia (AML), can be treated with molecularly driven targeted therapies.

Srdan Verstovsek, MD, explained the current treatment paradigm for patients with accelerated or blast phase MPNs as well as emerging therapies in this setting in a presentation during the Texas Virtual MPN Workshop.1

Current Paradigm and Unmet Needs

Verstovsek, professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, explained that there are 3 phases of MPNs: chronic, accelerated, and blast (or post-MPN AML), which are determined by the percentage of blasts in the peripheral blood or bone marrow. These phases affect each type of MPN: essential thrombocytopenia (ET), polycythemia vera (PV), and myelofibrosis. In the chronic phase there are less than 10% blasts found in the peripheral blood or bone marrow, and in the blast phase theres 20% or more.

Blast-phase MPNs are associated with a very poor prognosis. It unfortunately has not changed very much over many yearswe have a lot to do, Verstovsek said.

Additionally, those with blast-phase MPNs show limited responses to conventional treatments for AML. In an analysis of 91 patients who developed post-MPN AML, patients who were treated with conventional treatments did not show significant survival differences compared with those who were not treated. The median survival among patients who received induction chemotherapy was 3.9 months compared with 2.1 months for those who did not receive any chemotherapy.2

Stem cell transplant, however, does have a more significant impact on survival following induction chemotherapy. Only patients that achieve complete response [CR] and go for transplant do well, Verstovsek said.

One analysis showed that the rate of overall survival (OS) among patients who did not achieve a CR from induction chemotherapy prior to transplant was 22% compared with 69% among patients who did have a CR (P = .008).3 He said that overall, the chance of achieving a CR with induction chemotherapy is approximately 35% to 40%.4

An alternative to induction chemotherapy is azacitidine, which has shown comparable survival rates to chemotherapy in post-MPN AML. In a study of 73 patients with post-MPN AML, no statistically significant difference was observed in either event-free survival or OS between those treated with chemotherapy or azacitidine. The event-free survival was 4.2 months with induction chemotherapy and 5.8 months with azacitidine (P = .4443) and the median OS was 8.3 and 7.9 months, respectively (P = .9842). Response rates were also similar at 58.8% with chemotherapy and 54.6% with azacitidine.5

The patients that transform from chronic phase MPN to blastic phase MPN actually pass through accelerated phase MPN. That is rather a rule. Its extraordinarily rare that overnight the patient comes from chronic phase to blastic phase, usually you see blasts coming up, Verstovsek said. That is useful because we dont want to wait for patients to transform. If we can follow patients closely, we would be intervening with hypomethylating agents in the accelerated phase.

Research suggests that patients benefit more from HMAs in the accelerated phase than in the blast phase. A retrospective study of patients with high-risk myelofibrosis in the accelerated or blast phase who were treated with decitabine showed that the OS among patients in the blast phase was 6.9 months, but those in the accelerated phase had a median OS of 9.7 months. Among those who responded to decitabine, the median OS was 10.5 months for those in the blast phase and 11.8 months for those in the accelerated phase.6

As ruxolitinib (Jakafi) is standard of care in treating patients with myelofibrosis, the JAK inhibitor has been investigated in clinical trials in combination with HMAs for the treatment of patients with accelerated and blast phase MPNs. When we talk about transformation to accelerated/blastic phase, we are usually talking about [patients with] myelofibrosis transforming, they are in bad physical shape, they have a very big spleen, very big liver, so there is utility perhaps in giving them ruxolitinib, Verstovsek said.

In a phase 1/2 study of ruxolitinib and decitabine in 29 patients with blast phase MPN, treatment with up to 50 mg of ruxolitinib twice daily and 20 mg/m2 of intravenous decitabine for 5 days on a 4 to 6 week schedule led to a response rate of 45%, which included a CR rate of 7%. The median OS for patients who responded to treatment was 9.4 months compared with 6.2 months in those who did not respond.7

We already know that ruxolitinib is not active in preventing progression. On its own its not active in accelerated or blast phasethats already well known, Verstovsek said.

The National Comprehensive Cancer Network (NCCN) guidelines for MPNs now include that ruxolitinib or fedratinib (Inrebic) can be given close to the start of conditioning treatment for the improvement of splenomegaly or disease-related symptoms.8

Overall, Verstovsek suggested starting with HMAs for 2 to 3 cycles because it canbedelivered in the outpatient setting and is not as toxic as chemotherapy, leading to better quality of life for the patient.

Moving Toward a Molecularly Targeted Approach

New medications are being developed for de novo acute myeloid leukemia, so why not use some of them in the setting of post-MPN AML or even in accelerated phase MPN? Verstovsek suggested.

Mutational analyses have shown a significant difference in the mutation frequency found between de novo AML and accelerated or blast phase MPNs. One mutation that is found more often in accelerated or blast phase MPN is IDH1/2, and agents are already available to target these alterations.

Small studies have already shown promise for this approach of treating patients with IDH1/2-mutant accelerated or blast phase MPNs with an IDH1/2 inhibitor. In a small study of 12 patients with IDH1/2-mutant post-MPN AML treated with IDH1/2 inhibitorbased regimens, 3 of 7 patients treated in the frontline setting had a CR and a median duration of response of 17.5+ months was reported. Two patients treated in the frontline and 3 in the relapsed/refractory setting also had stable disease.1

Targeted agentsis the way of the futureidentifying patients based on genetic profile and targeting those mutations for which we have medications, Verstovsek said.

A study has also considered treatment with venetoclax (Venclexta)based combination regimens. The study included 29 patients treated in the frontline or relapsed/refractory setting. Six of the 14 patients treated in the frontline setting achieved a CR or complete response with incomplete hematologic recovery from treatment with the venetoclax regimen and showed a median duration of response of 6 months. However, there was a high degree of infections and mortality in the first 60 days of treatment.1

Additionally, when comparing the venetoclax regimen to other treatment regimens, no survival benefit was found with the use of venetoclax.

Verstovsek summarized that those with targetable mutations, such as IDH1/2 or FLT3 mutations, should receive these targeted treatments, and those with no targetable mutation should receive HMA-based therapy or intensive chemotherapy, and all patients are recommended to undergo allogeneic stem cell transplant if they achieve a complete response and are eligible for transplant.

References:

1. Verstovsek S. Therapy Strategies for Accelerated and Blastic Phase MPN. Presented at: Texas Virtual MPN Workshop; August 27-28, 2020; Virtual.

2. Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973-977. doi:10.1182/blood-2004-07-2864

3. Alchalby H, Zabelina T, Stubig T, et al; Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Bio Blood Marrow Trasplant. 2014;20(2):279-281. doi:10.1016/j.bbmt.2013.10.027

4. Mascarenhas J. A concise update on risk factors, therapy, and outcome of leukemic transformation of myeloproliferative neoplasms. Clin Lymph Myel Leuk. 2016;16(suppl):S124-S129. doi:10.1016/j.clml.2016.02.016

5. Venton G, Courtier F, Charbonnier A, et al. Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms. Am J Hematol. 2018;93(3):330-338. doi:10.1002/ajh.24973

6. Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leuk Res. 2015;39(9):950-956. doi:10.1016/j.leukres.2015.06.001

7. Bose P, Verstovsek S, Cortes JE, et al. A phase 1/2 study of ruxolitinib and decitabine in patients with post-myeloproliferative neoplasm acute myeloid leukemia. Leukemia. 2020;34(9):2489-2492. doi:10.1038/s41375-020-0778-0

8. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2020. Accessed August 28, 2020. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf

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Targeted Approach Considered for the Treatment of Accelerated/Blast Phase MPNs – Targeted Oncology