Understanding and Treating Accelerated Phase Myeloproliferative Neoplasms

Olatoyosi Sobulo Odenike, MD

Considering there are no standard treatment approaches for accelerated phase myeloproliferative neoplasm (MPN AP), treating patients with this disease is an ongoing therapeutic challenge, according to an expert.

In her presentation at the Society of Hematology Oncology 2021 Annual Conference, Olatoyosi Sobulo Odenike, MD, explored the risk factors for evolution to MPN AP/blast phase (BP), outcomes for current treatment methods, and potential targeted therapies.

MPN AP is defined as patients with 10% or more blasts in the peripheral and/or bone marrow, and MPN BP is 20% or more. After the chronic phase of the Philadelphia chromosome (Ph)-negative MPNs, such as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), evolves into MPN AP, the median survival is much shorter.

For ET and PV, overall survival (OS) is generally more than 10 years, and PMF, which also has the highest risk of evolution to MPN AP, has a median OS of 5 to 6 years. The median survival in MPN AP is 16 to 17 months for PMF. For patients who evolve to MPN BP, survival is even worse.

“Of note, even in the chronic phase of the disease, in patients who have 5% to 9% blasts…[have] outcomes that are very similar to those who have 10% or more blasts, arguing that patients who have blasts in this range are also on a continuum towards BP,” Odenike, a professor of medicine at the University of Chicago Medicine, said. “When the disease progresses to the BP, the OS is in the 3- to 5-month range.”

For patients in this setting, risk factors for transformation include receiving cytoreductive agents; increase in blasts, thrombocytopenia, anemia, or other lab parameters; and having PMF, as opposed to ET or PV. According to the Risk Scoring Systems used for MPNs, high-risk features are considered predictive for MPN AP/BP. These include baseline driver mutations, deleterious mutations, and germline susceptibility.

Identifying patients who are at high risk of progression is crucial, Odenike noted, because the survival rates after transplant are much higher in chronic phase compared with MPN AP/BP. When approaching treatment in patients with MPN AP/BP, Odenike posed questions to consider:

• whether the patient is fit for intensive induction;
• if they are eligible for transplant, and
• the degree of cytoreduction necessary prior to transplant, if any.

Retrospective data have shown a complete response (CR) rate plus CR with incomplete hematologic recovery (CRi) rate in the 30% to 40% range with intensive chemotherapy and CR rates in the 25% range with hypomethylating agents (HMAs) in patients with MPN AP. There was no OS advantage to one treatment over the other in the retrospective findings. However, without being able to receive an allogeneic stem cell transplant, there was not as much benefit to intensive chemotherapy. For patients who are transplant ineligible, fewer intensive regimens are preferred.

For patients with Ph-negative MPNs in the chronic phase, JAK inhibition has been a meaningful step forward in treatment. This is especially true for those who are symptomatic or have significant splenomegaly. Now the question has become whether it would be as useful in MPN AP/BP.

According to Odenike, there is no real benefit to JAK inhibition alone but there is some when it is combined with an HMA. The combination of ruxolitinib (Jakafi) and decitabine in 25 patients demonstrated a median survival of 9.5 months and an overall response rate (ORR) of 44%, 8% of which was CRi and 36% partial response. A similar trial showed a median OS of 8.4 months with the recommended phase 2 dose and an ORR of 45%. Although, it has still not been determined if the JAK inhibitor/HMA combination produces more efficacy than HMA alone for these patients.

The combination of an HMA plus venetoclax (Venclexta) received approval in acute myeloid leukemia, but the trial did not include patients with preexisting MPNs. Therefore, only retrospective data is available for this combination in MPN AP/BP. A small retrospective series have shown CR/CRi rates of around 43% in the frontline for MPN BP and a median OS of 7 months with venetoclax and an HMA.

Recently, IDH1/2 inhibitors have been approved in patients with acute myeloid leukemia and IDH mutations, and so these are also being looked at for MPN AP/BP in retrospective data. There is a potential benefit with IDH inhibitors, which have demonstrated a median survival of 9 months or more in this setting. Of note, some patients have stayed on single-agent therapy for several years after initiating treatment.

To treat patients with MPN AP/BP, using next-generation sequencing at the beginning of management allows for the detection of IDH1/2 and TP53. Patients with TP53 mutations can have higher chemotherapy-resistance, so Odenike prefers to use HMA-based therapy. “For other mutations, a majority we don’t have any targeted therapies for, I have a relative equipoise between an intensive approach versus HMA-based therapy,” Odenike said. “But I will only use intensive chemotherapy if the patient is also able to then undergo an allogeneic stem cell transplant.”

For this population, participating in clinical trials is also extremely important. In fact, some novel agents that are being investigated in myeloid malignancies include epigenomic modulators, post translational modulators, immune checkpoint inhibitors, and targeted agents.

“The hope is that we will have many more trials that will allow patients with MPN AP/BP disease to participate in an effort to improve overall outcomes,” Odenike concluded.

_Reference:

_{Odenike OS. Accelerated Phase of MPN: What Is It and What to Do About It. Presented at the Society of Hematology Oncology 2021 Annual Meeting; September 8-10. Accessed September 9, 2021.}