Molecular Landscape Informs Treatments for AP/BP MPN


Olatoyosi Odenike, MD

Olatoyosi Odenike, MD

When treating patients who present with accelerated- or blast-phase myeloproliferative neoplasms (MPN AP or MPN BP), Olatoyosi Odenike, MD, professor of medicine and director, Leukemia Program at the University of Chicago Medicine in Illinois, said the 3 most important considerations are the choice of initial therapy, whether the patient is eligible for allogeneic stem cell transplant (ASCT), and the degree to which cytoreduction is necessary prior to ASCT.

Few treatment options are available for patients with MPN that is in AP (10% or more blasts) or BP (20% or more blasts), with only ASCT offering the potential for cure, although only a minority of patients are eligible for this intervention. From a targeted therapy perspective, single agent hypomethylating agents (HMAs) or HMAs in combination with ruxolitinib (Jakafi®; Incyte) or venetoclax (Venclexta®; Genentech and AbbVie)can also be considered.

The paucity of approaches coupled with a median overall survival of 3 months for patients who present with BP and 12 to 18 months for patients in the AP adds “urgency to determine who is at highest risk for transformation because that is when intervention can have the most impact,” Odenike said during a presentation at the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023).1

The treatment choices for initial therapy are affected by the patient’s fitness and ability to undergo intensive induction. However, the choice for pursuing intensive or less intensive induction is somewhat unclear, as prospective randomized trials are lacking. “But retrospective trials that evaluate intense vs less intense approaches portray outcomes evenly, with no clear survival advantage of 1 approach over the other,” Odenike said, bringing up a study by McNamara, et al.2

Blood cells | Image Credit: abhijith3747 -

Cell in the blood | Image Credit: abhijith3747 -

For this analysis, intensive therapy was defined as chemotherapy; less intensive therapy could include low dose cytarabine, HMAs, or a clinical trial intervention. In the analysis, when intensive therapy was stratified by receipt of ASCT, many of the supposed benefits were found more closely tied to the transplant itself.2 The investigators also noted that patients who underwent intensive therapy but didn’t proceed to transplant had worse outcomes than those who received less intensive therapy.2

“Retrospective studies are subject to all kinds of bias,” Odenike said. “But this study is suggestive that we should have a path forward to transplant if we decide to go the intensive route.”

Molecularly Complex

The high mutational burden and molecular complexity of AP and BP MPN contributes to its poor outcomes, with almost half of patients exhibiting mutations in 4 or more genes. As more is learned about the genes implicated in the disease, the role of targeted therapies becomes more important.

“It's interesting to think about targeted therapies, since we are starting to better understand the molecular underpinnings of MPNs in general, including when they progress to the accelerated or blast phase,” Odenike said.

Distinct molecular differences exist between AP and BP MPN, which has been referred to as secondary acute myeloid leukemia (AML), and de novo AML, Odenike said. In many cases, AP/BP MPN appears to be enriched for IDH1 and IDH2, making it a potential path for targeted therapies. In particular, IDH1/2 mutations occur in about 25% of patients with BP and leads to epigenetic dysregulation.

IDH1/2 inhibitors have been shown to be active in IDH mutant AML, making these an established treatment for this disease.3,4 For patients with AP/BP MPN, clinical responses to IDH1/2 inhibitors have been positive, with 1 trial reporting a median duration of treatment of 258 days5 and others reporting significant clinical responses to IDH1/2 inhibition.6

As one of the only curative interventions, the focus on getting patients to ASCT and achieving the best responses is paramount. Better responses are seen with ASCT when patients are first cytoreduced and in remission, but outcomes are overall inferior compared with AML that arises de novo, according to Odenike. The same chemotherapy regimens to treat AML are available, but outcomes are not optimal. “Even when the patient is able to have an ASCT, the outcomes are only modestly improved. So, to me, this is a call to action,” Odenike said.

Investigational efforts to explore approaches in the myeloid space are currently focused on epigenomic modulators, novel posttranslational modulators, immune checkpoint inhibitors, and novel targeted agents, including BCL2/BCLXL, IDH1/2, kinase, and MDM2 inhibitors.

Odenike closed with a schema detailing how she treats patients with Philadelphia-negative MPN. In the accelerated and blast phase, she advocates for next-generation sequencing, to identify the molecular profile. “I recommend clinical trial enrollment if available,” she said. “If the patient has a TP53 mutation, those patients generally don't do well with intensive therapy. With other mutations, I have relative equipoise between intensive and a less intensive approach. But I would only treat using an intensive approach if I had a plan to quickly move the patient to transplant and if the patient is fit.”


1. Odenike O. Managing accelerated- and blast-phase MPN. Presented at: 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 7, 2023. Houston, Texas.

2. McNamara CJ, Panzarella T, Kennedy JA, et al. The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. Blood Adv. 2018;2(20):2658–2671. doi:10.1182/bloodadvances.2018021469

3. Green A, Beer P. Somatic Mutations of IDH1 and IDH2 in the Leukemic Transformation of Myeloproliferative Neoplasms. N Engl J Med. 2010;362(4):369-370. doi: 10.1056/NEJMc0910063

4. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405

5. Patel AA, Cahill K, Charnot-Katsikas A, et al. Clinical outcomes of IDH2-mutated advanced-phase Ph-negative myeloproliferative neoplasms treated with enasidenib. Br J Haematol. 2020;190(1):e48-e51. doi:10.1111/bjh.16709

6. Chifotides HT, Masarova L, Alfayez M, et al. Outcome of patients with IDH1/2-mutated post–myeloproliferative neoplasm AML in the era of IDH inhibitors. Blood Adv. 2020;4(21):5336–5342. doi:10.1182/bloodadvances.2020001528

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