Current clinical strategies and emergent treatment landscapes in leukemic transformation of Philadelphia-negative myeloproliferative neoplasms

ABSTRACT

Introduction: Transformation to acute myeloid leukemia (AML) of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative neoplasms (MPN) represents a challenging medical concern and an unmet clinical need, since it charts a very poor outcome and a low rate of response to standard treatments with the exception of allogeneic hematopoietic stem cell transplantation (HSCT). Recent novel insights into the molecular disease pathways and the genomic features characterizing the transformation of Ph-MPN have led to new therapeutic individualized approaches with the potential to modify the clinical management of these difficult-to-treat patients.

Areas covered: Literature review (MeSH headings/PubMed) of risk factors of MPNs progression and treatment options for transformed disease with traditional standard approaches, and novel and investigational agents was performed. One or combinations of related subject headings like transformed MPN, epigenetics, molecular alterations, HSCT, ruxolitinib, azacytidine, decitabine, gliterinib, novel agents, personalized therapy was screened. Informative papers were selected by the appropriate actual evidence and suggesting strategies for improving outcomes in the future.

Expert opinion: Current and emerging treatments for transformed Ph-MPN, are presented. Novel targeted or experimental agents to be used both before HSCT, to induce blast-free state, or to modify the disease prognosis and improve survival and quality of life are critically reviewed.

KEYWORDS:

• Acute myeloid leukemia
• decitabine
• myeloproliferative disorders
• transformed MPN
• personalized therapy

Article highlights

• Transformation of Ph-negative MPN into AML phase represents a clinical challenge and un unmet need. AML arising from Ph-negative MPN has a poorer outcome than de novo AML being associated with an aggressive course and a low response rate to available standard treatments.

• A comprehensive assessment of prognostic factors at diagnosis and during disease course should include molecular evaluation detecting not only classic somatic mutations but also other genetic and epigenetic changes to identify actionable mutations for which a targeted therapeutic approach is available.

• Progression is characterized by multiple somatic molecular mutations that arise from a stem cell harboring a JAK-2 or other MPN driver mutations and include high-risk mutations as ASXL1, IDH 1 and 2, TET2, EZH2, dysregulation of TP53 (conferring chemotherapeutic resistance), and also, less frequently, FLT-3.

• Epigenetic dysfunctions, as hypermethylation of tumor suppressors genes, and deregulation of the mitochondrial-mediated apoptosis programmed cell death pathway, also play an important role in the pathogenesis of AML transformation of Ph-MPN.

• HSCT is superior to all other treatment modalities in producing durable remission in 33% of MPN patients with leukemic transformation and remains the only viable treatment approach for AP/BP MPN. Survival may be improved through a coordinated and individualized approach of remission induction therapy pre-transplant.

• Patients ineligible for ICT followed by HSCT procedures can benefit of individualized new therapies and treatment combinations, including HMAs and novel targeted agents directed towards molecular mutations or other disease pathways.

Acknowledgments

This manuscript is dedicated to Barbara Monteleone, our valuable colleague and friend from Data Managing Team, Hematology Unit, S. Eugenio Hospital, ASL Roma2, taken too early.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.