Molecular, Genetic Studies Provide New Insights Into MDS/MPN

Michael R. Savona, MD

As molecular and genetic studies have provided new insights into myelodysplastic and myeloproliferative neoplasms (MDS/MPN), diagnostic criteria and therapeutic strategies for the diseases continue to evolve, according to a presentation at the 2016 Society of Hematologic Oncology annual meeting.

Most of the progress has related to characterization of the conditions included in the so-called “overlap syndrome” of MDS/MPN, although studies have begun to explore therapies specific to the conditions, said Michael R. Savona, MD, director of the Hematology Early Therapeutics Program at Vanderbilt-Ingram Cancer Center.

“MDS/MPN represents a great challenge in hematopathology, in that the pathologist has the bone marrow or biopsy but not necessarily the history and prior bone marrow biopsies,” said Savona. “That bone marrow biopsy could easily represent a patient with MDS who has developed myelofibrosis, a patient with myelofibrosis who has developed dysplasia, or a patient who has MDS/MPN at diagnosis.

“With few exceptions, MDS/MPN does not arise from previously diagnosed myeloid disease,” added Savona.

The 2008 World Health Organization (WHO) classification criteria remain in effect, with the addition of 1 provisional entity. The 2008 criteria recognized for MDS/MPN conditions: chronic myelomonocytic leukemia (CMML, the most common form of MDS/MPN), atypical chronic myeloid leukemia (BCR/ABL1-negative), juvenile myelomonocytic leukemia, and myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable (MDS/MPN U). As of 2016, the WHO criteria also included MDS/MPN with ring sideroblasts and marked thrombocytosis (MDS/MPN-RS-T).

Two of the conditions warranted more detailed discussion: atypical chronic myeloid leukemia (CML) and MDS/MPN-RS-T.

An uncommon form of MDS/MPN, atypical CML is associated with large precursor populations, such as promyelocytes and monocytes in peripheral blood. Patients have disproportional dysgranulopoeisis, including chromatin clumping. Atypical CML does not meet criteria for any of the other classifications of MDS/MPN.

One of the largest investigations of atypical CML involved 150 patients. The study showed that atypical CML is closely associated with the presence of various precursors, leukocytosis, and dysgranulopoiesis disproportional to other types of dysplasia.

“At least two of these three features are present in the vast majority of patients with atypical CML,” said Savona.

The 2016 criteria characterize MDS/MPN-RS-T as anemia with ring sideroblasts representing at least half of erythryoid precursors, no leukoerythroblastosis, and fewer than 5% blasts in bone marrow. Thrombocytosis is present, as well as proliferation of abnormal megakaryocytes that often resemble those associated with classic forms of MPN.

SF3B1mutations have been observed in as many as three-fourths of patients with MDS/MPN-RS-T. Unlike other MDS/MPN conditions, MDS/MPN-RS-T can arise from a prior myeloid disease, specifically refractory anemia with ring sideroblasts.

A recent investigation into mutations associated with MDS/MPNs revealed only 2 disease-defining mutations:TET2mutations in 50% to 60% of patients with CMML andSF3B1in patients with MDS/MPN-RS-T (Blood. 2015;125[12]:1857-1865).

Presence ofSF3B1mutations has been identified as a marker of favorable prognosis for patients with MDS/MPN morphologies, and absence of the mutations appears to be a negative prognostic marker (50% mortality after 3 years). Available data suggest a “dismal prognosis” for patients with atypical CML or MDS/MPN-U, said Savona.

The current treatment landscape for MDS/MPN is limited. DNA methyltransferase inhibitors are the only approved therapy for CMML. The treatment is effective, but for patients who progress or do not respond to DNMT inhibitors, no approved second-line therapy exists, said Savona. No approved therapy exists for any of the other conditions included under the MDS/MPN classification umbrella.

Several studies of investigational treatment strategies for MDS/MPN (CMML, almost exclusively) are in various stages of completion. Decitabine with or without hydroxyurea versus hydroxyurea alone is being evaluated in patients with advanced proliferative CMML. Eltrombopag is being investigated in patients with CMML associated with thrombocytopenia. Results are pending from a phase II trial of ruxolitinib/5-azacytidine combination therapy in CMML.

“The MDS/MPN International Working Group is looking specifically at novel therapies to include non-CMML overlap syndromes, and these studies will hopefully get started in 2017,” said Savona.