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Hello, I'm Michael Savona from Vanderbilt University Medical Center, here to talk about the challenge of tackling MDS/MPN at the SOHO Fourth Annual Meeting in Houston, Texas.
MDS/MPN were first brought about as a distinct sub-classification of myeloid disease in WHO 2008 classification schema. These include CMML, JMML, atypical CML, MDS/MPN-U. In 2008 MDS/MPN-U had a subcategory entitled RARS-T. RARS-T is now its own separate sub-classification: myelodysplastic, myeloproliferative neoplasms with ring sideroblasts and marked thrombocytosis, or MDS/MPN-RST.
MDS/MPNs represent a challenge to medical pathologists, as patients with prior history of myeloid disease can then go on and develop inverse features. For example, patients with MDS may develop fibrosis, and patients with MPNs may develop dysplasia, but patients with MDS/MPN are at diagnosis with characteristics of both dysplasia and proliferation.
CMML is the most common of the MDS/MPNs and is noted by monocytosis, and in the 2016 revision of the WHO myeloid classification schema, peripheral monocytosis with greater than 10% of the white blood cell count in the blood was noted to be a primary characteristic, as well as dysplasia in one or more lineage. In the absence of dysplasia, patients can still have a diagnosis of CMML if they have an acquired clonal subgenetic or molecular genetic abnormality, or if monocytosis persists for three months in the absence of a reactive cause.
Atypical CML is known by the combination of characteristics as follows: precursors in the blood of myeloid origin, dysgranulopoiesis disproportional to the overall dysplasia, and white blood cell count elevated greater than 13,000.
In the largest study of patients with CMML, it was found that about half of the patients with atypical CML had blood myeloid precursors greater than 10%, leukocytosis with a white cell count greater than 13,000, and dysgranulopoiesis. In the absence of this triumvirate of characteristics, two of the three characteristics are present in as much as 80% of patients with aCML.
By comparison, CNL is a similar disease with elevated white count, but unlike atypical CML, it is not an MDS/MPN overlap syndrome. Patients typically lack dysgranulopoiesis and the cells in the periphery, the neutrophils, tend to have toxic granulation without dysplasia. In addition, patients with CNL are known as CSF3R mutations in most cases. This is extraordinarily rare in patients with aCML.
Patients with MDS/MPN-RS-T, previously known as RARS-T, shouldn't have leukoerythroblastosis and should have less than 5% blasts in the blood. In addition, thrombocytosis is usually marked greater than 450,000 cells. There are proliferation of abnormal megakaryocytes similar to those seen in MPNs, as seen here in the bottom right panel, and the SF3B1 mutation is common. It's seen in as many as 75% to 80% of cases.
What's different about MDS/MPN-RST than the other overlap syndromes is that a previous diagnosis of MDS refractory anemia with ring sideroblasts can then transform into a MDS/MPN-RST. This is the only overlap syndrome in which a pre-existing condition of myeloid origin is allowed.
MDS/MPN-U is probably more common than we think it is, but it remains a diagnosis of exclusion. If patients with MDS/MPN do not have a classic canonical rearrangement of BCR-ABL or PDGF alpha or FGFR, if they lack monocytosis, if they lack CSF3R mutations, if they do not appear to have the triumvirate of early precursors in the blood, white blood cell count of greater than 13,000, and disproportional dysgranulopoiesis, then MDS/MPN-U diagnosis should be considered.
Attempts have been made to highlight or segregate different sub-classified MDS/MPNs through genetic testing. While there is some clue of each subtype, as denoted here by the incidence of genetic mutations, there is no clear sine qua non. In fact, only two mutations are seen in more than 50% of patients of two different sub-classifications, namely TET2 mutations seen in 50% to 60% of CMML, and SF3B1 mutations seen in three-quarters of the patients with RARS-T. It's important to remember the patients with CNL often, and usually do, have CSF3R mutations. This is largely not present in overlapped syndromes.
Likewise, patients with refractory anemia with ring sideroblasts or refractory cytopenias in multilineage dysplasia ring sideroblasts often can also have SF3B1. It's not exclusive to MDS/MPN overlap syndrome. This is an important clinical implication with the new TGF-beta ligand traps therapy now in testing. Patients with SF3B1 mutation tend to do better than patients without SF3B1 mutation. We know that SF3B1 wild-type patients have an inferior survival measured in approximately three years.
In the absence of SF3B1 mutation, patients can still be stratified with other mutations, namely ASXL1, SEPP1, cytogenetic abnormalities, or anemia. Patients who have all these characteristics tend to do very poorly regardless of SF3B1 mutations.
Likewise, for MDS/MPN-U and ACML, little work has been done. Median survival is poor, measured in months to years. Taken together, non-CMML MDS/MPN has a median survival of three months to seven years. If SF3B1-mutated MDS/MPN-RST is removed, the median survival is three months to three years. There have not been many clinical trials conducted in patients with MDS/MPN, and part of that is because there has not been dedicated response criteria developed.
Last year, 2015, the MDS/MPN International Working Group proposed MDS/MPN response criteria, which included marrow response and blood count response, as well as many other signs of clinical benefit, including spleen size reduction and symptom reduction.
Thank you for your attention. I hope you enjoyed SOHO.