Decoding MDS/MPN: How to Navigate the Complex World of Myeloid Neoplasms
"A comprehensive guide to understanding the challenges, classifications, and management of myelodysplastic/myeloproliferative neoplasms."
The landscape of chronic myeloid neoplasms spans a spectrum of conditions, from myelodysplastic syndromes (MDS), marked by ineffective hematopoiesis, to myeloproliferative neoplasms (MPN), characterized by proliferative features. Bridging these categories is a group of diseases recognized as MDS/MPN, sharing clinical, pathological, and molecular characteristics. In 2008, the World Health Organization (WHO) formally recognized this overlap, defining specific entities within this category.
Over the past decade, significant strides have been made in understanding MDS/MPN. Researchers have refined diagnostic criteria, developed risk-stratification models, and explored the underlying biology of these conditions. Treatment strategies have been adapted from those used for MDS and MPN, with ongoing efforts to define the clinical benefits of specific therapies for this unique group of patients.
This guide aims to illuminate recent efforts to better understand MDS/MPN, explore the diagnostic and management challenges, and define the areas where further progress is needed.
Unraveling the Diagnostic Challenges and Classification Updates in MDS/MPN
MDS/MPN are defined by features of both MDS and MPN, making the diagnosis a challenge. The WHO diagnostic criteria are summarized in Table 1. The revised WHO 2016 classification retained the original MDS/MPN subtypes with further refinement and nomenclature (Table 1). For CMML, persistent monocytosis more than 3 months is adequate for diagnosis, even with a lack of morphologic dysplasia. The challenge is excluding other causes of monocytosis, cytogenetic abnormalities, and somatic mutations, which may help identifying clonal hematopoiesis, ruling out the reactive process. The coexistence of TET-2 and SRSF2 somatic mutations are suggested to be highly specific for CMML.
- CMML (Chronic Myelomonocytic Leukemia): Diagnosed by persistent monocytosis (over 3 months). Subtypes (CMML-0, CMML-1, CMML-2) are classified based on blast percentages in the blood and bone marrow. Crucially, other causes of monocytosis must be ruled out, including infections and inflammatory conditions. Genetic markers can help confirm clonality.
- aCML (Atypical Chronic Myeloid Leukemia): Diagnosed as BCR/ABL1 negative. Requires exclusion of CML and presence of granulocytic dysplasia.
- RARS-T (Refractory Anemia with Ring Sideroblasts and Thrombocytosis): Now known as MDS/MPN-RS-T. Diagnosis requires a high platelet count and ring sideroblasts in the bone marrow. Common mutations include SF3B1, JAK2 and CALR.
- JMML (Juvenile Myelomonocytic Leukemia): Typically diagnosed in children with persistent monocytosis, absence of BCR-ABL or PDGFR fusion genes, and specific genetic abnormalities.
- MDS/MPN-U (Unclassifiable): Diagnosed when features of both MDS and MPN are present, but the condition doesn't fit into other defined categories. Requires careful exclusion of other possibilities.
Future Directions and the ABNL MARRO Study
The MDS/MPN International Working Group is actively working to advance therapies for MDS/MPN. Soon, they will begin the ABNL MARRO (A Novel therapy combinations in untreated MDS/MPN And Relapsed/Refractory Overlap Syndromes) basket trial. This trial will incorporate novel therapies with a DNA methyltransferase inhibition backbone for patients with previously treated or treatment-naïve MDS/MPN.