MDS/MPN-RS-T: Diagnostic Criteria, Clinical Features, and More

Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) is a rare hematologic disorder that shares characteristics of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). It primarily affects older adults and is characterized by anemia with ring sideroblasts, thrombocytosis, and dysplastic bone marrow features.

Accurate diagnosis is challenging due to overlapping features with other blood disorders, requiring careful evaluation of laboratory findings, genetic mutations, and clinical presentation. Understanding its distinct criteria, clinical manifestations, prognostic factors, and treatment options is crucial for optimizing patient care.

Distinctive Diagnostic Criteria

Diagnosing MDS/MPN-RS-T requires a nuanced approach due to its overlap with MDS and MPN. The World Health Organization (WHO) classification emphasizes the presence of ring sideroblasts, thrombocytosis, and dysplastic hematopoiesis. A definitive diagnosis integrates morphological, hematologic, and molecular findings to exclude other conditions with similar presentations.

A hallmark feature is the presence of ring sideroblasts—erythroid precursors containing iron-laden mitochondria visible on Prussian blue staining. WHO guidelines require at least 15% of erythroid precursors in the bone marrow to exhibit ring sideroblasts. This iron accumulation results from defective mitochondrial heme synthesis, often linked to SF3B1 mutations.

Thrombocytosis, defined by a platelet count exceeding 450 × 10⁹/L, is another key feature. Unlike essential thrombocythemia (ET), which presents with large, hyperlobulated megakaryocytes, MDS/MPN-RS-T features atypical megakaryocytes with dysplastic morphology, resembling those in MDS. While JAK2, CALR, and MPL mutations are commonly associated with classical MPNs, their presence in MDS/MPN-RS-T suggests a myeloproliferative component rather than excluding the diagnosis.

Bone marrow examination reveals a hypercellular marrow with erythroid dysplasia and megakaryocytic abnormalities but lacks significant fibrosis or panmyelosis, distinguishing it from primary myelofibrosis or polycythemia vera. Cytogenetic analysis may show abnormalities such as del(20q) or +8, but these findings are not exclusive to MDS/MPN-RS-T and must be interpreted alongside other diagnostic markers.

Clinical Features

Patients with MDS/MPN-RS-T present with hematologic abnormalities reflecting both ineffective erythropoiesis and increased platelet production. Anemia, often macrocytic, is a primary feature, leading to fatigue, pallor, and exertional dyspnea. Unlike anemia in other MPNs, which may result from disease progression or treatment, anemia in MDS/MPN-RS-T arises from intrinsic defects in erythroid maturation, sometimes leading to transfusion dependence.

Thrombocytosis can increase the risk of thrombotic events, though bleeding complications may occur due to platelet dysfunction. Microvascular disturbances such as headaches, dizziness, and erythromelalgia—burning pain in the extremities—are possible, though more commonly associated with ET. The relationship between thrombocytosis and thrombosis in MDS/MPN-RS-T is less defined than in classical MPNs, where JAK2 mutations play a prominent role.

Some patients experience systemic symptoms such as weight loss, night sweats, and low-grade fevers, though these are less common than in primary myelofibrosis. Splenomegaly, when present, may cause early satiety and abdominal discomfort, correlating with the degree of myeloproliferation.

Genetic Insights

The genetic landscape of MDS/MPN-RS-T is defined by mutations that drive both ineffective erythropoiesis and abnormal megakaryocyte proliferation. SF3B1 mutations, present in approximately 80% of cases, disrupt RNA splicing and mitochondrial iron metabolism, contributing to the formation of ring sideroblasts. These mutations are associated with a more indolent disease course.

JAK2 V617F mutations, found in about 50% of cases, activate the JAK-STAT pathway, promoting excessive platelet production and megakaryocytic expansion. Unlike classical MPNs, where JAK2 mutations are primary drivers, MDS/MPN-RS-T presents a hybrid phenotype with concurrent erythroid dysplasia. CALR and MPL mutations, though less common, reinforce the myeloproliferative component.

Additional mutations, including TET2, ASXL1, and DNMT3A, influence disease progression. TET2 mutations may enhance hematopoietic stem cell self-renewal, while ASXL1 mutations are linked to worse outcomes and a higher risk of progression to acute myeloid leukemia (AML). The prognostic impact of these mutations in MDS/MPN-RS-T remains under investigation.

Prognostic Assessment

Prognosis in MDS/MPN-RS-T varies based on genetic mutations, hematologic parameters, and patient-specific factors. Unlike other myeloid neoplasms with established prognostic scoring systems, MDS/MPN-RS-T lacks a dedicated risk model, requiring individualized evaluation. Survival can range from several years in indolent cases to rapid progression in high-risk patients.

Cytogenetic abnormalities provide prognostic insight, though their role in MDS/MPN-RS-T is less defined than in other MDS subtypes. While normal karyotypes are common, alterations such as del(20q) or +8 occur, though their prognostic significance is unclear. Patients with complex karyotypes or high-risk abnormalities, such as monosomy 7, are more likely to progress to AML. Large-scale studies are needed to clarify the prognostic impact of specific cytogenetic changes.

Treatment Approaches

Managing MDS/MPN-RS-T requires balancing myelodysplastic and myeloproliferative features. Treatment depends on symptom burden, transfusion dependence, thrombotic risk, and genetic mutations.

Erythropoiesis-stimulating agents (ESAs) are commonly used for anemia, particularly in patients with low serum erythropoietin levels. SF3B1-mutant patients often respond well to ESAs, achieving transfusion independence. Luspatercept, a TGF-beta pathway modulator, is an emerging option for refractory anemia.

Thrombocytosis management may involve cytoreductive therapy, particularly in JAK2-mutant patients or those with thrombotic history. Hydroxyurea is frequently used, though anagrelide may be preferred when preserving red cell production is a priority. Low-dose aspirin is often recommended for thrombotic risk reduction, especially in JAK2-mutant individuals.

For progressive or high-risk disease, hypomethylating agents like azacitidine or decitabine may be considered, though their role in MDS/MPN-RS-T is less defined than in other myeloid malignancies.

Supportive Measures

Supportive care is essential for maintaining quality of life and minimizing complications. Given the high prevalence of anemia, regular hemoglobin monitoring is necessary to determine transfusion needs. Chronic transfusions can lead to iron overload, requiring chelation therapy with agents like deferasirox or deferoxamine.

Thrombotic and hemorrhagic risks necessitate careful platelet management. While some patients benefit from cytoreduction, others may require adjustments in antiplatelet therapy based on bleeding tendencies.

Surveillance for disease progression is critical, as some patients may develop AML. Regular bone marrow assessments and molecular monitoring aid early detection, allowing timely intervention. Given the chronic nature of MDS/MPN-RS-T, a multidisciplinary approach involving hematologists, transfusion specialists, and supportive care teams is often necessary.