Editor's Note: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative intervention for Myelodysplastic Syndromes/Myeloproliferative Neoplasm (MDS/MPN) overlap syndromes. However, due to the high heterogeneity and low incidence of these disorders, the clinical field has long lacked unified criteria for evaluating post-transplant remission and relapse. At the recent European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting, Professor Donal McLornan, Co-Chair of the EBMT Scientific Council and Chair of the Chronic Malignancies Working Party (CMWP), formally presented expert recommendations on the definition of post-transplant remission and the optimization of outcomes on behalf of the Practice Harmonisation and Guidelines Committee. This summary provides a deep dive into the core content of this consensus to guide clinical practice and research.

I. Diagnostic Dilemmas and Classification Evolution: The Complex Landscape of MDS/MPN

MDS/MPN overlap syndromes occupy a unique “crossroads” in myeloid neoplasms, characterized by clinical features that simultaneously encompass myelodysplasia (dysplastic morphology, cytopenias, and increased blasts) and myeloproliferation (peripheral blood cytosis, hepatosplenomegaly, and systemic pro-inflammatory symptoms).

Professor Donal McLornan initiated his report by noting that the classification of these syndromes is constantly evolving due to their complex biological behavior. According to the 5th edition of the World Health Organization (WHO) classification and the International Consensus Classification (ICC), non-CML overlap syndromes primarily include: Chronic Myelomonocytic Leukemia (CMML), Atypical Chronic Myeloid Leukemia (aCML; now recommended by the ICC to be renamed as MDS/MPN with neutrophilia), Juvenile Myelomonocytic Leukemia (JMML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN unclassifiable (MDS/MPN-U).

Among these subtypes, with the exception of SF3B1-mutated MDS/MPN-RS-T, which has a relatively favorable prognosis, most patients experience a median overall survival (mOS) of only 12 to 18 months in the absence of a transplant. While allo-HCT is recognized as the standard of care following first-line therapy failure, EBMT registry data reveals a stark reality: across the approximately 700 collaborating centers in Europe, only about 150 such transplants are performed annually. This scarcity has led to poorly defined clinical trial endpoints, which in turn hampers the optimization of therapeutic regimens.

II. Prognostic Risk Stratification: Synergy Between Molecular Mutations and Clinical Phenotypes

Professor McLornan emphasized that the integration of molecular data is mandatory when assessing transplant timing and prognosis:

  1. CMML and aCML: These are often enriched with spliceosome mutations (e.g., SRSF2, U2AF1, ZRSR2) and mutations in TET2, ASXL1, SETBP1, and NRAS/KRAS. Specifically, ASXL1 mutations have been validated as an independent poor prognostic factor across multiple risk models.
  1. MDS/MPN with neutrophilia: The ICC classification highlights its highly aggressive nature, often accompanied by severe anemia and massive splenomegaly.
  1. Pre-transplant Status: The pre-transplant blast percentage, the presence of severe bone marrow fibrosis, and the degree of splenomegaly are critical clinical variables determining transplant outcomes.

III. Core Recommendations: Standardized Definitions of Post-Transplant Remission

To unify global efficacy reporting, the EBMT recommends categorizing post-transplant status into the following five dimensions:

1. Complete Remission (CR)

CR is the optimal post-transplant outcome and must simultaneously meet morphological, cytogenetic, and chimerism criteria:

  • Bone Marrow: Cellularity should be normal for age, with myeloblasts <5%.
  • Fibrosis Resolution: If bone marrow fibrosis (MF) was present at baseline, reticulin deposition post-transplant should be reduced to Grade 1 or less (per standard MF grading).
  • Dysplasia: Moderate-to-severe dysplasia should be absent. While minor dysplastic changes (e.g., early erythroid dysplasia) may occur early post-transplant, they require dynamic observation.
  • Peripheral Blood: Blood counts should normalize (ANC >1.0×10⁹/L, Platelets >100×10⁹/L), with no circulating blasts and resolution of clinical symptoms (e.g., splenomegaly, night sweats).
  • Chimerism: Whole blood or lineage-specific chimerism must show >95% donor origin.

2. CR with Poor Graft Function (PGF)

This category distinguishes disease relapse from pure hematopoietic dysfunction. Patients meet morphological CR criteria (blasts <5%) but exhibit persistent, unexplained cytopenias in two or more lineages (e.g., Platelets <30×10⁹/L, Hemoglobin <85g/L, Neutrophils <1.5×10⁹/L). This state requires the exclusion of CMV infection, drug toxicity, or Graft-versus-Host Disease (GVHD).

3. Persistent Disease

This refers to the failure to achieve CR criteria post-transplant, with the sustained presence of baseline morphological abnormalities, cytogenetic abnormalities, or molecular markers (where the Variant Allele Frequency [VAF] of JAK2, TET2, SRSF2, etc., does not significantly decrease). These patients typically exhibit mixed chimerism.

4. Progressive Disease (PD)

PD is defined as the further deterioration of the disease without having achieved CR, including:

  • Acquisition of new pathogenic molecular mutations or cytogenetic abnormalities.
  • An increase in blast percentage.
  • Worsening of bone marrow fibrosis.
  • A continuous decline in donor chimerism that cannot be reversed by tapering immunosuppression.

5. Relapse

The reappearance of disease evidence after achieving CR.

  • Morphological Relapse: Bone marrow blasts ≥5% or the appearance of extramedullary lesions.
  • Molecular/Cytogenetic Relapse: Re-detection of original molecular markers (e.g., rising VAF) or karyotypic abnormalities.

IV. Outcome Optimization: Monitoring Timeline and Intervention Strategies

Professor McLornan noted that due to the high risk of early relapse in MDS/MPN overlap syndromes (particularly within the first year), dynamic monitoring of minimal residual disease (MRD) and chimerism is essential.

1. Recommended Monitoring Frequency

  • Donor Chimerism: Recommended at months 1, 3, 6, 9, and 12 post-transplant. A continuous decline necessitates high vigilance for relapse.
  • Bone Marrow Assessment: Key time points are around Day 100 and Month 6 post-transplant. The Day 100 assessment serves as the cornerstone for determining whether a complete morphological remission has been attained.
  • Molecular MRD: The utilization of Next-Generation Sequencing (NGS) to monitor characteristic mutations identified at diagnosis is recommended. Detecting a persistent low-level VAF may suggest residual disease rather than frank relapse and must be interpreted alongside chimerism data.

2. Relapse Management and Prevention

For post-transplant MRD conversion or declining chimerism, the committee recommends differentiated interventions based on the patient’s phenotype:

  • Proliferative Phenotypes: For relapses characterized by rising blood counts or splenomegaly, Donor Lymphocyte Infusion (DLI) should be prioritized.
  • Dysplastic Phenotypes: A combination of DLI and hypomethylating agents (HMAs, such as azacitidine or decitabine) is recommended. HMAs not only reduce tumor burden but may also enhance the Graft-versus-Leukemia (GVL) effect of DLI through epigenetic modulation.
  • Second Transplantation: Primarily reserved for younger patients with primary or secondary graft failure who maintain a good performance status (PS). For relapsed patients, the value of a second transplant must be carefully weighed, and enrollment in clinical trials is generally recommended.

V. Conclusion and Industry Outlook

Professor Donal McLornan concluded his report by stating that the treatment of MDS/MPN overlap syndromes via allo-HCT is at a critical transition from “experience-based” to “standardized” management. This EBMT recommendation document represents the first global effort to establish unified outcome evaluation criteria for these rare and complex myeloid neoplasms.

Core Conclusions:

  1. Heterogeneity Mandates Individualization: MDS/MPN is not a monolithic disease; post-transplant management must differentiate between “proliferative” and “dysplastic” phenotypes.
  1. Data Granularity: Clinicians reporting transplant outcomes must include a four-dimensional dataset: morphology, degree of fibrosis, molecular status, and chimerism. Quantitative analysis should replace qualitative description.
  1. The Urgency of International Collaboration: Given the low case volume, single-center studies are no longer sufficient to provide high-quality evidence. Future efforts must utilize international platforms like EBMT and CIBMTR to conduct larger prospective studies to validate the clinical relevance of these definitions.
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