MDS/MPN Overlap: The Time is Now for Uniform Response Criteria

Myelodysplastic syndromes (MDS)/myeloproliferative neoplasms (MPNs) are clonal myeloid disorders possessing both dysplastic and proliferative features that cannot be classified as one or the other – and for which there are no standard adult treatment recommendations.

In an effort to identify meaningful clinical and biologic endpoints to improve management and disease outcomes, an international consortium has developed a standardized response criteria for clinical trials, according to a report in Blood.

“We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms,” wrote Michael Savona, MD, from Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues.

MDS/MPN, as characterized by the World Health Organization, includes:

  • Chronic myelomonocytic leukemia (CMML)
  • Juvenile myelomonocytic leukemia (JMML)
  • Atypical BCR-ABL1 negative chronic myeloid leukemia (aCML)
  • Myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U)
  • Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), considered a provisional entity

“There are very few trials specifically for patients with MDS/MPN overlap diseases,” Dr. Savona told ASH Clinical News. “In addition, clinicians are limited in criteria for determining best treatment options and outcomes in these patients.”

In fact, “overall survival is variable, measured in years for many RARS-T or low-risk CMML patients, and months for many aCML or high-risk CMML patients,” Dr. Savona and colleagues explained. The collaborative project comprised laboratory and clinical experts in MDS/MPN and involved three independent academic MDS/MPN workshops held between March 2013 and June 2014.

Dr. Savona pointed out that “creative attempts” have been made to combine MDS International Working Group (IWG) criteria and the Myelofibrosis IWG-Myelofibrosis Research and Treatment criteria. However, “if patients with MDS/MPN are included on clinical trials (e.g., CMML patients on MDS trial), one set of standard response-assessment criteria is used,” he told ASH Clinical News.

The group proposes a model of disease assessment that combines the strengths and familiarity of prior assessment tools for MDS and myelofibrosis, while incorporating additions to account for clinically relevant endpoints. The TABLE outlines current understanding of the distribution of molecular aberrations in MDS/MPN.

For instance, the proposed guidelines incorporate aspects of standard response guidelines for MDS and MPN, including improvement in peripheral blood counts and/or transfusions needs, a decrease in blast percentage, and reduction in spleen size. The authors suggested that “biologic endpoints could be considered for evaluation of response, and may be helpful to interpret impact on disease.”

Biologic endpoints may be particularly useful when myelosuppressive therapies are employed — such treatment can make it difficult to discriminate drug-related cytopenias from disease-related progression, the authors explained.

Other potential biologic endpoints may include karyotype analysis and identifying chromosomal abnormalities.

“Hopefully, we can validate these proposed criteria retrospectively and prospectively in a timely manner,” Dr. Savona stated. “In the event that we find that the proposed criteria for assessing response in MDS/MPN are valid in all of these diseases, one could imagine using these response criteria in clinical trials for patients with MDS/MPN.”

Dr. Savona also commented on the potential of using the new European Society of Medical Oncology (ESMO) clinical practice guidelines for MDS in concert with the group’s proposed MDS/MPN criteria.

“Typically, MDS/MPN overlap disorders are, by definition, pathophysiologically diverse and distinct from MDS,” he noted. “The ESMO clinical practice guidelines for MDS are well constructed and useful for MDS. They may be instructive in situations in which certain MDS/MPN disorders behave more like MDS.”

Savona M, Malcovati L, Komrokji R, et al. An International Consortium Proposal of Uniform Response Criteria for Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) in Adults. Blood. 2015 January 26. [Epub ahead of print.]

TABLE. Proposed Criteria for Measurement of Treatment Response in Adult MDS/MPN
Complete remission (presence of all of the following improvements)
  • Bone marrow: ≤ 5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal maturation of all cell lines and return to normal cellularity
  • Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤ grade 1 per WHO fibrosis grading)
  • Peripheral blood
    • WBC ≤ 10 x 109 cells/L
    • Hgb ≥ 11 g/dL
    • Platelets ≥ 100 x 109/L; ≤ 450 x 109/L
    • Neutrophils ≥ 1.0 x 109/L
    • Blasts 0%
    • Neutrophil precursors reduced to ≤ 2%
    • Monocytes < 1 x 109/L
  • Extramedullary disease: Complete resolution of extramedullary disease present prior to therapy (e.g., cutaneous disease, disease related serous effusions, etc.), including palpable hepatosplenomegaly
  • Provisional category of CR with resolution of symptoms: CR as per above, and complete resolution of disease-related symptoms as noted by the MPN-SAF TSS
  • Persistent low level dysplasia is permitted given subjectivity of assignment of dysplasia
Complete cytogenetic remission
Resolution of previously present chromosomal abnormality (known to be associated with myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping with minimal of 20 metaphases, or fluorescence in situ hybridization (FISH)
Partial remission
Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast equivalents) reduced by 50%, but remaining > 5% of cellularity EXCEPT in cases of MDS/MPN with ≤ 5% bone marrow blasts at baseline
Marrow response
  • Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices as above.
  • Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining > 5% of cellularity, OR reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow evaluations spaced at least 2 months apart
Clinical benefit (requires one of the following in the absence of progression or CR/PR and independent of marrow response (CB response must be verified at ≥ 8 weeks) to be considered a clinical benefit)
  • Erythroid response:
    • Hgb increase by ≥ 2.0 g/dL
    • Transfusion independence (TI) for ≥ 8 weeks for patients requiring at least
    • 4 PRBC transfusions in the previous 8 weeks
    • Only RBC transfusions given based on physician’s judgment for a pretreatment Hgb of ≤ 8.5 g/dL will count in the RBC TI response evaluation.
  • Platelet response:
    • Transfusion independence when previously requiring platelet transfusions of at least a rate of 4 platelet transfusions in the previous 8 weeks
    • Pretreatment ≤ 20 x 109/L: Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%
    • Pretreatment > 20 x 109/L but ≤ 100 x 109/L: Absolute increase of ≥ 30 x 109/L
  • Neutrophil response:
    • Pretreatment ≤ 0.5 x 109/L at least 100% increase and an absolute increase ≥ 0.5 x 109/L
    • Pretreatment > 0.5 x 109/L and ≤ 1.0 x 109/L At least 50% increase and an absolute increase ≥ 0.5 x 109/L
  • Spleen response: Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable.
  • Symptom response: Improvement in symptoms as noted by decrease of ≥ 50% as per the MPN-SAF TSS scoring < 20 were not considered eligible for measuring clinical benefit.