An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies

Abstract

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.

CMML: Clinical and molecular aspects

“…Recently, the CPSS was integrated with molecular data to derive CPSS-mol that accounts for the poor prognosis of ASXL1, RUNX1, NRAS and SETBP1 mutations, and thus requires access to NGS for practicality [57]. Two other scores integrating clinical and molecular features, one from the Mayo clinic and the other from an international consortium have also been proposed [62,63]. All of these recent scores seem to perform similarly, and an international consensus has yet to emerge.…”

When clinical heterogeneity exceeds genetic heterogeneity: thinking outside the genomic box in chronic myelomonocytic leukemia

“…Leukopenia and neutropenia are less frequently appreciated in CMML, but macrocytic anemia and/or thrombocytopenia are common. 4 In some cases, thrombocytopenia can be immune related, whereas in others reflecting the underlying disease process. 16 The bone marrow aspirate often demonstrates dysplasia in any or all hematopoietic lineages.…”

“…Further, 30% of cases transform to acute myeloid leukemia (AML), and nearly all cases are refractory or relapse to standard therapies. 4 Recent preclinical studies have begun to elucidate the molecular underpinnings of CMML. Genomic analysis, including 2 exome sequencing studies, identified 3 highly recurrent mutated genes (ASXL1, TET2, and SRSF2) along with other mutated genes that implicate alternative pre-messenger RNA splicing, epigenetic modifications, and cytokine signaling pathways as key components of CMML molecular pathology.…”

TET2 mutations were predictive of inferior prognosis in the presence of ASXL1 mutations in patients with chronic myelomonocytic leukemia

“…Somatic mutations have been detected in about 90% of patients with chronic myelomonocytic leukemia (CMML) and the most frequent mutations occur in epigenetic regulators (TET2, 40-60%), histone modification and chromatin regulation (ASXL1, 30-50%), splicing components (SRSF2, 30-50%), transcription factors (RUNX1, 10-20%), and signaling regulator genes (SETBP1, 10-20%) (1)(2)(3)(4)(5). In proximately, over 40% CMML patients have at least two mutations (3,5,6).…”

“…In proximately, over 40% CMML patients have at least two mutations (3,5,6). The diverse combinations of mutations detected in CMML suggest multi-step pathogenesis of the disease in some cases.…”