Mrinal M. Patnaik, MD, is assistant professor of medicine and assistant professor of oncology at the Mayo Clinic Division of Hematology in Rochester, MN. His primary study passions are myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).
He has actually conducted extensive study in to CMML, along with much more compared to twenty books in the past 2 years about this rare and aggressive clonal bone marrow disorder of late adulthood. Dr Patnaik’s study concentration is in epigenetic and chromatin dysregulation in CMML, and transcriptional abnormalities stemming from mutations in epigenetic-regulator genes enjoy TET2, ASXL1, and EZH2.
In this question-and-answer session, Cancer Therapy Advisor asked Dr Patnaik concerning the evolving learning of CMML’s molecular underpinnings, diagnosis, prognostication, and progression.
Cancer Therapy Advisor: CMML is categorized as an MDS/myeloproliferative neoplasm (MPN) “overlap syndrome,” enjoy juvenile myelomonocytic leukemia or atypical chronic myeloid leukemia, exhibiting features of MDS and MPN.1 Does the distinction in between MDS- and MPN-phenotype CMML reflect differences in the molecular underpinnings of the disease?
Dr Patnaik: Yes, the MDS/MPN overlap syndromes enjoy CMML are unique entities. So for a long time, we have actually borrowed from either MPN or MDS strategies to regulate them. along with the advent of molecular testing and much more awareness, we are now certain that these are unique entities and have to be recognized.
In the MDS/MPN overlap, in adults, the a lot of common health problem that we notice is CMML. Within each health problem there is a continuum of progression. Patients along with CMML present along with either MDS-enjoy or MPN-enjoy features. Based on the underlying health problem biology and surrogate markers such as bone marrow blasts and cytogenetics, ultimately 20% to 30% of patients improvement to acute myeloid leukemia (AML).
This secondary AML is fairly resistant to treatment and is associated along with unsatisfactory patient outcomes.
Cancer Therapy Advisor: Why is that?
Dr Patnaik: The molecular signature of “de novo” AML is various from secondary AML. Secondary AML has actually accrued considerably much more epigenetic dysregulation, splicing abnormalities, and a great deal of times, the patients undergo cytogenetic clonal evolution. In numerous cases, they’ve chosen out through receiving prior treatments, such as hypomethylating agents or others epigenetic modifiers, that make it harder to address from a health problem standpoint—and from a host perspective, these patients have actually currently been through so a lot that their ability to resist induction chemotherapy is poor. In addition, drug resistance mechanisms are additionally upregulated in patients along with secondary AML.
Cancer Therapy Advisor: What recent clinical advances have actually ensued in CMML?
Dr Patnaik: We have actually earned advances in molecular biology and have actually been able to demonstrate the mutational landscape and the impact of these mutations in patients along with CMML.
Cancer Therapy Advisor: Which gene mutations are associated along with CMML? Are there prognostic biomarkers?
Dr Patnaik: Several prognostic models have actually been made for patients along with CMML.1 The 2 contemporary molecularly integrated models contain the Molecular Mayo Model and the GFM model.
This health problem does have actually a unique molecular signature. Roughly 60% of cases have actually mutations in TET2, which controls methylation and hydroxymethylation.
About 40% to 50% have actually mutations in SRSF2, which is a splicing factor that has actually been revealed to be deleterious in MPN and younger patients along with CMML (age < 65 years).
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However, the worst mutation acquired is ASXL1, seen in Roughly 40% of patients along with CMML. Frame shift and nonsense ASXL1 mutations predict for a shortened general survival. Additionally, the presence of these mutations potentially predict for unsatisfactory responses to hypomethylating agents. RAS mutations are frequently associated along with an MPN-enjoy phenotype.1
Although univariate analysis studies along with RAS mutations have actually located inferior outcomes in CMML, these findings have actually not been substantiated in multivariate models.
