FEATURES
CMML: A Unique Overlap
Syndrome Receiving
Increased Attention
For many years, chronic myelomonocytic leukemia (CMML) has been treated as a form of myelodysplastic syndrome (MDS), de-
spite its unique clinical and biological characteristics.
“Everyone recognized that, clearly, there were some patients who had highly proliferative features that weren’t at all typical
of MDS, but CMML was still considered to be part of MDS for decades,” Mrinal Patnaik, MBBS, a hematologist at the Mayo Clinic
in Rochester, Minnesota, told ASH Clinical News.
Inclusion of CMML under the umbrella of MDS for so long – beginning with the 1976 and 1982 French-American-British MDS
classifications – has hindered a deeper understanding of the disease that might have resulted from studying it as a separate
entity. There also are no CMML-specific approved drugs.
In recent years, clinicians and researchers have ramped up efforts to clarify the pathogenesis, natural disease progression,
and presentation of CMML. ASH Clinical News spoke with Dr. Patnaik and other specialists about these efforts, as well as the
challenges of defining uniform response criteria to guide clinical trials of CMML-specific treatments.
What Is CMML?
CMML is a clonal hematopoietic stem cell disorder that frequent-
ly progresses to acute myeloid leukemia (AML). It is classified as
a rare disease and is estimated to occur in four of every million
people in the U.S. each year. It occurs more commonly in men
and rarely in young people – 90 percent of the people diagnosed
with CMML are age 60 or older. 1
Its incidence may be slightly higher than previously estimated,
according to Eric Padron, MD, fromthe Moffitt Cancer Center in
Tampa, Florida, because it often is recognized only when a patient
with MDS seeks a second opinion. The disease is an “overlap”
syndrome that displays characteristics of both MDS (such as
peripheral blood cytopenias) and myeloproliferative neoplasms
(MPNs; such as leukocytosis and splenomegaly).
The 2001 World Health Organization (WHO) classification
of leukemias and other hematopoietic neoplasms first separat-
ed CMML from MDS and created a distinct category of MDS/
MPN overlap syndromes. In 2008, the WHO separated CMML
via blast proportion into CMML-0 (<5% blasts), CMML-1
(5-9% blasts), and CMML-2 (10-19% blasts). Finally, in 2016,
the WHO again revised its classification, including recommend-
ing that CMML be classified into two subtypes: proliferative
(MPN-CMML) and dysplastic (MDS-CMML) depending on the
patient’s white blood cell count. 2
Dr. Patnaik said that the WHO’s decision to confirm that
CMML should not be put into either MDS or MPN but should
stand alone was a positive step forward. In addition, investigators
have identified certain genetic mutations such as SRSF2, ASXL1,
CBL, SETBP1, and JAK2 that are not exclusive to CMML but are
more commonly found in patients with CMML than MDS without
proliferative features, which can aid diagnosis.
Expected survival for patients diagnosed with CMML ranges
24
Focus on Myeloid Malignancies
from just a few months to a few years, depending on a variety of
risk factors that are not yet well defined.
Fifteen to thirty percent of patients will progress to AML, at
which point survival rates drop to 4.7 months without a hemato-
poietic cell transplantation (HCT) and 14.3 months with an HCT.
“The whole story with CMML is that it is a spectrum in the pro-
cess of evolution to AML,” said Dr. Patnaik. “So, about 30 percent of
all patients with CMML will eventually transform to AML within
three to five years. When that happens, survival is very poor.”
One known prognostic factor for survival is CMML subtype.
The dysplastic and proliferative subtypes affect patients very
differently: Patients with the dysplastic subtype have low blood
counts and their natural history and clinical problems related to
marrow failure are more similar to patients with MDS; those with
the proliferative subtype have high blood counts and often have
constitutional symptoms or symptoms related to organomegaly.
Patients with proliferative forms of the disease also have shorter
survival and a higher risk of transformation to AML.
How Is CMML Treated?
There is only one curative treatment for CMML: allogenic HCT.
Unfortunately, only a minority of CMML patients will qualify for
the procedure. 3 Complicating matters further, there are no studies
that define when a transplant is the most appropriate option for
CMML. Dr. Padron recommends that all patients with high-risk
disease who are young and fit enough to be considered transplant
candidates should be referred for consideration of an HCT.
Two other treatments are approved for CMML, both hypo-
methylating agents approved for MDS for which the FDA indica-
tion included CMML: azacitidine and decitabine. However, the
pivotal trials included few patients with CMML, and response
rates are low, especially in proliferative forms of the disease.