“There’s an injustice that has been done to this disease, going
back almost a decade,” Dr. Patnaik said, referring to the WHO’s
2008 classification, which introduced the MDS/MPN category of
diseases that displayed proliferative and dysplastic characteristics.
“Essentially all the trials that included patients with CMML
used disease response criteria designed for MDS,” he explained.
“There is clear evidence that [treatment with hypomethylating
agents] does not alter the disease biology. In fact, in Europe, if
a patient has proliferative CMML, hematologists can’t even use
these drugs.”
Instead, doctors tend to treat patients with drugs that target
specific symptoms of CMML, such as cytopenias, splenomegaly,
and infections with transfusions, blood cell growth factors, and
antibiotics. While these can improve patients' quality of life, Eric
Solary, MD, and Raphael Itzykson, MD, wrote in Blood, ”they
barely modify disease evolution. ... Improved understanding of
CMML pathophysiology will hopefully lead to the exploration of
novel targets that potentially would be curative.” 4
How Do We Know if a Treatment Is Working?
The higher prevalence of MDS had a negative effect on CMML
clinical trials. “For a long time, the community was so interest-
ed in MDS that CMML-specific trials were almost absent,” Dr.
Patnaik added. For example, he said, drug studies can enroll 400
patients with MDS, and 10 with CMML.
A major impediment to conducting CMML-specific drug trials
has been a lack of uniform response criteria. Without these, it is ex-
tremely difficult to prove to regulatory agencies that a drug is work-
ing, even if a doctor can tell a patient is doing better. This decreases
the likelihood of trials being supported or even considered.
“One of the difficulties in trying to understand how patients
with different types of CMML respond to different therapies is
that we never had [disease-specific] response criteria at all,” said
Michael Savona, MD, a hematologist at Vanderbilt University
in Nashville, Tennessee. “When we go to different trial sponsors
to try to access new drugs, the most common response we get is,
‘Well, how do you know if it’s working?’ And, to be honest, we
don’t have a very good answer.”
Defining response criteria is a challenge because the natural
history and prognosis of CMML are poorly understood. There
are about 10 prognostic scoring systems that have been proposed
for CMML, explained Dr. Padron, adding that “there are no good
data telling us when the best timing is for transplant.”
To fill in the knowledge gaps, Dr. Padron and colleagues have
launched a project to sequence nearly 1,000 patients with CMML
both before and after treatment “to see whether we can confirm
what the prognostic mutations are and try to answer that question
of which prognostic scoring system we should be using.”
In 2015, Drs. Savona and Padron were part of an internation-
al working group that published a proposal of uniform response
criteria for CMML, which they hope will be independently
validated and refined over time. 5
“The FDA is quite keen on quality-of-life–associated response
elements, and my sense is that if we can improve some of these
quality-of-life metrics, specifically how patients are feeling and
their spleen size, then that will translate to improved survival,”
said Dr. Savona, who was first author on the response criteria pa-
per. The proposal included criteria for measuring improvements
in blood counts and reduction in myeloblasts, similar to MDS, but
also meaningful reductions in spleen size and clinical symptoms. 5
At the end of 2018, the European Hematology Association and
the European LeukemiaNet released new guidelines for CMML
diagnosis and management that update and revise criteria put forth
by the MDS International Working Group (IWG) in 2000 and 2006. 6
“While response to treatment can be evaluated by IWG
2006 criteria in [dysplastic] CMML, recently proposed ad hoc
MDS/MPN criteria should be preferably adopted,” the guideline
panel wrote. “With respect to pivotal phase III clinical trials, we
recommend robust primary endpoints such as overall survival,
progression-free survival, or event-free survival, and incorpora-
tion of the MDS/MPN criteria as secondary endpoints.”
Where to Next?
While the recently proposed international response criteria have
increased interest in studying and developing treatments for
CMML, researchers still have a long way to go. The patient pop-
ulation is exceptionally heterogeneous and the disease relatively
rare, making clinical validation a challenge.
Studying this rare disease might require new trial designs. Dr.
Savona is the principal investigator of the ABNL-MARRO study,
an initiative from the MDS/MPN IWG and Vanderbilt Univer-
sity Medical Center in which Drs. Patnaik, Padron, Solary, and
Itzykson are also involved. 7 ABNL-MARRO, or “A Basket study of
Novel therapy for untreated MDS/MPN and Relapsed/Refractory
Overlap Syndromes,” will enroll patients with MDS/MPN overlap
syndromes in the U.S. and several European countries.
The basket design allows new compounds and therapy com-
binations to be introduced easily among MDS/MPN IWG clinical
sites where patients with MDS/MPN are treated. Researchers also
will study the biology and pathophysiology of the diseases to identi-
fy potential markers of severity, prognosis, and response.
“We’re proud of this study because it is going to open across
the U.S. and Europe with the same protocol,” said Dr. Savona. “It's
been the challenge of my career to try to operationalize something
across different countries like this.” —By Emma Yasinski ●
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