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Decitabine Yields Similar Survival Despite Superior Responses Versus HU in MP-CMML

February 22, 2023

March 2023

Thomas R. Collins

Thomas R. Collins is a medical journalist based in West Palm Beach, Florida. 

Despite superior response rates, the hypomethylating agent (HMA) decitabine did not produce event-free survival (EFS) rates that were better than hydroxyurea (HU) in patients with advanced myeloproliferative chronic myelomonocytic leukemia (MP-CMML), according to findings published in the Journal of Clinical Oncology. These findings come from what is thought to be the first randomized trial dedicated to CMML in about 20 years, said author Raphael Itzykson, MD, PhD, of Hospital Saint-Louis in Paris.

“It is a relatively rare entity that was grouped with myelodysplastic syndrome (MDS) until the 2001 WHO [World Health Organization] classification,” Dr. Itzykson said. “So, we had [patients with CMML] accrued to many MDS studies for years, with too few of them to have a powered sub-study focused on CMML cases.”

HMAs have been assessed in MP-CMML in retrospective studies and non-randomized prospective trials, and researchers have found that decitabine produced durable responses in patients with advanced MP-CMML in phase II studies.

The present study was a phase III trial with 170 patients (median age = 72) from 47 centers in France, Germany, and Italy who were enrolled from October 2014 to September 2019. Patients were randomized to receive intravenous decitabine with or without HU for the first three cycles or oral HU only.

Patients had advanced disease based on criteria used in previous studies. Since the randomization, however, independently validated criteria for advanced, high-risk CMML based only on hematologic and cytogenetic data, known as the molecular CMML Prognostic Scoring System criteria, have been developed. A subsequent analysis found that the study did involve a high-risk patient population based on those new criteria, researchers said.

Patients in the HU arm started at 1 g/day, with dose adjustments up to 4 g/day to maintain a target white blood cell count. Patients in the decitabine arm received 20 mg/m2 intravenously once a day on days one through five of each 28-day cycle. Patients continued to receive treatment until death, transformation to WHO-defined acute myelomonocytic leukemia, or progression.

After a median follow-up of 17.5 months, 135 patients had an event, with nearly identical numbers for each arm – 68 in the decitabine group and 67 in the HU group. For 30 patients, the first event was progression of myeloproliferation; for 39, it was blast count progression; for 20, it was transformation to acute myeloid leukemia (AML); and for 46, it was death.

The median EFS was 12.1 months in the decitabine arm and 10.3 months in the HU arm. The estimates for two-year EFS were 34% for the decitabine arm and 22% for the HU arm, which did not amount to a significant difference (p=0.27).

Despite the lack of difference in EFS, more patients in the decitabine arm had a response after three treatment cycles, at least numerically – 56% compared to 31% in the HU arm (p=0.002). Complete response (CR) was more frequent in the decitabine arm (12%) compared with the HU arm (2%; p=0.017). In addition, the two-year cumulative incidence of progression or transformation to AML was lower in the decitabine arm (38%) versus HU (61%; p=0.005).

Dr. Itzykson said there are a few hypotheses for the findings. The most likely is that the greater anti-leukemic effects of decitabine compared to HU are counterbalanced by increased toxicity. He said it is also possible that the responses seen with decitabine are merely superficial and that neither agent has truly disease-modifying potential. It is also possible, he said, that the responses observed with decitabine are meaningful and modestly disease-modifying but that HU is as well through mechanisms that are unknown.

More patients in the decitabine group were hospitalized (60% vs. 40%) and more patients in the decitabine group had infections of grade 3 or higher (33% vs. 18%), researchers reported. Grade 3 or higher cardiovascular events occurred more often in the decitabine group as well (20% vs. 7%), and researchers said cardiovascular monitoring might be necessary when starting patients on decitabine.

“Future studies will aim at translating the superior response rate noted with [decitabine] in this study into a significant long-term survival benefit,” researchers said. “Our results stress the need for international, randomized clinical trials in rare and heterogeneous neoplasms such as CMML.”

Dr. Itzykson said two approaches to this could include using combination regimens and better antimicrobial prophylaxis in HMA-treated patients with CMML.

The role of parenteral decitabine will depend on access, he said, adding, “Oral decitabine and other oral HMAs are certainly the future.”

Any conflicts of interest declared by the authors can be found in the original article.

Thomas R. Collins is a medical journalist based in West Palm Beach, Florida.


Itzykson R, Santina V, Thepot S, et al. Decitabine versus hydroxyurea for advanced proliferative chronic myelomonocytic leukemia: results of a randomized phase III trial within the EMSCO network [published online ahead of print, 2022 Dec 1]. J Clin Oncol. doi: 10.1200/JCO.22.00437.


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