Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network

Abstract

PURPOSE Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System–mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407 ).

Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management

“…136 The lack of efficacy of HMA in MP-CMML subtypes was further highlighted by a prospective randomized phase III clinical trial assessing the efficacy of decitabine versus hydroxyurea in higher risk MP-CMML patients (n = 170, decitabine n = 84, and hydroxyurea n = 86; DACOTA trial-NCT02214407). 137 The primary endpoint of the trial was event-free survival (EFS), with an event being defined as death or transformation to AML. Higher risk MPN-CMML was defined by the presence of extramedullary disease or ≥2 of the following criteria; BM blasts >5%, ANC ≥ 16 Â 10 9 /L, HB <10 g/dL, platelet count <100 000/mL, and spleen size >5 cm below the left costal margin.…”

“…Although decitabine significantly reduced the risk of CMML progression to AML (cause-specific HR 0.62; 95% CI 0.41-0.94; p = .005), it was associated with higher mortality (cause-specific HR 1.55; 95% CI 0.82-2.9; p = .04), with the median OS being 18.4 months for decitabine versus 23.1 months for hydroxyurea ( p = .72). 137 A complete list of the studies, including the dose and schedule of the drugs used, toxicities, response rates, and survival are shown in Table 4.…”

“…A smaller prospective phase II study of decitabine in CMML ( n = 43) demonstrated a CR rate of 16%, with an ORR of 47% 136 . The lack of efficacy of HMA in MP‐CMML subtypes was further highlighted by a prospective randomized phase III clinical trial assessing the efficacy of decitabine versus hydroxyurea in higher risk MP‐CMML patients ( n = 170, decitabine n = 84, and hydroxyurea n = 86; DACOTA trial‐NCT02214407) 137 . The primary endpoint of the trial was event‐free survival (EFS), with an event being defined as death or transformation to AML.…”

“…At the last follow‐up (median 17.5 months), the trial demonstrated no significant advantage of decitabine over hydroxyurea in MP‐CMML, with a median EFS of 12.1 months in the decitabine arm and 10.3 months in the hydroxyurea arm (HR 0.83, 95% CI 0.59–1.16; p = .27). Although decitabine significantly reduced the risk of CMML progression to AML (cause‐specific HR 0.62; 95% CI 0.41–0.94; p = .005), it was associated with higher mortality (cause‐specific HR 1.55; 95% CI 0.82–2.9; p = .04), with the median OS being 18.4 months for decitabine versus 23.1 months for hydroxyurea ( p = .72) 137 . A complete list of the studies, including the dose and schedule of the drugs used, toxicities, response rates, and survival are shown in Table 4.…”

A Route for Investigating Psoriasis: From the Perspective of the Pathological Mechanisms and Therapeutic Strategies of Cancer

“…Vorinostat, an anti-tumor epigenetic modulator commonly used in the treatment of hematologic cancer, targets HDACs to inhibit keratinocyte proliferation and is undergoing preclinical studies for the treatment of psoriasis [ 75 , 76 ]. Decitabine, a DNA methyltransferase inhibitor, is used to treat myelodysplastic syndromes and ameliorates the imiquimod-induced mouse model of psoriasis [ 77 , 78 ].…”