General AML

Epigenetic priming with decitabine followed by MEC in adults with R/R AML

Priming with hypomethylating agents such as decitabine (DEC) has been demonstrated to induce apoptosis and sensitize Acute Myeloid Leukemia (AML) cells to chemotherapeutics.

As a result, a phase I/II dose escalation study (NCT01729845) of mitoxantrone, etoposide and cytarabine (MEC) preceded by DEC priming (DEC/MEC) was carried out by Anna B. Halpern and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, USA. The authors aimed to determine the maximum tolerated dose of DEC in the phase I portion of this study and also determine the efficacy and toxicity of that dose in an expansion cohort in the phase II portion of this study. The results of the study were  published ahead of print in Leukemia on 30th May 2017.

In total, fifty-two adult R/R AML patients (median age = 55 years) were enrolled in this study. Patients were assigned to receive intravenous DEC for either 5, 7, or 10 days. Following a 5-day break, patients were then administered a standard dose of MEC.

The key results of the study were:
  • The Recommended Phase 2 Dose (RP2D) was 7-day priming with DEC before MEC
  • Complete Remission (CR) rate in patients (n = 46) treated at or above the RP2D was 22% with 17.4% achieving (n = 8) Minimal Residual Disease (MRD) negativity
  • The Overall Response Rate (ORR) in patients treated at or above the RP2D was 33%
  • Death occurred in patients treated at or above the RP2D within 28 days of treatment induction including respiratory failure due to pneumonia (n = 1), sepsis and multisystem failure (n = 4), intracranial hemorrhage (n =1) and progressive disease (n = 1)
  • Common grade 3–5 toxicities that occurred include cytopenias, infection and neutropenic fever
  • CR rates of patients treated with historical Granulocyte-Colony Stimulating Factor (G-CSF), clofarabine and cytarabine (G-CLAC) or G-CSF, cladribine, cytarabine and mitoxantrone (G-CLAM) compared to patients treated with DEC/MEC; 49.2% vs 39.0% vs 22%
  • Median Overall Survival (OS) in patients treated with G-CLAC, G-CLAM and DEC/MEC; 5 vs 8 vs 5 months

In summary, DEC/MEC is feasible and showed “anti-leukemic activity that was comparable to other contemporary salvage regimens” in R/R AML patients. However, the authors highlighted that their study found “no evidence that DEC/MEC is substantially better than other cytarabine-based regimens currently used” for R/R AML.

The authors further noted that as a result of this study, a follow-up non-randomized phase I study (NCT02921061) assessing the importance of DEC timing relative to G-CLAM in newly diagnosed and R/R AML patients is currently underway.

Abstract

DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide, and cytarabine following ‘priming’ with 5–10 days of decitabine (dec/MEC) in 52 adults (median age 55 [range: 19–72]years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6–12 patients, all dose levels were well-tolerated. As response rates appeared similar with 7 and 10-days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea, and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC and G-CLAM). Thus, while meeting the pre-specified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML.

References
  1. Halpern A.B. et al. Mitoxantrone, etoposide, and cytarabine (MEC) following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms: A phase 1/2 study. Leukemia. 2017 May 30. DOI: 10.1038/leu.2017.165. [Epub ahead of print].