GCLAM with dose-escalated mitoxantrone for newly diagnosed AML

Anna B. Halpern from Clinical Research Division, Fred Hutchinson Cancer Research Center/University of Washington, Seattle, WA, USA, and colleagues conducted a phase I/II trial (NCT02044796)  of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed acute myeloid leukemia (AML). The results of the study were published online in the April 2018 issue of Leukemia .

In total, 121 patients (median age = 60 years, range 21–81) were enrolled. Of them, 84 patients (69%) had AML, 14 patients (12%) had MDS with excess blasts-2 (MDS-EB-2), 3 patients (2%) had blastic plasmacytoid dendritic cell neoplasm (BPDCN), and 20 (17%) had a treatment-related myeloid neoplasm (t-AML in 15, t-MDS in 5). The phase I proportion of the study aimed to determine the maximum tolerated dose (MTD).  Thirty-three patients were enrolled in the phase I portion of the study and received either 12 (dose level [DL] 1), 14 (DL2), 16 (DL3) or 18 (DL4) mg/m2/day of mitoxantrone on Day 1–3 as part of GCLAM, for cohorts including 6–12 patients.

The phase II proportion of the study aimed to examine response and duration of remission rates at the recommended phase II dose (RP2D). Ninety-four patients received GCLAM at the RP2D. Median follow-up was 1.92 years.

Key findings:
Phase I
  • One dose limiting toxicity (DLT) of respiratory failure occurred at both DL3 (16 mg/m2) and 4 (18 mg/m2)
  • 28-day treatment-related mortality (TRM) rate: 3%
  • RP2D: 18 mg/m2/day
Phase II
  • Efficacy
    • Complete remission (CR): 79% (74/94)
      • Minimal residual disease negative (MRDneg) CR: 71% (67/94)
    • CR/CR with incomplete count recovery (CRi): 86% (81/94)
      • MRDneg CR/CRi rate: 76% (72/81)
    • Median overall survival (OS) in the RP2D cohort: 33.3 months
    • Median relapse free survival (RFS) in the RP2D cohort: 26 months
  • Safety
    • Two deaths occurred in patients treated at the RP2D within 28 days due to sepsis and multisystem organ failure, TRM = 2% (0–8%)
    • Most common grade 3–5 toxicities: cytopenias, infections and neutropenic fever
    • Common grade 3–4 toxicities: maculopapular rash, nausea and hypoxia, with the latter occurring primarily in the setting of infection

The authors also compared the outcomes of this phase I/II study to two historical controls. The GCLAM group were first compared with patients (n = 100, median age = 56 years) who were treated at the Fred Hutchison Cancer Center with 7 + 3 at daunorubicin doses ≥ 60 mg/m2 or idarubicin doses ≥ 10 mg/m2 .

  • MRDneg CR in the GCLAM and 7 +3 group: 71% vs 53%, P = 0.01
  • 2-year cumulative incidence of relapse in the GCLAM and “7 + 3” groups: 33% vs 28%, P = 0.31

Matched patients from the GCLAM (n = 34) group was also compared to 245 matched patients (median age < 60) treated with “7 + 3” on SWOG S0106 study.

  • 2-year cumulative incidence of relapse in the GCLAM and SWOG “7 + 3” groups: 14% vs 42%, P < 0.01
  • CR and CR/CRi rates in GCLAM and SWOG “7 + 3” cohorts: OR = 3.5 (1.0–12.2), P = 0.05 vs OR = 4.59 (1.03–20.4), P = 0.04, respectively
  • MRDneg CR in the GCLAM cohort: OR = 2.69 (0.5–14.16), P = 0.25
  • Survival rate was the same in the two cohorts: HR for GCLAM = 1.03 (0.54–1.98), P = 0.92

In conclusion, these findings showed that GCLAM with mitoxantrone at 18 mg/m2/day is “safe” and induces high-quality remissions in patients with newly-diagnosed AML. The authors highlighted that “the seeming superiority of GCLAM over 7 + 3 was observed with CR with MRD and CRi with/without MRD, as well as with CR without MRD”. Halpern et al. further added that “a 3-arm randomized trial might compare “7 + 3”, FLAGIda, and GCLAM to decide which is best for future use as intensive induction chemotherapy regimen”.

References
  1. Halpern A.B. et al. Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. Leukemia. 2018 Apr 17. DOI: 10.1038/s41375-018-0135-8. [Epub ahead of print].