CLAG-M therapy for patients with relapsed or refractory acute myeloid leukemia

In a Letter to the Editor of Haematologica, Anna B. Halpern and colleagues from the University of Washington, Seattle, US, reported data from a phase I/II study (NCT02044796) of cladribine, high-dose cytarabine, mitoxantrone, and granulocyte-colony stimulating factor (G-CSF) with dose-escalated mitoxantrone (CLAG-M) for patients with relapsed/refractory (RR) acute myeloid leukemia (AML) or other high-grade myeloid neoplasms.

Between February 2014 and April 2017, 60 patients (median age = 61 years; range: 33–77) with a treatment-related mortality score of ≤ 6.9 (corresponds to a ≤ 6.9 probability of 4-week mortality) were enrolled in this study. In the phase I portion of this study, 26 patients in groups of 6–12 received 12, 14, 16 or 18 mg/m² of intravenous (IV) mitoxantrone on days 1–3. G-CSF was given subcutaneously on days 0–5, cladribine IV at 5 mg/m² (days 1–5), and cytarabine IV at 2 g/m² (days 1–5).

Key findings from the phase I portion study:

• One dose-limiting toxicity (DLT) of nausea occurred at dose level (DL) 1
• Two DLTs of encephalopathy and cardiogenic shock occurred at DL 2, respectively
• Recommended phase 2 dose (RP2D) of CLAG-M: 16 mg/m² mitoxantrone

In the phase II stage of the study, 40 patients (median age = 63 years; range: 33–77), including six patients enrolled in the phase I portion received CLAG-M with mitoxantrone at the RP2D.

Key findings from the phase II portion of the study:

• Responses after 1–2 treatment cycles
  • Complete remission (CR) rate: 28% (11/40)
    • Nine (22%) patients in CR were measurable residual disease (MRD) negative
  • CR with incomplete hematologic recovery (CRi): 32% (13/40)
    • Ten (25%) patients in CRi were MRD negative
  • CR/CRi rate: 60% (24/40)
  • One patient achieved morphologic leukemia-free state
  • Eleven patients had resistant disease
  • Four-and eight-week mortality rate: 5%
  • The most common grade 3–5 non-hematologic toxicities were infections and neutropenic fever
• Fourteen of the 24 responders underwent hematopoietic cell transplant
• With a median follow-up of 20 months in living patients, the median overall survival (OS) and relapse-free survival were 11 and 12 months, respectively

In order to investigate whether escalation of mitoxantrone increases the anti-leukemic efficacy of CLAG-M, the outcomes of 51 patients (including 40 patients treated at RP2D and 11 patients treated off-study) treated with CLAG-M with mitoxantrone at 16 mg/m² were compared to 30 patients (all treated off study) treated with CLAG-M with mitoxantrone at 10 mg/m². In addition, outcomes of this study were compared to other high-dose regimens including GCLAC (GCSF/clofarabine/cytarabine; n = 56) and decitabine-primed MEC (d/MEC: decitabine/mitoxantrone/etoposide/cytarabine; n = 36).

• Compared to patients treated with CLAG-M with mitoxantrone at 10 mg/m², CLAG-M with mitoxantrone at 16 mg/m² significantly associated with longer OS: HR = 2.65 (95% CI, 1.44–4.89), P = 0.0018
• Patients treated with CLAG-M had a significantly longer OS than those treated with d/MEC: HR = 2.02 (95% CI, 1.15–3.53), P = 0.01
• There were no significant difference in OS between CLAG-M-treated patients and GCLAC-treated patients: HR = 1.46 (95% CI, 0.86–2.49), P = 0.16

CLAG-M with escalated mitoxantrone up to 16 mg/m² “appears safe and relatively well tolerated in fit younger and older adults with RR AML and other high-grade myeloid neoplasms.” The key limitation of the study includes the small sample size.