PHASE 1 TRIAL OF G-CSF, CLADRIBINE, CYTARABINE, AND DOSE-ESCALATED MITOXANTRONE (G-CLAM) IN ADULTS WITH NEWLY DIAGNOSED AML OR HIGH-RISK MDS
Author(s): ,
Asma Anwar
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Anna Halpern
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Bart Scott
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Pamela Becker
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Megan Othus
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Paul Hendrie
Affiliations:
University of Washington,Seattle,United States
,
Elizabeth Ranker
Affiliations:
Seattle Cancer Care Alliance,Seattle,United States
,
Andrea Perdue
Affiliations:
Seattle Cancer Care Alliance,Seattle,United States
,
Tara Chen
Affiliations:
University of Washington,Seattle,United States
,
Sarah Buckley
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Kaysey Orlowski
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Morgan Powell
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Frederick Appelbaum
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
,
Elihu Estey
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
Roland Walter
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
EHA Library. Anwar A. Jun 13, 2015; 100715; P574
Asma Anwar
Asma Anwar
Contributions
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Abstract
Abstract: P574

Type: Poster Presentation

Presentation during EHA20: From 13.06.2015 17:15 to 13.06.2015 18:45

Location: Poster area (Hall C)

Background
Standard-dose cyarabine with an anthracycline (“7+3”) has remained the mainstay of induction chemotherapy for newly diagnosed AML. Recently, some randomized studies have demonstrated improved outcomes with regimens containing high-dose cytarabine, cladribine, or escalated doses of anthracyclines during induction.

Aims
Given these findings and the previously established tolerability and efficacy of G-CLAM in relapsed/refractory AML, we aimed to determine the maximum tolerated dose (MTD) of mitoxantrone within G-CLAM in adults with newly diagnosed AML or high-risk MDS (>10% blasts).

Methods
Eligibility included a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a risk of early death with standard induction chemotherapy of ≤3%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal). Excluded were patients with concomitant illness with expected survival <1 year and those with active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day on days 1-3, as compared to 10 mg/m2/day used in standard-dose G-CLAM). Other drug doses were G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). A second identical course of G-CLAM was given in the case of persistent disease. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia or infection or constitutional symptoms, if recovery to grade ≤2 within 14 days.

Results
31 patients (20M, 11F), median age 58 (range: 27-77) years, median TRM score 2.83 (range: 0.15-5.54) with newly diagnosed AML (n=25), or high-risk MDS (n=6) and cytogenetically favorable (n=1), intermediate (n=23), and adverse (n=6) disease characteristics were enrolled (failed karyotyping: n=1; MRC criteria). One DLT occurred each at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD in our study. One patient died within 28 days of treatment initiation from thrombocytopenia-related intracranial hemorrhage. Overall, 29/31 patients (93.5%, exact 95% confidence interval [CI]: 78.6-99.2%) achieved a CR (n=24 [77.4%, 95% CI: 58.9-90.4%]), CRp (n=2 [6.5%, 95% CI: 0.8-21.4%]), or CRi (n=3 [9.7%, 95% CI: 2.0-25.8%]) with 1-2 cycles of chemotherapy; one patient at dose levels 1 and 2 each had persistent disease. Only 2 patients required 2 cycles to best response. 26/29 (89.7%, 95% CI: 72.7-97.8%) had no evidence of residual disease by flow cytometry at best response. After multivariable adjustment, the CR rate was similar and overall response rate was favorable as compared to 300 patients treated with 7+3 on the SWOG S0106 trial (OR=1.25, p=0.64, and OR=4.68, p=0.045, respectively). Among responders, median times to an absolute neutrophil count ≥500 and a platelet count of 50,000 were 25 (range: 19-38) and 24 (range: 18-45) days, respectively. Besides infections and neutropenic fever, maculopapular rash, nausea, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events.

Summary
G-CLAM with mitoxantrone up to 18 mg/m2/day is feasible, well tolerated, and effective in newly diagnosed AML/high-risk MDS. A phase 2 study has been initiated.

Keyword(s): Acute myeloid leukemia, Dose escalation, Induction chemotherapy, Phase I

Session topic: Acute myeloid leukemia - Clinical 4

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