Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms

Abstract

Outcomes with “7+3” are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. 121 patients, median age 60 (range: 21–81) years, were enrolled. In phase 1, cohorts of 6–12 patients were assigned to 12–18mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). 4-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7+3 at our center and 245 matched patients treated with 7+3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.

Advances in acute myeloid leukemia

“…• Fludarabine, high dose cytarabine, and idarubicin (FLAG-ida) has been shown to be an effective regimen 102 ○ Superior rates of remission and reduced risk of relapse compared with a 10 day cytarabine plus daunorubicin regimen were shown, but also with increased toxicity and thus no improvement in overall survival • Other intensive cytotoxic regimens incorporating clofarabine have been investigated [103][104][105] • Cladribine, another nucleoside analog, has also been investigated in combination with daunorubicin and cytarabine (eg, the "DAC regimen"), with response rates of up to 70% in de novo acute myeloid leukemia (AML) and 40-50% in relapsed/refractory AML 83 blasts to linger in an immature state. 8 The addition of the isocitrate dehydrogenase inhibitors blocks this process and allows for resumption of more normal differentiation, sometimes leading to the complication of "differentiation syndrome," in which the rapid maturation of many immature white blood cells leads to dyspnea, fever, pulmonary infiltrates, and hypoxia.…”

The important role of intensive induction chemotherapy in the treatment of acute myeloid leukemia

“…• Intensive chemotherapy, often followed by hematopoietic cell transplantation, continues to be a standard of care for AML and offers the best chance for long-term remission • Newer intensive strategies for AML include novel chemotherapy designs and chemotherapy as a backbone in combination with targeted agents • Many older adults with AML benefit from receiving intensive chemotherapy with a curative intent, and a more holistic approach to determining eligibility for intensive treatment is recommended guidelines [5,7]; however, while these regimens have all demonstrated efficacy in AML, studies have not consistently supported the use of one regimen over another [24][25][26][27][28].…”

CLAG-M with dose-escalated mitoxantrone for adults with acute myeloid leukemia

“…Because randomized trials demonstrated dose-dependent anti-leukemic efficacy of anthracyclines during induction chemotherapy [3-5], we recently conducted a single-center phase 1/2 trial (ClinicalTrials.gov: NCT02044796) testing CLAG-M with escalated doses of mitoxantrone in separate cohorts of fit adults ≥18 years with either newly-diagnosed or relapsed/refractory AML and other high-grade myeloid neoplasms (≥10% myeloblasts in blood and/or marrow) [6, 7]. In both cohorts, medical fitness was defined by a treatment-related mortality (TRM) score of ≤6.9, a score that corresponds to a ≤6.9% probability of 4-week mortality [8].…”

“…In the newly-diagnosed arm, we enrolled 121 patients with a median age of 60 (range: 21-81) years [6]. Because all 4 mitoxantrone doses were well-tolerated, 18 mg/m 2 was declared the RP2D in this arm.…”