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New Regimen for Poor Risk AML
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: A novel regimen is introduced for the treatment of high-risk acute myelogenous leukemia. In a single-institution phase II trial, flavopiridol, a synthetic flavone, in combination with cytosine arabinoside and mitoxantrone induced durable complete remissions in new patients with secondary leukemia and in those with relapsed disease.
Source: Karp JE, et al. Clin Cancer Res. 2007;13:4467-4472.
Based upon promising phase I data1, Karp and colleagues at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University performed a phase II trial of timed sequential therapy (TST) using three drugs, flavopiridol (L-86-8275), cytosine arabinoside, and mitoxantrone. Flavopiridol is synthetic flavone derivative,2 isolated from the stem bark of the Indian tree Dysoxylum binectariferum that has been shown to induce apoptosis in a number of neoplastic cell lines, including acute myelogenous leukemia.3 Based upon its demonstrated mechanism of action there was rationale to combine flavopiridol with other cell-cycle specific drugs. The Hopkins group chose cytosine arabinoside and mitoxantrone based upon both theoretic considerations and activity demonstrated in the Phase I trial.
For the current study, flavopiridol was administered at a dose of 50 mg/m2 over 1 hour daily X 3 beginning on day 1. Cytosine arabinoside (ara C), 2 gm/m2 as a 72 hour continuous infusion began on day 6. Mitoxantrone, 40 mg/m2 was administered as a single bolus infusion (30-60 minutes) on day 9, 12 hours after completion of the ara C infusion. Patients who achieved complete or partial remission after cycle 1 were eligible to receive a second cycle beginning no earlier than 30 days after cycle 1. To ameliorate the secretory diarrhea associated with flavopiridol4 octreotide was administered q8 hours prior to and for one day after flavopiridol infusions. Other supportive measures, including antibiotic and antiviral prophylaxis were also aggressively maintained.
A total of 62 patients were entered on this phase II trial. Patients had either poor-risk, newly diagnosed (n=15), relapsed (n=24) or refractory AML (n=23). The 15 patients with newly diagnosed AML had a median age of 61 years, with 10 having antecedent myelodysplasia, 2 treatment-related AML and 3 with prior myeloproliferative disease. All newly diagnosed patients had at least 2 poor-risk factors (age >60, secondary AML, adverse cytogenetic features, or poor performance status (ECOG PS > 2). For the 24 patients with relapsed AML, the median duration of CR was 9 months (range 4-22 months). Flavopiridol caused a >50% decrease in peripheral blood blasts in 44% by median day 2 and >80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three died during therapy (2 multiorgan failure, 1 fungal pneumonia). Complete remissions were achieved in 12 of 15 newly diagnosed secondary AML, in 18 of 24 who were in first relapse after a short CR from primary therapy, and in 2 of 13 who had primary refractory disease and 0 of 10 who were refractory after multiple chemotherapy regimens. Disease free survival for all CR patients was 40% at two years, and for those with newly diagnosed secondary AML it was 50% at two years.
Tumor lysis syndrome occurred in 53% but was manageable. Other adverse effects included mucositis and cardiac arrhythmia but these were, for the most part, grade 2 or less.
Thus, flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. Using a timed, sequential protocol, durable CRs were achieved in a significant portion of patients with newly-diagnosed secondary AML and in those with relapse after a short initial remission. The data compare favorably with other sequential regimens used in the same setting5,6 and provide optimism that more effective therapy for these difficult to treat leukemias is around the corner.
1. Karp JE, et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res. 2005;11(23):8403-8412.
2. Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst. 2000;92(5):376-387.
3. Yu C, et al. The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. Cancer Res. 2003;63(8):1822-1833.
4. Tan AR, et al. Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol. 2002;20(19):4074-4082.
5. Bolanos-Meade J, et al. Timed sequential therapy of acute myelogenous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide. Leuk Res. 2003;27(4):313-321.
6. Karp JE, et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004;10(11):3577-3585.