Abstract

The cell cycle inhibitor FL targets cyclin-dependent kinases, induces checkpoint arrest and interrupts transcriptional elongation. We demonstrated in an in vitro model that F causes apoptosis in leukemic blasts and increases A cytotoxicity in remaining blasts (

Clin Cancer Res
9
:
307
–315,
2003
). Based on these observations, we have conducted a Phase II trial of timed sequential therapy (TST) with FL 50 mg/m2 daily x 3 days followed by A 2 gm/m2/72 hr infusion beginning day 6 and M 40 mg/m2 day 9 (FLAM). A total of 42 adults (median age 50, range 23–75) received FLAM for acute myelogenous leukemia (AML, 37 pts) or acute lymphoblastic leukemia (ALL, 5 pts). Four pts had new AML (myelodysplasia- or treatment-related), 19 were in relapse after first complete remission (CR; median duration 8 mos, range 1.5 – 20), and 19 had refractory leukemia (9 primary). Four pts had prior allo- or auto-stem cell transplants, 13 (31%) had secondary AML and 25 (60%) had adverse cytogenetics, including 2 with Ph+ ALL. FLAM was well-tolerated with death occurring in only 3/42 (7%, fungemia, respiratory distress, multi-organ failure). Grade ≥ 3 non-hematologic toxicities consisted of oral mucositis (2/42, 5%), diarrhea (1/42, 2%), cardiac arrhythmia or decreased ejection fraction (3/42, 7%). F induced tumor lysis in 14 (33%) within 24 hrs of first F dose and a ≥ 50% fall in WBC after 2 F doses in 18 (43%). Median time to neutrophils ≥ 500/mm3 was day 30 day (range 24–46) and platelets ≥50,000/mm3 was day 35 (range 24 – 55). CR was achieved after 1 course of FLAM in 15/37 (41%) AML: 3/4 new patients (including complex cytogenetics), 11/19 relapse and 1/9 primary refractory. CR was achieved in 1/5 (20%) ALL in a patient with relapsed Ph+ ALL. Two of 4 with prior transplant achieved CR, while no patient who was refractory to multiple chemotherapies achieved CR. Of the 15 achieving CR, 13 received additional therapy. Eight pts (7 CR, 1 partial response; median age 45, range 26–62; 1 new diagnosis, 6 relapse, 1 primary refractory) went on to receive allo-transplant in second CR, with CR 2 durations 4.5–12+ mos. An additional 2 pts (ages 45, 46) who had relapsed after allo-transplant in CR1 were able to receive donor lymphocyte infusions (DLI) after FLAM and remain in CR2 of 8+ mos duration. Three pts over age 65 received a second cycle of FLAM in CR, with CR durations of 8.5+, 10, and 10.5 mos. Induction chemotherapy with FLAM yields a significant CR rate in pts with newly diagnosed poor-risk AML or in pts with short CR1, and allows eligible pts to proceed to allo-transplant in CR2.

Topics:
acute lymphocytic leukemia, allopurinol, brachial plexus neuritis, cancer, cardiac arrhythmia, cell transplants, chemotherapy regimen, chemotherapy, neoadjuvant, complete remission, cyclin-dependent kinases

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2005, The American Society of Hematology
2005