Fludarabine, cytarabine, and mitoxantrone (FLAM) for the treatment of relapsed and refractory adult acute lymphoblastic leukemia. A phase study by the Polish Adult Leukemia Group (PALG)

Abstract

Outcome of adults with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission (CR) or who relapse soon after initial response is poor. The goal of this phase II study by the Polish Adult Leukemia Group (PALG) was to evaluate safety and efficacy of a new salvage regimen (FLAM) consisting of sequential fludarabine, cytarabine, and mitoxantrone. Fifty patients were included with primary (n = 13) or secondary (n = 5) refractoriness, early (<12 months) first relapse (n = 15), first relapse after hematopoietic cell transplantation (HCT) regardless CR duration (n = 13), and second or subsequent relapse (n = 4). Median age was 31(18-60) years, 28% of patients were bcr/abl-positive. CR rate equaled 50% and was significantly higher for patients in whom FLAM was administered as a second-line therapy compared to those more heavily pre-treated (66 vs 13%, p = 0.02). Seventeen patients had leukemia regrowth after initial cytoreduction, whereas, eight patients died in aplasia. The incidence of early death was higher in patients aged > or =40 years compared to the younger subgroup (33 vs 8%, p=0.03). Septic infections were the most frequent severe complication. At 3 years, the probability of disease-free survival for patients who achieved CR equaled 16%. Seven patients underwent allogeneic HCT. FLAM regimen is feasible for relapsed and refractory adults with ALL and could be recommended in particular for younger patients as a second-line treatment. However, as the remission duration is short, allogeneic HCT (alloHCT) should be considered as soon as possible.

Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation

“…4,[13][14][15][16][17] The overall CR rate of 42% for the first salvage approach in the present study was within the range reported from other retrospective studies (31%-44%). [3][4][5][6] Clearly, remission rates depend on chemotherapy sensitivity, which is lower in early relapse compared with late relapse and lowest in patients with refractory disease after the first salvage approach.…”

Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells

“…The chemotherapeutic drug AraC (1-b-D-arabinofuranosylcytosine, cytarabine), a deoxycytidine analog, is one of the most important antileukemic agents currently available for the treatment of AML [15,16], relapsed and refractory acute lymphoblastic leukemia [17][18][19], as well as a subset of malignant lymphoma [20]. Ara-C enters the cell mainly via equilibrative nucleoside transporter 1 (hENT1), and is phosphorylated to Ara-CMP by deoxycytidine kinase (dCK).…”

Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells

“…1-3), relapsed and refractory acute lymphoblastic leukemia (ALL; refs. [4][5][6], and other malignancies (7)(8)(9)(10). The chemotherapeutic efficacy of cytarabine varies dramatically between individuals.…”