A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThe prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia. Design and MethodsSixty patients received either continuous-infusion doxorubicin (12 mg/m 2 /day) and continuousinfusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m 2 ) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors. ResultsMyelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm. ConclusionsWith the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities. (ClinicalTrials.gov Identifier: NCT00600977).

Treatment of older patients with acute lymphoblastic leukemia

“…Therefore induction therapy is the most critical phase for management. In older patients, induction mortality has a wide range (0% to 42%) (Table 2), 14,[16][17][18][19][20][21][22][23][24][25] and early death occurs also before the onset of chemotherapy. The most frequent cause of death in induction is infection.…”

“…16 The results of liposomal anthracyclines in elderly ALL are not convincing so far. 17,18 Asparaginase is an essential compound in the treatment of ALL. The PETHEMA group reported the results of an intensive induction regimen, including asparaginase for older ALL patients.…”

Aggressive chemotherapy in frail patients with diffuse large B-cell lymphoma: The role of pegylated liposomal doxorubicin

“…Cardiac toxicity and granulocytopenia-related infection are probably the most relevant [1][2][3][4][5] . Thus, most studies refused to included patients with poor prognostic factors (Elderly, comorbodities, and patients with antecedents of cardiac damage).…”

“…The introduction of liposomal and pegylated liposomal anthracyclines open a new options in treatment of this setting of patients because these drugs showed similar antitumoral activity and reduced cardiac toxicity [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] .…”

Infections in Leukemia

“…However the incidence of gram negative infections and ≥ grade3 /4 infections (i.e. requiring IV antibiotics) may be reduced by the use of pegylated liposomal doxorubicin possibly due to reduced overall myelotoxicity (125).…”