Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia

Abstract

To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly patients with acute myeloid leukemia (AML) and to evaluate the feasibility of autologous transplantation using PBSC after consolidation in those with a good performance status, 160 patients (median age 69 years), with AML at diagnosis, 118 of them with de novo AML and 42 with AML secondary to myelodysplastic syndrome or toxic exposure (sAML), received induction treatment with idarubicin, 8 mg/m 2 /day or mitoxantrone, 7 mg/m 2 /day, on days 1, 3, and 5, both combined with VP-16, 100 mg/m 2 /day on days 1 to 3 and cytarabine (araC), 100 mg/m 2 /day, on days 1 to 7. G-CSF, 5 g/kg/day, was administered after chemotherapy in patients aged more than 70 years. Patients in complete remission (CR) received one course of consolidation using the same schedule as for induction except the araC administration was shortened to 5 days. Some patients younger than 70 years were then scheduled for autologous stem cell harvest on days 5 to 7 of G-CSF, 5 g/kg/day, initiated after hematopoietic recovery from consolidation. Autologous transplantation was performed following an additional chemotherapy conditioning. Ninety-five patients (59%) achieved CR, without significant difference between the idarubicin (56% CR) and mitoxantrone (63% CR) group. There was also no significant difference in CR rate between de novo AML (63%) and secondary AML (55%) (P = 0.12). Patients aged Ͻ70 years had 67% CR, while patients aged у70 years had 49% (P = 0.02). There was no significant difference in the duration of aplasia between the two arms. Median time to neutrophil recovery was 22 days in patients who received G-CSF following induction and 27 days in patients who did not (P = 0.006). Severe extrahematologic toxicities of induction did not differ between the two arms and included sepsis (39%), diarrhea (13%), hyperbilirubinemia (8%), hemorrhage (6%) and vomiting (6%). Overall, 14 patients (9%), died from toxicity of induction. First consolidation was administered in 74 patients of whom seven (9%) died from toxicity. Nineteen patients have received transplantation. Median time to recovery of neutrophils Ͼ0.5 × 10 9 /1 was 13 days and of platelets Ͼ50 × 10 9 /l 43 days following consolidation. There were two toxic deaths. Median disease-free survival and survival from time of achieving CR of non transplanted patients are 6 and 7 months respectively without difference between the two arms. Fourteen transplanted patients relapsed at a median of 5 months post-transplant. We conclude that this regimen is well tolerated and has a good efficacy to induce CR, without a significant difference in efficacy and toxicity between idarubicin and mitoxantrone. Intensive postinduction, including transplantation, is feasible; however, this procedure did not seem to prevent early relapse in the majority of patients. Neither the high rate of CR nor consolidation nor transplant procedure in a selected group of patients did translate into improved DFS and/or survival.

Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients

“…Our previous reports as well as data obtained from other transplant centers confirm that procedure-related toxicity and mortality may be reduced by using nonmyeloablative or reduced intensity conditioning prior to transplantation of allogeneic stem cells, while retaining the antitumor effects of alloreactive donor lymphocytes. 5,6,[8][9][10] Nevertheless, data regarding SCTrelated toxicity in elderly patients are scarce and focus more concentrated on autologous [11][12][13][14][15] than allogeneic SCT. 10,[16][17][18] In this report, we present our cumulative experience in elderly patients (X60 years) undergoing allogeneic SCT with RIC for hematological malignancies.…”

Blood and marrow transplantation in elderly acute myeloid leukaemia patients – older certainly is not better

“…The finding that only 13% of the initial population went on to receive an autotransplant is consistent with other studies that reported feasibility rates of 12, 6 and 6% of elderly AML patients. [40][41][42] The outcomes for these feasibility studies in particular are depicted in Table 2.…”

“…Table 1 reviews the data for the studies that investigated the role of autologous stem cell transplantation specifically in the elderly AML patient. [37][38][39][40][41][42][43] Cahn et al 37 retrospectively compared European Group for Blood and Marrow Transplantation (EBMT) data for 111 CR1 AML patients older than 50 years versus 786 younger (median age 35 years) patients. Leukemia free survival (LFS) and OS rates at 4 years were significantly inferior in older patients, 34 versus 43% (P ¼ 0.004) and 35 versus 48% (P ¼ 0.004), respectively.…”

“…33 Preparative regimens for autografting likely should contain myeloablative doses of combination chemotherapy, that is, higher relapse rates are associated with single-agent conditioning regimens. 40 Conclusions regarding the role of autografting in elderly AML patients remain guarded. Those in whom the procedure appears feasible are a highly selected group, usually subjects who do not have unfavourable risk cytogenetics, are in CR1, are devoid of comorbid conditions, have a good performance status, are able to proceed to consolidation and mobilization and subsequently receive a transplant.…”

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial

“…1 There is general agreement that some sort of consolidation treatment should be used in elderly AML pts after reaching CR. Its intensity, however, is an open question.…”