Condensed Versus Standard Schedule of High-Dose Cytarabine Consolidation Therapy with Pegfilgrastim Growth Factor Support in Acute Myeloid Leukemia

Abstract

Background: The concept of intensive post-remission chemotherapy in acute myeloid leukemia (AML) is based on the observation that despite achievement of a first complete remission (CR) after intensive induction therapy virtually all patients relapse in the absence of further treatment. Moreover, randomized studies showed that intensive post-remission consolidation chemotherapy was superior to prolonged low-dose maintenance therapy in younger patients. With regard to consolidation therapy, the landmark study conducted by the Cancer and Leukemia Group B established the current standard for patients aged 60 years and younger with high-dose cytarabine (HDAC) 3g/m² bidaily on days days 1, 3, and 5. Aims: to compare a compressed schedule of high-dose cytarabine (HDAC) on days 1, 2, and 3 with the standard HDAC given on days 1, 3, and 5 as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in patients in first CR receiving repetitive consolidation cycles for acute myeloid leukemia. Methods: Patients (18 to 60 years) were accrued between 2004 and 2009. They were randomized up-front 1:10 between the standard German intergroup-arm (Büchner et al. J Clin Oncol. 2012;30:3604-10) and the AMLSG 07-04 study (NCT00151242). Induction therapy in the AMLSG 07-04 study consisted of two cycles of idarubicin, cytarabine and etoposide +/- all-trans retionoic acid (ATRA) and +/- valproic acid (VPA) in a 2 by 2 factorial design. After recruitment of 392 patients the randomization for VPA was stopped due to toxicity. For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic cell transplantation from a matched related or unrelated donor. All other patients were assigned to 3 cycles of HDAC from 2004 to November 2006 with cytarabine 3g/m² bidaily, on days 1, 3, 5 and pegfilgrastim on day 10 (HDAC-135) and from December 2006 to 2009 patients were treated with a condensed schedule with cytarabine 3g/m², bidaily, on days 1,2,3 and pegfilgrastim on day 8 (HDAC-123). Patients randomized into the German AML intergroup arm were treated for consolidation therapy with cytarabine 3g/m² bid on days 1, 3, 5 (HDAC-135) without prophylactic growth-factor support. Results:Overall 568 patients receiving 1376 consolidation cycles were included into the study. According to up-front randomization 41 were treated with HDAC-135 without prophylactic growth factor support in the German AML Intergroup protocol, 135 with HDAC-135 and 392 with HDAC-123 with intended prophylactic pegfilgrastim at day 10 and 8, respectively, in the AMLSG 07-04 protocol. Time from start to chemotherapy until hematological recovery with leukocytes >1.0G/l and neutrophils >0.5G/l was significantly (p<0.0001, each) and in median 4 days shorter in patients receiving HDAC-123 compared to HDAC-135, and further reduced by 2 days (p<0.0001) by the addition of pegfilgrastim. Treatment with ATRA and VPA according to initial randomization had no impac on hematological recovery times. Rates of infections were significantly reduced by HDAC-123 compared to HDAC-135 (p<0.0001) and pegfilgrastim yes versus no (p=0.002). Days in hospital and platelet transfusions were also significantly reduced in patients receiving HDAC-123 compared to HDAC-135. Relapse-free and overall survival were similar with HDAC-123 and HDAC-135 (p=0.48, p=0.90, respectively). Conclusion: Data from our study suggest that consolidation therapy with a condensed schedule of HDAC-123 is superior to that of standard HDAC-135 in terms of faster hematological recovery, lower infection rate and fever days in hospital. In addition, the administration of one dose of pegfilgrastim after chemotherapy further shortened hematological recovery and reduced infection rate. Importantly, similar efficacy in terms of relapse-free and overall survival rates after HDAC-123 and HDAC-135 were observed. Disclosures Lübbert: Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Teva: Other: Travel; Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

Acute myeloid leukemia: 2021 update on risk‐stratification and management

“…Chemotherapy for Group A emphasizes cytarabine in individual doses of 1‐3 g/m 2 daily or BID for 3 days per cycle for three cycles, often given as 3 g/m 2 every 12 hours on days 1, 3, and 5. However, a German‐Austrian AML Study Group found administration of this dose on days 1, 2, and 3 to 392 patients was associated with a median 4‐day reduction in time to ANC >500 from start of chemotherapy and with fewer platelet transfusions than in 176 historical patients given the 1, 3, and 5 schedule 137 . Cytarabine doses of 1 g/m 2 twice daily for 3‐4 days for three courses after CR is achieved are very probably as effective as higher doses and/or more courses irrespective of cytogenetic group 138 .…”

Model-Based Optimal AML Consolidation Treatment

“…We suspect that the higher values agglomerate biological phenomena that are not correctly described or fully covered by the current model. Nevertheless, the model exhibited the same behavior as in clinical trials with pegfilgrastim [5], i.e., a prolonged WBC recovery time of several days without G-CSF, compared to Figure S5.…”

“…A global sensitivity analysis was conducted to identify the impact of each parameter, respectively constant, on the variability of two model outputs [74]. The model outputs of interest were the leukemic cells in the bone marrow (x l1 ) at the end of a consolidation cycle and the nadir of circulating white blood cells similar to the two objective function terms in the optimization problem (5). The sensitivity analysis was performed in R (version 3.6.1) using the packages mrgsolve (version 0.10.0) for solving the ODE system (1) and sensitivity (version 1.17.0, sobolmartinez function) for the global sensitivity analysis.…”

“…Older patients (> 60 years) receive an intermediate dosage of 1 g/m 2 Ara-C (d) infusions in the same intervals (d135). In recent years, studies have proposed a dense treatment schedule at which either high-dose or intermediatedose Ara-C is administered on days 1, 2, and 3 (D123 or d123) to reduce the WBC recovery time and increase survival [5,6].…”

Safety and feasibility of outpatient high-dose cytarabine and intermediate-dose cytarabine for consolidation therapy in acute myeloid leukemia

“…Our rate of hospitalization 15 Interestingly, the rate of neutropenic fever per cycle is lower than what was reported in other studies. 6,7,[10][11][12] However, there is heterogeneity in how the rate of neutropenic fever is reported. 12 The incidence of adverse events reported in our cohort is consistent with previously reported experience with HiDAC or IDAC consolidation therapy.…”