Does high‐dose cytarabine cause cumulative toxicity in patients undergoing consolidation therapy for acute myeloid leukemia? (2013)

High dose cytarabine (HiDAC) is the standard consolidation treatment for younger adult patients with favorable risk acute myeloid leukemia (AML) 1. However, there is an active discussion regarding the rationale and controversies surrounding the use of HiDAC in the treatment of patients with AML 2. The ideal number of HiDAC chemotherapy cycles during the consolidation phase is not known, but patients who receive at least three cycles appear to have higher overall survival (OS) and lower incidence of relapse, when compared to patients who receive fewer cycles, in particular patients with core factor binding AML 3. It is believed that there is an increased risk of cumulative toxicity with increased number of HiDAC cycles 2. Cumulative toxicity is defined as the state at which repeated administration of a drug may produce side effects that are more pronounced than those produced by the first dose. Whether cumulative toxicity from HiDAC is real or not would have significant implications in the care of patients with AML undergoing consolidation therapy. Although the studies we discuss here have significant differences in patient size (small or large), center number (single or multicenter), type of study (prospective or retrospective), and geographical place (Europe, USA, or Japan), these study results are remarkably consistent 4-8. No study reported increased mortality by increased number of HiDAC cycles. The frequency of neutropenic fever, the duration of neutropenia, and neutropenic fever were not increased by the HiDAC cycle number 5, 7, 8. Rather, it has been described that the numbers of functionally active neutrophils (exhibiting anti-bacterial effects) often survive until day 10 or even 12 in HiDAC-treated patients 9. WBC per HIDAC cycle from one of these patients is shown in Fig. 1. The number of platelet and red blood cell transfusions 5, 7 and duration of thrombocytopenia 7 remained stable throughout the HiDAC cycles 5, 7. Documented fungal infections 8, empirical intravenous antifungal use 8, duration of antibiotic use 7, and the frequency of pneumonia 5 were similar between HiDAC cycles. No accumulated central nervous system, hepatic, or renal toxicity reported during HiDAC cycles 5, 7. Someone may argue that there is a decline in the number of patients from HiDAC cycle number 1 to HiDAC cycle 3 or 4, which reflects accumulative toxicity 4, 6, 7. Although it could, the decline was not only caused by toxicity, patient refusal, or dead in remission but also resulted from relapse and undergoing allogeneic hematopoietic cell transplantation (alloHCT). More importantly, it is obvious that patient number will decrease from beginning to the end of any therapy. Therefore, the primary question remains whether the decline rate is higher with HiDAC compared to other consolidations and the rate of decline worsens with each cycle of HiDAC. Two major prospective studies comparing HiDAC with other consolidations 4, 7 showed that completion rate of the planned consolidation therapy course was similar in the HiDAC cohort compared to the other cohort. Thomas et al. noted that “despite the repetition of consolidation courses in the arm with HiDAC, toxicity was more acceptable in this arm than the arm with only one course of time-sequential chemotherapy (TSC)” (the other consolidation cohort comprised of daunorubicin, mitoxantrone, and cytarabine) 7. Withdrawal from the study was observed in 3/151 (2%) in the HIDAC cohort compared to 7/155 (4.5%) in the multiagent chemotherapy (MAC) cohort 4. One study indicated that perhaps toxicity was more common with HiDAC compared to that with MAC 6. However, mortality rates were similar in both cohorts in the study. In addition, alloHCT was the most common reason for both cohorts not to pursue the following planned cycle. There was no evidence of accumulating toxicity of HiDAC with increased number of HiDAC cycles; the nadir of leukocyte count rates and the duration of leukopenia were the same throughout the HiDAC cycles even this study 6. This article does not intend to discuss of HiDAC efficacy or safety compared with other consolidations. However, it shows that the published studies do not support the perception that there is accumulating hematologic or non-hematologic toxicity with increased cycle number of HiDAC. This is an interesting phenomenon and should be investigated. For at least hematologic toxicity, it might be speculated that deepening response with each HiDAC cycle may ablate suppressive effect of AML cells on normal granulocyte-macrophage colony formation 10. In addition, the number and functions of surviving neutrophils remain similar between each HiDAC cycle number, which can in part explain similar rate of infections. In conclusion, the evidence does not support the accumulative toxicity of HiDAC, and decline in patient number with each cycle is not worse than that observed with other intensive consolidation regimens. Andres Wiernik1 Wolfgang R. Sperr2 Daniel Weisdorf1 Peter Valent2 Celalettin Ustun1* 1Department of Medicine, Division of Hematology, Oncology, andTransplantation, University of Minnesota, Minneapolis, Minnesota; 2Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria