A Single Institution Comparison of Mitoxantrone, Etoposide and Cytarabine (MEC) Vs High-Dose Cytarabine and Mitoxantrone (Ara-C Couplets) for Treatment of Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background:

Relapsed or refractory acute myeloid leukemia (R/R AML) is a common occurrence and remains a therapeutic challenge due to its poor prognosis. Hematopoietic cell transplantation (HCT) is the only curative approach for R/R AML, and while chemotherapy regimens are generally used as a bridge to HCT, the ideal second-line therapy is unknown. For decades cytarabine (Ara-C) has been the backbone of a number of regimens that are frequently used in this R/R setting. At our academic institution patients who can tolerate aggressive therapy are treated with either MEC (mitoxantrone 8 mg/m² IV, etoposide 80 mg/m² IV and intermediate dose cytarabine 1 g/m² daily for 5 days) or Ara-C couplets (mitoxantrone 30 mg/m² x 1 and high dose cytarabine (2 g/m²) twice daily, on days 1 and 5). MEC is among the most studied regimens for R/R AML; up to 66% of patients achieve complete remission (CR), with a median survival of 36 weeks (Arcese et al., J Clin Oncol . 1991). The Ara-C couplets regimen has been shown to have a similar overall response rate of 55%, in a single study (Larson et al., Leukemia & Lymphoma . 2012). Currently, there are no studies that have directly compared these two treatments. The objective of this single institution retrospective analysis is to assess the efficacy and toxicity of MEC and Ara-C couplets therapy.

Methods:

R/R AML patients treated from January 1998 through May 2015 were identified using our hospital and pharmacy billing records. From a review of 118 patient charts a total of 51 R/R AML adult patients were identified who had received either MEC or Ara-C couplets, and all were included in this analysis. The efficacy and toxicity of the two regimens were compared by assessing the rates of CR, progression free survival (PFS), overall survival (OS), the duration of hospitalization, hematologic and non-hematologic toxicities and success in proceeding to HCT.

Results:

Fifteen patients, ages 20-64, were treated with MEC, and 36 patients, ages 22-75, were treated with Ara-C couplets. Baseline characteristics, including gender, race, and Charlson Comorbidity Index (CCI) were well balanced. Within the MEC group, there were an equal number of White, Black and Hispanic patients (n=4), and 3 patients who identified as other. Amongst the Ara-C couplets patients, 14 were White, 11 Black, 7 Hispanic, and 4 identified as other. Six of the MEC patients (9%) and 9 of the Ara-C couplets patients (25%) had unfavorable cytogenetics. The time from initial diagnosis to relapse or refractory disease was similar between the 2 groups, 253 days (MEC) and 244 days, respectively (p=0.38)

CR was achieved in 64% of the MEC patients and 57% of the Ara-C couplets patients (p=0.75). OS was 6.5 months and 8 months respectively (p=0.35). PFS was 5.2 months in the MEC group and 4 months in the Ara-C couplets group (p=0.86). In both groups, 47% of patients (7 in MEC, 17 in Ara-C couplets) underwent HCT. Within the MEC group, the median number of days to ANC and platelet recovery was 45 days and 65 days respectively, and was similar within the Ara-C couplets group, 40 days and 55 days, respectively. The median duration of hospitalization for patients receiving MEC was 34 days while the median for those receiving Ara-C couplets was 31 days (p=0.2).

The most common adverse event was febrile neutropenia, occurring in 100% of the MEC and 89% of the Ara-C couplets patients (p=0.3). Non-hematologic toxicities were minimal and there were no significant differences between groups in terms of pulmonary, liver or gastrointestinal toxicities. Within the Ara-C couplets group, one patient experienced grade 3, and another grade 4 cardiac toxicity (CHF).

Conclusions:

This is the first study that directly compares MEC and Ara-C couplets regimens in R/R AML patients; two salvage therapies commonly used at our institution. We show that both therapies are equally effective as second-line regimens with equivalent toxicities in a racially diverse population (n= 51). Our data suggests either regimen can be considered in those able to tolerate aggressive therapy and can serve as a bridge to HCT. A significant portion of patients with AML relapse, and, surprisingly, very few comparative studies have been performed in this population. In the future, large multi-center studies should be performed in order to establish the optimal chemotherapy regimen for these patients.