Efficacy and Relative Costs Of Re-Induction Chemotherapy With Clofarabine and Cytarabine For Adults With AML

Chemotherapy for adults with Acute Myeloid Leukemia (AML) has undergone little change in 30 years. Unfortunately, many patients relapse following an initial response to chemotherapy, and there is no standard salvage chemotherapy regimen in AML. There have been no randomized trials comparing various intensive re-induction regimens (i.e., MEC – Mitoxantrone/cytarabine/etoposide; FLAG-Ida – Fludarabine/cytarabine/idarubicin/g-csf; CLAG – cladribine/cytarabine/g-csf), and reported rates of complete remission (CR) with these regimens range from 25-60%. The only potentially curative therapy for relapsed AML is an allogeneic stem cell transplant (SCT), and SCT outcomes are improved for patients in second CR compared to those transplanted with refractory disease. Clofarabine is a second-generation purine analog, inhibiting ribonucleotide reductase and DNA polymerase. The CLASSIC I trial randomized older patients with relapsed/refractory AML to either clofarabine/cytarabine to low-dose cytarabine, with improved CR (35%) and event-free survival and no significant difference in overall survival. Single arm clinical trials with a combination of clofarabine and cytarabine report CR rates of 25-60% in the setting of relapsed AML. Our institution has treated patients with relapsed or refractory AML with the clofarabine/cytarabine regimen off clinical trial from September, 2011, to January, 2013. Here, we report the outcomes in the context of chemotherapy drug costs (Table 1).

We conducted a retrospective chart review of 20 consecutive adult patients with AML treated at the University of Kansas Medical Center from September, 2011 to January, 2013, with the combination of clofarabine (40mg/m2/day days 1-5) followed 4 hours later by cytarabine (1g/m2/day days 1-5). Data collected included age, sex, AML cytogenetics, number of prior therapies, remission rates, toxicities, number of patients proceeding on to stem cell transplant and length of hospitalization.

The median age was 67 years (range 34-74) with a male predominance (12/20 patients) and average of 2 prior therapies (range 1-3). Cytogenetics at diagnosis are available for 18 patients: 11 with poor risk; 6 with intermediate risk; 1 with favorable risk (normal cytogenetics, NPM1 mutated). We observed a 30% CR rate, with 5/6 patients in CR going on to SCT (one patient who achieved CR had evidence of leukemia recurrence at evaluation for planned SCT). The average length of stay was 33 days (5-70). Three patients had short hospitalizations (less than 14 days) or outpatient administration of chemotherapy and all three required re-admission for neutropenic fever and /or sepsis. Seven patients underwent SCT following clofarabine and cytarabine re-induction: 5 in CR and 2 with active disease at the time of SCT. Six patients received an allogeneic SCT at our institution, 5 in CR and 1 with active disease; 1 patient received SCT at another institution. One patient had relapse of AML following SCT in CR2 at day 128 post-SCT. The other 4 patients in CR at time of SCT remain alive without relapse at 215, 293, 608 and 647 days after clofarabine/cytarabine. The patient who was transplanted with active leukemia died 113 days after clofarabine/cytarabine. One patient who did not achieve CR but had a decrease in blast percentage continues to receive decitabine monthly and is alive after 14 doses at the time of this writing despite lack of CR.

Our single institution experience with clofarabine/cytarabine for refractory or relapsed AML a CR rate of 30%, consistent with published literature. It also allowed 5 patients to receive SCT in CR2, and of those, 4 remain alive and in remission; one additional patient remains alive although with residual leukemia. However, length of hospitalization was 33 days and there is significant underlying drug cost disparity. The regimen of clofarabine and cytarabine is effective in inducing CR in adult patients with relapsed and refractory AML, albeit at a higher drug-specific cost than other regimens.

No relevant conflicts of interest to declare.