Infectious Complications in Patients with Relapsed Acute Myeloid Leukemia (AML) Receiving Clofarabine Versus Fludarabine-Containing Salvage Chemotherapy Regimens

Purine nucleoside analogs, such as fludarabine and clofarabine, are attractive agents in AML due to their direct cytotoxic effects as well as their ability to enhance the cellular uptake of cytarabine into leukemic blasts. However, these agents are known to cause lymphopenia, raising the concern of an increased risk of infections than might be expected from the use of conventional chemotherapy. We have prioritized relapsed AML patients to a randomized trial comparing idarubicin and cytarabine combined with either clofarabine or fludarabine (CIA vs FIA). We here compare the infectious complications between the two regimens in the context of a randomized salvage trial.

We compared the outcomes of patients receiving CIA (clofarabine 15 mg/m² daily for 5 days, idarubicin 10 mg/m² daily for 3 days, and cytarabine 1,000 mg/m² daily for 5 days) vs FIA (fludarabine 30 mg/m² daily for 5 days, idarubicin 10 mg/m² daily for 3 days, and cytarabine 1,000 mg/m² daily for 5 days) from August 2011–August 2012. Patients received induction followed by up to 6 consolidation cycles using the same drugs according to an attenuated schedule. Variables analyzed included episodes of neutropenic fever, pneumonia or other infections, and diagnosis of atypical infections, among others. Atypical infections were defined as Pneumocystis jirovecii, Nocardia, mycobacterial infections, Listeria, Legionella, Mucormycosis, viral pneumonia, or radiographic evidence of atypical pneumonia (REAP). All patients received prophylaxis with antibacterial, antiviral, and mold-active antifungal agents. Patients were followed from day one of therapy until death, next salvage, or allo-SCT.

50 patients (n=30 CIA, n=20 FIA) were analyzed. Patients' characteristics were similar between both groups (Table 1). Prior exposure rates to clofarabine or fludarabine for the CIA and FIA groups were 13% vs 20% (p=0.69) and 23% vs 30% (p=0.74), respectively. Median follow up for both groups was similar (57.5 days for CIA, 62 days for FIA). Culture or biopsy proven diagnoses of atypical infections were low in each group, however, numerically there were more cases in the CIA group (3/30 in CIA, 0/20 in FIA; p=0.2). The patients in the CIA group all experienced atypical fungal infections (Mucormycosis, cutaneous Curvularia, and Exserohilum sinusitis requiring surgical debridement, N=1 each). There were also more cases of REAP in the CIA group (3/30 in CIA, 0/20 in FIA; p=0.2). These cases were interpreted by the Radiologist as atypical, unconventional, or possibly viral pneumonia. Overall, there were 16 bloodstream infections in the CIA group (occurring in 14 patients [47%], one Candidemia, all others bacterial) versus 9 in the FIA groups (occurring in 7 patients [35%], two Candidemia, all others bacterial) (p=0.59). There were more diagnoses of pneumonia in the CIA group (60% versus 40%). We compared the infection rates to those from a group of patients receiving standard chemotherapy in the frontline setting. In this cohort, 14/49 patients (29%) developed bacteremia, and 15/49 (31%) were diagnosed with pneumonia.

Viral infections occurred in 2 patients (7%) of patients on CIA (RSV in one patient, Influenza B and HSV in one patient) compared to 3 patients (15%) on FIA (CMV reactivation, Herpes Zoster, and HSV, all in one patient each).

In the short term, and with available follow-up, the use of clofarabine does not appear to be associated with a significant increase in infection rates compared to fludarabine.

Off Label Use: Clofarabine for AML. Kantarjian:Pfizer: Research Funding; Sanofi: Research Funding; Micromet: Research Funding.