Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution

Abstract

First-line therapy of severe aplastic anemia (SAA) with high-dose cyclophosphamide causes toxicity and increased short-term mortality. We investigated cyclophosphamide at a lower, more moderate dose in combination with aggressive supportive care to determine whether severe infections might be avoided and hematologic outcomes defined for this regimen. From 2010 to 2012, 22 patients received cyclophosphamide at 120 mg/kg plus cyclosporine and antibacterial, antiviral, and antifungal prophylaxis. Toxicity was considerable, mainly due to prolonged absolute neutropenia, which occurred regardless of pretherapy blood counts, and persisted an average of 2 months. Granulocyte transfusions for uncontrolled infection were required in 5 patients, confirmed fungal infections were documented in 6, and 9 patients died. Nine patients (41%) responded at 6 months. After a median follow-up of 2.2 years, relapse occurred in 2 patients, and cytogenetic abnormalities (including monosomy 7) were observed in 4 patients. Although cyclophosphamide has activity in SAA, its toxicity is not justified when far less dangerous alternatives are available. This trial was registered at www.clinicaltrials.gov as #NCT01193283.

Figures

Figure 1

Duration of very severe neutropenia (<0.2 × 109/L) after Cy and voriconazole levels. (A) The average duration of very severe neutropenia was 70 days (range, 15 to 240 days) for the entire cohort, whereas for responders it was 36 days (range, 15 to 64 days), and for nonresponders, it was 94 days (range, 20 to 240 days). (B) The average voriconazole level for the entire cohort was 2.4 mg/L (range, 0.47 to 8.130 mg/L), among responders, it was 1.3 mg/L (range, 0.47 to 2.9 mg/L), and among nonresponders, it was 3.2 mg/L (range, 1.1 to 8.1 mg/L). Each data point represents the average voriconazole level for each patient throughout the duration of very severe neutropenia. The target voriconazole level was 1 to 5.5 mg/L (dotted lines). The patients who required granulocyte transfusions for uncontrolled infections despite maximum antimicrobial support are depicted in red. ANC, absolute neutrophil count.

Figure 2

Clonal evolution, late events (relapse + clonal evolution), and survival rates following Cy + CsA. (A) The cumulative incidence of clonal evolution at 1 year was 22% (95% CI, 0% to 39%). (B) An additional 2 patients relapsed, bringing the total incidence of late events (relapse + clonal evolution) to 28% (95% CI, 4% to 46%) at 2 years. (C) The 2-year survival for this cohort was 72% (95% CI, 55% to 94%). Day 0 in this survival curve is the first day of Cy. Dotted lines represent 95% confidence intervals.