Prolonged Hematologic Toxicity from the Hyper-CVAD Regimen; Manifestations, Frequency, and Natural History in a Cohort of 125 Consecutive Patients.

Hyper-CVAD is a dose-intensive regimen which has been employed in the last decade to treat patients with a range of hematologic malignancies, with impressive efficacy. This regimen has been associated with considerable short-term hematologic toxicity, which has been mostly described as transient and reversible. However, recent reports have highlighted a concerning early rate of MDS or AML on medium-term follow-up. While cases of MDS/AML may be the most extreme end of the spectrum of hematopoietic stem cell damage, in the current retrospective study we describe other prolonged hematologic sequelae of this regimen. All patients were previously untreated and received Hyper-CVAD for the treatment of NHL or ALL. 125 patients (pts) with a median age of 47 (range, 15–76) were followed up for a median of 23 months (range, 1–84). The median number of Hyper-CVAD cycles was 6 (range, 2–9). Follow-up for blood counts was censored at the next cytotoxic therapy. At 3 months post therapy, 78 patients were evaluable. Thirty-two (41%) had achieved full blood count recovery and 45 (59%) had persisting cytopenias. Dose intensity delivered was significantly associated with persisting cytopenias (p = 0.028), but age (p = 0.61), underlying disease (0.49) and bone marrow involvement at diagnosis (p = 0.81) were not. Of the patients who had not normalised all counts by 3 months, anemia was present in 56% (median 106 g/L, range 76–119), neutropenia in 47% (median 1.27 × 109/L, range 0.03–1.75) and thrombocytopenia in 76% (median 96 × 109/L, range 9–120). One, two and three lineage cytopenias were present in 42%, 42% and 16% of pts, respectively. The median time to normalisation of counts for those with post-treatment cytopenias in the respective lineages was 9 months (range, 6–12) for Hb, 6 months (range, 6–30) for neutrophils, and 6 months (range, 6–30) for platelets. The median time to normalisation of the lowered counts was 9 months (n = 18) in those with multi-lineage cytopenias and 6 months (n = 12) in those with one lineage cytopenia. At 1 year following Hyper-CVAD with no further therapy, 49 patients were evaluable and 3 (6%), 7 (14%), and 9 (18%) still had anemia, neutropenia or thrombocytopenia respectively. MDS/AML was diagnosed in 3 patients at 4, 21, and 21 months after therapy. Of these patients, one received an autologous stem cell transplant 2 months after Hyper-CVAD, one was cytopenic at 3 months, and one was lost to follow-up until re-presenting with AML. These results indicate a considerable rate of prolonged hematologic toxicity after Hyper-CVAD, and a minor rate of MDS at this limited follow-up. These findings likely reflect cumulative damage to hematopoietic stem cells.