Efficacy
The Dumas study included patients with CR1/ CRi1 AML, who received 1 to 3 cycles of HDAC 3 g/m2 every 12 hours for three days (18 g/m2) per 1 of 2 schedules: HDAC- 123 (3 g/m2 per 12 hours, days 1, 2, and 3) or HDAC-135 (3 g/m2 per 12 hours, days 1,3, and 5) and pegfilgrastim (6 mg on day 5 with HDAC-123 or day 7 with HDAC-135 in a routine setting), or a standard daily dose of G-CSF (5 mg/kg per day from day 8 in clinical trials). All patients were systematically readmitted for management of pancytopenia on days 10 to 12, according to blood cell counts. A total of 221 AML patients fulfilled the inclusion criteria and were retrospectively included in this study: 92 (41.6%) in the HDAC-123 arm and 129 (58.4%) in the HDAC-135 arm, which matched with respect to demographic features, disease characteristics, and prognostic factors. Virtually all patients received prophylactic G-CSF except one patient during the first course, five during the second course, and one during the third course. During the three consolidation cycles, median haematological recovery times regarding WBC (>1.0 x 109/L) and neutrophils (>0.5 x 109/L) were significantly shorter with HDAC-123 compared with HDAC-135, whereas the median platelet recovery time (>50.0 x 109/L) was considerably shorter in the HDAC-123 arm only after the third cycle. The average difference in haematological recovery times between both arms was 3 to 4 days for each consolidation cycle.r
Multivariate analyses of factors associated with neutrophil recovery showed that HDAC-135 was consistently associated with a longer delay following all three consolidation cycles. However, it was associated with a longer delay only for the third consolidation cycle for platelet recovery. Finally, the shorter median recovery time for neutrophils and platelets by an average of 3 to 4 days for all three consolidation cycles in the HDAC-123 arm translated into a significant decrease in the period of hospitalisation during each cycle and, thus, for the whole post-remission program (32 days in the HDAC-123 arm compared with 41 days in the HDAC-135 arm, P <0 .0001). r
The median follow-up periods were 53.2 months in the HDAC-123 arm and 60.8 months in the HDAC-135 arm. The median overall survival (OS) was 93.2 months in the HDAC-123 arm and 97.0 months in the HDAC-135 arm (P =0 .23). The median relapse-free survival (RFS) was 83.5 months in the HDAC-123 arm and 73.6 months in the HDAC-135 arm (P =0.77). Although, both regimens were associated with similar RFS, cumulative incidence of relapse (CIR), and OS, there was a considerable difference in haematological toxicity. Patients receiving the HDAC-123 regimen spent nine days less in hospital over the whole period of postremission treatment. Indeed, clinically relevant durations of leukopenia, neutropenia, and thrombocytopenia were significantly shortened by 3 to 4 days with use of the HDAC-123 regimen compared with the HDAC-135 regimen.r
The prospective study by Jarimillo et al.r compared three cycles of consolidation chemotherapy with HDAC-135 with the condensed schedule HDAC-123. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively. There was no difference (P=0.90) between HDAC-135 and HDAC-123 in terms of OS. However, multivariable analysis revealed that HDAC-123 (HR, 1.94; P<0.0001) and treatment with pegfilgrastim (HR, 1.58; P<0.0001) were significantly associated with shorter WBC recovery, whereas older age was associated with longer WBC recovery (HR of a 10-year age difference, 0.89; P = 0.001).The need for platelet transfusions was markedly reduced from a median of 8 units in the HDAC-135 schedule to a median of 4 units in the HDAC-123 schedule (P<0.0001).
Figure 1 - Survival outcomesr
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