A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia.

BACKGROUND: Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). METHODS: Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. RESULTS: The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). CONCLUSIONS: FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.

Engraftment syndrome emerges as the main cause of transplant-related mortality in pediatric patients receiving autologous peripheral blood progenitor cell transplantation.

The authors examined data from 166 children who received autologous peripheral blood progenitor cell (PBPC) transplantation to ascertain the incidence of early transplant-related mortality (TRM) and the contributing risk factors. Eleven patients (6.6%) (6 boys, 5 girls) died within 180 days following PBPC infusion. The median age was 4 years (range 2-17). The overall probability of TRM was 6.9 +/- 2% at day +180. On univariate analysis, the status of disease at transplantation (complete remission vs. not in complete remission) was identified as the only pretransplant significant predicting factor for TRM (14% of patients who were not in complete remission died within 180 days after PBPC infusion, whereas only 2% of patients in complete remission died) (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, P = 0.01). Age, gender, conditioning, and number of CD34+ cells infused were not significantly associated with TRM. In the postinfusion phase, patients who developed multiorgan dysfunction during the neutropenic period, especially when the lung was the first failing organ (RR 16.1, 95% CI 7.16-36.18, P = 0.0001), and those with engraftment syndrome (RR 2.81, 95% CI 1.49-5.24, P = 0.001) had an increased risk for TRM. On multivariate analysis, development of engraftment syndrome was the only significant variable that influenced TRM. In conclusion, the authors found for the first time that engraftment syndrome emerges as the main cause of TRM after autologous PBPC transplantation in children with malignancies.