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.

A prognostic model for survival after salvage treatment with FLAG-Ida +/- gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia.

The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG-Ida or FLAG-Ida plus Gentuzumab-Ozogamicin (FLAGO-Ida) of the Programa Español de Tratamientos en Hematología (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG-Ida and 38 FLAGO-Ida; 92 were older than 60 years. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 51%, with 9% of induction deaths. Three covariates were associated with lower CR/CRi: high-risk cytogenetics and t(8;21) at diagnosis, no previous allogeneic stem cell transplantation (allo-SCT) and relapse-free interval <1 year. Allo-SCT was performed in second CR in 60 patients (23%). The median overall survival (OS) of the entire cohort was 0·7 years, with 22% OS at 5-years. Four independent variables were used to construct the score: cytogenetics, FLT3-internal tandem duplication, length of relapse-free interval and previous allo-SCT. Using this stratification system, three groups were defined: favourable (26% of patients), intermediate (29%) and poor-risk (45%), with an expected 5-year OS of 52%, 26% and 7%, respectively. The SALFLAGE score discriminated a subset of patients with an acceptable long-term outcome using FLAG-Ida/FLAGO-Ida regimen. The results of this retrospective analysis should be validated in independent external cohorts.

Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry: a bridge to individualized medicine.

BACKGROUND: We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. PATIENTS AND METHODS: Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. RESULTS: The sensitivity of single drugs is assessed for standard efficacy (EMAX) and potency (EC50) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. CONCLUSION: We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection.

Results of treatment with azacitidine in patients aged ≥ 75 years included in the Spanish Registry of Myelodysplastic Syndromes.

The tolerability of azacitidine (AZA) allows its administration in elderly patients. The objective of this study was to analyze the clinical and biological characteristics, transfusion independence (TI), overall survival (OS) and toxicity in a series of 107 patients ≥ 75 years of age from the Spanish Registry of Myelodysplastic Syndromes (MDS) treated with AZA. The median age (range) was 78 (75-90) years. According to the World Health Organization (WHO) classification, 86/102 (84%) had MDS, 10/102 (10%) had mixed myeloproferative/myelodysplastic disorder and 6/102 (6%) had acute myeloblastic leukemia. Regarding MDS by the International Prognostic Scoring System on initiation of AZA, 38/84 (45%) were low-intermediate-1 risk and 46/84 (55%) were intermediate-2-high risk. Ninety-five patients (89%) were red blood cell or platelet transfusion dependent. The AZA schedule was 5-0-0 in 39/106 (37%) patients, 5-2-2 in 36/106 (34%) patients and 7 consecutive days in 31/106 (29%) patients. The median number of cycles administered was 8 (range, 1-30). Thirty-eight out of 94 (40%) patients achieved TI. Median OS (95% confidence interval [CI]) was significantly better in patients achieving TI (n = 38) compared to patients who did not (n = 56) (22 [20.1-23.9] months vs. 11.1 [4.8-17.5] months, p = 0.001). No significant differences were observed in TI rate and OS among the three different schedules. With a median follow-up of 14 (min-max, 1-50) months, the median OS (95% CI) of the 107 patients was 18 (12-23) months and the probability of OS (95% CI) at 2 years was 34% (22-46%). Cycles were delayed in 31/106 (29%) patients and 47/101 patients (47%) were hospitalized for infection. These results show that treatment with AZA was feasible and effective in this elderly population, with 40% achieving TI, having a better OS than patients not achieving it. The schedule of AZA administration did not affect efficacy and toxicity.

Transfusion dependence development and disease evolution in patients with MDS and del(5q) and without transfusion needs at diagnosis.

Patients with isolated del(5q) and MDS are considered to have good prognosis as compared to other MDS subtypes. Most patients suffered of anemia and 50% of them required transfusions at diagnosis. It is known that for patients with MDS and del(5q) in transfusion dependence(TD), Lenalidomide is the first choice treatment. However, there are no data regarding natural evolution of anemia in patients diagnosed in MDS and del(5q) without TD, factors that may impact on the development of TD or disease outcome. In the present study we have performed a retrospective multicenter analysis on 83 patients with low-int 1 MDS and del(5q) without TD. During the study 61 patients became TD at a median of 1.7 years and only the Hb level 9 g/dL was associated with poorer TFS (p = 0.007) in the multivariate analysis. Among these 61 TD patients, 49 received treatment (19 Lenalidomide). Median follow up was 48 months, estimated OS at 2 and 5 year was 92% and 50% respectively. In the multivariate analysis for OS, platelets <100,000 mm(-3) and Lenalidomide treatment retained the statistical significant impact. LFS at 2 and 5 years was 86% and 73% respectively, and median time to sAML was 8.16 years (CI 95%: 6.05-10.27). In the multivariate analysis only thrombocytopenia retained statistical significance. In summary, this retrospective study show that level of Hb is an important parameter in order to determine the time until TD, it should be also stressed the importance of an early treatment in order to prevent TD development and shorter survival.