Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia.

PURPOSE: Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSC) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays. EXPERIMENTAL DESIGN: We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 patients with AML who received intensive conventional chemotherapy treatment. RESULTS: The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (HR, 3.82; P < 0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR, 2.84; P = 0.001). Interestingly, 1-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-. CONCLUSIONS: In this study, we confirm the prognostic impact of post-induction multiparametric flow cytometry Bulk MRD in patients with AML. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.

Cost-effectiveness of midostaurin in the treatment of newly diagnosed FLT3-mutated acute myeloid leukemia in France.

BACKGROUND: Midostaurin (MIDO) combined with standard chemotherapy was approved by the European Medicines Agency in 2017 for the treatment of adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) based on results from the RATIFY trial. METHODS: A cost-effectiveness model was developed to compare MIDO and standard-of-care (SOC) to SOC alone in France. Per Haute Autorité de Santé (HAS) guidelines, a partitioned survival model with eight health states was used: diagnosis/induction, complete remission, relapse, hematopoietic stem cell transplantation (HSCT), HSCT recovery, post-HSCT recovery (stabilized after HSCT recovery), post-HSCT relapse, and mortality. A lifetime horizon was used beginning at diagnosis with a "cure model,", which assumed natural mortality after trial cut-off. Utility values were obtained from a systematic literature review and included disutilities. Resource utilization was based on HAS clinical guidelines and a survey of French physicians and included drugs and administration, adverse events, routine medical care, HSCT, and end-of-life care costs. RESULTS: In RATIFY and after extrapolation, MIDO improved survival compared to SOC, translating into MIDO-treated patients gaining 1.12 life years (LYs) and 1.23 quality-adjusted life years (QALYs) versus SOC. The incremental cost-effectiveness ratio (ICER) for MIDO versus SOC was €68,781 per LY and €62,305 per QALY. Sensitivity analyses showed consistency with base case findings. CONCLUSIONS: MIDO represents a clinically significant advancement in the management of newly diagnosed FLT3-mutated AML. In this analysis, MIDO add-on therapy showed gains in LYs and QALYs versus SOC alone and was found to be a cost-effective option at a €100,000 per QALY threshold for end-of-life treatment.

Are social inequalities in acute myeloid leukemia survival explained by differences in treatment utilization? Results from a French longitudinal observational study among older patients.

BACKGROUND: Evidences support social inequalities in cancer survival. Studies on hematological malignancies, and more specifically Acute Myeloid Leukemia (AML), are sparser. Our study assessed: 1/ the influence of patients' socioeconomic position on survival, 2/ the role of treatment in this relationship, and 3/ the influence of patients' socioeconomic position on treatment utilization. METHODS: This prospective multicenter study includes all patients aged 60 and older, newly diagnosed with AML, excluding promyelocytic subtypes, between 1st January 2009 to 31st December 2014 in the South-West of France. Data came from medical files. Patients' socioeconomic position was measured by an ecological deprivation index, the European Deprivation Index. We studied first, patients' socioeconomic position influence on overall survival (n = 592), second, on the use of intensive chemotherapy (n = 592), and third, on the use of low intensive treatment versus best supportive care among patients judged unfit for intensive chemotherapy (n = 405). RESULTS: We found an influence of patients' socioeconomic position on survival (highest versus lowest position HRQ5: 1.39 [1.05;1.87] that was downsized to become no more significant after adjustment for AML ontogeny (HRQ5: 1.31[0.97;1.76] and cytogenetic prognosis HRQ5: 1.30[0.97;1.75]). The treatment was strongly associated with survival. A lower proportion of intensive chemotherapy was observed among patients with lowest socioeconomic position (ORQ5: 0.41[0.19;0.90]) which did not persist after adjustment for AML ontogeny (ORQ5: 0.59[0.25;1.40]). No such influence of patients' socioeconomic position was found on the treatment allocation among patients judged unfit for intensive chemotherapy. CONCLUSIONS: Finally, these results suggest an indirect influence of patients' socioeconomic position on survival through AML initial presentation.

Induction-related cost of patients with acute myeloid leukaemia in France.

OBJECTIVE: The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost. SETTING: "Induction" patient's hospital stay from admission for "induction" to discharge after induction. METHOD: The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors. MAIN OUTCOME MEASURE: Only direct medical costs were included: treatment and hospitalisation. RESULTS: Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P < 10⁻4). This result is robust and was confirmed by sensitivity analysis. CONCLUSION: Consideration of economic constraints in health care is now a reality. Only the control of length of hospital stay may lead to a decrease in induction-related cost for patients with AML.