Intensive Chemotherapy with or without Midostaurin in Adults ≥60 years old with FLT3-Mutated AML: A FILO-DATAML-PETHEMA Real-World Study

doi:10.21203/rs.3.rs-7123525/v1

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Intensive Chemotherapy with or without Midostaurin in Adults ≥60 years old with FLT3-Mutated AML: A FILO-DATAML-PETHEMA Real-World Study

https://doi.org/10.21203/rs.3.rs-7123525/v1

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The addition of midostaurin (MIDO) to intensive chemotherapy (IC) improves survival in younger adults with FLT3-mutated acute myeloid leukemia (AML); however, real-world data in elderly patients (≥ 60 years) are limited. This large, retrospective, multicenter study from three European registries (PETHEMA, FILO, DATAML) evaluated MIDO + IC (n = 194) versus IC alone (n = 371) in 565 patients with FLT3-mutated AML aged ≥ 60 years (median age 67.5 years; 35.6% ≥70 years).

After a median follow-up of 46.0 months, MIDO + IC was associated with lower day-60 early death (8.2% vs 21.4%, p < 0.0001) and higher composite complete remission (CRc) rates (78.9% vs 63.1%, p < 0.0001). Median overall survival (OS) was 24.2 months for MIDO + IC versus 8.6 months for IC (p < 0.0001), with 5-year OS rates of 40.6% vs 12.9%, respectively. Event-free survival (EFS; median 13.5 vs 4.6 months; 5-year EFS: 36.0% vs 10.1%) and relapse-free survival (RFS; median 20.2 vs 8.0 months; 5-year RFS: 45.4% vs 15.7%) were also significantly improved (both p < 0.0001). The 5-year cumulative incidence of relapse was lower with MIDO + IC (47.8% vs 67.1%, p < 0.001). In multivariable analyses, midostaurin was an independent favorable prognostic factor for CRc (aOR 1.97 [95% CI: 1.29–2.98]), OS (aHR 0.46 [95% CI: 0.36–0.58]), EFS (aHR 0.49 [95% CI: 0.39–0.60]), and RFS (aHR 0.47 [CI: 0.36–0.62]) (all p ≤ 0.002). These benefits were confirmed by propensity score matching (n = 236).

This large real-world study demonstrates that combining midostaurin with IC significantly improves remission rates and survival outcomes in elderly patients with FLT3-mutated AML, supporting its consideration in this population.

Health sciences/Medical research/Clinical trial design/Clinical trials/Biostatistics

Health sciences/Diseases/Cancer/Cancer therapy/Targeted therapies

FLT3 mutations are among the most frequent genetic alterations (≈ 30%) in acute myeloid leukemia (AML), particularly internal tandem duplications (ITD, ≈ 25%), which are associated with high leukemic burden and poor prognosis; point mutations in the tyrosine kinase domain (TKD, ≈ 5%) also occur, however, the effect of FLT3-TKD mutations on patient prognosis remains uncertain (1, 2) (Schlenk, NEJM 2008; Daver, Leukemia 2019). FLT3 remains a well-validated therapeutic target, and midostaurin (MIDO), a type I multikinase inhibitor with activity against both FLT3-ITD and TKD mutations (3) (Weisberg, Genes Cancer 2010), was the first FLT3 inhibitor to demonstrate a survival benefit when combined with intensive chemotherapy (IC). In the pivotal phase 3 RATIFY trial (CALGB 10603), the addition of MIDO to standard « 7 + 3 » induction chemotherapy with daunorubicin and high-dose cytarabine (HDAC) consolidation significantly improved overall survival (OS) and event-free survival (EFS) in newly diagnosed FLT3-mutated AML patients aged 18 to 59 years (4) (Stone, NEJM 2017).

However, RATIFY excluded patients aged ≥ 60 years, leaving a substantial evidence gap in this increasingly prevalent age group. The German-Austrian AMLSG 16 − 10 trial, a phase 2 study including patients up to 70 years, based on a historical control, suggested improved outcomes with MIDO in older patients receiving daunorubicin-based chemotherapy (5) (Schlenk, Blood 2019). Yet, real-world data on the use of MIDO in patients ≥ 60 years remain limited, particularly in those treated with idarubicin-based regimens, which are frequently used. More recently, observational studies have reported on MIDO use in real-life cohorts using idarubicin-based backbones (6–8) (Diebold, Leuk Lymphoma 2024; Lee, Haematologica 2023; Sierra, Blood Adv 2023), but results remain heterogeneous and inconclusive.

The aim of our study was to assesses the real-world safety and efficacy of combining MIDO with intensive chemotherapy in elderly patients over 60 years of age by compiling a large real-life series of patients. This retrospective multicenter study aims at bridging this gap by evaluating real-world outcomes of MIDO therapy in elderly patients, providing critical insights into its clinical utility and informing future treatment strategies for this population.

Patients

This retrospective, multicenter study included data from adult patients registered in three observational databases: the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) registry (NCT02607059), the French Innovative Leukemia Organization (FILO) registry, and the French Toulouse-Bordeaux (DATAML) registry. For this analysis, patients were eligible if they were aged ≥ 60 years, had newly diagnosed Acute Myeloid Leukemia (AML) according to the World Health Organization (WHO) 2016 classification (9)(Arber, Blood 2015), and harbored a FLT3 mutation. Patients with acute promyelocytic leukemia and core-binding factor (CBF) AML were excluded. The study period for patient inclusion was from January 1, 2005, to August 31, 2023. The study was conducted in accordance with the Declaration of Helsinki. The protocols of the participating registries were approved by the respective institutional review boards or ethics committees of the participating centers or cooperative groups, and written informed consent for data collection and anonymized research use was obtained from all patients at the time of registration in their respective databases.

Genetic analysis

FLT3-ITD and TKD mutations and NPM1 mutations were identified at local participating institutions as part of the standard diagnostic workup at the time of patient inclusion, using either polymerase chain reaction (PCR)-based assays or next-generation sequencing (NGS) methods prevalent at the time. The FLT3-ITD allelic ratio (AR) was determined locally and collected; for analytical purposes, it was categorized using a threshold of > 0.5 versus ≤ 0.5. Cytogenetic risk stratification was performed according to the United Kingdom Medical Research Council (MRC) classification (10) (Grimwade, Blood 2010).

Study design

This study was designed as a retrospective, multicenter analysis of registry data to evaluate the efficacy of IC with or without MIDO in elderly patients (≥ 60 years) with newly diagnosed FLT3-mutated AML. The overall study design and patient flow are illustrated in the flow chart diagram (Fig. 1).

Induction Chemotherapy

Patients received various intensive chemotherapy regimens. The most common first induction course consisted of idarubicin and cytarabine based chemotherapy « 7 + 3 regimen » or « 5 + 2 regimen »( idarubicin 12 mg/m²/day on days 1–3, with cytarabine 100–200 mg/m²/day on days 1–7 or idarubicin 8–12 mg/m²/day on days 1–2, with cytarabine 100–200 mg/m²/day on days 1–5), which in some cases included lomustine (11) (idarubicin 8 mg/m²/day on days 1–5, cytarabine 100 mg/m²/day on days 1–7, with lomustine 200 mg/m² on day 1) or gemtuzumab ozogamycin (idarubicin 12 mg/m²/day on days 1–3, cytarabine 100–200 mg/m²/day on days 1–7, with gemtuzumab ozogamicin 3 mg/m² on days 1, 4, and 7). Other patients received daunorubicin and cytarabine based chemotherapy (daunorubicin 60–90 mg/m²/day on days 1–3, with cytarabine 100–200 mg/m²/day on days 1–7), including CPX-351 induction regimen (Liposomal daunorubicin 44 mg/m² and cytarabine 100 mg/m² on days 1, 3, and 5). A small proportion of patients received other diverse chemotherapy regimens as detailed in Supplementary Table S1. For patients in the midostaurin group (IC + MIDO), midostaurin was administered orally at a dose of 50 mg twice daily on days 8 through 21 of the induction cycle, concurrently with IC.

Consolidation Therapy: Patients achieving CR or CRi after induction were eligible for consolidation therapy. Consolidation regimens included intermediate or high-dose cytarabine (I/HDAC) -based chemotherapy or CPX-351 (HiDAC : cytarabine 3 g/m² twice daily on days 1, 3, and 5; IDAC : cytarabine 1.5 g/m² twice daily on days 1, 3, and 5 or CPX-351 : liposomal daunorubicin 29 mg/m² and cytarabine 65 mg/m² on days 1 and 3), less intensive outpatient "mini-consolidation regimen" (12) (idarubicin 8 mg/m² on day 1, cytarabine 50 mg/m² twice daily IV on days 1 to 5), or autologous stem cell transplantation (SCT). Patients in the IC + MIDO group who achieved remission continued to receive midostaurin 50 mg twice daily on days 8 to 21 during consolidation chemotherapy cycles.

Maintenance Therapy

Following consolidation, an attempt was made to provide midostaurin maintenance monotherapy to responding patients in the IC + MIDO group. Maintenance consisted of midostaurin 50 mg twice daily for up to 12 cycles of 28 days each, or until relapse or unacceptable toxicity. However, due to market access restrictions, great heterogeneity was foreseen.

Allogeneic Stem Cell Transplantation (HSCT)

Allogeneic HSCT was considered for eligible patients based on individual risk assessment, donor availability, and institutional guidelines and practices.

Definition of response criteria, survival endpoints, and hematologic recovery

Response to treatment, including complete remission (CR), complete remission with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR), were defined according to the European LeukemiaNet (ELN) 2022 recommendations (13). Composite complete remission (CRc) was defined as achieving either CR or CRi. Primary refractory AML was defined as failure to achieve CR or CRi after one course of induction chemotherapy. Relapse was defined as ≥ 5% bone marrow blasts, reappearance of blasts in peripheral blood, or development of extramedullary disease after achieving remission. Hematologic recovery criteria are implicitly included within the ELN 2022 definitions of CR and CRi. Early death was assessed at day 30 and day 60 post-induction initiation.

Statistical analysis

The sample size for this retrospective analysis was determined by the number of eligible patients (≥ 60 years with FLT3-mutated AML) available within the PETHEMA, FILO, and DATAML registries during the specified study period who met all inclusion criteria.

Prior to analysis, data were verified for missing, aberrant, or inconsistent values. After corrections, the database was locked for analysis. All analyses, particularly multivariable models, were performed on a complete-case basis for the variables included in each model. Descriptive statistics were used to summarize patient and treatment characteristics: numbers and frequencies (of non-missing data) for qualitative variables; and number of missing values, mean, standard deviation (SD), median, interquartile range (IQR; 25th-75th percentiles), and range (min-max) for quantitative variables.

Survival outcomes (OS, EFS, RFS) were estimated using the Kaplan-Meier method, and curves were compared using the log-rank test. The median follow-up was calculated using the reverse Kaplan-Meier technique. Due to differing follow-up durations between treatment groups, patients in the IC without midostaurin group were censored at 60 months for comparative survival analyses to mitigate potential bias. CIR was estimated using cumulative incidence functions, considering non-relapse mortality as a competing event, and compared using Gray’s test.

Comparisons of baseline patient and treatment characteristics between the IC with midostaurin and IC without midostaurin groups were performed using Student’s t-test or Mann-Whitney U test for continuous variables (based on normality and homoscedasticity) and the χ2-test or Fisher’s exact test for categorical variables, as appropriate.

To assess the independent prognostic impact of midostaurin, multivariable Cox proportional hazards models were used for OS, EFS, and RFS, and a multivariable logistic regression model was used for CRc rates. Variables considered for inclusion in the multivariable models were treatment group (midostaurin vs. no midostaurin), age (≥ 70 vs. <70 years), sex (male vs female), ECOG performance status (0–1 vs. ≥2), AML status (de novo vs. secondary), baseline white blood cell (WBC) count (≥ 30 x10⁹/L vs. <30 x10⁹/L), cytogenetic risk (favorable/intermediate vs. adverse), FLT3-ITD mutation presence, FLT3-ITD ratio (> 0.5 vs. ≤0.5), FLT3-TKD mutation presence, NPM1 mutation status, and allogeneic HSCT (as a time-dependent covariate for survival endpoints only). A stepwise selection procedure was applied until only variables significantly and independently associated with the outcome (p < 0.05) remained in the final model. The proportional-hazards assumption for Cox models was checked using “log-log” plots for each covariate. Interactions between significant independent covariates and midostaurin treatment were tested in the final models.

As a sensitivity analysis to account for potential baseline imbalances between treatment groups, a propensity score matching (PSM) analysis was performed. A logistic regression model was generated to estimate each patient's propensity score for receiving midostaurin. Covariates included in the propensity score model were age, sex, ECOG performance status, AML status, baseline WBC count, cytogenetic risk, FLT3-ITD mutation, FLT3-ITD ratio, FLT3-TKD mutation, NPM1 mutation, and French-American-British (FAB) classification. The model's performance was assessed using the Hosmer-Lemeshow statistic and the c-statistic.

All reported p-values were two-sided, and a p-value < 0.05 was considered statistically significant. Statistical analyses were performed using STATA® version 18.0 (StataCorp LLC, College Station, TX, USA).

Study Population

A total of 583 patients with FLT3-mutated AML were initially identified and fulfilled the inclusion criteria. After excluding 17 duplicates patients and 1 patient with a rare acute promyelocytic leukemia transcript, the analyzed cohort comprised 565 patients. The overall study design and patient flow are illustrated in the flow chart diagram (Figure 1). The characteristics of these 565 patients are detailed in Table 1. Among them, 65.7% (371) received intensive chemotherapy without midostaurin (IC group), collected between January 2005 and June 2017, and 34.3% (194) received IC combined with midostaurin (IC+MIDO group), collected between June 2017 and August 2023.

The median age for the entire cohort was 67.5 years (range: 60.0-81.4 years), with 35.6% (201) aged ≥70 years. Males constituted 52.2% of the patients, and 19% had secondary AML. Regarding cytogenetic risk according to the MRC classification, the majority of patients (93.1%) belonged to the intermediate-risk group.

FLT3-ITD mutations were present in 85.5% (483) of patients. Significant baseline differences were observed between the IC and IC+MIDO groups (Table 1). The IC group had a higher median white blood cell count (WBC) (54.9 × 10⁹/L [IQR, 18.2–133.2] vs. 25.4 × 10⁹/L [IQR, 6.3–96.6] for IC+MIDO; p < 0.001), a greater proportion with ECOG performance status ≥ 2 (27.2% vs. 13.4%; p < 0.001), and a higher prevalence of FLT3-ITD mutations (88.7% vs. 79.4%; p = 0.002). The prevalence of FLT3-TKD mutations, identified in 21.5% (98) of the cohort, did not significantly differ between groups (19.5% in IC vs. 24.2% in IC+MIDO; p = 0.229). NPM1 mutations, found in 61.4% (341) of patients, were also similarly distributed (58.8% vs. 66.5%; p = 0.076).

Induction Chemotherapy, Response Rates, and Consolidation Therapy

The induction chemotherapy regimens are detailed in Supplementary Table S1. Predominantly, idarubicin-based regimens were administered, with idarubicin plus cytarabine ("7+3") given to 48.3% (273) of patients, and idarubicin "7+3" combined with lomustine (CCNU) to 32.4% (183) of patients. Gemtuzumab ozogamicin was added to an idarubicin-based regimen for 3 patients. Daunorubicin-based regimens were used in 8.9% (50) of patients, which included standard daunorubicin "7+3" for 6.2% (35) and CPX-351 for 2.7% (15). Others intensive chemotherapy regimens were administered to 3.7% (21) of patients.

After excluding 7 patients who died before day 8 of induction (all from the IC group), early death (ED) rates were significantly lower in the IC+MIDO group compared to the IC group. ED by day 30 occurred in 3.6% (7) of IC+MIDO patients versus 16.2% (59) of IC patients (p<0.0001). Similarly, ED by day 60 was 8.2% (16) in the IC+MIDO group versus 21.4% (78/364) in the IC group (p<0.0001).

Following one cycle of first-line induction chemotherapy, the composite complete remission (CRc) rate, defined as CR plus CRi, was significantly higher in the IC+MIDO group at 78.9% (153) compared to 63.1% (234) in the IC group (p<0.0001). Detailed responses are presented in Table 2. The overall response rate (ORR; CRc + partial remission [PR]) was 80.9% (157) for IC+MIDO versus 66.6% (247) for IC. Failure of one cycle of first-line induction chemotherapy (progression or stable disease) was comparable between the IC+MIDO group (13.4%; 26) and the IC group (14.6%; 54). Absence of response evaluation after induction was significantly less frequent in the IC+MIDO group (4.6%; 9) compared to the IC group (18.9%; 70; p<0.0001).

Multivariable logistic regression analysis showed that midostaurin treatment was independently associated with an increased likelihood of achieving CRc (aOR 1.97, [95% CI: 1.29–2.98], p=0.002). In contrast, age ≥70 years (aOR 0.61, [95% CI: 0.42–0.89], p=0.010), ECOG ≥2 at diagnosis (aOR 0.64, [95% CI: 0.41–0.99], p=0.047), and adverse cytogenetic risk (aOR 0.39, [95% CI: 0.19–0.83], p=0.015) were each associated with a reduced likelihood of achieving CRc (Table 3).

Consolidation therapy was administered to patients achieving CRc (N=387). I/HDAC regimens were received by 230 patients: 124 in the IC group and 106 in the IC+MIDO group. The median number of I/HDAC cycles was 2 (range: 1-3) in the IC group and 2 (range: 1-4) in the IC+MIDO group; patients in the IC+MIDO group tended to receive a greater number of cycles (p=0.003). Less intensive outpatient mini-consolidations were administered to 105 patients: 74 in the IC group and 31 in the IC+MIDO group. The median number of mini-consolidation cycles was 4 (range: 1-7) in the IC group and 5 (range: 1-7) in the IC+MIDO group, with no significant difference observed (p=0.272). Autologous stem cell transplantation was performed in 4.7% (18) CRc patients. Allogeneic HSCT was performed in 18.0% (35) of patients in the IC+MIDO group compared to 10.8% (40) in the IC group (p=0.015). Patients in the IC+MIDO arm achieving remission continued midostaurin during consolidation cycles.

MAINTENANCE

A total of 61 patients initiated maintenance therapy with midostaurin. Among the 106 patients who started consolidation chemotherapy, 55,7% (59) subsequently proceeded to midostaurin maintenance. Additionally, of the 35 patients who underwent allogeneic HSCT, 17.1% (6) received post-transplant maintenance with midostaurin.

Outcomes

To mitigate potential bias from differing follow-up durations between treatment groups, patients in the IC group were censored at 60 months for comparative survival analyses. The median follow-up for the entire cohort, after this censoring, was 46.0 months (IQR, 31.5-60.0 months).

Overall survival (OS) was significantly improved in the IC+MIDO group compared to the IC group (p<0.0001; Figure 2A). The median OS was 24.2 months (IQR, 10.5-NR) for the IC+MIDO group versus 8.6 months (IQR, 2.4-21.7) for the IC group. One-year, 3-year, and 5-year OS rates for the IC+MIDO group were 69.0%, 44.6%, and 40.6%, respectively, compared to 38.1%, 18.9%, and 12.9% for the IC group.

In the subgroup of patients <70 years (n=364), median OS was 36.4 months (IQR, 11.8-NR) with IC+MIDO versus 8.9 months (IQR, 3.1-23.5) with IC (p<0.0001; Figure 2B). For patients aged ≥70 years (n=201), median OS was 16.3 months (IQR, 5.6-NR) with IC+MIDO versus 7.8 months (IQR, 1.7-20.1) with IC (p=0.003; Figure 2C). Among NPM1-mutated patients (n=341), median OS was not reached (IQR, 11.4-NR) with IC+MIDO versus 8.6 months (IQR, 2.4-23.2) with IC (p<0.0001; Figure 2D).

A Cox proportional hazards model for OS (Table 3) showed that ECOG performance status ≥2 (aHR 1.36, 95% CI: 1.07-1.72, p=0.01), secondary AML (aHR 1.37, 95% CI: 1.08-1.75, p=0.01), baseline WBC count ≥30x10⁹/L (aHR 1.27, 95% CI: 1.03-1.56, p=0.028), and FLT3-ITD allelic ratio >0.5 (aHR 1.45, 95% CI: 1.15-1.83, p=0.002) were independently associated with shorter OS. Conversely, treatment with midostaurin (IC+MIDO) was independently associated with longer OS (aHR 0.46, 95% CI: 0.36-0.58, p<0.001).

Event-free survival (EFS) was significantly longer with IC+MIDO (Figure 2E); median EFS was 13.5 months (IQR, 3.8-NR) versus 4.6 months (IQR, 1.1-13.8) with IC (p<0.0001). The 1-year, 3-year, and 5-year EFS rates for the IC+MIDO group were 52.5%, 36.0%, and 36.0%, respectively, compared to 27.0%, 13.2%, and 10.1% for the IC group. EFS outcomes for NPM1-mutated patients are presented in Supplementary Figure S1A. For patients <70 years and ≥70 years, EFS outcomes are shown in Supplementary Figure S2A and Figure S3A, respectively.

Relapse-free survival (RFS) was also significantly improved in the IC+MIDO group (Figure 2F), with a median RFS of 20.2 months (IQR, 8.4-NR) compared to 8.0 months (IQR, 3.9-22.4) for the IC group (p<0.0001). The 1-year, 3-year, and 5-year RFS rates for the IC+MIDO group were 63.4%, 45.4%, and 45.4%, respectively, compared to 40.0%, 20.4%, and 15.7% for the IC group. RFS outcomes for NPM1-mutated patients are presented in Supplementary Figure S1B. For patients <70 years and ≥70 years, RFS outcomes are shown in Supplementary Figure S2B and Figure S3B, respectively. Multivariate analyses for EFS and RFS (Table 3) indicated that midostaurin was significantly and independently associated with improved outcomes for both.

The cumulative incidence of relapse (CIR) was significantly lower in the IC+MIDO group compared to the IC group (p<0.001; Figure 2G). At 1 year, 3 years, and 5 years, CIR for the IC+MIDO group was 32.2%, 45.3%, and 47.8%, respectively, versus 48.5%, 64.4%, and 67.1% for the IC group. CIR for NPM1-mutated patients is presented in Supplementary Figure S1C. For patients <70 years and ≥70 years, CIR outcomes are shown in Supplementary Figure S2C and Figure S3C, respectively. Sensitivity analyses censoring patients at the time of allogeneic HSCT yielded similar results for RFS and CIR (Supplementary Figure 4).

Sensitivity Analysis Using Propensity Score Matching

To further account for potential baseline differences between the IC and IC+MIDO groups, a propensity score matching (PSM) analysis was performed. A multivariable logistic regression model was generated to estimate each patient's propensity score for receiving midostaurin. Covariates included in this model were age, sex, ECOG performance status, AML status, WBC count, cytogenetic risk, FLT3-ITD mutation, FLT3-ITD allelic ratio, FLT3-TKD mutation, NPM1 co-mutation, and FAB classification. The model's performance was assessed using the Hosmer-Lemeshow χ2 statistic (p=0.244) and the c-statistic (0.72, 95% CI: 0.68-0.77). Prior to matching, the mean propensity score was 0.361 (±0.190) in the IC group (N=260 with complete data for PSM) and 0.511 (±0.160) in the IC+MIDO group (N=192 with complete data for PSM). Using these scores, 118 patients receiving midostaurin were matched on a 1:1 basis with 118 patients not receiving midostaurin. In the matched sample of 236 patients, mean propensity scores were well balanced between the IC+MIDO group (0.465 ± 0.143) and the IC group (0.465 ± 0.144). Outcomes (CRc, OS, EFS, and RFS) were then compared between these matched groups.

In the propensity score-matched cohort (N=236), the CRc rate was significantly higher in the IC+MIDO group (79.7%, 94/118) compared to the IC group (60.2%, 71/118; p<0.001). Treatment with midostaurin in the matched cohort also resulted in significantly improved survival outcomes (Figure 3). Median OS was 24.2 months (IQR, 10.5-NR) for the IC+MIDO group versus 8.9 months (IQR, 1.9-19.7) for the IC group (p<0.0001). Median EFS was 13.8 months (IQR, 3.7-NR) for IC+MIDO versus 3.5 months (IQR, 1.0-10.4) for IC (p<0.0001). Similarly, median RFS was 20.1 months (IQR, 8.0-NR) for IC+MIDO compared to 8.0 months (IQR, 3.5-45.4) for IC (p=0.0019).

Our real-world study on a large cohort of elderly patients (≥ 60 years) with newly diagnosed FLT3-mutated AML suggests that the addition of midostaurin to intensive chemotherapy is associated with improved OS compared to IC alone. This finding, from a retrospective analysis, aligns with the robust survival benefits demonstrated for midostaurin in younger patients (< 60 years) in the pivotal RATIFY trial (4) and extends observations from the AMLSG 16 − 10 clinical trial (5) and the Sierra et al. phase 3b study (8), which included older patients (≥ 60 years). Although the primary endpoint of the Sierra et al. study was safety, and survival data were not systematically collected post-treatment, both this study and the AMLSG trial supported the feasibility and activity of midostaurin combinations in older adults.

The baseline characteristics of our cohort reflect a challenging, older population, with a median age of 67.5 years and 35.6% (201) of patients aged ≥ 70 years. This contrasts with the RATIFY trial, which was limited to patients < 60 years. In comparison, our cohort is representative of older patients, aligning more closely with the 61–70-year-old subset of the AMLSG 16 − 10 trial and the population studied by Sierra et al., in which 47.2% of patients were over 60 years (despite a median age of 59) and only a limited number of patients aged ≥ 70 years. The inclusion of a significant number of patients over 70 years of age in our real-world setting provides valuable insights into a group often underrepresented in clinical trials. However, we acknowledge notable baseline differences between our IC and IC + MIDO groups, particularly regarding FLT3-ITD mutation prevalence, ECOG performance status, and WBC counts, which necessitated adjustments in our analyses, including propensity score matching, to mitigate selection bias.

The CRc rate of 78.9% observed in our IC + MIDO group is comparable and encouraging when contextualized with other studies. For instance, the AMLSG 16 − 10 trial reported a CR + CRi rate of 77.9% in patients aged 61–70 years treated with midostaurin plus chemotherapy. Similarly, the Sierra et al. phase 3b study showed an overall CR + CRi of 80.7%, with 82.5% in patients > 60 to ≤ 70 years and 64.1% in those > 70 years. The CR rate in the RATIFY midostaurin arm was 58.9% (CR + CRi not explicitly reported as a combined primary endpoint). Furthermore, our finding of a lower 5-year CIR (47.8%) in the IC + MIDO group is a clinically relevant observation, consistent with later analyses of the RATIFY study that demonstrated a reduction in CIR with midostaurin.

A distinctive feature of our study is the predominant use of idarubicin-based induction regimens, reflecting common real-world practice in many European centers. This contrasts with the RATIFY trial, which exclusively used daunorubicin (60 mg/m²) in its standard "7 + 3" backbone, and the AMLSG 16 − 10 trial, which also employed daunorubicin-based chemotherapy. The Sierra et al. study, however, allowed for both daunorubicin (60–90 mg/m²) and idarubicin (12 mg/m²), with 55.1% of patients receiving idarubicin, and reported similar CR + CRi rates irrespective of the anthracycline used. Our results with various regimens predominantly based on idarubicin contribute to the evidence supporting midostaurin's efficacy with different anthracycline partners.

Regarding post-remission therapy, our data did not show a clear impact of HSCT on outcomes in this elderly population, which warrants careful interpretation. In RATIFY (< 60 years), HSCT was performed in 57% of patients, and the benefit of midostaurin was observed in patients transplanted in first remission. The AMLSG 16 − 10 trial (up to 60 years) had a high rate of allogeneic HSCT (72.4% of remitters) and showed favorable outcomes with the midostaurin-chemotherapy-HSCT sequence. The differing impact of HSCT in our cohort might be influenced by advanced age, patient selection for transplant, or other unmeasured confounders typical of real-world data.

The retrospective nature of our analysis is a primary limitation, introducing potential selection bias, despite statistical adjustments. Differences in baseline characteristics (e.g., poorer ECOG scores and higher WBC counts in the IC group, and a higher prevalence of FLT3-ITD in that group before matching) underscore this. The extended accrual period may also encompass evolving standards of care and HSCT guidelines, which likely influenced outcomes. Furthermore, the lack of systematic NPM1 mutation-based minimal residual disease (MRD) assessment is a limitation, given its prognostic significance. Nevertheless, the most relevant finding remains the OS of 24.2 months observed in the IC + MIDO group, independently of cross-arm comparisons.

Looking forward, prospective studies are crucial, particularly to define the role of maintenance therapy with FLT3 inhibitors in this older. Midostaurin maintenance was explored in RATIFY, AMLSG 16 − 10, and Sierra et al., but its optimal use, duration, and benefit, especially post-HSCT in older patients, require further investigation. This is particularly relevant in the context of other maintenance options like oral azacitidine (CC-486) and emerging, more potent FLT3 inhibitors such as quizartinib, whose safety and efficacy in combination or as maintenance in older, less fit patients with FLT3-mutated AML warrant dedicated trials. However, due to market access restrictions across participating centers, the use of midostaurin maintenance therapy was highly heterogeneous. Consequently, this aspect was not systematically studied nor consistently captured in the registry database. Further prospective studies specifically addressing the role and optimal conditions of maintenance therapy with midostaurin in older patients with FLT3-mutated AML are warranted to clarify its potential benefit in this population.

An important limitation of our study is the inherent bias when making historical comparisons. In fact, a part of the study period, patient´s characteristics were different between cohorts, and this could be especially relevant for the higher induction mortality rate observed in patients receiving IC alone. Also, higher ITD mutation frequency in the IC alone group, along with trends for higher allo-HCT rate in recent periods, could relate to higher CIR in patients without midostaurin. Overall, our results support the clinical benefit provided by midostaurin, but they are also showing improvements in general management of older AML patients undergoing IC in modern era.

In conclusion, despite the inherent limitations of a retrospective registry-based comparison, our findings suggest that the combination of midostaurin with intensive chemotherapy is feasible and associated with very good response rates and encouraging survival outcomes in a difficult-to-treat, real-world population of elderly patients with FLT3-mutated AML. These results complement data from prospective trials and support the consideration of this combination for fit older adults.

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Tables 1 to 4 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

MIDOLATable1Baseline.docx
Table 1
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Supplementary Figure 2
MIDOLATable2Response.docx
Table 2
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Supplementary Figure 3
MIDOLATable3RegLog.docx
Table 3
MIDOLATable4CoxOS.docx
Table 4
MIDOLAFigureS1.jpg
Supplementary Figure 1
MIDOLATableS1ICT.docx
Supplementary Table 1
MIDOLATableS2CoxEFS.docx
Supplementary Table 2
MIDOLAFigureS4.jpg
Supplementary Figure 4
MIDOLATableS3CoxRFS.docx
Supplementary Table 3

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Intensive Chemotherapy with or without Midostaurin in Adults ≥60 years old with FLT3-Mutated AML: A FILO-DATAML-PETHEMA Real-World Study

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