Proportion of Patients with AML and FLT3 Mutations

Overall, 819 of the 2282 patients (35.9%) diagnosed with AML from the Midi-Pyrénées registry and 1244 of the 1953 patients (63.7%) diagnosed with AML from the Hauts-de-France registry were eligible for inclusion in the study (Table 1). In the Midi-Pyrénées and Hauts-de-France cohorts, 172 (21.0%) and 263 (21.1%) of the eligible patients, respectively, had a documented FLT3 mutation (Table 1). A total of 71 patients in the Midi-Pyrénées cohort and 91 in the Hauts-de-France cohort had documented R/R AML; 61 (85.9%) and 81 (89.0%) of these patients, respectively, acquired R/R status with an index date on or before December 31, 2017.

Table 1 Study populationsDemographic and Clinical Characteristics of Patients with FLT3-Mutated R/R AMLMidi-Pyrénées Cohort

The median age at AML diagnosis was 61.0 years; the median age at the index date was 61.7 years. Most patients were female (54.1%) with de novo AML (82.0%) and intermediate 1 cytogenetic risk status (78.7%) (ELN 2010 criteria) (Table 2). Proportions of patients with an Eastern Cooperative Oncology Group (ECOG) performance status < 2 were similar at the time of diagnosis (62.3%) and at the index date (59.0%). Comorbidity data were available for 32 (52.5%) patients aged 60 years or older at the time of diagnosis. The most common comorbidities were high blood pressure (37.5%), history of cardiovascular disease (34.4%), diabetes (12.5%), and history of cancer (12.5%); almost two-thirds (65.6%) of these patients had a Charlson Comorbidity Index score of 0.

Table 2 Demographic and clinical characteristics at diagnosis or index date and treatment characteristics before the index dateHauts-de-France Cohort

The median age was 55.7 years at the time of AML diagnosis and 56.9 years at the index date (Table 2). Most patients were female (56.8%) with de novo AML (92.6%). Data related to ECOG performance status at the date of diagnosis were missing for most patients (70.4%).

Treatments Before Acquiring R/R Status and OutcomesMidi-Pyrénées Cohort

Of the 61 patients with FLT3-mutated R/R AML, most received intensive induction chemotherapy with idarubicin–cytarabine combination regimens: 20 patients (32.8%) received an idarubicin–cytarabine combination regimen and 24 (39.3%) received an idarubicin–cytarabine–lomustine combination regimen. A daunorubicin–cytarabine combination regimen was administered in 13 (21.3%) patients (Table 2). In addition to intensive chemotherapy, 40 (65.6%) patients received hydroxyurea and 24 (39.3%) received dexamethasone before the index date.

Achievement of CR/CRi with induction chemotherapy before the index date was reported in 50 (82.0%) patients; 11 (18.0%) of these patients also received allogeneic HSCT before the index date. One patient (1.6%) received autologous HSCT before the index date but did not achieve CR/CRi.

Hauts-de-France Cohort

Among the 71 patients with R/R FLT3-mutated AML, the most common induction chemotherapy regimens were idarubicin–cytarabine–lomustine (n = 45, 55.6%) and daunorubicin–cytarabine (n = 29, 35.8%) (Table 2). Idarubicin–cytarabine (n = 7, 8.6%) and other types of induction chemotherapy were administered in the setting of clinical trials for 45 (55.6%) patients (Table 2); 28 (62.2%) of these 45 patients received daunorubicin–cytarabine combination regimens either in the comparator or in the interventional arm. In addition to intensive chemotherapy, hydroxyurea was administered in 20 (24.7%) patients before the index date.

Most patients (n = 79, 97.5%) achieved CR/CRi before the index date, including 76 (93.8%) patients who achieved CR. Of the 79 patients who achieved CR/CRi after intensive induction chemotherapy, 13 (16.0%) also received allogeneic HSCT before the index date. Most patients (n = 66, 81.5%) received consolidation therapy, most frequently with high-dose cytarabine (n = 34/66, 51.5%).

Eight patients received salvage therapy as first-line therapy; seven of these patients received high-dose cytarabine (high-dose cytarabine plus amsacrine, n = 5; high-dose cytarabine plus anthracycline, n  = 1; high-dose cytarabine, n = 1).

Treatments After the Index Date and OutcomesMidi-Pyrénées Cohort

Of the 42 patients with R/R FLT3-mutated AML who did not participate in a clinical trial, 31 (73.8%) received salvage therapy after the index date (Table 3). Salvage treatments were highly variable with six patients receiving high-dose cytarabine, two patients receiving anthracycline plus cytarabine, and the remaining 21 patients receiving a range of other therapies. Data related to allogeneic HSCT after acquiring primary R/R status were missing for most patients (78.6%) (Table 3). Eight patients received allogeneic HSCT after reaching primary R/R status and the median time to allogeneic HSCT in these patients was 4.0 months after the index date. Information on autologous HSCT treatment after the index date was missing for all patients.

Table 3 Treatments in patients with FLT3-mutated AML after achievement of primary R/R status (population of patients not participating in clinical trials)

Fourteen of the 42 patients (33.3%) achieved CR/CRi after salvage therapy (Table 3). Five of these 14 patients achieved CR, salvage therapy failed in 10 (23.8%) patients, and data were missing for 18 (42.9%) patients.

Hauts-de-France Cohort

Of the 32 patients with R/R FLT3-mutated AML who did not participate in a clinical trial, 31 (96.9%) received post-index therapy, which included palliative care (n = 9), amsacrine plus cytarabine (n = 8), demethylating agents (n = 6), high-dose cytarabine (n = 2), intensive chemotherapy plus gemtuzumab ozogamicin (n = 2), fludarabine plus high-dose cytarabine plus novantrone (n = 1), and others (n = 3). Nine (28.1%) patients received allogeneic HSCT after the index date, and the median time to allogeneic HSCT in these patients was 3.5 months after the index date. Nine (28.1%) patients achieved CR/CRi after salvage treatment and treatment failure was reported in 22 (68.8%) patients (Table 3).

OS After the Index DateMidi-Pyrénées Cohort

Of the 49 patients with R/R FLT3-mutated AML who were analyzed for OS, 38 (77.6%) died after the index date. The median survival time was 5.2 (IQR 2.3–11.1) months (Fig. 1). Twenty-five (80.6%) of the 31 patients who did not participate in a clinical trial and 13 (72.2%) of the 18 patients who participated in a trial had died; median OS was 4.9 (IQR 1.5–9.4) months and 6.4 (IQR 2.6–17.3) months, respectively.

Fig. 1

Overall survival (OS) after the index date in the Midi-Pyrénées cohort. HSCT hematopoietic

Ten (90.9%) of the 11 patients who received HSCT and 28 (73.7%) of the 38 patients who did not receive HSCT had died; median OS was 7.6 (IQR 2.7–12.9) months and 4.9 (IQR 1.6–9.9) months, respectively.

Hauts-de-France Cohort

Of the 78 patients with R/R FLT3-mutated AML who were analyzed for OS, 54 (69.2%) patients died after the index date; median OS was 6.1 (IQR 2.5–35.2) months (Fig. 2). Twenty-four (75.0%) of 32 patients who did not participate in a clinical trial and 40 (87.0%) of 46 patients who participated in a trial had died; median OS was 3.8 (IQR 2.1–21.9) months and 7.5 (IQR 3.6–NA) months, respectively.

Fig. 2

Overall survival (OS) after the index date in the Hauts-de-France cohort. HSCT hematopoietic

Twenty-four (36.9%) of 65 patients who did not receive HSCT and 10 (76.9%) of 13 patients who received HSCT had died; median OS was 7.0 (IQR 2.4–35.2) months and 6.1 (IQR 3.6–18.5) months, respectively.

EFS After Index Date

Analysis of EFS was limited to the Midi-Pyrénées cohort. Of the 49 patients with R/R FLT3-mutated AML who were analyzed for EFS, 40 (81.6%) experienced an event after the index date; median EFS was 2.3 (IQR 1.5–7.0) months (Fig. 3). Overall, 18 of the 49 patients had participated in a clinical trial and 31 had not; respective numbers of patients who experienced an event were 26 (83.9%) and 14 (77.8%), respectively, and corresponding median EFS was 2.7 (IQR 1.0–6.8) months and 2.0 (IQR 1.6–12.9) months, respectively.

Fig. 3

Event-free survival (EFS) after the index date in the Midi-Pyrénées cohort