FLT3

Midostaurin combined with chemotherapy and single-agent maintenance therapy in patients with FLT3-ITD mutant acute myeloid leukemia

The presence of fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITDs) in patients with acute myeloid leukemia (AML) have been previously shown to confer an unfavorable prognosis, due to the constitutive activation of the receptor tyrosine kinase and the downstream dysregulation of cellular proliferation.1,2 In turn, this results in low complete remission (CR) rates and high relapse rates.2 The multi-targeted kinase inhibitor, midostaurin, has been approved for use in adult patients with FLT3-ITD mutations in combination with intensive chemotherapy and as maintenance therapy, by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).

Richard F. Schlenk from the NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany, and colleagues conducted a multi-institutional, prospective, single-arm phase II trial (AMLSG 16–10, NCT01477606) to assess the effect of midostaurin in combination with high-dose cytarabine (HiDAC) with subsequent allogeneic hematopoietic cell transplantation (alloHCT) and single-agent midostaurin maintenance therapy in adult patients with FLT3-ITD positive AML (n = 284 patients; median age = 54.1 years; range, 18–70; n = 198 younger [18–60 years]; n = 86 older [61–70 years]). This study provides important data with regard to the feasibility and efficacy of midostaurin in older patients (60–70 years) and the use of the inhibitor as maintenance after alloHCT. The primary endpoint of the study was event-free survival (EFS) compared to historical controls.3

Patients were first treated with one induction cycle of ‘7 + 3’. Midostaurin was administered at a dose of 50 mg twice daily, day 8 to 48h prior to next therapy. Where patients achieved partial response (PR) an optional second cycle of induction was available. Patients achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) received consolidation therapy. Following induction therapy, patients underwent alloHCT or if alloHCT was not possible, patients received HiDAC. Following alloHCT or HiDAC, midostaurin maintenance (50 mg/bi-daily for 365 days) was given to patients, starting 30–100 days following transplantation or immediately, respectively.

Key findings:
Efficacy
  • Median follow-up time was 28.9 months (95% CI, 25.0–33.6)
  • Median EFS: 13.2 months (95% CI, 10.0–18.3)
  • Median overall survival (OS): 26.0 months (95% CI, 18.9–37.0)
  • CR/CRi rate in FLT3-ITD positive AML patients following induction therapy: 76.4% (217/284)
    • CR/CRi rates were comparable in younger and older FLT3-ITD positive AML patients: 75.8% vs 9%, P = 0.76
  • Rate of patients who received alloHCT following achievement of CR/CRi: 72.4%
  • Maintenance therapy started in 97 patients (34%)
    • In 75 patients following alloHCT
    • In 22 patients following consolidation with HiDAC
  • Median time on maintenance therapy following alloHCT vs HiDAC, respectively: 9 months vs 5 months
  • EFS at 2 years in younger vs older patients: 39% (95% CI, 33–47%) vs 34% (95% CI, 24–47%)
  • OS at 2 years in younger vs older patients: 53% (95% CI, 46–61%) vs 46% (95% CI, 35–59%)
  • Overall significant improvement of EFS by midostaurin, HR = 0.58 (95% CI, 0.48–0.70), P < 0.001
    • Significant improvement of EFS in older patients by midostaurin: HR = 0.42 (95% CI, 0.29–0.61)
Safety
  • Most common grade ≥3 adverse events (AEs) occurring in > 30% of patients during induction therapy included infection (59%) and febrile neutropenia
  • Most common grade ≥3 adverse events (AEs) occurring in > 30% of patients during maintenance therapy included gastrointestinal events (70%), infection (51%), blood/marrow events (47%), pain (38%), metabolic (38%), constitutional (36%), immunological (34%), and dermatological (30%)
  • Grade ≥3 adverse events (AEs) with midostaurin therapy were comparable to rates observed in the RATIFY study
  • In older patients, cardiac toxicities were significantly more frequent (22%), including arrhythmias (10%)
  • Higher frequency of pulmonary AEs (14%) in particular, pneumonia, in older patients

In conclusion, this phase II study showed that midostaurin in combination with intensive chemotherapy can be safely administered in older patients with FLT3-ITD positive AML. Furthermore, the results show that compared to historical controls, midostaurin significantly improved EFS in older and younger patients with FLT3-ITD positive AML. The researchers stated that the role of midostaurin maintenance needs to be further explored in a randomized setting.

References
  1. Kayser S. et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009 Sep 17; 114(12):2386-92. DOI: 10.1182/blood-2009-03-209999. [Epub 2009 Jul 14]
  2. Kayser S. et al. Midostaurin treatment in FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Expert Rev Clin Pharmacol. 2017 Nov; 10(11):1177-1189. DOI: 10.1080/17512433.2017.1387051. [Epub 2017 Oct 10]
  3. Schlenk R.F. et al. Midostaurin added to chemotherapy and continued single agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2018 Dec 18. DOI: 10.1182/blood-2018-08-869453. [Epub ahead of print].
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