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Please note that Rydapt ®▼ (midostaurin) is not subject to additional monitoring in Northern Ireland.
Rydapt is indicated:
- in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by Rydapt single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive.
- as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN), or mast cell leukaemia (MCL).
RATIFY: International, randomised controlled Phase 3 trial of RYDAPT with standard of care* (SOC) vs placebo plus SOC in newly diagnosed FLT3+ AML adult patients.1
- SOC: A cycle was 28 days. Chemotherapy dosing during induction was cytarabine IV, 200 mg/m2/d on Days 1–7, and daunorubicin IV, 60 mg/m2/d on Days 1–3. During consolidation, high-dose cytarabine was given at a dose of 3 g/m2/d IV over a period of 3 hours every 12 hours on Days 1, 3 and 5.1
Primary endpoint: Overall survival defined as the time from randomisation to death from any cause.1
Study design:
Rydapt should be dosed every day during maintenance therapy until relapse, for up to 12 cycles.
Results: RYDAPT therapy resulted in a significant improvement in overall survival compared with placebo plus SOC.*†
The difference between groups in median overall survival may be large because of the inflection points on the Kaplan–Meier curves; however, the corresponding hazard ratio for death more accurately reflects the magnitude of benefit.
- A higher proportion of patients achieved protocol-defined complete remission with RYDAPT and SOC vs placebo and SOC1
- More patients in the RYDAPT and SOC group underwent SCT during their first complete remission compared with placebo and SOC1 (28.1% of the patients in the RYDAPT group vs 22.7% in the placebo group; p=0.10 by Fisher’s exact test)
RYDAPT + SOC: Making the opportunity for extended overall survival vs placebo a reality.1,2
Overall survival according to subtype
- RYDAPT with SOC increased OS vs placebo with SOC in FLT3 positive AML1
High ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively)
Overall survival in risk groups stratified by European LeukemiaNet Recommendations 20173
- In an unplanned post-hoc exploratory analysis of a subset (n=318) of RATIFY patients with FLT3-ITD3
- 5-year OS rates, according to risk category were as follows:3
- Adverse: 0.43 (95% CI, 0.32–0.56) with RYDAPT and SOC* vs 0.20 (95% CI, 0.12–0.35) with placebo and SOC*
- Intermediate: 0.52 (95% CI, 0.40–0.67) with RYDAPT and SOC* vs 0.34 (95% CI, 0.23–0.49) with placebo and SOC*
- Favourable: 0.73 (95% CI, 0.60–0.89) with RYDAPT and SOC* vs 0.53 (95% CI, 0.40–0.72) with placebo and SOC*
Risk groups characterised by European LeukemiaNet Recommendations 2017
- Adverse (n=122): NPM1wt/FLT3-ITDhigh AML (n=92), NPM1mut/FLT3-ITDhigh AML exhibiting high-risk molecular markers (n=8), and NPM1wt/FLT3-ITDlow AML with high-risk molecular markers and/or adverse risk cytogenetics (n=22)3
- Intermediate (n=111): NPM1mut/FLT3-ITDhigh AML (n=93) and NPM1wt/FLT3-ITDlow AML (n=18), both subgroups without the concurrent presence of the high-risk molecular markers RUNX1, ASXL1, and TP53. Also, NPM1wt/FLT3-ITDlow AML without adverse-risk cytogenetics3
- Favourable (n=85): NPM1mut/FLT3-ITDlow AML cases, irrespective of additional high-risk gene mutation or additional chromosomal abnormalities3
In an unplanned post-hoc exploratory analysis overall survival of patients, restrospectively classified accordingly to ELN risk group and treatment3
Footnotes
AML, acute myeloid leukaemia; BID, twice daily; CI, confidence interval; CR, complete remission; ELN, European LeukemiaNet; HR, hazard ratio; ITD, internal tandem duplication; IV, intravenous; OS, overall survival; q12h, every 12 hours; SCT, stem cell transplant; SOC, standard of care; TKD, tyrosine kinase domain.
*SOC: A cycle was 28 days. Chemotherapy dosing during induction was cytarabine IV, 200 mg/m2/d on Days 1–7, and daunorubicin IV, 60 mg/m2/d on Days 1–3. During consolidation, high-dose cytarabine was given at a dose of 3 g/m2/d IV q12h on Days 1, 3 and 5.
†Transplantation was allowed but not specifically mandated per study protocol.
‡One-sided p by stratified log-rank test.
References
- Stone RM, et al. N Engl J Med. 2017;377(5):454–464.
- Döhner K, et al. Blood. 2020;135(5):371–380.
- RYDAPT Summary of Product Characteristics 2023.