Table 2.
Clinical trials of FLT3 inhibitors in relapsed or refractory disease or patients not suitable for standard therapy.
| Agent (Reference Number) | Study Design and Population | Therapeutic Schedule | Treatment Outcome | Adverse Effects |
|---|---|---|---|---|
| First generation FLT3 inhibitors | ||||
| Sorafenib [51] | Phase I/II (n = 43) FLT3 mutation, not required Median age, 64 yrs |
AZA 75 mg/m2/d D1–7 Sorafenib 400 mg bid |
ORR 46%, CR 16%, CRi 27%, PR 3% DoR of CR/CRi, 2.3 mos Median OS—6.2 mos → Sorafenib with AZA, effective in relapsed AML pts with FLT3-ITD (+) |
Fatigue, LFT elevation, Diarrhea |
| Sorafenib [52] | Phase II (n = 27) FLT3 mutated Unsuitable for standard CTx Median age, 74 yrs (61–86 yrs) |
AZA 75 mg/m2/d D1–7 Sorafenib 400 mg bid |
ORR, 78% (CR, 26%; CRi/CRp, 44%; PR, 7%) mDoR—14.5 mos 3 pts, received allo-SCT OS—8.3 mo in entire group, 9.2 mos in responder → the regimen, well tolerable in elderly pts with FLT3 (+) |
Infection, Hyperbilirubin Anemia, Diarrhea, Fatigue |
| Midostaurin [53] | Phase IIB (n = 95) AML, MDS (RAEB, CMML FLT3 mutations, not required 64%, ≥ 65 yrs |
Midostuarin, 50 or 100 mg bid | FLT3 mutation +—blast reduction, 71% FLT3-WT—blast reduction, 49% CR/Cri—0; PR—1/35 Blast reduction (≥50%)—49% → midostaurin, clinical efficacy in both pts with FLT3 (+) and WT. |
Nausea, vomiting |
| Midostaurin [41] | Phase I/II (n = 54) AML, high risk MDS FLT3 mutation, not required Median age, 65 yrs |
AZA D1–7 and Midostaurin 25 mg bid (cohort I) or 50 mg bid (cohort II) (MTD 50 mg bid) |
ORR—26% (CR 1/54, CRi 6/54, MLFS, 6/54, PR 1/54) mDoR—20 wks -pts not exposed FLT3 inhibitor, longer (p = 0.05) -pts not received SCT, longer (p = 0.01) mOS—22 wks → midostaurin with AZA, effective and safe in AML and high-risk MDS pts |
Neutropenia, thromvocytopenia Anemia, EF reduction Diarrhea Nausea/vomiting |
| Second generation FLT3 inhibitor | ||||
| Gilteritinib [54] | Phase I/II (n = 265), R/R setting FLT mutation, not required Median age, 64 yrs |
Dose-escalation cohort vs. Dose-expansion cohorts (120–200 mg, given) -MTD of gilteritinib, 300 mg/d |
ORR—40% → Gilteritinib—well tolerable |
Diarrhea, Anemia, Fatigue, LFT ↑ |
| Gilteritinib [55] | Phase I (n = 24) Japanes patient with R/R AML |
Dose-escalating, 20/40/80/120/200/300 mg MTD of gilteritinib, 200 mg |
ORR in FLT3 (+)—80% ORR in FLT3 WT—4/11 (36.4%) -120 mg/d gilteritinib, recommend → gilteritinib, well tolerated and effective in Japanese R/R AML pts. |
Grade 3 LDH ↑, Amylase ↑ Syncope |
| Giltertinib [56] | Phase III (n = 371) R/R AML with FLT3 mutation |
2:1 ratio received gliteritinib, 120 mg/d or 1/4 salvages—MEC, FLAG-IDA, LDAC, AZA |
OS in gilteritinib ↑—SC group (9.3 vs. 5.6 mos; p < 0.001) CR/CRh, gilteritinib > SC group (34 vs. 15.3%, p = 0.001) → Gilteritinib, longer survival and higher remission rate than salvage CTx in R/R pts. |
Cytopenia, QTc prolongation Pancreatitis, PRES, Differentiation syndrome |
| Quizartinib [60] | Phase I (n = 76) patients with R/R AML FLT3 mutation, not required Median age, 59.5 yrs |
MTD of quizartinib 200 mg/d | In 17 FLT3-ITD (+) pts, -2CR, 3CRp, 5CRi, 13PR → 23 pts. In 37 FLT3-ITD (-) pts -2CRp, 3PR → 5 pts. In 22 FLT3 intermediate/not-tested status -1CR, 1CRp, 5PR → 7 pts. |
Nausea, Vomiting, QTc prolongation, |
| Quizartinib [62] | Phase II (n = 76) R/R FLT3-ITD mutated AML after second-line or allo-SCT |
30 mg/d (A) or 60 mg/d (B) Phase II (n = 76) R/R FLT3-ITD (+) AML after second-line or allo-SCT |
CRc, 47%, DoR—22–26 wks 30 mg/d group—ORR, 61%; mOS—20.7 wks 60 mg/d group—ORR, 71%; mOS—25.4 wks |
QTc prolongation, Nausea, Diarhea Vomiting |
| Quizartinib [63] | Phase II (n = 52) AML, high-risk MDS, CMML, FLT3-ITD required for enrollment Median age, 67 yrs |
AZA, 75 mg/m2 SC/IV for 7 days LDAC, 20 mg SC twice daily 10 days Quizartinib, 60 or 90 mg |
Response, 35 → 8 of LDAC arm (23%), 27 of AZA arm (77%) ORR, 67% (CR-8, CRp-7, CRi-18, PR-18, PR-2) ORR, 73%—FLT3-ITD+ (n = 48) 11 received to allo-SCT |
Hypokalemia, Hypotension, Hypophosphatemia, Hyponatremia, QTc prolongation |
| Crenolanib [66] | Phase I (n = 13) R/R FLT3 mutated AML Median age, 51 yrs |
Idarubicin 12 mg/m2/d D1–3 Cytarabine 1.5 g/m2/d D1–4 Crenolanib 60–100 mg tid start on D5 → continued until 72 before next cycles |
ORR—36% (CR, 1/CRi, 3) mOS—259 days → full-dose crenolanib, safely combined with idarubicin and HDAC in R/R AML pts. |
Nausea, Vomiting, Diarrhea, Abdominal pain |
| Crenolanib [67] | Phase II (n = 8), R/R FLT3 mutation, not rquired Median age, 64 yrs |
HAM—Cytarabine 1.0 g/m2/d D1–6 and mitoxantrone 10 mg/m2 D1–3 vs. Crenolanib 100 mg tid start on D8 |
CR—2/6, CRi—2/6 → full-dose crenolanib, well-tolerable with HAM in R/R elderly AML pts. |
AST/ALT elevation |
AZA, azacitidine; ORR, overall response rate; CRi, complete remission with incomplete count recovery; PR, partial remission l DOR, duration of remission; OS, overall survival; CRp, Complete Remission with incomplete platelet recovery; MLFS, median leukemia-free survival; DOR, duration of response; EF, ejection fraction; MEC, mitoxantrone, etoposide, cytoxane; HDAC, high-dose ara-C; FLAG, fludarbine, ara-C; all-SCT, allogeneic stem cell transplantation; HI, hematologic improvement; EFS, event-free survival; NR, no response.