Table 2.
Studies using IDH1 inhibitors in IDH1-mutated untreated AML
| IDH1 inhibitor | Ivosidenib AG-120 | Ivosidenib or enasidenib + intensive chemotherapy | Ivosidenib + azacitidine | Ivosidenib or enasidenib + azacitidine | Olutasidenib (FT-2102) | Olutasidenib (FT-2102) + azacitidine |
|---|---|---|---|---|---|---|
| Schedule | 500 mg/24 hrs (28-day cycle) | IVO 500 mg/24 hrs or ENA 100 mg/24 hrs + Ara-C (200 mg/m2/d x7d) + DNR (60 mg/m2/day x3 days) or IDA (12 mg/m2/day x3 days)a |
IVO 500 mg/24 hrs or placebo + AZA 75 mg/m2 7 days (28-day cycle) | IVO 500 mg/24 hrs or ENA 100–200 mg/24 hrs + AZA 75 mg/m2 7 days |
150–300 mg/24 hrs or 150 mg/12 hrs or 100 mg/24 hrs with food; selected dose 150 mg/12 hrs |
150 mg/24 hrs or 150 mg/12 hrs + AZA 75 mg/m2 7 days (28-day cycle) |
| Design | PROSP, Phase I, MC38,48 | PROSP, Phase I, MC52 | RCT, PROSP, Phase III, MC49 | PROSP, Phase Ib/II, MC50,51 | PROSP, Phase I, MC53 | PROSP, Phase I/II, MC56 |
| Clinical trial | NCT02074839 | NCT02632708 | NCT02677922 | NCT03173248 | NCT02719574 | NCT02719574 |
| Inclusion criteria | IDH1mut-untreated AML; ≥18 years and ECOG-PS score of 0 to 2 |
IDH1/2mut newly diagnosed AML (we will be focused in IDH1 treated with IVO) |
IDH1mut-untreated AML ineligible for intensive chemotherapy |
IDH1/2mut newly diagnosed AML ineligible for intensive chemotherapy (we will be focused in IDH1 treated with IVO) |
IDH1mut-untreated AML with no prior therapy with IDH1 inhibitors | IDH1mut-untreated AML |
| N | 34: 7 de novo, 27 sAML Prior HMA: 14 |
60; 42 de novo, 18 sAML Prior HMA: 4 |
NA (plans to enroll 392 patients) | 23 | 3 | 4 |
| Median age | 76.5 (64–87) | 62.5 (24–76) | NA | 76 (61–88) | 71 (35–87)b | 66 (31–88)c |
| CR [n (%)]; mCRD | n=33 CR: 10 (30.3); NE; CR1y: 77.8% CR-CRh: 14 (42.4); NE; CR-CRh1y: 66.7% OR: 19 (57.6); 8.3; OR1y: 59.5% |
N=49; de novo 34; sAML 15 CR: 35 (71); NA De novo CR: 27 (79) sAML CR: 8 (53) CR-CRi/CRp: 39 (80); NA De novo CR-CRi/CRp: 31 (91) sAML CR-CRi/CRp: 8 (53) |
CR: 10 (44); NA CRi/CRp: 5 (22); NA PR: 0 (0); NA MLFS: 3 (13); NA OR: 18 (78); NA |
CR: 0 (0); NA CRi/MLFS: 1 (33); NA OR: 1 (33); NA |
CR: 2 (50); NA CRi/MLFS: 1 (25); NA OR: 3 (75); NA |
|
| Median OS | 12.6 m (23 m follow-up) | NE; OS1y: 79% | NA | NE | NA | NA |
| Safety:
AE in >20% patients all grades (%) AE grade≥3: [n (%)] IDH-DS: [n (%)] |
AEs in >20% patients, all grades (%);AE grade ≥3: [n (%)] Diarrhea (53); 2 (6) Fatigue (44); 3 (9) Nause (38); 2 (6) Decreased appetite (32); 1 (3) Leukocytosis (27); 1 (3) Anemia (27); 4 (12) Peripheral edema (27) Thrombocytopenia (24); 5 (15) Dyspnea (24); 1 (3) Hypomagnesemia (24) Dizziness (24) Arthralgia (21); 1 (3) Hypokalemia (21); 1 (3) Constipation (21); 1 (3) Abdominal pain (21); 1 (3) Insomnia (21) Serious AEs (≥5%) IDH-DS 5 (14.7) Febrile neutropenia 3 (8.8) Pneumonia 3 (8.8) Prolong QT interval 2 (5.9) IDH-DS, total 6 (18); G≥3: 3 (9) |
Induction period AE grade ≥3: [n (%)] IDH-DS 2 (3) Leukocytosis 0 (0) Prolong QT interval 1 (2) Bilirubin increased 4 (7) 30-day mortality: 3 (5) 60-day mortality: 5 (8) AEs in >10% patients G ≥3 (%): Febrile neutropenia (62) Hypophosphatemia (13) Hypokalemia (10) Colitis (10) Hypertension (10) Bilirubin increased (7) Lung infection (5) Sepsis (7) IDH-DS G ≥3: 2 (3) |
NA | AEs in >20% patients, all grades (%); AE grade ≥3: [n (%)] Nausea 14 (61); 1 (4) Anemia 12 (52); 10 (44) Thrombocytopenia 11 (48); 10 (44) Febrile neutropenia 9 (39); 9 (39) Constipation 9 (39); 1 (4) Diarrhea 9 (39); 1 (4) Vomiting 8 (35); 1 (4) Dizziness 8 (35); 1 (4) Pyrexia 7 (30); 1 (4) Fatigue 7 (30); 0 (0) Insomnia 7 (30); 0 (0) Hypokalemia 7 (30); 0 (0) QT interval prolongation 6 (26); 3 (13) Back pain 5 (22); 0 (0) Headache 5 (22); 0 (0) Cough 5 (22); 0 (0) Serious AEs: Febrile neutropenia 8 (35) IDH-DS: 3 (13) |
AEs in >5% patients G ≥3 (%)b: Thrombocytopenia (26) Febrile neutropenia (23) Anemia (19) Pneumonia (13) Neutropenia (7) Hypokalemia (7) Pyrexia (7) Leukocytosis (6) IDH-DS: 3 (11) Prolong QT interval: 1 (4) |
AEs in >5% patients G ≥3 (%)c: Febrile neutropenia (27) Anemia (19) Thrombocytopenia (19) Leukocytosis (19) Fatigue (15) Hypertension (15) Neutropenia (15) Nausea (12) Pneumonia (12) Hypokalemia (12) Abdominal pain (8) IDH-DS: 3 (13) |
Notes: OS and CR has been estimated in months in the cases that it was reported in days (1 month =30 days) and weeks (1 month =4.3 weeks). aConsolidation chemotherapy: ≤4 cycles while continuing treatment with the mutated IDH inhibitor. Those who complete or are ineligible for consolidation may continue maintenance treatment with ivosidenib or enasidenib for ≤2 years from the start of induction. bAEs of the entire cohort including 21 relapsed or refractory AML, 3 untreated AML, and 4 MDS. cAEs of the entire cohort including 19 relapsed or refractory AML, 4 untreated AML, and 1 MDS.
Abbreviations: ≥2ndR, second or beyond relapse; AML, acute myeloid leukemia; ALT, alanine aminotransferase; Ara-C, cytarabine; AST, aspartate aminotransferase; AZA, azacitidine; CR, complete remission; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete recovery; CRp, complete remission without platelet recovery; DNR, daunorubicin; ECOG-PS, Eastern Cooperative Oncology Group performance-status; EFS, event-free survival; ENA, enasidenib; ER, early relapse <1 year; HMA, hypomethylating agent; HSCT, hematopoietic stem cell transplantation; IDA, idarubicin; IDH, isocitrate dehydrogenase; IDH1mut, isocitrate dehydrogenase 1 mutated; IDH-DS, IDH differentiation syndrome; IVO, ivosidenib; LR, late relapse >1 year; MC, multicenter; mCRD, median CR duration; mDFS, median disease-free survival; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia-free state; mOS, median overall survival; MRD, measurable residual disease; N, population of the cohort; NA, not available; NE, could not be estimated; OR, overall response; OS, overall survival; PROSP, prospective study; R, relapse; RCT, randomized clinical trial; RETROSP, retrospective study; RF, refractory; RFS, relapse-free survival; sAML, secondary AML; UC, unicentric or single center; y, year.