IDH1-mutated relapsed or refractory AML: current challenges and future prospects

Figures & data

Figure 1 Summary of evidence search and selection.

Abbreviations: AML, acute myeloid leukemia; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; IDH1^mut, isocitrate dehydrogenase 1 mutated.

Table 1 Studies using IDH1 inhibitors in IDH1-mutated relapsed or refractory AML

IDH1 inhibitor	Ivosidenib (AG-120)	IDH305	Olutasidenib (FT-2102)	Olutasidenib (FT-2102) + azacitidine
Schedule	500 mg/24 hrs (28-day cycle)	75–150–300–450–550-750–900 mg/12 hrs (21-day cycle)	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/m^2 7 days (28-day cycle)
Design	PROSP, Phase I, MC^Citation38,Citation39	PROSP, Phase I, MC^Citation57	PROSP, Phase I, MC^Citation53	PROSP, Phase I/II, MC^Citation56
Clinical trial	NCT02074839	NCT02381886	NCT02719574	NCT02719574
Inclusion criteria	IDH1^mut R/R AML; ≥18 years and ECOG-PS score of 0 to 2	IDH1^mut R/R AML and MDS; also evaluated in glioma and other solid tumors	IDH1-^mut R/R AML with no prior therapy with IDH1 inhibitors	IDH1^mut R/R AML
N	179: 106 RF, 17 ER, 43 R HSCT, 26≥2^ndR-LR	21 (NA distribution of R and RF AML); 3 MDS	21	19
Median age	67.0 (18–87)	NA	71 (35–87)^b	66 (31–88)^c
CR [n (%)]; mCRD	CR: 43 (24.0); 10.1 months CR-CRh: 57 (31.8); 8.2 months OR: 75 (41.9); 6.5 months	CR: 2 (9.5); NA CRi: 1 (4.8); NA PR: 4 (19); NA	CR: 3 (14); NA CRi/MLFS: 4 (19); NA OR: 7 (33); NA	CR: 0 (0); NA CRi/MLFS: 6 (32); NA OR: 6 (32); NA
Median OS	9.0 months (follow-up 15.3 months)	NA	NA	NA
Safety: AE in >20% patients all grades (%) AE grade≥3: [n (%)] IDH-DS: [n (%)]	AEs in >20% patients, all grades (%): Diarrhea (34); 4 (2) Leukocytosis (31); 14 (8) Nausea (31); 1 (1) Febrile neutropenia (29); 52 (29) Fatigue (29); 3 (2) Prolong QT interval (26); 18 (10) Dyspnea (25); 7 (4) Peripheral edema (24); 0 (0) Pyrexia (23); 2 (1) Anemia (22); 36 (20) Cough (21); 1 (0) AE grade≥3: [n (%)] IDH-DS G≥3: 7 (4) Thrombocytopenia G≥3: 3 (2) Platelet count decreased G≥3: 3 (2) Hypoxia G≥3: 2 (1) IDH-DS 19 (11); G≥3: 9 (5)	AEs in >10% patients, all grades (%) in AML, glioma or other solid tumors: Bilirubin increased (31) AST increased (17) ALT increased (16) Nausea (14) In AML/MDS, AEs >5% patients: Bilirubin increased (8) Lipase increased (8) In AML/MDS, grade≥3: Bilirubin increased (4) IDH-DS: NA	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 estimated in months in cases reported in days (1 month =30 days) and weeks (1 month =4.3 weeks). ^aEvaluated after a median follow-up of 14.8 m in primary efficacy population, which included the first 125 IDH1^mut relapsed or refractory AML receiving 500 mg daily at least 6 months before cutoff. ^bAEs of the entire cohort including 21 relapsed or refractory AML, 3 untreated AML, and 4 MDS. ^cAEs of entire cohort including 19 relapsed or refractory AML, 4 untreated AML, and 1 MDS.

Abbreviations: ≥2^ndR, second or beyond relapse; AML, acute myeloid leukemia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CR, complete remission; CRh, complete remission with partial hematologic recovery; Cri, complete remission with incomplete recovery; ECOG-PS, Eastern Cooperative Oncology Group performance-status; EFS, event-free survival; ER, early relapse <1 year; HSCT, hematopoietic stem cell transplantation; IDH, isocitrate dehydrogenase; IDH1^mut, isocitrate dehydrogenase 1 mutated; IDH-DS, IDH differentiation syndrome; LR, late relapse >1 year; mCRD, median CR duration; mDFS, median disease-free survival; MDS,myelodysplastic syndrome; MLFS, morphologic leukemia-free state; mOS, median overall survival; MC, multicenter; N, population of the cohort; NA, not available; OR, overall response; OS, overall survival; PROSP, prospective study; R, relapse; RETROSP, retrospective study; RF, refractory; RFS, relapse-free survival; R/R AML, relapsed/refractory AML; UC, unicentric or single center.

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/m^2/d x7d) + DNR (60 mg/m^2/day x3 days) or IDA (12 mg/m^2/day x3 days)^a	IVO 500 mg/24 hrs or placebo + AZA 75 mg/m^2 7 days (28-day cycle)	IVO 500 mg/24 hrs or ENA 100–200 mg/24 hrs + AZA 75 mg/m^2 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/m^2 7 days (28-day cycle)
Design	PROSP, Phase I, MC^Citation38,Citation48	PROSP, Phase I, MC^Citation52	RCT, PROSP, Phase III, MC^Citation49	PROSP, Phase Ib/II, MC^Citation50,Citation51	PROSP, Phase I, MC^Citation53	PROSP, Phase I/II, MC^Citation56
Clinical trial	NCT02074839	NCT02632708	NCT02677922	NCT03173248	NCT02719574	NCT02719574
Inclusion criteria	IDH1^mut-untreated AML; ≥18 years and ECOG-PS score of 0 to 2	IDH1/2^mut newly diagnosed AML (we will be focused in IDH1 treated with IVO)	IDH1^mut-untreated AML ineligible for intensive chemotherapy	IDH1/2^mut newly diagnosed AML ineligible for intensive chemotherapy (we will be focused in IDH1 treated with IVO)	IDH1^mut-untreated AML with no prior therapy with IDH1 inhibitors	IDH1^mut-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: ≥2^ndR, 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; IDH1^mut, 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.

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