Venetoclax therapies in pediatric myeloid disease
| Study . | Pts, n (age, range) . | Disease . | Combination therapies . | Venetoclax . | Response . | HCT post ven . | Survival post-HCT . | Toxicities . |
|---|---|---|---|---|---|---|---|---|
| Karol et al26 | 38 (10 y, 3-22) | rel-AML (33), refr-AML (4), refr-MPAL (1) [KMT2Ar (12); FLT3 (5); TP53 (4)] [median disease burden: 33% (18-68)] | Cytarabine (1000 mg/m2 per dose for 8 doses) ± idarubicin (12 mg/m2 as a single dose) | 240 or 360 mg/m2 per day (28 d)∗ [2 cycles] | In 35 pts evaluable for response: ORR 69% (24), CR (20; 13 MRD neg; 4 CRi); PR (4); NR (11) In 20 pts treated at R2PD: ORR 80%, CR/CRi (14), PR (2), NR (4) | 16 of 20 pts achieving CR | N/A† | Grade 3-4 AEs: febrile neutropenia (25), BSI (6), IFI (6) |
| Winters et al27 | 8 (11 y, 2-20) | MDS-EB (2) t-MDS/AML (1) r/r AML (5) [FLT3 (3), TP53 (2)] | Azacytidine (75 mg/m2 per d; days 1-7) | Adult-equivalent dose of 800 mg (28 d) [median no. cycles: 1 (1-9)] | CR 75% (6; 1 CRi) NR 25% (2) | 4 + 2 pending/8 | N/A | Grade 3-4 neutropenia (8) |
| Bobeff et al28 | 5 (national survey: age <10 y) | MDR-AML (2), rel- AML (1), t-AML (1) refr-MPAL (1) [KMT2Ar (2)] | Cytarabine + idarubicin (2), cytarabine (1), cytarabine + azacitdine (2), azacitdine (1) | 360 mg/m2 per day (28 d) [median no. cycles: 1 (1-2)] | CR 60% (3; 1 CRi), NR 40% (2) | 2/5 | 1 alive disease-free | N/A |
| Marinoff et al29 | 10 (10 y, 1-29) | t-MDS/AML (2), r/r AML (6), MDS (1), MDR-AML (1)‡ [GATA2 (1), KMT2Ar (2), GLIS2 (1), SDS (1)] | Cytarabine (1000 mg/m2 per dose for 8 doses) (5), decitabine (20 mg/m2 per day for 5 d) (4), azacitdine (1) | Adult-equivalent dose of 400 mg [median no. cycles: 1 (1-3)] | CR 10% (1), PR/SD 50% (5), NR/PD 40% (4) | ½0 | 1/2 alive disease-free | Grade 3-4 AEs: cytopenia, infections (5) |
| Pfeiffer et al30 | 28 (13, 1-21) | Refr-AML (5); rel-AML (23) [adverse genetics in 12] | Cytarabine (17), cytarabine + idarubicin (5), cytarabine + azacitdine (3), decitabine (2), azacitidine (1) | 240-360 mg/m2 per day [median no. cycles: 2 (1-7)] | CR 92% (26) (2 CRi), PR/NR 18% (2) | 28/28 | 20/28 alive disease-free, 8 relapse§ | N/A (no impact on GVHD incidence or neutrophil and platelet engraftment) |
| Trabal et al32 | 43 (18, 1-21) | r/r AML (43) [KMT2Ar (17), FLT3-ITD (10), NPM1 (4), TP53 (3), IDH1/2 (2)] | HMA (37), cytotoxic agents (6) [+ trametinib (1), GO (7), TKI (5), MCL-1 inhibitor (1)] | median dose 93 mg/m2 per day (28 d cycles; effective duration median 14 d) [median no. cycles: 2 (1-9)] | CR 37% (16, 6 Cri), PR 5% (2), NR 51% (22) N/E. 7% (3) | 11/43 | 6/11 alive disease-free‖ | Grade 3 neutropenia/febrile neutropenia (49%) |
| Masetti et al31 | 31 (10.2, 1.3-17.4) | MDS-EB (4), rel-AML (11), refr AML (7), t-MDS/AML (9) [KMT2Ar (8), FLT3 (5)] [median disease burden, 20% (0-80)] | HMA (19), cytotoxic agents (9), HMA + cytotoxic (3) [+ gilteritinib (1)] | median 350 mg/m2 per day (28 d) [median no. cycles 2 (1-15)] | CR, 51.6% (16; 6 MRD neg; 5 CRi), PR, 19.4% (6), NR, 25.8% (8) | 20/31 | 15/20 alive disease-free¶ | Grade 3-4 cytopenia (4), IFI (3) (1 TF due to severe pancytopenia) |
| Niswander et al33 | 29 (8, 0-19) | r/r AML (27), MPAL (2) [KMT2Ar (8), GLIS2 (4), FLT3 (1)] [median disease burden, 10.5% (0.01-91.5)] | Azacitidine 100 mg/m2 (days 1-5) [+GO (9)] | Adult-equivalent dose of 800 mg (28 d) [median no. cycles 2 (0-6)] | CR with MRD neg, 44.8% (13) | 12/29 | 7/12 alive disease-free | Severe cytopenia (7), bacteremia (6), IFI (2) |
| Study . | Pts, n (age, range) . | Disease . | Combination therapies . | Venetoclax . | Response . | HCT post ven . | Survival post-HCT . | Toxicities . |
|---|---|---|---|---|---|---|---|---|
| Karol et al26 | 38 (10 y, 3-22) | rel-AML (33), refr-AML (4), refr-MPAL (1) [KMT2Ar (12); FLT3 (5); TP53 (4)] [median disease burden: 33% (18-68)] | Cytarabine (1000 mg/m2 per dose for 8 doses) ± idarubicin (12 mg/m2 as a single dose) | 240 or 360 mg/m2 per day (28 d)∗ [2 cycles] | In 35 pts evaluable for response: ORR 69% (24), CR (20; 13 MRD neg; 4 CRi); PR (4); NR (11) In 20 pts treated at R2PD: ORR 80%, CR/CRi (14), PR (2), NR (4) | 16 of 20 pts achieving CR | N/A† | Grade 3-4 AEs: febrile neutropenia (25), BSI (6), IFI (6) |
| Winters et al27 | 8 (11 y, 2-20) | MDS-EB (2) t-MDS/AML (1) r/r AML (5) [FLT3 (3), TP53 (2)] | Azacytidine (75 mg/m2 per d; days 1-7) | Adult-equivalent dose of 800 mg (28 d) [median no. cycles: 1 (1-9)] | CR 75% (6; 1 CRi) NR 25% (2) | 4 + 2 pending/8 | N/A | Grade 3-4 neutropenia (8) |
| Bobeff et al28 | 5 (national survey: age <10 y) | MDR-AML (2), rel- AML (1), t-AML (1) refr-MPAL (1) [KMT2Ar (2)] | Cytarabine + idarubicin (2), cytarabine (1), cytarabine + azacitdine (2), azacitdine (1) | 360 mg/m2 per day (28 d) [median no. cycles: 1 (1-2)] | CR 60% (3; 1 CRi), NR 40% (2) | 2/5 | 1 alive disease-free | N/A |
| Marinoff et al29 | 10 (10 y, 1-29) | t-MDS/AML (2), r/r AML (6), MDS (1), MDR-AML (1)‡ [GATA2 (1), KMT2Ar (2), GLIS2 (1), SDS (1)] | Cytarabine (1000 mg/m2 per dose for 8 doses) (5), decitabine (20 mg/m2 per day for 5 d) (4), azacitdine (1) | Adult-equivalent dose of 400 mg [median no. cycles: 1 (1-3)] | CR 10% (1), PR/SD 50% (5), NR/PD 40% (4) | ½0 | 1/2 alive disease-free | Grade 3-4 AEs: cytopenia, infections (5) |
| Pfeiffer et al30 | 28 (13, 1-21) | Refr-AML (5); rel-AML (23) [adverse genetics in 12] | Cytarabine (17), cytarabine + idarubicin (5), cytarabine + azacitdine (3), decitabine (2), azacitidine (1) | 240-360 mg/m2 per day [median no. cycles: 2 (1-7)] | CR 92% (26) (2 CRi), PR/NR 18% (2) | 28/28 | 20/28 alive disease-free, 8 relapse§ | N/A (no impact on GVHD incidence or neutrophil and platelet engraftment) |
| Trabal et al32 | 43 (18, 1-21) | r/r AML (43) [KMT2Ar (17), FLT3-ITD (10), NPM1 (4), TP53 (3), IDH1/2 (2)] | HMA (37), cytotoxic agents (6) [+ trametinib (1), GO (7), TKI (5), MCL-1 inhibitor (1)] | median dose 93 mg/m2 per day (28 d cycles; effective duration median 14 d) [median no. cycles: 2 (1-9)] | CR 37% (16, 6 Cri), PR 5% (2), NR 51% (22) N/E. 7% (3) | 11/43 | 6/11 alive disease-free‖ | Grade 3 neutropenia/febrile neutropenia (49%) |
| Masetti et al31 | 31 (10.2, 1.3-17.4) | MDS-EB (4), rel-AML (11), refr AML (7), t-MDS/AML (9) [KMT2Ar (8), FLT3 (5)] [median disease burden, 20% (0-80)] | HMA (19), cytotoxic agents (9), HMA + cytotoxic (3) [+ gilteritinib (1)] | median 350 mg/m2 per day (28 d) [median no. cycles 2 (1-15)] | CR, 51.6% (16; 6 MRD neg; 5 CRi), PR, 19.4% (6), NR, 25.8% (8) | 20/31 | 15/20 alive disease-free¶ | Grade 3-4 cytopenia (4), IFI (3) (1 TF due to severe pancytopenia) |
| Niswander et al33 | 29 (8, 0-19) | r/r AML (27), MPAL (2) [KMT2Ar (8), GLIS2 (4), FLT3 (1)] [median disease burden, 10.5% (0.01-91.5)] | Azacitidine 100 mg/m2 (days 1-5) [+GO (9)] | Adult-equivalent dose of 800 mg (28 d) [median no. cycles 2 (0-6)] | CR with MRD neg, 44.8% (13) | 12/29 | 7/12 alive disease-free | Severe cytopenia (7), bacteremia (6), IFI (2) |
AEs, adverse events; BSI, bloodstream infection; CRi, complete response with incomplete recovery; EFS, event-free survival; GVHD, graft-versus-host disease; IFI, invasive fungal infection; MDR-AML, myelodysplastic related AML; MPAL, mixed-phenotype acute leukemia; N/A, not available; N/E, not evaluable; NR, nonresponse; ORR, overall response rate; PD, progression of disease; pts, patients; refr-AML, refractory AML; rel-AML, relapsed AML; SD, stable disease; SDS, Shwachman-Diamond syndrome; TF, treatment failure; TKI, tyrosine kinase inhibitor; TP53, tumor protein 53.
RP2D of venetoclax plus chemotherapy = 360 mg/m2 per day (600 mg maximum).
1-year OS (whole cohort): 20 of 38 dead.
One patient with SDS who developed AML.
Median follow-up of 344 days (111-1056) from HCT: 1-year OS, 80.5%; 1-year EFS, 69.2%; cumulative incidence of relapse at 1-year post-HCT, 30.8%; and cumulative incidence of relapse at 2 years post-HCT, 43.2%.
Median OS and EFS duration, 8.7 months (range, 0.2-53 months) and 3.7 months (range, 0.1-53), respectively.
30-month estimated OS after the start of venetoclax treatment, 29.9% in the whole cohort and 74.4% for patients who underwent HCT.