Trials with upfront targeted or subset-specific therapy in adult Ph− ALL
| Study (reference) . | ALL subset . | Combination treatment . | Age (y) . | No. . | CR (%) . | CRD/ RFS (%) . | OS (%) . | EFS (%) . | FUP . | Annotations . |
|---|---|---|---|---|---|---|---|---|---|---|
| Rituximab/ofatumumab (anti-CD20 antibody) | ||||||||||
| MDACC27 | CD20+ B-ALL | Hyper-CVAD + R ×8 in cycles 1-4, ×4 in maintenance cycles 6, 18 | 68 | 100 | 70 | 75 | — | 3 y | Better outcome vs no R patients (P < .001 for CRD, P = .003 for OS); outcome not improved by R in patients aged 60+ | |
| GMALL28 | CD20+ B-ALL | GMALL 07/2003 + R ×8 (SR), ×3 (HR) in induction/consolidation | 15-55 | 117 | 94 | 64 | 75 | — | 3 y | Better outcome vs no R patients (P < .009 for CRD), with better/faster MRD clearing (MRD < 0.01% 60% at day 21) |
| GRAALL-200329 | CD20+ B-ALL | A: SOC B: SOC + R ×16-18 during induction/consolidation | 40 (24-53) | 105 104 | 94 92 | — | 50 61 | 43 55 | 4 y | Better outcome vs no R patients (P < .04 for EFS, P =. 02 for relapse incidence) |
| UKALL 1430 | CD20+/− B-ALL (29% Ph+) | A: SOC B: SOC + R ×4 in induction | 25-65 | 288 289 | 92 94 | — | — | 42 48 | 3 y | No overall benefit from R (P = .28), better outcome with R after MAC SCT (EFS 72% vs 50%, P = .03) |
| MDACC31 | CD20+/− B-ALL | Hyper-CVAD + ofatumumab ×8 in induction/consolidation | 41 (18-71) | 46 CD20+ 23 CD20− | 93 | — | 66 70 | 61 65 | 4 y | CD20+: EFS and OS with R 43% (P = .119) and 48% (P = .123); CD20-: EFS and OS with R 50% (P = .89) and 62% (P = .61) |
| Blinatumomab | ||||||||||
| GIMEMA LAL 231732 | CD19+ B-ALL | SOC + blinatumomab ×2 in consolidation | 18-65 | 146 | 90 | 56-87 | 65-91 | 48-85 | 1.5 y | 95% MRD negative after blinatumomab I (P = .001); OS by age (P = .0009) and DFS/EFS by Ph-like (P = .006) and MRD (P = .0002) |
| GRAALL-2014- QUEST33 | CD19+ B-ALL (high risk) | SOC + blinatumomab ×5 in consolidation/ maintenance | 35 (18-60) | 95 | NR | 69-90 | 92 | — | 1.5 y | 74% MRD negative after blinatumomab; DFS by high or very high risk class (P = .018) |
| MDACC34 | B-ALL | Hyper-CVAD + blinatumomomab ×2 after induction and/or x2-4 after consolidation ± R/ofatumumab (CD20+) ± InO ×4 after consolidation | 34 (17-59) | 58 (20 with InO) | 100 | 84 | 85 | — | 3 y | 76% and 95% MRD negative after cycle 1 and overall, resp.; no relapse/death in InO-treated group (OS 100%) |
| MDACC35 | B-ALL | Hyper-CVAD 4 cycles (50% dose reduction) + blinatumomab ×4 after induction and ×3 after consolidation + R/ofatumumab (CD20+) in induction/consolidation | 37 (29-45) | 38 | 100 | 73 | 81 | — | 3 y | Amended to Hyper-CVAD 2 cycles (75% dose reduction) in HR patients; overall MRD negativity 97%; OS 88% no HR feature vs 76% any HR feature |
| HOVON36 | CD19+ B-ALL (37% Ph+) | SOC + blinatumomab ×2 (prephase and after consolidation I) | 53 (18-70) | 71 | 77 | — | 53 (Ph−) | 68 (Ph−) | 2 y | 53% and 91% MRD negative after blinatumomab I and II, resp.; EFS and OS 71% and 73% in patients ≤60 years |
| GMALL0837 | CD19+ B-ALL (MRD positive) | Blinatumomab 1 cycle in MRD positive patients after consolidation I | 18-35 | 63 | all CR/MRD+ | — | — | 71 | 3 y | 55% molecular CR after blinatumomab I; subsequent SCT indicated in all patients |
| ECOG-ACRIN (phase 3)38 | CD19+ B-ALL (MRD negative) | A: SOC consolidation B: SOC consolidation + blinatumomab x4 | 51 (30-70) | 112 112 | 81 | — | NR 71.4 | — | 5 y | CR rate on all study patients (n = 488); median OS arm B not reached (NR, >70% at 5 years) vs 71.4 months (P = .003) |
| Nelarabine (T-specific nucleoside analog) | ||||||||||
| MDACC39 | T-ALL/LBL | Hyper-CVAD + nelarabine after course 8 (×2) or 5 and 7 (×1 each) | 30 (13-78) | 81 | NR | — | 57 | 52 | 5 y | OS non-ETP 63% vs ETP 32% (P < .001); non-ETP: OS nelarabine 83% vs no nelarabine 38% (P = .003) |
| UKALL 14 (Phase 3)40 | T-ALL | A: SOC B: SOC + nelarabine ×1 after induction II | 25-65 | 75 69 | 90 87 | — | 61 65 | 57 61 | 3 y | No benefit from single nelarabine course (3 doses), all P values not significant |
| Study (reference) . | ALL subset . | Combination treatment . | Age (y) . | No. . | CR (%) . | CRD/ RFS (%) . | OS (%) . | EFS (%) . | FUP . | Annotations . |
|---|---|---|---|---|---|---|---|---|---|---|
| Rituximab/ofatumumab (anti-CD20 antibody) | ||||||||||
| MDACC27 | CD20+ B-ALL | Hyper-CVAD + R ×8 in cycles 1-4, ×4 in maintenance cycles 6, 18 | 68 | 100 | 70 | 75 | — | 3 y | Better outcome vs no R patients (P < .001 for CRD, P = .003 for OS); outcome not improved by R in patients aged 60+ | |
| GMALL28 | CD20+ B-ALL | GMALL 07/2003 + R ×8 (SR), ×3 (HR) in induction/consolidation | 15-55 | 117 | 94 | 64 | 75 | — | 3 y | Better outcome vs no R patients (P < .009 for CRD), with better/faster MRD clearing (MRD < 0.01% 60% at day 21) |
| GRAALL-200329 | CD20+ B-ALL | A: SOC B: SOC + R ×16-18 during induction/consolidation | 40 (24-53) | 105 104 | 94 92 | — | 50 61 | 43 55 | 4 y | Better outcome vs no R patients (P < .04 for EFS, P =. 02 for relapse incidence) |
| UKALL 1430 | CD20+/− B-ALL (29% Ph+) | A: SOC B: SOC + R ×4 in induction | 25-65 | 288 289 | 92 94 | — | — | 42 48 | 3 y | No overall benefit from R (P = .28), better outcome with R after MAC SCT (EFS 72% vs 50%, P = .03) |
| MDACC31 | CD20+/− B-ALL | Hyper-CVAD + ofatumumab ×8 in induction/consolidation | 41 (18-71) | 46 CD20+ 23 CD20− | 93 | — | 66 70 | 61 65 | 4 y | CD20+: EFS and OS with R 43% (P = .119) and 48% (P = .123); CD20-: EFS and OS with R 50% (P = .89) and 62% (P = .61) |
| Blinatumomab | ||||||||||
| GIMEMA LAL 231732 | CD19+ B-ALL | SOC + blinatumomab ×2 in consolidation | 18-65 | 146 | 90 | 56-87 | 65-91 | 48-85 | 1.5 y | 95% MRD negative after blinatumomab I (P = .001); OS by age (P = .0009) and DFS/EFS by Ph-like (P = .006) and MRD (P = .0002) |
| GRAALL-2014- QUEST33 | CD19+ B-ALL (high risk) | SOC + blinatumomab ×5 in consolidation/ maintenance | 35 (18-60) | 95 | NR | 69-90 | 92 | — | 1.5 y | 74% MRD negative after blinatumomab; DFS by high or very high risk class (P = .018) |
| MDACC34 | B-ALL | Hyper-CVAD + blinatumomomab ×2 after induction and/or x2-4 after consolidation ± R/ofatumumab (CD20+) ± InO ×4 after consolidation | 34 (17-59) | 58 (20 with InO) | 100 | 84 | 85 | — | 3 y | 76% and 95% MRD negative after cycle 1 and overall, resp.; no relapse/death in InO-treated group (OS 100%) |
| MDACC35 | B-ALL | Hyper-CVAD 4 cycles (50% dose reduction) + blinatumomab ×4 after induction and ×3 after consolidation + R/ofatumumab (CD20+) in induction/consolidation | 37 (29-45) | 38 | 100 | 73 | 81 | — | 3 y | Amended to Hyper-CVAD 2 cycles (75% dose reduction) in HR patients; overall MRD negativity 97%; OS 88% no HR feature vs 76% any HR feature |
| HOVON36 | CD19+ B-ALL (37% Ph+) | SOC + blinatumomab ×2 (prephase and after consolidation I) | 53 (18-70) | 71 | 77 | — | 53 (Ph−) | 68 (Ph−) | 2 y | 53% and 91% MRD negative after blinatumomab I and II, resp.; EFS and OS 71% and 73% in patients ≤60 years |
| GMALL0837 | CD19+ B-ALL (MRD positive) | Blinatumomab 1 cycle in MRD positive patients after consolidation I | 18-35 | 63 | all CR/MRD+ | — | — | 71 | 3 y | 55% molecular CR after blinatumomab I; subsequent SCT indicated in all patients |
| ECOG-ACRIN (phase 3)38 | CD19+ B-ALL (MRD negative) | A: SOC consolidation B: SOC consolidation + blinatumomab x4 | 51 (30-70) | 112 112 | 81 | — | NR 71.4 | — | 5 y | CR rate on all study patients (n = 488); median OS arm B not reached (NR, >70% at 5 years) vs 71.4 months (P = .003) |
| Nelarabine (T-specific nucleoside analog) | ||||||||||
| MDACC39 | T-ALL/LBL | Hyper-CVAD + nelarabine after course 8 (×2) or 5 and 7 (×1 each) | 30 (13-78) | 81 | NR | — | 57 | 52 | 5 y | OS non-ETP 63% vs ETP 32% (P < .001); non-ETP: OS nelarabine 83% vs no nelarabine 38% (P = .003) |
| UKALL 14 (Phase 3)40 | T-ALL | A: SOC B: SOC + nelarabine ×1 after induction II | 25-65 | 75 69 | 90 87 | — | 61 65 | 57 61 | 3 y | No benefit from single nelarabine course (3 doses), all P values not significant |
A, B: study arms in randomized trials; CR, complete remission; CRD/RFS, CR duration/relapse-free survival; FUP, follow-up; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; GRAALL, Group for Research on Adult ALL; GMALL, German Multicenter Group for Adult ALL; HOVON, Hemato-Oncology Foundation for Adults in The Netherlands; InO, inotuzumab ozogamicin; LBL, lymphoblastic lymphoma; MAC SCT, myeloablative conditioned SCT; MDACC, MD Anderson Cancer Center; NR, not reported; R, rituximab; SOC, standard of care (chemotherapy).