Selected trials/studies evaluating nelarabine in the R/R setting
| Study . | Design . | Population (n) . | Mean age, y (range) . | Previous Tx . | Chemotherapy dosage . | Response . | Survival . | Side effects/toxicity . | Remarks . |
|---|---|---|---|---|---|---|---|---|---|
| Monotherapy | |||||||||
| Kurtzberg et al42 | Phase 1 | 93 pts with hematologic malignancies: 59 adults, 34 children. 39 pts with T-ALL/LBL | Adults 48 (22-75); children 10 (3-19) | Median 3 (range 1-11) | MTD: Children: 60 mg/kg per d, ×5 d Adult: 40 mg/kg per day, ×5 d. Given every 21-28 d. | ORR (CR + PR) 31%. ORR in T-ALL/LBL 54% (23% CR, 31% PR) | NA | Neurologic events attributable to nelarabine in 67 (72%) pts; 50% of children and 85% of adults. | |
| Berg et al43 COG P9693 | Phase 2 trial. Strata 1 and 2: T-ALL relapse with bone marrow involvement of ≥25%. Stratum 3: CNS relapse Stratum 4: extramedullary non-CNS relapse, both T-ALL/LBL and T-LBL in strata 3 and 4. | Initial enrollment 153; final enrollment 121; response evaluation, 106 (reported only for 650 mg/m2 per day in strata 1 and 2 and 400 mg/m2 per day in strata 3 and 4). | 11.5 (0.6-21.7) | Stratum 1: marrow involvement, first relapse. Stratum 2: marrow involvement, ≥2 lines of therapy. | 18 pts received 900 mg/m2 per day, 83 pts received 650 mg/m2 per day (T-ALL cohort), and 50 pts received 400 mg/m2 per day (strata 3 and 4). Final dose for evaluation: 650 mg/m2 per day in strata 1 and 2; 400 mg/m2 per day in strata 3 and 4. Therapy given every 21 d. | Stratum 1: ORR 55% (18 of 33; 16 CR, 2 PR). Stratum 2: ORR 27% (8 of 30; 7 CR, 1 PR) Stratum 3: ORR 33% (7 of 21; 5 CR, 2 PR) Stratum 4: ORR 14% (3 of 22; 3 PR). | NA | 31 episodes of grade ≥3 neurologic events in 27 pts (18%). Grade 3/4 were 28% (5 of 18) in the 900 mg/m2 per day cohort and 17% (22 of 133) in the 650 mg/m2 per day and 400 mg/m2 per day cohorts. | In strata 1, 2, and 4, no CNS treatment during first 2 cycles. Afterward, IT therapy based on physician’s discretion. |
| DeAngelo et al44 CALGB 19801 | Phase 2 | 39 (26 T-ALL, 13 T-LBL). | 34 (16-66) | 11 (28%) nelarabine was second line; 28 (72%) ≥2 previous lines of therapy | Days 1, 3, and 5 at 1500 mg/m2 per day every 22 d. | ORR 41%, CR 26% (10), CRi 5% (2), and PR 4 10% (4). | 1-y OS 28% (95% CI, 15-43). Median OS 20 wk (95% CI, 13-36). Median DFS, 20 wk (95% CI, 11-56). | Grade 3/4 neutropenia, 37%; thrombocytopenia, 26%; 1 grade 4 neurologic reversible event; 6 pts (18%), grade 3 neurologic event. | |
| Gökbuget et al45 GMALL | Phase 2 | 126 (107 with T-ALL and 19 with T-LBL) | 33 (18-81) | Primary refractory: 10%; first relapse: 58%; second relapse: 10%; s/p allo-HSCT: 21% | Days 1, 3, and 5 at 1500 mg/m2 per day, every 21 d. | CR, 45 (36%); PR, 12 (10%); 80% of CR pursued allo-HSCT. | 1-y OS, 24%; in pts who achieved CR and completed allo-SCT: 49%. Prognostic factors: thymic type vs others, response and age (<45 vs ≥45 y). | Grade 3/4 neurotoxicity, 7% of pts (overall neurologic events, 16%). Grade 3/4 neutropenia, 37%; thrombocytopenia, 17%. | |
| Candoni et al46 | Retrospective | 118 adults (77 with T-ALL and 41 with T-LBL) | 37 (17-74) | Second line: 53 (45%) Third line: 47 (40%) ≥4 lines: 18 (15%) | Days 1, 3, and 5 at 1500 mg/m2 per day every 21 d. | CR: 36% (43 of 118). PR: 14% (16 of 118). | 1-y OS, 38%. 3-y OS, 40% among pts who proceeded with allo-SCT. | Grade 3/4 neutropenia and thrombocytopeni: 45% and 42%, respectively; 8% grade 3/4 neurotoxicity. | |
| Combination therapy | |||||||||
| Commander et al48 | Retrospective | 7 (5 T-ALL; 2 T-LBL) | 13 (2-19) | 2 previous therapies (range, 1-3) | Nelarabine (650 mg/m2 per day) days 1-5 or days 7-11. CTX (440 mg/m2 per day) and Eto (100 mg/m2 per day), days 7-11 or days 1-5, respectively. | CR, 71% (5 of 7), 4 proceeded with allo-SCT. | NA | All pts experienced grade 3/4 neutropenia and thrombocytopenia. Grade 3: 4 of 7 sensory, 1 of 7 motor, and 1 of 7 mood alteration. No grade 4 neurotoxicity. | Excluded pts with CNS3 involvement, IT- MTX was given 6 d before or 2 d after nelarabine. |
| Luskin et al49 | Retrospective | 5 (2T-ALL; 3 T-LBL). | 58 (50-63) | First relapse regimen in 4 of 5 cases. Pts with CNS relapse were excluded. | Nelarabine (650 mg/m2 per day) days 1-5 or days 7-11. CTX (440 mg/m2 per day) and Eto (100 mg/m2 per day), days 7-11 or days 1-5, respectively. | CR in 3 of 5 pts; 2 proceeded with allo-SCT: 1 had relapse 2 mo s/p allo-SCT; the other patient is still in remission, 8 mo s/p allo-SCT. | NA | One death due to neurotoxicity (was the only patient who received IT with NECTAR). One death due to sepsis. One grade 2 neurotoxicity. | |
| Whitlock et al50 T2008-002 | Phase 1 3 DL | 23 (13 T-ALL, 10 T-LBL). 21 evaluated for response. DL1: n = 6 DL2: n = 7 DL3/expansion: n = 10 | 9.7 (1.4-18.8) | First relapse or initial induction failure. Pts with isolated EMD or CNS relapse were excluded. | All given on days 1-5. Nelarabine: 480 mg/m2 per day (DL1), 650 mg/m2 per day (DL2 and 3). Eto: 100 mg/m2 per day (all DL) CTX: 330 mg/m2 per day (DL1 and 2), 440 mg/m2 per day (DL3). Therapy given every 21 d. | ORR, 38% (CR, CRp, PR); CR + CRp, 24% (8 of 21), 33% in T-ALL and 44% in T-LBL. | NA | Grade 3/4 sensory neuropathy, 9%; motor neuropathy, 9%, 3 DLT d/t neurotoxicity. | IT was given no less than 7 d before, or at least 21 d after, alloSCT. |
| Shimony et al51 | Retrospective | 44 (31 T-ALL; 13 T-LBL); 14 of 26 pts who were evaluable with ETP-ALL, 8 with CNS relapse. | 19 (2-69) | Second line: 28 (64%); third line: 12 (27%); fourth or fifth line: 4 (9%). | Combination therapy (n = 29), most common NCE (n = 23); monotherapy (n = 15). Nelarabine dose was either 650 mg/m2 for 5 d (n = 27) or 1500 mg/m2 on days 1, 3, and 5 (n = 17). Therapy given every 21-28 d. | CR 55% (24 of 44): 62% and 40% in the combination and monotherapy groups, respectively. | Median OS of entire group, 12.8 (95% CI, 7- NR); 24-mo OS of entire group, 37.6% (95% CI, 22-53); 24-mo OS in combination, 52.9% (95% CI, 32-70) vs 8% (95% CI, 1-30); 26 pts proceeded to allo-SCT. | All and grade 3/4 neurotoxicity: 27% vs 17% and 13% vs 7% in monotherapy and combination groups, respectively. Grade 3/4 anemia and thrombocytopeni: 76% vs 20% and 66% vs 27% in combination vs monotherapy groups, respectively. | Allo-HSCT and combination vs monotherapy associated with survival benefit in MVA. |
| Study . | Design . | Population (n) . | Mean age, y (range) . | Previous Tx . | Chemotherapy dosage . | Response . | Survival . | Side effects/toxicity . | Remarks . |
|---|---|---|---|---|---|---|---|---|---|
| Monotherapy | |||||||||
| Kurtzberg et al42 | Phase 1 | 93 pts with hematologic malignancies: 59 adults, 34 children. 39 pts with T-ALL/LBL | Adults 48 (22-75); children 10 (3-19) | Median 3 (range 1-11) | MTD: Children: 60 mg/kg per d, ×5 d Adult: 40 mg/kg per day, ×5 d. Given every 21-28 d. | ORR (CR + PR) 31%. ORR in T-ALL/LBL 54% (23% CR, 31% PR) | NA | Neurologic events attributable to nelarabine in 67 (72%) pts; 50% of children and 85% of adults. | |
| Berg et al43 COG P9693 | Phase 2 trial. Strata 1 and 2: T-ALL relapse with bone marrow involvement of ≥25%. Stratum 3: CNS relapse Stratum 4: extramedullary non-CNS relapse, both T-ALL/LBL and T-LBL in strata 3 and 4. | Initial enrollment 153; final enrollment 121; response evaluation, 106 (reported only for 650 mg/m2 per day in strata 1 and 2 and 400 mg/m2 per day in strata 3 and 4). | 11.5 (0.6-21.7) | Stratum 1: marrow involvement, first relapse. Stratum 2: marrow involvement, ≥2 lines of therapy. | 18 pts received 900 mg/m2 per day, 83 pts received 650 mg/m2 per day (T-ALL cohort), and 50 pts received 400 mg/m2 per day (strata 3 and 4). Final dose for evaluation: 650 mg/m2 per day in strata 1 and 2; 400 mg/m2 per day in strata 3 and 4. Therapy given every 21 d. | Stratum 1: ORR 55% (18 of 33; 16 CR, 2 PR). Stratum 2: ORR 27% (8 of 30; 7 CR, 1 PR) Stratum 3: ORR 33% (7 of 21; 5 CR, 2 PR) Stratum 4: ORR 14% (3 of 22; 3 PR). | NA | 31 episodes of grade ≥3 neurologic events in 27 pts (18%). Grade 3/4 were 28% (5 of 18) in the 900 mg/m2 per day cohort and 17% (22 of 133) in the 650 mg/m2 per day and 400 mg/m2 per day cohorts. | In strata 1, 2, and 4, no CNS treatment during first 2 cycles. Afterward, IT therapy based on physician’s discretion. |
| DeAngelo et al44 CALGB 19801 | Phase 2 | 39 (26 T-ALL, 13 T-LBL). | 34 (16-66) | 11 (28%) nelarabine was second line; 28 (72%) ≥2 previous lines of therapy | Days 1, 3, and 5 at 1500 mg/m2 per day every 22 d. | ORR 41%, CR 26% (10), CRi 5% (2), and PR 4 10% (4). | 1-y OS 28% (95% CI, 15-43). Median OS 20 wk (95% CI, 13-36). Median DFS, 20 wk (95% CI, 11-56). | Grade 3/4 neutropenia, 37%; thrombocytopenia, 26%; 1 grade 4 neurologic reversible event; 6 pts (18%), grade 3 neurologic event. | |
| Gökbuget et al45 GMALL | Phase 2 | 126 (107 with T-ALL and 19 with T-LBL) | 33 (18-81) | Primary refractory: 10%; first relapse: 58%; second relapse: 10%; s/p allo-HSCT: 21% | Days 1, 3, and 5 at 1500 mg/m2 per day, every 21 d. | CR, 45 (36%); PR, 12 (10%); 80% of CR pursued allo-HSCT. | 1-y OS, 24%; in pts who achieved CR and completed allo-SCT: 49%. Prognostic factors: thymic type vs others, response and age (<45 vs ≥45 y). | Grade 3/4 neurotoxicity, 7% of pts (overall neurologic events, 16%). Grade 3/4 neutropenia, 37%; thrombocytopenia, 17%. | |
| Candoni et al46 | Retrospective | 118 adults (77 with T-ALL and 41 with T-LBL) | 37 (17-74) | Second line: 53 (45%) Third line: 47 (40%) ≥4 lines: 18 (15%) | Days 1, 3, and 5 at 1500 mg/m2 per day every 21 d. | CR: 36% (43 of 118). PR: 14% (16 of 118). | 1-y OS, 38%. 3-y OS, 40% among pts who proceeded with allo-SCT. | Grade 3/4 neutropenia and thrombocytopeni: 45% and 42%, respectively; 8% grade 3/4 neurotoxicity. | |
| Combination therapy | |||||||||
| Commander et al48 | Retrospective | 7 (5 T-ALL; 2 T-LBL) | 13 (2-19) | 2 previous therapies (range, 1-3) | Nelarabine (650 mg/m2 per day) days 1-5 or days 7-11. CTX (440 mg/m2 per day) and Eto (100 mg/m2 per day), days 7-11 or days 1-5, respectively. | CR, 71% (5 of 7), 4 proceeded with allo-SCT. | NA | All pts experienced grade 3/4 neutropenia and thrombocytopenia. Grade 3: 4 of 7 sensory, 1 of 7 motor, and 1 of 7 mood alteration. No grade 4 neurotoxicity. | Excluded pts with CNS3 involvement, IT- MTX was given 6 d before or 2 d after nelarabine. |
| Luskin et al49 | Retrospective | 5 (2T-ALL; 3 T-LBL). | 58 (50-63) | First relapse regimen in 4 of 5 cases. Pts with CNS relapse were excluded. | Nelarabine (650 mg/m2 per day) days 1-5 or days 7-11. CTX (440 mg/m2 per day) and Eto (100 mg/m2 per day), days 7-11 or days 1-5, respectively. | CR in 3 of 5 pts; 2 proceeded with allo-SCT: 1 had relapse 2 mo s/p allo-SCT; the other patient is still in remission, 8 mo s/p allo-SCT. | NA | One death due to neurotoxicity (was the only patient who received IT with NECTAR). One death due to sepsis. One grade 2 neurotoxicity. | |
| Whitlock et al50 T2008-002 | Phase 1 3 DL | 23 (13 T-ALL, 10 T-LBL). 21 evaluated for response. DL1: n = 6 DL2: n = 7 DL3/expansion: n = 10 | 9.7 (1.4-18.8) | First relapse or initial induction failure. Pts with isolated EMD or CNS relapse were excluded. | All given on days 1-5. Nelarabine: 480 mg/m2 per day (DL1), 650 mg/m2 per day (DL2 and 3). Eto: 100 mg/m2 per day (all DL) CTX: 330 mg/m2 per day (DL1 and 2), 440 mg/m2 per day (DL3). Therapy given every 21 d. | ORR, 38% (CR, CRp, PR); CR + CRp, 24% (8 of 21), 33% in T-ALL and 44% in T-LBL. | NA | Grade 3/4 sensory neuropathy, 9%; motor neuropathy, 9%, 3 DLT d/t neurotoxicity. | IT was given no less than 7 d before, or at least 21 d after, alloSCT. |
| Shimony et al51 | Retrospective | 44 (31 T-ALL; 13 T-LBL); 14 of 26 pts who were evaluable with ETP-ALL, 8 with CNS relapse. | 19 (2-69) | Second line: 28 (64%); third line: 12 (27%); fourth or fifth line: 4 (9%). | Combination therapy (n = 29), most common NCE (n = 23); monotherapy (n = 15). Nelarabine dose was either 650 mg/m2 for 5 d (n = 27) or 1500 mg/m2 on days 1, 3, and 5 (n = 17). Therapy given every 21-28 d. | CR 55% (24 of 44): 62% and 40% in the combination and monotherapy groups, respectively. | Median OS of entire group, 12.8 (95% CI, 7- NR); 24-mo OS of entire group, 37.6% (95% CI, 22-53); 24-mo OS in combination, 52.9% (95% CI, 32-70) vs 8% (95% CI, 1-30); 26 pts proceeded to allo-SCT. | All and grade 3/4 neurotoxicity: 27% vs 17% and 13% vs 7% in monotherapy and combination groups, respectively. Grade 3/4 anemia and thrombocytopeni: 76% vs 20% and 66% vs 27% in combination vs monotherapy groups, respectively. | Allo-HSCT and combination vs monotherapy associated with survival benefit in MVA. |
CI, confidence interval; CRi, CR with incomplete count recovery; CRp, CR with incomplete platelet recovery; DLT, dose-limiting toxicity; d/t, 3 DLT due to neurotoxicity; EMD, extramedullary disease; Eto, etoposide; MVA, multivariable analysis; NA, not available; NECTAR, nelarabine, cyclophosphamide, etoposide; NR, not reached; pts, patients; s/p, status post; T-NHL, T-cell non-Hodgkin lymphoma; Tx, treatment.