Selected trials/studies evaluating nelarabine in the upfront setting
| Study . | Design . | Population (n) . | Median age, y (range) . | Regimen backbone . | Nelarabine dose and schedule . | Response . | Survival . | Side effects/toxicity attributed to nelarabine . | Remarks . |
|---|---|---|---|---|---|---|---|---|---|
| Dunsmore et al52 AALL00P2 | Phase 1 | 92 pts with T-ALL/LBL | 10 (1.6-20.8) | Multidrug regimen based on BFM86 | Pts received 5-6 cycles of nelarabine (either 400 or 650 mg/m2 per day for 5 d). Rapid early responders (n = 16) did not receive nelarabine. | 5-y EFS for pts receiving nelarabine (n = 70) 73% vs 69% without (n = 16). | Grade 3/4 PN occurred in 15% of pts who received nelarabine and in no pts who did not receive nelarabine (P = .203). Central neurotoxicity, excluding seizures, occurred in 4% of pts (3 of 72) treated with nelarabine vs 25% of pts treated without nelarabine. | ||
| Dunsmore et al.56 COG 0434 | Phase 3, 2 × 2 pseudofactorial design: randomization of escalating dose MTX vs HD-MTX in all pts; randomization of nelarabine vs no nelarabine in subset of pts at intermediate and high risk. | 1562 pts eligible and evaluable for induction with T-ALL; 659 for nelarabine randomization. Only pts with T-ALL were reported in this publication. | In the nelarabine cohort: <10 y, n = 329 10-15 y, n = 220; ≥16 y, n = 110 | COG BFM-based backbone | 650 mg/m2 per day, ×5 d during consolidation, delayed intensification, and maintenance (first 3 cycles). | With vs without nelarabine: 5-y DFS: 88.2% (±2.4%) vs 82.1% (±2.7%), P = .023. 5-y OS: 90.3% (± 2.2%) vs 87.9 (± 2.3%), P = .168 5-y CIR of CNS relapse: 1.3% (±0.63%) vs 6.9% (±1.4), P = .0001. | Grade 3/4, with nelarabine vs without: sensory PN, 8% vs 5.7%, P = .223; motor PN, 9% vs 8%, P = .664. Grade 3/4 CNS neurotoxicity, 3.4% vs 2.1%, P = .298. | ||
| Abaza et al662 | Phase 2 | 67 pts, 40 T-ALL; 26 T-LBL; 1 MPAL | 37 (18-78) | HyperCVAD/ HDMTX + ara-C followed by POMP maintenance.60 Pts were allowed to receive 1 cycle of induction or achieving CR after ≤2 cycles before enrollment | 650 mg/m2 per day ×5 d, ×2 every 21-35 d before POMP therapy. Protocol was amended after 30 pts to include nelarabine after cycles 4 and 5 of hyperCVAD; 2 additional nelarabine cycles given instead of cycles 6 and 7 of POMP. | 12 (18%) were at CR at the time of enrollment. Among 55 others, ORR in 96% (53 of 55), CR in 93% (51/55). | 3-y OS, 65% (95% CI, 51-76). Median OS, 82 mo. OS in T-LBL vs T-ALL: 71% vs 62%, P = .41). | 72% experienced neurotoxicity: PN (69%), headache (6%), and AMS (4%). Only 5 pts (7%) experienced grade 3 AMS, headache, PN, and pain. | Updated in ASH 202063 and ASH 202264 as abstracts with addition of PEG-asparaginase and venetoclax, respectively. |
| Rowntree et al666 UKALL14 | Phase 3 | 175 pts, randomized to SOC vs SOC + nelarabine | 38 (25-65) | Multidrug with phase 1 and 2 inductions, followed by risk stratification, and then either intensification, consolidation or maintenance or alloSCT87 | 1.5 g/m2 on days 1, 3, and 5 following second phase of induction. | CR rate after induction phase 1 + 2 (before nelarabine) was 90.7% in the SOC arm and 87.0% in the SOC + nelarabine | 3-y EFS: 57% (95% CI, 45-68) in the SOC arm vs 62% (95% CI, 49-72) in the SOC + nelarabine arm, P = .61) 3-y OS 62% (95% CI, 49-72) SOC vs 66% (95% CI, 53-76) SOC + nelarabine, P = .73). An "as-treated" analysis did not change conclusions. | No increase in grade 3/4 neurotoxicity in pts with nelarabine, 6 events (9.0%) reported in the SOC arm and 7 events (11.9%) in the SOC + nelarabine arm. | Of those randomized to receive SOC + nelarabine, 48 (71.0%) received the agent, as those with persistent therapy-related toxicities were excluded. |
| Gökbuget et al667 GMALL 08/2013 | Prospective trial with several randomizations | 281 pts (208 T-ALL; 73 T-LBL) | 30 (18-55) | A 2-phase induction, up to 8 cycles of PEG-asparaginase with up to 7 cycles of HDMTX, a reinduction and maintenance up to 2.5 y (none in LBL)88 | SR pts received 2 cycles nelarabine/CTX: 1500 mg/m2 and 200 mg/m2 on days 1, 3, and 5 as consolidation (C) 3 and 5. CNS prophylaxis included IT chemotherapy and CNS irradiation (24 Gy). Risk stratification was based on phenotype and MRD. In pts at HR, allo-HSCT was indicated after consolidation 1. Pts with molecular failure after consolidation 1 received 1 cycle of nelarabine before alloSCT. | Molecular CR (negative with a sensitivity of at least 0.01%) was achieved in 70%, different by immunophenotype: 82% in thymic-ALL, 48% in early T-ALL and 64% in mature T-ALL. | 3-yr OS for all pts was 78%. 3-yr OS of T-ALL was 84% for thymic, 69% for early, and 61% for mature T-ALL (P =.008). | Grade 3/4 toxicities in ≥5%: anemia, 7%/3%; lymphopenia, 5%/16%; thrombopenia, 7%/4%, neutropenia 5%/8%, leukopenia,15%/20%). One pt developed a Guillain-Barré syndrome after nelarabine, which was reversible. | |
| Sato et al.59 ALL-T11 | Prospective phase 2 trial with randomization in very HR pts | 349 eligible pts: 168 (48%) NR, 103 (30%) HR, and 39 (11%) very HR | 9 (IQR 6-13) | Modified AIEOP-BFM-ALL 2000 based regimen | Nelarabine 650 mg/m2 per day ×5 d: HR pts, 6 cycles Pts at very HR: 1-2 cycles (all pts at very HR were designated for alloSCT) | CR rate at the end of the induction 55%; consolidation IB 91% | 3-y EFS: HR, 90.8%; very HR, 86.8%; 3-y OS: HR, 94.9% Very HR, 86.8% | Grade 3 peripheral motor and sensory neuropathy in 11 (3%) and 6 (2%) of 349 pts, respectively; 8 of 11 of motor neuropathy and all 6 cases of sensory neuropathy are attributed to nelarabine; 18 pts required nelarabine dose reduction. |
| Study . | Design . | Population (n) . | Median age, y (range) . | Regimen backbone . | Nelarabine dose and schedule . | Response . | Survival . | Side effects/toxicity attributed to nelarabine . | Remarks . |
|---|---|---|---|---|---|---|---|---|---|
| Dunsmore et al52 AALL00P2 | Phase 1 | 92 pts with T-ALL/LBL | 10 (1.6-20.8) | Multidrug regimen based on BFM86 | Pts received 5-6 cycles of nelarabine (either 400 or 650 mg/m2 per day for 5 d). Rapid early responders (n = 16) did not receive nelarabine. | 5-y EFS for pts receiving nelarabine (n = 70) 73% vs 69% without (n = 16). | Grade 3/4 PN occurred in 15% of pts who received nelarabine and in no pts who did not receive nelarabine (P = .203). Central neurotoxicity, excluding seizures, occurred in 4% of pts (3 of 72) treated with nelarabine vs 25% of pts treated without nelarabine. | ||
| Dunsmore et al.56 COG 0434 | Phase 3, 2 × 2 pseudofactorial design: randomization of escalating dose MTX vs HD-MTX in all pts; randomization of nelarabine vs no nelarabine in subset of pts at intermediate and high risk. | 1562 pts eligible and evaluable for induction with T-ALL; 659 for nelarabine randomization. Only pts with T-ALL were reported in this publication. | In the nelarabine cohort: <10 y, n = 329 10-15 y, n = 220; ≥16 y, n = 110 | COG BFM-based backbone | 650 mg/m2 per day, ×5 d during consolidation, delayed intensification, and maintenance (first 3 cycles). | With vs without nelarabine: 5-y DFS: 88.2% (±2.4%) vs 82.1% (±2.7%), P = .023. 5-y OS: 90.3% (± 2.2%) vs 87.9 (± 2.3%), P = .168 5-y CIR of CNS relapse: 1.3% (±0.63%) vs 6.9% (±1.4), P = .0001. | Grade 3/4, with nelarabine vs without: sensory PN, 8% vs 5.7%, P = .223; motor PN, 9% vs 8%, P = .664. Grade 3/4 CNS neurotoxicity, 3.4% vs 2.1%, P = .298. | ||
| Abaza et al662 | Phase 2 | 67 pts, 40 T-ALL; 26 T-LBL; 1 MPAL | 37 (18-78) | HyperCVAD/ HDMTX + ara-C followed by POMP maintenance.60 Pts were allowed to receive 1 cycle of induction or achieving CR after ≤2 cycles before enrollment | 650 mg/m2 per day ×5 d, ×2 every 21-35 d before POMP therapy. Protocol was amended after 30 pts to include nelarabine after cycles 4 and 5 of hyperCVAD; 2 additional nelarabine cycles given instead of cycles 6 and 7 of POMP. | 12 (18%) were at CR at the time of enrollment. Among 55 others, ORR in 96% (53 of 55), CR in 93% (51/55). | 3-y OS, 65% (95% CI, 51-76). Median OS, 82 mo. OS in T-LBL vs T-ALL: 71% vs 62%, P = .41). | 72% experienced neurotoxicity: PN (69%), headache (6%), and AMS (4%). Only 5 pts (7%) experienced grade 3 AMS, headache, PN, and pain. | Updated in ASH 202063 and ASH 202264 as abstracts with addition of PEG-asparaginase and venetoclax, respectively. |
| Rowntree et al666 UKALL14 | Phase 3 | 175 pts, randomized to SOC vs SOC + nelarabine | 38 (25-65) | Multidrug with phase 1 and 2 inductions, followed by risk stratification, and then either intensification, consolidation or maintenance or alloSCT87 | 1.5 g/m2 on days 1, 3, and 5 following second phase of induction. | CR rate after induction phase 1 + 2 (before nelarabine) was 90.7% in the SOC arm and 87.0% in the SOC + nelarabine | 3-y EFS: 57% (95% CI, 45-68) in the SOC arm vs 62% (95% CI, 49-72) in the SOC + nelarabine arm, P = .61) 3-y OS 62% (95% CI, 49-72) SOC vs 66% (95% CI, 53-76) SOC + nelarabine, P = .73). An "as-treated" analysis did not change conclusions. | No increase in grade 3/4 neurotoxicity in pts with nelarabine, 6 events (9.0%) reported in the SOC arm and 7 events (11.9%) in the SOC + nelarabine arm. | Of those randomized to receive SOC + nelarabine, 48 (71.0%) received the agent, as those with persistent therapy-related toxicities were excluded. |
| Gökbuget et al667 GMALL 08/2013 | Prospective trial with several randomizations | 281 pts (208 T-ALL; 73 T-LBL) | 30 (18-55) | A 2-phase induction, up to 8 cycles of PEG-asparaginase with up to 7 cycles of HDMTX, a reinduction and maintenance up to 2.5 y (none in LBL)88 | SR pts received 2 cycles nelarabine/CTX: 1500 mg/m2 and 200 mg/m2 on days 1, 3, and 5 as consolidation (C) 3 and 5. CNS prophylaxis included IT chemotherapy and CNS irradiation (24 Gy). Risk stratification was based on phenotype and MRD. In pts at HR, allo-HSCT was indicated after consolidation 1. Pts with molecular failure after consolidation 1 received 1 cycle of nelarabine before alloSCT. | Molecular CR (negative with a sensitivity of at least 0.01%) was achieved in 70%, different by immunophenotype: 82% in thymic-ALL, 48% in early T-ALL and 64% in mature T-ALL. | 3-yr OS for all pts was 78%. 3-yr OS of T-ALL was 84% for thymic, 69% for early, and 61% for mature T-ALL (P =.008). | Grade 3/4 toxicities in ≥5%: anemia, 7%/3%; lymphopenia, 5%/16%; thrombopenia, 7%/4%, neutropenia 5%/8%, leukopenia,15%/20%). One pt developed a Guillain-Barré syndrome after nelarabine, which was reversible. | |
| Sato et al.59 ALL-T11 | Prospective phase 2 trial with randomization in very HR pts | 349 eligible pts: 168 (48%) NR, 103 (30%) HR, and 39 (11%) very HR | 9 (IQR 6-13) | Modified AIEOP-BFM-ALL 2000 based regimen | Nelarabine 650 mg/m2 per day ×5 d: HR pts, 6 cycles Pts at very HR: 1-2 cycles (all pts at very HR were designated for alloSCT) | CR rate at the end of the induction 55%; consolidation IB 91% | 3-y EFS: HR, 90.8%; very HR, 86.8%; 3-y OS: HR, 94.9% Very HR, 86.8% | Grade 3 peripheral motor and sensory neuropathy in 11 (3%) and 6 (2%) of 349 pts, respectively; 8 of 11 of motor neuropathy and all 6 cases of sensory neuropathy are attributed to nelarabine; 18 pts required nelarabine dose reduction. |
alloSCT, allogeneic stem cell transplantation; AMS, altered mental status; ara-C, cytarabine; ASH, American Society of Hematology; CI, confidence interval; CIR, cumulative incidence of relapse; CVAD, cyclophosphamide, vincristine, cytarabine, doxorubicin; HD, high dose; IQR, interquartile range; MPAL, mixed phenotype acute leukemia; PN, peripheral neuropathy; SR, standard risk.