Treatment options for T-ALL

Chemotherapy with or without prophylactic cranial radiation therapy.

Protocols of the former Pediatric Oncology Group (POG) treated children with T-ALL differently from children with B-ALL. On the POG-9404 protocol, patients with T-ALL were treated using a regimen based on the DFCI 87-001 protocol, which included multiple doses of L-asparaginase and doxorubicin during postinduction therapy, as well as prophylactic cranial radiation therapy. Patients were randomly assigned to either the high-dose methotrexate arm or the control arm.[4]

Protocols of the former Pediatric Oncology Group (POG) treated children with T-ALL differently from children with B-ALL. On the POG-9404 protocol, patients with T-ALL were treated using a regimen based on the DFCI 87-001 protocol, which included multiple doses of L-asparaginase and doxorubicin during postinduction therapy, as well as prophylactic cranial radiation therapy. Patients were randomly assigned to either the high-dose methotrexate arm or the control arm.[4]

Patients randomly assigned to receive high-dose methotrexate achieved a superior outcome (10-year EFS rates were 78% with high-dose methotrexate vs. 68% for the control arm).[5,6]

In the POG-9404 study, patients were also randomly assigned to receive doxorubicin with or without dexrazoxane to determine the efficacy of dexrazoxane in preventing late cardiac mortality.[7][Level of evidence B1]

In the POG-9404 study, patients were also randomly assigned to receive doxorubicin with or without dexrazoxane to determine the efficacy of dexrazoxane in preventing late cardiac mortality.[7][Level of evidence B1]

There was no difference in EFS between patients with T-ALL who were treated with dexrazoxane and patients who were not treated with dexrazoxane (cumulative doxorubicin dose, 360 mg/m2).[7]

In the POG-9404 study, patients were also randomly assigned to receive doxorubicin with or without dexrazoxane to determine the efficacy of dexrazoxane in preventing late cardiac mortality.[7][Level of evidence B1]

The frequency of grade 3 and grade 4 toxicities that occurred during therapy was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms. Three years after initial diagnosis, left ventricular shortening fraction and left ventricular wall thickness were both significantly worse in patients who received doxorubicin alone than in patients who received dexrazoxane, indicating that dexrazoxane was cardioprotective.[7]

In the POG-9404 study, patients were also randomly assigned to receive doxorubicin with or without dexrazoxane to determine the efficacy of dexrazoxane in preventing late cardiac mortality.[7][Level of evidence B1]

With combined data from three COG trials that randomized dexrazoxane with doxorubicin therapy (P9404, P9425, and P9426) and had a median follow-up of 12.6 years, dexrazoxane did not appear to compromise long-term survival.[8][Level of evidence A1]

On protocols of the former Children’s Cancer Group (CCG), children with T-ALL received the same treatment regimens as did children with B-ALL. Protocol and treatment assignment were based on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-ALL met National Cancer Institute (NCI) high-risk criteria.

On protocols of the former Children’s Cancer Group (CCG), children with T-ALL received the same treatment regimens as did children with B-ALL. Protocol and treatment assignment were based on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-ALL met National Cancer Institute (NCI) high-risk criteria.

Results from the CCG-1961 trial for high-risk ALL, which included patients with T-ALL, showed that an augmented Berlin-Frankfurt-Münster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphological rapid response to initial induction therapy (estimated 5-year EFS rate, 83%).[9,10] With this approach, patients with a presenting WBC count greater than 200,000 had similar outcomes to those with a WBC count of less than 200,000.[11][Level of evidence B1]

On protocols of the former Children’s Cancer Group (CCG), children with T-ALL received the same treatment regimens as did children with B-ALL. Protocol and treatment assignment were based on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-ALL met National Cancer Institute (NCI) high-risk criteria.

Overall results from POG-9404 and CCG-1961 were similar, although POG-9404 used a higher cumulative dose of anthracyclines and cranial radiation therapy for every patient, while CCG-1961 used cranial radiation therapy only for patients with slow morphological response.[10,5]

On protocols of the former Children’s Cancer Group (CCG), children with T-ALL received the same treatment regimens as did children with B-ALL. Protocol and treatment assignment were based on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-ALL met National Cancer Institute (NCI) high-risk criteria.

Among children with NCI standard-risk T-ALL treated on the CCG-1952, COG-1991, and POG-9404 trials, the 7-year EFS rates were comparable with those of patients treated with the CCG regimens that used significantly less anthracycline in a less intensive chemotherapy backbone without the prophylactic cranial irradiation included in POG-9404.[12] However, the patients with NCI standard-risk T-ALL had an inferior EFS and OS compared with patients with NCI standard-risk B-ALL treated with the same regimens on the CCG-1952 and COG-1991 trials.[12]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL.

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL.

Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) in the context of a BFM regimen for patients with newly diagnosed T-ALL.[13-15]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) in the context of a BFM regimen for patients with newly diagnosed T-ALL.[13-15]

The pilot study showed a 5-year EFS rate of 73% for all patients who received nelarabine and 69% for those patients with a slow early response.[16]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL.

The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

The overall 5-year EFS rate was 83.8%, and the OS rate was 89.5%. On multivariable analysis, high end-induction MRD (>0.1%) and elevated presenting WBC count (>200 × 103) were each independent predictors of inferior outcome.[18]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

Results indicated a better disease-free survival (DFS) for patients who were randomly assigned to the escalating-dose methotrexate arm (5-year DFS rate, 91.5%) than for patients randomly assigned to the high-dose methotrexate arm (5-year DFS rate, 85.3%; P = .005).

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

For intermediate-risk and high-risk patients, treatment with nelarabine was associated with a superior outcome (5-year DFS rate, 88.2% with nelarabine vs. 82.1% without nelarabine; P = .029). The 5-year cumulative incidence of central nervous system (CNS) relapse was significantly lower for patients treated with nelarabine (1.3% vs. 6.9% in the no-nelarabine arm).

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

The best outcome for intermediate-risk and high-risk patients was observed in those randomly assigned to both the escalating-dose methotrexate and nelarabine arms (5-year DFS rate, 91.4%). The worst outcome was observed in patients randomly assigned to receive high-dose methotrexate and no nelarabine (5-year DFS rate, 78.1%).

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

For patients with CNS3 disease, all of whom were assigned to receive high-dose methotrexate and 18 Gy of cranial radiation therapy, nelarabine was associated with significantly superior DFS.[19]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › The COG AALL0434 (NCT00408005) trial enrolled 1,562 evaluable patients aged 1 to 31 years with T-ALL. Patients received an augmented BFM regimen and were randomly assigned to receive an interim maintenance phase with either high-dose methotrexate with leucovorin rescue or escalating-dose methotrexate without leucovorin but with pegaspargase.[3] Intermediate-risk and high-risk patients were also randomly assigned to receive either six courses of nelarabine during postinduction treatment or no nelarabine.[17] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation. Only 10% of patients considered to be low risk were not irradiated. Patients assigned to the escalating-dose methotrexate arm received cranial radiation therapy earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the escalating-dose methotrexate arm also received two additional doses of pegaspargase. Results were as follows:[3,17,18]

Patients with initial induction failure (M3 marrow at day 29, n = 43) were nonrandomly assigned to receive high-dose methotrexate and nelarabine; 20 of these patients were removed from the protocol therapy to undergo allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR). The overall 5-year EFS rate for induction-failure patients was 53%, with no difference in outcomes between HSCT and chemotherapy.

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL.

In the successor COG AALL1231 (NCT02112916) trial for T-ALL, patients were randomly assigned to receive or not receive the proteasome inhibitor bortezomib during induction and delayed intensification phases. Patients with initial induction failure (M3 marrow at day 29) or high MRD (≥0.1%) at end of consolidation were nonrandomly assigned to receive three additional intensified chemotherapy blocks postconsolidation. Other nonrandomized changes to treatment included the use of dexamethasone during induction (instead of prednisone) and omission of cranial radiation therapy for all but the very high-risk patients. Because the results of AALL0434 trial were not known at the time that AALL1231 opened, nelarabine was not included in the chemotherapy backbone. The trial was designed to enroll 1,200 patients but closed to accrual early (after 824 evaluable patients had enrolled) once the results of the nelarabine randomization on AALL0434 were released.[20]

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › In the successor COG AALL1231 (NCT02112916) trial for T-ALL, patients were randomly assigned to receive or not receive the proteasome inhibitor bortezomib during induction and delayed intensification phases. Patients with initial induction failure (M3 marrow at day 29) or high MRD (≥0.1%) at end of consolidation were nonrandomly assigned to receive three additional intensified chemotherapy blocks postconsolidation. Other nonrandomized changes to treatment included the use of dexamethasone during induction (instead of prednisone) and omission of cranial radiation therapy for all but the very high-risk patients. Because the results of AALL0434 trial were not known at the time that AALL1231 opened, nelarabine was not included in the chemotherapy backbone. The trial was designed to enroll 1,200 patients but closed to accrual early (after 824 evaluable patients had enrolled) once the results of the nelarabine randomization on AALL0434 were released.[20]

Comparing patients with T-ALL assigned to receive bortezomib versus patients who did not receive bortezomib, there was no difference in the 4-year EFS rate (82.9% vs. 81.5%; P = .396) or the 5-year OS rate (87.9% vs. 88.3%; P = .469).

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › In the successor COG AALL1231 (NCT02112916) trial for T-ALL, patients were randomly assigned to receive or not receive the proteasome inhibitor bortezomib during induction and delayed intensification phases. Patients with initial induction failure (M3 marrow at day 29) or high MRD (≥0.1%) at end of consolidation were nonrandomly assigned to receive three additional intensified chemotherapy blocks postconsolidation. Other nonrandomized changes to treatment included the use of dexamethasone during induction (instead of prednisone) and omission of cranial radiation therapy for all but the very high-risk patients. Because the results of AALL0434 trial were not known at the time that AALL1231 opened, nelarabine was not included in the chemotherapy backbone. The trial was designed to enroll 1,200 patients but closed to accrual early (after 824 evaluable patients had enrolled) once the results of the nelarabine randomization on AALL0434 were released.[20]

Subset analyses were performed comparing similar patients with T-ALL scheduled to receive 12 Gy cranial radiation therapy on the AALL0434 trial (90.8% of patients), but not on the AALL1231 trial (9.5% of patients). Excluding patients who received nelarabine (AALL0434) or bortezomib (AALL1231), the 4-year EFS (P = .412), OS (P = .600), cumulative incidence of CNS relapse (P = .456), and overall relapse (P = .836) rates were not significantly different between the studies, indicating that the omission of cranial radiation (in the context of the AALL1231 chemotherapy backbone) did not adversely impact outcome.

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › In the successor COG AALL1231 (NCT02112916) trial for T-ALL, patients were randomly assigned to receive or not receive the proteasome inhibitor bortezomib during induction and delayed intensification phases. Patients with initial induction failure (M3 marrow at day 29) or high MRD (≥0.1%) at end of consolidation were nonrandomly assigned to receive three additional intensified chemotherapy blocks postconsolidation. Other nonrandomized changes to treatment included the use of dexamethasone during induction (instead of prednisone) and omission of cranial radiation therapy for all but the very high-risk patients. Because the results of AALL0434 trial were not known at the time that AALL1231 opened, nelarabine was not included in the chemotherapy backbone. The trial was designed to enroll 1,200 patients but closed to accrual early (after 824 evaluable patients had enrolled) once the results of the nelarabine randomization on AALL0434 were released.[20]

While the 4-year EFS rates were similar between the AALL1231 and AALL0434 trials (P = .131), the 4-year OS rate on the AALL1231 trial was inferior to that on the AALL0434 trial (87% vs. 90%, P = .006).

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › In the successor COG AALL1231 (NCT02112916) trial for T-ALL, patients were randomly assigned to receive or not receive the proteasome inhibitor bortezomib during induction and delayed intensification phases. Patients with initial induction failure (M3 marrow at day 29) or high MRD (≥0.1%) at end of consolidation were nonrandomly assigned to receive three additional intensified chemotherapy blocks postconsolidation. Other nonrandomized changes to treatment included the use of dexamethasone during induction (instead of prednisone) and omission of cranial radiation therapy for all but the very high-risk patients. Because the results of AALL0434 trial were not known at the time that AALL1231 opened, nelarabine was not included in the chemotherapy backbone. The trial was designed to enroll 1,200 patients but closed to accrual early (after 824 evaluable patients had enrolled) once the results of the nelarabine randomization on AALL0434 were released.[20]

While the cumulative incidence of relapse was similar in both studies (P = .562), there was a higher rate of treatment-related mortality on the AALL1231 trial, compared with the AALL0434 trial (6.1% vs. 2.0%). Rates of treatment-related mortality were higher on the AALL1231 trial during both induction (1.5% vs. 0.4%, P = .002) and postinduction treatment phases (3.9% vs. 2.1%, P = .008).

In the COG, children with T-ALL are not treated on the same protocols as children with B-ALL. › In the successor COG AALL1231 (NCT02112916) trial for T-ALL, patients were randomly assigned to receive or not receive the proteasome inhibitor bortezomib during induction and delayed intensification phases. Patients with initial induction failure (M3 marrow at day 29) or high MRD (≥0.1%) at end of consolidation were nonrandomly assigned to receive three additional intensified chemotherapy blocks postconsolidation. Other nonrandomized changes to treatment included the use of dexamethasone during induction (instead of prednisone) and omission of cranial radiation therapy for all but the very high-risk patients. Because the results of AALL0434 trial were not known at the time that AALL1231 opened, nelarabine was not included in the chemotherapy backbone. The trial was designed to enroll 1,200 patients but closed to accrual early (after 824 evaluable patients had enrolled) once the results of the nelarabine randomization on AALL0434 were released.[20]

Despite intensification of the chemotherapy backbone, outcome was poor for patients with T-ALL assigned to the very high-risk group (5.2% of patients). The 4-year EFS rate was 31.3% for patients on the no-bortezomib arm, compared with 7.8% for patients on the bortezomib arm (P = .033).