Treatment options for patients with BCR::ABL1-positive ALL

The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with BCR::ABL1 ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[97,102]

The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with BCR::ABL1 ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[97,102]

The 5-year DFS rate for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate was 70% (± 12%). These patients fared better than historical controls who were treated with chemotherapy alone (without imatinib mesylate), and at least as well as the other patients on the trial who underwent allogeneic transplant. The 5-year DFS rate was 66% for patients who underwent sibling-donor transplant (n = 21) and 59% for those who underwent unrelated donor transplant (n = 13).

The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with BCR::ABL1 ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[97,102]

Patients with additional cytogenetic abnormalities had worse outcomes (P = .05).

The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in the COG-AALL0031 trial.[106][Level of evidence B4] On this trial, dasatinib was started on day 15 of induction, while on the AALL0031 trial, imatinib was started postinduction.

The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in the COG-AALL0031 trial.[106][Level of evidence B4] On this trial, dasatinib was started on day 15 of induction, while on the AALL0031 trial, imatinib was started postinduction.

Introduction of a TKI during induction on the AALL0631 trial resulted in better early response compared with the AALL0031 trial (no TKI during induction). The end-induction (day 29) CR rate was 98% (n = 59) on the AALL0622 trial, compared with 89% (n = 91) on the AALL0031 trial (P = .01), and rates of low end-induction MRD (<0.01%) were superior on the AALL0622 trial compared with the AALL0031 trial (59% vs. 25%; P < .001).

The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in the COG-AALL0031 trial.[106][Level of evidence B4] On this trial, dasatinib was started on day 15 of induction, while on the AALL0031 trial, imatinib was started postinduction.

Outcomes in the two trials were similar: the 5-year OS rates were 81% and 86%, and the 5-year DFS rates were 68% and 60% for AALL0031 and AALL0622, respectively.

The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in the COG-AALL0031 trial.[106][Level of evidence B4] On this trial, dasatinib was started on day 15 of induction, while on the AALL0031 trial, imatinib was started postinduction.

Excessive toxicity with dasatinib was not observed.

The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in the COG-AALL0031 trial.[106][Level of evidence B4] On this trial, dasatinib was started on day 15 of induction, while on the AALL0031 trial, imatinib was started postinduction.

In a subset analysis that included patients who had diagnostic banked samples available, the IKZF1 deletion was identified in 57% of patients and was associated with inferior EFS and OS.

The EsPhALL2004 trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improved outcome for pediatric BCR::ABL1 ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk on the basis of early response measures and remission status at the end of induction. Good-risk patients (n = 90) were randomly assigned to receive imatinib or no imatinib; poor-risk patients (n = 70) were directly assigned to treatment with imatinib. Interpretation of this study is limited because of the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual because of the publication of the results of the COG AALL0031 trial on which imatinib had been given continuously with chemotherapy.[103]

The EsPhALL2004 trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improved outcome for pediatric BCR::ABL1 ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk on the basis of early response measures and remission status at the end of induction. Good-risk patients (n = 90) were randomly assigned to receive imatinib or no imatinib; poor-risk patients (n = 70) were directly assigned to treatment with imatinib. Interpretation of this study is limited because of the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual because of the publication of the results of the COG AALL0031 trial on which imatinib had been given continuously with chemotherapy.[103]

The overall DFS of patients treated on this trial appeared to be better than historical controls, and when analyzed as-treated (and not by intent-to-treat), good-risk patients who received imatinib had a superior DFS (4-year DFS rate was 75% for patients who received imatinib and 56% for patients who did not receive imatinib).[107]

The subsequent EsPhALL2010 (NCT00287105) trial was a result of an amendment to the 2004 trial, which included earlier initiation of imatinib therapy at day 15 of induction and continuous dosing of imatinib until the end of therapy or 1 year after transplant. A subsequent amendment in the trial also changed the indication for HSCT in first CR to only the poor-risk patients.[108]

The subsequent EsPhALL2010 (NCT00287105) trial was a result of an amendment to the 2004 trial, which included earlier initiation of imatinib therapy at day 15 of induction and continuous dosing of imatinib until the end of therapy or 1 year after transplant. A subsequent amendment in the trial also changed the indication for HSCT in first CR to only the poor-risk patients.[108]

Earlier introduction of imatinib (during induction) resulted in an increased rate of CR to 97% at the end of induction (from 78% in the previous trial) and fewer patients being allocated to HSCT (38% on amended trial vs. 81% on initial trial).

The subsequent EsPhALL2010 (NCT00287105) trial was a result of an amendment to the 2004 trial, which included earlier initiation of imatinib therapy at day 15 of induction and continuous dosing of imatinib until the end of therapy or 1 year after transplant. A subsequent amendment in the trial also changed the indication for HSCT in first CR to only the poor-risk patients.[108]

The EFS and OS rates were similar between the amended trial and the initial trial, even though significantly fewer patients received HSCT in first CR on the amended trial.

The subsequent EsPhALL2010 (NCT00287105) trial was a result of an amendment to the 2004 trial, which included earlier initiation of imatinib therapy at day 15 of induction and continuous dosing of imatinib until the end of therapy or 1 year after transplant. A subsequent amendment in the trial also changed the indication for HSCT in first CR to only the poor-risk patients.[108]

The EsPhALL chemotherapy backbone combined with continuous dosing of imatinib was associated with a high rate of toxicity (primarily infections) and treatment-related mortality.

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

The 5-year EFS rate was 54.6%, and the 5-year OS rate was 91.5%, indicating a high rate of salvageability after relapse.

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

For patients with standard-risk ALL, the 5-year EFS rate was 52.1%, and the OS rate was 82.3%.

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

For patients with high-risk ALL, the 5-year EFS rate was 56.8%, and the OS rate was 78.2%.

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

The 3-year EFS rate on the AALL1122 trial (65.5%) was statistically noninferior to that of the EsPhALL 2010 trial (59.1%), on which patients received imatinib combined with the same chemotherapy backbone. However, fewer patients on the AALL1122 trial underwent HSCT in first CR, compared with the EsPhALL 2010 trial (14% vs. 38%). Fewer patients on the AALL1122 trial received cranial radiation (15% vs. 100%).

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

Frequency of infections were high (grade 3 or higher sepsis, 34%; grade 3 or higher fungal infection, 14%), and the treatment-related mortality rate was 8% (8% in those receiving chemotherapy with dasatinib, 13% in those undergoing HSCT in first CR).

The CA180-372/COG AALL1122 (NCT01460160) study was a joint COG and European intergroup single-arm, phase II trial that tested the combination of dasatinib and the EsPhALL chemotherapy backbone for patients with newly diagnosed BCR::ABL1–positive ALL. Dasatinib was given starting at day 15 of induction therapy, and only CNS3 patients or those allocated to HSCT received cranial radiation. Nineteen of 109 patients (18%) were considered high risk based on high time point 2 (end-induction IB) MRD or detectable MRD (any level) after three consolidation blocks of chemotherapy. All other patients were considered standard risk (82%). Fifteen patients (14%), all assigned to the high-risk group, underwent HSCT in first CR. All remaining patients were allocated to receive 2 years of chemotherapy with dasatinib.[90]

MRD on this trial was assessed by three methodologies: IG/TCR PCR, flow cytometry, and BCR::ABL1 PCR. Concordance between assays was highest for IG/TCR PCR and flow cytometry, while BCR::ABL1 PCR results were more frequently discordant. The BCR::ABL1 PCR assay more often demonstrated persistent positivity when the other assays yielded nondetectable results. The outcome of patients who continued to have detectable BCR::ABL1 PCR results, but were MRD negative by the other two assays, was similar to that of patients with nondetectable results by all three assays.

The Chinese Children’s Cancer Group ALL-2015 trial randomly assigned 189 patients to receive either dasatinib or imatinib combined with a multiagent regimen based on SJCRH ALL protocols. On this trial, dasatinib was administered at a higher dose (80 mg/m2 instead of 60 mg/m2) and imatinib was administered at a lower dose (300 mg/m2 instead of 340 mg/m2) than they were administered on previous pediatric BCR::ABL1 ALL trials conducted by COG and EsPhALL.[109][Level of evidence A1]

The Chinese Children’s Cancer Group ALL-2015 trial randomly assigned 189 patients to receive either dasatinib or imatinib combined with a multiagent regimen based on SJCRH ALL protocols. On this trial, dasatinib was administered at a higher dose (80 mg/m2 instead of 60 mg/m2) and imatinib was administered at a lower dose (300 mg/m2 instead of 340 mg/m2) than they were administered on previous pediatric BCR::ABL1 ALL trials conducted by COG and EsPhALL.[109][Level of evidence A1]

With a median follow-up of 26.4 months, the 4-year EFS and OS rates were 71% and 88.4%, respectively, for patients randomly assigned to receive dasatinib, compared with 48.9% and 69.2%, respectively, for patients randomly assigned to receive imatinib.

The Chinese Children’s Cancer Group ALL-2015 trial randomly assigned 189 patients to receive either dasatinib or imatinib combined with a multiagent regimen based on SJCRH ALL protocols. On this trial, dasatinib was administered at a higher dose (80 mg/m2 instead of 60 mg/m2) and imatinib was administered at a lower dose (300 mg/m2 instead of 340 mg/m2) than they were administered on previous pediatric BCR::ABL1 ALL trials conducted by COG and EsPhALL.[109][Level of evidence A1]

Toxicity was similar between the two treatment arms.

The Chinese Children’s Cancer Group ALL-2015 trial randomly assigned 189 patients to receive either dasatinib or imatinib combined with a multiagent regimen based on SJCRH ALL protocols. On this trial, dasatinib was administered at a higher dose (80 mg/m2 instead of 60 mg/m2) and imatinib was administered at a lower dose (300 mg/m2 instead of 340 mg/m2) than they were administered on previous pediatric BCR::ABL1 ALL trials conducted by COG and EsPhALL.[109][Level of evidence A1]

Caution is needed in interpreting these results because of the short median follow-up time and because the outcomes of patients who received imatinib on this trial were inferior to the outcomes of imatinib-treated patients reported in previous trials.