Standard-risk ALL

Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone.[71-73] The delayed intensification phase on such regimens, including those of the COG, consists of an 8-week phase of reinduction (including dexamethasone and an anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 4 to 6 months after remission is achieved.[35,71,74]

The former Children's Cancer Group (CCG) study (CCG-1991/COG-1991) for standard-risk ALL used dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating IV methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[75][Level of evidence B1]

The former Children's Cancer Group (CCG) study (CCG-1991/COG-1991) for standard-risk ALL used dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating IV methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[75][Level of evidence B1]

A second delayed intensification phase provided no benefit in patients who were rapid early responders (M1 or M2 marrow by day 14 of induction).

The former Children's Cancer Group (CCG) study (CCG-1991/COG-1991) for standard-risk ALL used dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating IV methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[75][Level of evidence B1]

Escalating IV methotrexate during the interim maintenance phases, compared with oral methotrexate during these phases, produced a significant improvement in EFS, which was because of a decreased incidence of isolated extramedullary relapses, particularly those involving the CNS.

The former Children's Cancer Group (CCG) study (CCG-1991/COG-1991) for standard-risk ALL used dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating IV methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[75][Level of evidence B1]

Successful therapies for patients with standard-risk ALL that have decreased the use of drugs associated with long-term toxicities have focused on children with B-ALL, not T-ALL.[61,62,64,65,67,68] The COG, Dutch Children's Oncology Group (DCOG), DFCI, NOPHO, and other large cooperative groups have excluded patients with T-cell ALL from low and standard-risk therapies. Patients with NCI standard-risk features but a T-cell immunophenotype had an inferior EFS and OS compared with patients with NCI standard-risk B-ALL treated on the same regimens on CCG1952 and CCG1991.[76]

The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]

The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]

The 6-year EFS rate for all patients was 89%, and the OS rate was 96%.

The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]

For standard-risk low patients, this study evaluated the addition of four doses of pegaspargase (added in consolidation and interim maintenance phases) to standard therapy, which included two doses of pegaspargase (administered in induction and delayed intensification phases). Standard-risk low patients had highly favorable outcomes (6-year DFS and OS rates were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively). The augmentation of standard-risk low therapy with additional pegaspargase did not improve outcomes.[63][Level of evidence B4]

The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]

For standard-risk average patients, the augmented consolidation regimen did not improve rates of continuous complete remission (CCR) or OS. The 6-year rates of CCR and OS for the standard-risk average cohort were 88% to 89% and 95% to 96%, respectively.

The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]

Standard-risk average patients with end-induction MRD levels of 0.01% to <0.1% had an inferior outcome compared with those with MRD levels of <0.01% (6-year CCR rates, 77% vs. 91%, respectively). Augmented consolidation was not associated with a better outcome in standard-risk average patients with higher levels of MRD.

The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]

The standard-risk high cohort achieved a relatively favorable 6-year CCR rate of 86% and an OS rate of 93%.

In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified on the basis of MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[78][Level of evidence B1]

In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified on the basis of MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[78][Level of evidence B1]

There was no significant difference in EFS between patients who received one and those who received two delayed intensification phases.

In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified on the basis of MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[78][Level of evidence B1]

There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase.

In the AIEOP ALL-BFM-2000 (NCT00430118) trial, standard-risk patients (defined as those with undetectable MRD at days 33 and 78 and absence of high-risk cytogenetics) were randomly assigned to receive treatment with a single delayed-intensification phase of either standard intensity or reduced intensity (shorter duration, with reduced total dosages of dexamethasone, vincristine, doxorubicin, and cyclophosphamide).[79]

In the AIEOP ALL-BFM-2000 (NCT00430118) trial, standard-risk patients (defined as those with undetectable MRD at days 33 and 78 and absence of high-risk cytogenetics) were randomly assigned to receive treatment with a single delayed-intensification phase of either standard intensity or reduced intensity (shorter duration, with reduced total dosages of dexamethasone, vincristine, doxorubicin, and cyclophosphamide).[79]

Reduced-intensity delayed intensification was associated with an inferior 8-year DFS rate (89% vs. 92%, P = .04), resulting from an increased risk of relapse.

In the AIEOP ALL-BFM-2000 (NCT00430118) trial, standard-risk patients (defined as those with undetectable MRD at days 33 and 78 and absence of high-risk cytogenetics) were randomly assigned to receive treatment with a single delayed-intensification phase of either standard intensity or reduced intensity (shorter duration, with reduced total dosages of dexamethasone, vincristine, doxorubicin, and cyclophosphamide).[79]

In a subset analysis, for patients with the ETV6::RUNX1 fusion, no difference in outcome between the two treatment arms was observed (8-year DFS rate, approximately 94% for both arms).

The Malaysia-Singapore ALL MS2010 trial for patients with favorable-risk B-ALL evaluated a deintensified, modified BFM regimen. This regimen omitted anthracyclines, had fewer doses of high-dose methotrexate, and fewer doses of low-dose cytarabine.[80]

The Malaysia-Singapore ALL MS2010 trial for patients with favorable-risk B-ALL evaluated a deintensified, modified BFM regimen. This regimen omitted anthracyclines, had fewer doses of high-dose methotrexate, and fewer doses of low-dose cytarabine.[80]

The long-term EFS in this trial (6-year EFS rate, 96.5%) was noninferior, compared with the predecessor trial conducted by the same group.

The Malaysia-Singapore ALL MS2010 trial for patients with favorable-risk B-ALL evaluated a deintensified, modified BFM regimen. This regimen omitted anthracyclines, had fewer doses of high-dose methotrexate, and fewer doses of low-dose cytarabine.[80]

This regimen was also less toxic, with significantly decreased rates of bacteremia and septic shock/intensive care unit admissions.

Patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 (NCT00222612) trial used augmented postinduction therapy (extra doses of pegaspargase and vincristine and an escalated-dose of IV methotrexate without leucovorin rescue) to treat standard- or intermediate-risk patients with high levels of end-induction MRD.[51][Level of evidence B1]

Patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 (NCT00222612) trial used augmented postinduction therapy (extra doses of pegaspargase and vincristine and an escalated-dose of IV methotrexate without leucovorin rescue) to treat standard- or intermediate-risk patients with high levels of end-induction MRD.[51][Level of evidence B1]

Augmented postinduction therapy resulted in an increased EFS that was comparable to that of patients with low levels of end-induction MRD.