High-risk ALL

The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and pegaspargase during interim maintenance and additional vincristine and pegaspargase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[56]

The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and pegaspargase during interim maintenance and additional vincristine and pegaspargase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[56]

The augmented-therapy regimen in the CCG-1882 trial produced significantly better EFS and OS rates (75% and 78%) than did the standard CCG modified-BFM therapy (55% and 66.7%).

The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and pegaspargase during interim maintenance and additional vincristine and pegaspargase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[56]

There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).[82]

In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[83]

The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.

The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.

Augmented therapy was associated with an improvement in EFS. There was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[57,84][Level of evidence A1]

The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.

The cumulative incidence of osteonecrosis at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[85][Level of evidence A3]

In the UKALL2003 (NCT00222612) trial, patients with high end-induction MRD (>0.01%) and/or high-risk cytogenetics were randomly assigned to receive either a standard-intensity or an augmented BFM chemotherapy backbone.[86]

In the UKALL2003 (NCT00222612) trial, patients with high end-induction MRD (>0.01%) and/or high-risk cytogenetics were randomly assigned to receive either a standard-intensity or an augmented BFM chemotherapy backbone.[86]

The 10-year EFS rate was 87.1% for patients assigned to the augmented chemotherapy backbone, compared with 82.1% for those assigned the standard-intensity chemotherapy backbone (P = .09).

In the UKALL2003 (NCT00222612) trial, patients with high end-induction MRD (>0.01%) and/or high-risk cytogenetics were randomly assigned to receive either a standard-intensity or an augmented BFM chemotherapy backbone.[86]

Patients with high-risk cytogenetics had a significantly lower risk of relapse when treated with augmented therapy (10-year relapse rate, 22.1% vs. 52.4% with standard-intensity therapy; P = .016).

In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase. Only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) plus pegaspargase during the interim maintenance phase (the first phase only for those receiving two of these phases).[8,46]

In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase. Only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) plus pegaspargase during the interim maintenance phase (the first phase only for those receiving two of these phases).[8,46]

The methotrexate randomization was terminated early when planned interim monitoring indicated that high-dose methotrexate was associated with superior outcome. The 5-year EFS rate of patients randomly assigned to high-dose methotrexate was 79.6%, compared with 75% for those randomly assigned to the Capizzi methotrexate arm. High-dose methotrexate was also associated with a superior 5-year OS (P = .025).[8]

In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase. Only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) plus pegaspargase during the interim maintenance phase (the first phase only for those receiving two of these phases).[8,46]

Patients with MRD less than 0.01% at end of induction had a 5-year EFS rate of 87%, compared with 74% for those with MRD 0.01% to 0.1%. Those with MRD levels greater than 0.1% fared worse.[46]

In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase. Only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) plus pegaspargase during the interim maintenance phase (the first phase only for those receiving two of these phases).[8,46]

High-dose methotrexate was associated with a superior EFS rate in patients with end-induction MRD greater than 0.01% (high-dose methotrexate, 68%; Capizzi methotrexate, 58%; P = .008).[46]

In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[87,88]

In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[87,88]

The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.

In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[87,88]

A greater long-term protective effect was noted in girls than in boys.

On the POG-9404 trial, patients with T-ALL were randomly assigned to receive dexrazoxane or not before each dose of doxorubicin (cumulative dose 360 mg/m2).[89]

On the POG-9404 trial, patients with T-ALL were randomly assigned to receive dexrazoxane or not before each dose of doxorubicin (cumulative dose 360 mg/m2).[89]

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).

On the POG-9404 trial, patients with T-ALL were randomly assigned to receive dexrazoxane or not before each dose of doxorubicin (cumulative dose 360 mg/m2).[89]

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. The frequency of grade 3 and 4 toxicities that occurred during therapy was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms.

In the CCG-1961 study, alternate-week dosing of dexamethasone during delayed intensification was studied with the goal of reducing the frequency of osteonecrosis.[85] Patients with high-risk B-ALL and a rapid early morphological response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Patients randomly assigned to one delayed intensification phase received daily dosing of dexamethasone (21 consecutive days), while those randomly assigned to two delayed intensification phases received alternate-week dosing of dexamethasone (days 0–6 and 14–21) during each delayed intensification phase.

In the CCG-1961 study, alternate-week dosing of dexamethasone during delayed intensification was studied with the goal of reducing the frequency of osteonecrosis.[85] Patients with high-risk B-ALL and a rapid early morphological response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Patients randomly assigned to one delayed intensification phase received daily dosing of dexamethasone (21 consecutive days), while those randomly assigned to two delayed intensification phases received alternate-week dosing of dexamethasone (days 0–6 and 14–21) during each delayed intensification phase.

For patients aged 10 years or older at diagnosis, those who received two delayed intensification phases (alternate-week dosing of dexamethasone) had a significantly lower risk of symptomatic osteonecrosis (5-year cumulative incidence of 8.7%, compared with 17% for patients receiving one delayed intensification phase with continuous dexamethasone dosing; P = .001).

In the CCG-1961 study, alternate-week dosing of dexamethasone during delayed intensification was studied with the goal of reducing the frequency of osteonecrosis.[85] Patients with high-risk B-ALL and a rapid early morphological response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Patients randomly assigned to one delayed intensification phase received daily dosing of dexamethasone (21 consecutive days), while those randomly assigned to two delayed intensification phases received alternate-week dosing of dexamethasone (days 0–6 and 14–21) during each delayed intensification phase.

The greatest impact was seen in females aged 16 to 21 years, who showed the highest incidence of osteonecrosis with standard therapy containing continuous dexamethasone; the incidence of osteonecrosis with alternative-week dexamethasone was 5.6%, compared with 57.6% for those receiving continuous dosing.