Late-relapsing B-ALL

In BFM studies, patients are considered to be intermediate risk if they have a late isolated marrow relapse or an early or late combined marrow/extramedullary relapse. In the ALL-REZ BFM P95/96 study from this group, end-reinduction MRD (assessed by a polymerase chain reaction–based assay) significantly predicted outcomes of children with intermediate-risk relapsed B-ALL treated with chemotherapy alone in second CR (no HSCT).[28]

In BFM studies, patients are considered to be intermediate risk if they have a late isolated marrow relapse or an early or late combined marrow/extramedullary relapse. In the ALL-REZ BFM P95/96 study from this group, end-reinduction MRD (assessed by a polymerase chain reaction–based assay) significantly predicted outcomes of children with intermediate-risk relapsed B-ALL treated with chemotherapy alone in second CR (no HSCT).[28]

Patients with low MRD (<0.1%) had a 10-year EFS rate of 73%, while those with high MRD (≥0.1%) had a 10-year EFS rate of 10%. On multivariate analysis, end-reinduction MRD was the strongest independent prognostic factor.

In a subsequent BFM study (ALL-REZ BFM 2002 [NCT00114348]), patients with intermediate-risk relapse were allocated to allogeneic HSCT if they had high MRD at the end of the first month of treatment. Those who had low end-reinduction MRD were treated with chemotherapy only (no HSCT).[71]

In a subsequent BFM study (ALL-REZ BFM 2002 [NCT00114348]), patients with intermediate-risk relapse were allocated to allogeneic HSCT if they had high MRD at the end of the first month of treatment. Those who had low end-reinduction MRD were treated with chemotherapy only (no HSCT).[71]

The EFS rate was 64% for patients with high end-reinduction MRD treated with allogeneic HSCT in second CR, which was significantly better than what had been observed on the previous P95/96 trial, during which such patients received chemotherapy without HSCT. The improvement in EFS was primarily because of a significantly lower risk of relapse in the cohort who underwent HSCT in second CR (cumulative incidence of relapse, 27% on the 2002 trial compared with 59% on the P95/96 trial).

In a subsequent BFM study (ALL-REZ BFM 2002 [NCT00114348]), patients with intermediate-risk relapse were allocated to allogeneic HSCT if they had high MRD at the end of the first month of treatment. Those who had low end-reinduction MRD were treated with chemotherapy only (no HSCT).[71]

Patients with late marrow-involved relapses and low end-reinduction MRD, treated with chemotherapy only, had a 5-year EFS rate of 76%, confirming the results seen in the previous P95/96 trial. However, the chemotherapy-only strategy resulted in a significantly worse outcome for patients with early-combined relapses (marrow plus extramedullary site) and low end-reinduction MRD. The 5-year EFS rate was only 37% for these patients. Because of these data, patients with early-combined relapses are now considered high risk on BFM trials.

In a subsequent BFM study (ALL-REZ BFM 2002 [NCT00114348]), patients with intermediate-risk relapse were allocated to allogeneic HSCT if they had high MRD at the end of the first month of treatment. Those who had low end-reinduction MRD were treated with chemotherapy only (no HSCT).[71]

For patients with late marrow-involved relapses and high end-reinduction MRD (defined as ≥0.1%), level of MRD was prognostically significant. The 10-year EFS rate was significantly worse for those with MRD levels of ≥1% compared with those with MRD levels of ≥0.1% to <1% (56% vs. 74%, respectively; P = .02). Conversely, for patients with low end-reinduction MRD (<0.1%), there was no significant difference in EFS between those with very low MRD (<0.01%) versus those with MRD levels between 0.01% and <0.1%.[21]

The United Kingdom ALLR3 trial assigned patients who relapsed more than 6 months after completion of front-line therapy to HSCT if their end-reinduction MRD was ≥0.01% or to chemotherapy for those with MRD of <0.01%.[18]

The United Kingdom ALLR3 trial assigned patients who relapsed more than 6 months after completion of front-line therapy to HSCT if their end-reinduction MRD was ≥0.01% or to chemotherapy for those with MRD of <0.01%.[18]

Of the 228 patients treated, 220 patients achieved CR; 127 patients were allocated to HSCT (high MRD) and 93 were allocated to chemotherapy (low or not evaluable MRD). The 5-year EFS rates were 72% for patients with low MRD versus 56% for patients with high MRD. The 5-year OS rates were 87% for low MRD and 64% for high end-reinduction MRD.

The United Kingdom ALLR3 trial assigned patients who relapsed more than 6 months after completion of front-line therapy to HSCT if their end-reinduction MRD was ≥0.01% or to chemotherapy for those with MRD of <0.01%.[18]

On the basis of these data, investigators from the United Kingdom recommend HSCT for late-relapsing patients with B-ALL who have MRD of ≥0.01% after reinduction therapy and chemotherapy alone for those with end-reinduction MRD of <0.01%.

In the COG AALL1331 (NCT02883049) trial, patients with low-risk relapsed ALL were randomly assigned to receive either standard chemotherapy or standard chemotherapy with three blocks of blinatumomab replacing one block of intensive chemotherapy. Low risk was defined as end-reinduction MRD levels of <0.1% in patients with either bone marrow relapse occurring more than 36 months after diagnosis or extramedullary relapse occurring more than 18 months after diagnosis.[72]

In the COG AALL1331 (NCT02883049) trial, patients with low-risk relapsed ALL were randomly assigned to receive either standard chemotherapy or standard chemotherapy with three blocks of blinatumomab replacing one block of intensive chemotherapy. Low risk was defined as end-reinduction MRD levels of <0.1% in patients with either bone marrow relapse occurring more than 36 months after diagnosis or extramedullary relapse occurring more than 18 months after diagnosis.[72]

For all 255 patients in the protocol, the 4-year DFS rates were 61.2% for patients who received blinatumomab and 49.5% for patients who received standard chemotherapy (P = .0849). The 4-year OS rates were 90.4% for patients who received blinatumomab, compared with 79.6% for patients who received standard chemotherapy (P = .11).

In the COG AALL1331 (NCT02883049) trial, patients with low-risk relapsed ALL were randomly assigned to receive either standard chemotherapy or standard chemotherapy with three blocks of blinatumomab replacing one block of intensive chemotherapy. Low risk was defined as end-reinduction MRD levels of <0.1% in patients with either bone marrow relapse occurring more than 36 months after diagnosis or extramedullary relapse occurring more than 18 months after diagnosis.[72]

For patients with bone marrow relapse with or without extramedullary involvement, the 4-year DFS rates were 72.7% for patients who received blinatumomab and 53.7% for those who received standard chemotherapy (P = .015). The 4-year OS rates were 97.1% for patients who received blinatumomab, compared with 84.8% for the chemotherapy-only group (P = .02).

In the COG AALL1331 (NCT02883049) trial, patients with low-risk relapsed ALL were randomly assigned to receive either standard chemotherapy or standard chemotherapy with three blocks of blinatumomab replacing one block of intensive chemotherapy. Low risk was defined as end-reinduction MRD levels of <0.1% in patients with either bone marrow relapse occurring more than 36 months after diagnosis or extramedullary relapse occurring more than 18 months after diagnosis.[72]

The outcomes were poor for patients with isolated extramedullary relapse, regardless of treatment arm. Outcomes for these patients were inferior to those of similar patients in previous trials. The 4-year DFS rates were 36.6% for patients who received blinatumomab and 38.8% for those who received chemotherapy only (P = .62). The 4-year OS rates were 76.5% for the blinatumomab group, compared with 68.8% for the chemotherapy-only group (P = .53).

In the COG AALL1331 (NCT02883049) trial, patients with low-risk relapsed ALL were randomly assigned to receive either standard chemotherapy or standard chemotherapy with three blocks of blinatumomab replacing one block of intensive chemotherapy. Low risk was defined as end-reinduction MRD levels of <0.1% in patients with either bone marrow relapse occurring more than 36 months after diagnosis or extramedullary relapse occurring more than 18 months after diagnosis.[72]

Patients who received blinatumomab experienced much lower rates of toxicities such as mucositis, febrile neutropenia, and sepsis than patients who received standard chemotherapy. For example, 11% of patients who received standard chemotherapy developed sepsis, compared with less than 2% of patients who received blinatumomab. Similarly, febrile neutropenia occurred in 3% of patients who received blinatumomab, compared with 48% of those who received standard chemotherapy.

The COG AALL0433 (NCT00381680) trial included patients with intermediate-risk relapse of B-ALL (defined as late marrow-involved relapse occurring >36 months from initial diagnosis, or very early isolated extramedullary relapse occurring <18 months from initial diagnosis). Patients received three induction blocks, followed either by an intensive chemotherapy backbone (with radiation therapy for patients with CNS or testicular involvement) or allogeneic HSCT (if matched-sibling donors were available). The trial also included a randomized comparison of standard versus intensified vincristine dosing. Of the 271 eligible patients, 257 (95%) achieved second CR. Of these patients, 74 (29% of those in second CR) received HSCT, 47 of whom had matched-sibling donors and 27 of whom had other donors.[31]

The COG AALL0433 (NCT00381680) trial included patients with intermediate-risk relapse of B-ALL (defined as late marrow-involved relapse occurring >36 months from initial diagnosis, or very early isolated extramedullary relapse occurring <18 months from initial diagnosis). Patients received three induction blocks, followed either by an intensive chemotherapy backbone (with radiation therapy for patients with CNS or testicular involvement) or allogeneic HSCT (if matched-sibling donors were available). The trial also included a randomized comparison of standard versus intensified vincristine dosing. Of the 271 eligible patients, 257 (95%) achieved second CR. Of these patients, 74 (29% of those in second CR) received HSCT, 47 of whom had matched-sibling donors and 27 of whom had other donors.[31]

For all 271 eligible patients, the 3-year EFS and OS rates were 63.6% and 72.3%, respectively.

The COG AALL0433 (NCT00381680) trial included patients with intermediate-risk relapse of B-ALL (defined as late marrow-involved relapse occurring >36 months from initial diagnosis, or very early isolated extramedullary relapse occurring <18 months from initial diagnosis). Patients received three induction blocks, followed either by an intensive chemotherapy backbone (with radiation therapy for patients with CNS or testicular involvement) or allogeneic HSCT (if matched-sibling donors were available). The trial also included a randomized comparison of standard versus intensified vincristine dosing. Of the 271 eligible patients, 257 (95%) achieved second CR. Of these patients, 74 (29% of those in second CR) received HSCT, 47 of whom had matched-sibling donors and 27 of whom had other donors.[31]

For patients with late marrow-involved relapses (n = 242), the 3-year EFS and OS rates were 66.3% and 74.8%, respectively.

The COG AALL0433 (NCT00381680) trial included patients with intermediate-risk relapse of B-ALL (defined as late marrow-involved relapse occurring >36 months from initial diagnosis, or very early isolated extramedullary relapse occurring <18 months from initial diagnosis). Patients received three induction blocks, followed either by an intensive chemotherapy backbone (with radiation therapy for patients with CNS or testicular involvement) or allogeneic HSCT (if matched-sibling donors were available). The trial also included a randomized comparison of standard versus intensified vincristine dosing. Of the 271 eligible patients, 257 (95%) achieved second CR. Of these patients, 74 (29% of those in second CR) received HSCT, 47 of whom had matched-sibling donors and 27 of whom had other donors.[31]

For patients with late marrow relapses, MRD at the end of the first month of treatment (end-reinduction MRD) was a significant prognostic factor. For patients with end-reinduction MRD less than 0.1%, the 3-year EFS rate was 84.9%, versus 53.7% for those with MRD higher than 0.1%.

The COG AALL0433 (NCT00381680) trial included patients with intermediate-risk relapse of B-ALL (defined as late marrow-involved relapse occurring >36 months from initial diagnosis, or very early isolated extramedullary relapse occurring <18 months from initial diagnosis). Patients received three induction blocks, followed either by an intensive chemotherapy backbone (with radiation therapy for patients with CNS or testicular involvement) or allogeneic HSCT (if matched-sibling donors were available). The trial also included a randomized comparison of standard versus intensified vincristine dosing. Of the 271 eligible patients, 257 (95%) achieved second CR. Of these patients, 74 (29% of those in second CR) received HSCT, 47 of whom had matched-sibling donors and 27 of whom had other donors.[31]

Adjusting for median time to HSCT, patients who received HSCT had an improved 3-year DFS rate (P = .03), but not OS rate (P = .46), compared with patients who received chemotherapy alone.

The COG AALL0433 (NCT00381680) trial included patients with intermediate-risk relapse of B-ALL (defined as late marrow-involved relapse occurring >36 months from initial diagnosis, or very early isolated extramedullary relapse occurring <18 months from initial diagnosis). Patients received three induction blocks, followed either by an intensive chemotherapy backbone (with radiation therapy for patients with CNS or testicular involvement) or allogeneic HSCT (if matched-sibling donors were available). The trial also included a randomized comparison of standard versus intensified vincristine dosing. Of the 271 eligible patients, 257 (95%) achieved second CR. Of these patients, 74 (29% of those in second CR) received HSCT, 47 of whom had matched-sibling donors and 27 of whom had other donors.[31]

The vincristine randomization was stopped early because of excessive toxicity, particularly in older patients.