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MRD positivity prognostic of poor outcomes even after intensive therapy for B-ALL
Intensive therapy for pediatric and young adult patients with B-precursor acute lymphoblastic leukemia who have minimal residual disease after induction therapy delayed relapse, according to study results.
However, intensive therapy appeared unable to overcome the poor prognostic significance of minimal residual disease (MRD), results also showed.
MRD is highly predictive of relapse in children and young adults with B-precursor ALL (B-ALL). MRD status is used to determine risk stratification. The Children’s Oncology Group started using MRD as a variable to determine the intensity of post-induction therapy in 2003, according to study background.
Michael J. Borowitz, MD, PhD, director of the division of hematologic pathology, deputy director of education and clinical affairs in the department of pathology, and professor of pathology and oncology at Johns Hopkins University in Baltimore, and colleagues sought to evaluate the effect of MRD-guided post-induction therapy on survival outcomes of patients with high-risk ALL.
The analysis included 2,479 patients with precursor B-ALL aged 1 year to 30 years.
EFS served as the primary outcome measure for most analyses. Other outcomes measured included OS and DFS.
Researchers randomly assigned patients in a 2x2 factorial design to receive 28 days of high-dose methotrexate or Capizzi methotrexate during interim maintenance, or prednisone or dexamethasone during induction.
Researchers then assigned patients who had MRD levels 0.1% or greater — measured using 6-color flow cytometry — after induction or who were morphologic slow responders to undergo a second interim maintenance and delayed intensification phase.
Of the eligible patients at day 29, most had MRD levels less than 0.01% (n = 1,788), whereas 281 patients had levels between 0.01% and 0.1%, 230 had levels between 0.1% and 1%, 123 had levels between 1% and 10%, and 51 had levels of 10% or greater.
Three hundred fifty-five relapses occurred during the study. More relapses occurred among patients with MRD levels of 0.01% or greater (n = 193) compared with patients with levels less than 0.01% (n = 162).
Overall, 87±1% of patients who had end-induction MRD levels less than 0.01% achieved 5-year EFS compared with 74±4% of patients with MRD levels between 0.01% and 0.1%.
For approximately the first 18 months, the EFS of patients with MRD levels between 0.1% and 1% resembled the EFS curve of patients with MRD less than 0.01%; however, the curve of patients with higher MRD dropped off and crossed the curve of patients with MRD between 0.01% and 0.1% at 3 years.
Among patients with MRD levels between 0.1% and 1%, only 23% of relapses occurred by 2 years and 52% of relapses occurred by 3 years. However, 52% of relapses occurred by year 2 and 67% occurred by year 3 in the 0.01% to 0.1% cohort, and 48% of relapses occurred by year 2 and 72% by year 3 for the MRD less than 0.01% cohort.
Researchers noted the fact that patients with MRD less than 0.1% did not receive a second interim maintenance or delayed intensification phase may have influenced this EFS curve and delayed relapsed in these patients.
MRD is also a prognostic factor for OS. The 8-year OS rate among MRD-negative patients was 93±3%.
“Interestingly, the inflection point of the OS curve for patients with MRD between 0.1% and 1% is shifted to the right by about a year, indicating that the therapeutic intensification for this group delayed, but did not prevent, relapse and death,” Borowitz and colleagues wrote.
Persistence of MRD of 0.01% or more at week 12 of therapy was associated with poor outcomes. The 5-year DFS among MRD-positive patients was 39±7% compared with 79±5% among patients who converted from MRD-positive to MRD-negative (P < .0001).
High-dose methotrexate also demonstrated superior outcomes compared with Capizzi methotrexate as a post-induction regimen. However, MRD-negative patients (˂0.01%) again achieved superior 5-year EFS whether they received Capizzi methotrexate (86±2% vs. 58±2%) or high-dose methotrexate (88±2% vs. 68±4%) compared with MRD-positive patients.
“The differences in outcome between high-dose methotrexate and Capizzi methotrexate arm were only a few percentage points, while outcome was 20 (for high-dose methotrexate) and 28 (for Capizzi methotrexate) percentage points worse for MRD-positive patients compared to those who were negative,” the researchers wrote. “Thus, while better chemotherapy can improve outcome, the effect of MRD remains dramatic.”
MRD also was prognostic for poorer outcomes regarding steroid therapy. Patients assigned dexamethasone during induction had a 5-year EFS of 89±2% if they were MRD-negative and 65±4% if they were MRD-positive (P < .0001). The 5-year EFS rates among patients assigned prednisone were 86±2% for MRD-negative patients and 61±4% for MRD-positive patients (P < .0001).
Results of a multivariable analysis indicated patients with MRD levels of 0.01% or greater at day 29 experienced significantly worse EFS (HR = 2.4; 95% CI, 1.97-2.99).
“These results show the continued major importance of MRD analysis for risk assignment of subjects with high-risk B-ALL, even as therapies for this disease improve overall outcome,” Borowitz and colleagues wrote. “The best MRD threshold to identify good risk groups at day 29 of induction therapy was 0.01%.
“They further show that multi-parameter flow cytometry is an effective method for measuring MRD, and that the procedure can be standardized … to provide … results that ensure subjects receive appropriate therapy no matter where their treatment is given.” – by Anthony SanFilippo
Disclosure: The researchers report no relevant financial disclosures.