Blood cancers

MRD “highly prognostic” in kids with late relapsed B-cell precursor ALL


Minimal residual disease measured at the end of induction therapy may be a way of identifying children with B-cell precursor-acute lymphoblastic leukaemia (ALL) and late bone marrow relapse who will benefit the most from a stem cell transplantation, long term follow-up of the ALLR3 trial shows.

The international open label randomised trial involved children with relapsed acute lymphoblastic leukaemia treated at 31 Children’s Cancer and Leukaemia cooperative group centres, including Australia.

Initial results from the trial published in 2010 showed improved 3-year progression-free survival and overall survival in patients who were randomised to a mitoxantrone-based remission induction regimen.

The current long-term follow-up study, published in Lancet Haematology,  involved 228 patients with late bone marrow relapses occurring more than 6 months after completion of front-line therapy. Its primary endpoint was progression-free survival of patients stratified by minimal residual disease.

Overall, 110 of the patients with high minimal residual disease at the end of induction (stratified at a cut off of ≥10−4 cells) were allocated to undergo stem-cell transplantation (HSCT). Eighty-two patients with low minimal residual disease  (<10−4 cells) at the end of induction were allocated to receive chemotherapy.

In the patients allocated to undergo HSCT, four relapses and three deaths were reported before the procedure, and 11 patients were not transplanted.

Of the 92 patients transplanted, 58 (63%) remained in second complete remission, 13 (14%) died of complications, and 21 (23%) relapsed after stem-cell transplantation.

In the patients allocated to receive chemotherapy, one early treatment-related death was reported and 11 patients were transplanted.

Of the 70 patients who continued on chemotherapy, 49 (70%) remained in second complete remission, two (3%) died of complications, and 19 (27%) relapsed.

After a median follow-up of 84 months, progression-free survival was 72% (95% CI 60–81) in patients with low minimal residual disease and 56% (46–65) in those with high minimal residual disease (p=0·0078), the research team reported.

“Patients with low minimal residual disease (defined as <10-4 cells) had significantly better progression-free survival and overall survival than did those with high minimal residual disease, suggesting this is the preferred level to ascertain eligibility of patients for stem cell transplantation,” they wrote.

High-risk cytogenetic groups and IKZF1, PAX5, or NR3C1 deletions or NRAS mutations were associated with higher levels of minimal residual disease and poorer outcomes.

They noted that while patients with high MRD who went on to receive an HSCT had “reasonable outcomes” transplant related mortality and relapse rates after transplantation remained problematic.

“Patients who have a higher minimal residual disease at end of induction and persistent minimal residual disease before stem-cell transplantation might benefit from enrolment into trials exploring experimental therapies,” they suggested.

According to editorialist Associate Professor David T Teachey from the Children’s Hospital of Philadelphia,  one of the most important observations in the study was the high survival rates for patients with low minimal residual disease at the end of induction and no extramedullary disease who were treated with chemotherapy without prophylactic cranial radiation.

He noted that the therapeutic landscape for acute lymphoblastic leukaemia was markedly different today compared to 2003 when accrual for the ALLR3 trial opened.

“Nevertheless, the importance of carefully designed randomised trials such as ALLR3 that ask salient clinical and biological questions will continue to influence the standard of care for patients with B-cell precursor acute lymphoblastic leukaemia,” he concluded.

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