New research highlights the critical importance of measuring minimal residual disease (MRD) in children and young adults undergoing stem cell transplantation for acute lymphoblastic leukemia (ALL). A comprehensive analysis of data from the international FORUM trial, published in in Haematologica, demonstrates that the presence of even low levels of leukemia cells after treatment significantly impacts the success of transplantation.
What is Minimal Residual Disease?
Minimal residual disease refers to the small number of leukemia cells that remain in the body after initial treatment, even when tests show no obvious signs of disease. Detecting MRD requires highly sensitive tests capable of identifying these cells at very low levels – typically defined as less than 0.01% of cells. The FORUM trial used this threshold to categorize patients as MRD-positive or MRD-negative.
The FORUM Trial and its Findings
The FORUM trial is a landmark, randomized phase III study that compared different conditioning regimens – total body irradiation (TBI) versus chemotherapy – prior to hematopoietic stem cell transplantation (HSCT) for pediatric ALL. The extended FORUM cohort included patients aged to years who underwent transplantation from a matched donor and had at least one MRD measurement taken before, during, or after HSCT.
The study revealed a significant correlation between MRD status before transplantation and outcomes. Patients who were MRD-positive prior to HSCT had a three-year event-free survival (EFS) rate of , compared to for those who were MRD-negative (P<0.001). Similarly, the cumulative incidence of relapse was significantly higher in the MRD-positive group ( vs. ; P<0.001). Interestingly, the level of MRD positivity before transplant (less than 0.1% versus greater than or equal to 0.1%) did not significantly affect outcomes.
The impact of MRD was also evident after transplantation. Patients who were MRD-positive at days post-HSCT had a significantly lower EFS ( vs. ; P<0.001) and a higher cumulative incidence of relapse ( vs. ; P<0.001). However, the researchers noted that being MRD-positive after transplant did not automatically mean relapse would occur.
Specific Subgroups and Conditioning Regimens
The study also explored whether the type of conditioning regimen used before transplantation influenced the impact of MRD. The combination of MRD-negativity before HSCT and the use of TBI/etoposide conditioning was associated with a two-fold lower risk of relapse. Conversely, MRD-positivity was linked to a two-fold higher risk of treatment failure or death. Notably, the detrimental effect of pre-HSCT MRD was not observed in patients with T-cell ALL.
Implications for Treatment
These findings reinforce the importance of achieving MRD-negativity prior to proceeding with HSCT for childhood ALL, particularly in patients with B-cell ALL, where the negative impact of MRD positivity was most pronounced. The data suggest that more intensive treatment strategies may be needed to eliminate residual disease before transplantation in patients who initially test positive for MRD.
As stated in a report from Lymphoblastic-Hub.com, “Pre-transplant MRD status represents a strong prognostic factor for pediatric ALL transplant outcomes, with MRD negativity (<0.01%) recommended prior to transplantation, particularly in B-ALL where the detrimental effect of MRD positivity was most pronounced.”
The researchers emphasize that monitoring MRD levels both before and after HSCT provides valuable information for predicting outcomes and tailoring treatment strategies. Further research is ongoing to refine MRD detection methods and develop interventions to effectively eliminate residual disease, ultimately improving the chances of long-term remission for children and young adults with ALL.
The study authors concluded that MRD status before HSCT and at days post-HSCT is a strong prognostic factor for children undergoing transplantation for ALL.
