Role of MRD Monitoring in Childhood Acute Lymphoblastic Leukemia after Allogeneic Transplantation.
Authors: Balduzzi Adriana , Bonanomi Sonia , Manenti Tech Monica , Dassi Maria , Cazzaniga Giovanni , Riva Maria Rosa , Tech Simona Songia , Perseghin Paolo , Mascaretti Luca , Uderzo Cornelio , Biondi Andrea 
Published: October 2019

Abstract
Relapse of acute lymphoblastic leukemia (ALL) after allogeneic transplant has very poor prognosis; whether early prediction of relapse by means of minimal residual disease (MRD) analysis could allow effective treatment is still to be assessed. Eighteen patients at high risk of relapse were prospectively monitored in a single transplant center. MRD analysis and clinical follow up were completed for the first series of 11 patients. This includes 9 males and 2 females (median age 11ys, range 2–16) who received allogeneic hematopoietic cell transplantation (HCT) from compatible (5), one locus mismatched (1) or haploidentical (1) related or unrelated (4) donor for ALL in 1st (5), 2nd (4), or 3rd (2) complete remission (CR), after conditioning regimen containing total body irradiation (TBI) and etoposide (9) or others, and GVHD prophylaxis consisting of cyclosporine, associated with ATG in transplant from other than compatible related donor. Grafts consisted of unmanipulated bone marrow (9), containing a median of 6.6x106CD34+/Kg (range 1.7–8.6) and 57.2x106CD3+/Kg (range 24.4–96.2), or peripheral (1), containing 11x106CD34+/Kg and 174x106CD3+/Kg, or positively selected peripheral (1) containing 12x106CD34+/Kg and 0.04x106CD3+/Kg. Five patients developed grade II–IV acute GVHD, requiring ATG in 4 cases. Five of 11 patients are alive in CR at a median of 15 months (range 11–21), 1 died in CR at 7 months, 5 relapsed at a median of 8 months (range 3–23), and 3 of them died. Patients were monitored by clone-specific RQ-PCR of one (4) or two (7) Ig/TcR markers, with a sensitivity of at least 10−4. At the time of transplant 7 patients were positive at the analysis of the MRD, while 4 were negative; patients were monitored at 1, 3, 6, 9 and 12 months after transplantation, or according to clinical requirements. Among the 4 MRD negative patients, 1 remained negative and is in CR at 19 months, 1 became positive 6 months after unrelated transplant and relapsed 2 months later, 1 relapsed 30 months after haploidentical transplant, a long time after MRD monitoring had stopped, while 1 died in CR. Among the 7 MRD positive patients, 2 remained always MRD positive and relapsed 3 and 7 months after transplant, and 5 experienced MRD negativity at a certain time after transplant; 1 of 5 became MRD positive at the 6th month after transient negativity and relapsed 3 months later, 3 of 5 became negative since the 1st or 3rd month, remained negative, and are alive in CR at 9, 12, and 13 months after transplant, while the remaining 1 alternated negative and positive MRD results and is in CR at 6 months. In 5 patients quantitative MRD data allowed early immunosuppression tapering or discontinuation, yielding severe GVHD in 1, and DLI treatment was planned in 2, but refused in 1; 2 of these 5 are in CR, while 3 relapsed, despite 1 experienced transient MRD 1-log reduction and 1 negativization. In conclusion, MRD monitoring after BMT might direct either early immunosuppression tapering or DLI for prevention of relapse in high risk childhood ALL transplanted patients.