Results of hematopoietic stem cells transplantation with TCRαβ+/CD19+-depletion from haploidentical donors in pediatric acute leukemia patients in complete remission
Anna A. Bogoyavlenskaya, Larisa N. Shelikhova, Maria A. Ilyushina, Zhanna B. Shekhovtsova, Dmitry N. Balashov, Irina P. Shipitsina, Darya A. Shasheleva, Rimma D. Khismatullina, Sergey L. Blagov, Anna M. Lyvshits, Konstantin V. Mytrakov, Svetlana N. Kozlovskaya, Elena E. Kurnikova, Jakov O. Muzalevsky, Alexey S. Kazachenok, Irina I. Kalinina, Natalya V. Myakova, Galina A. Novichkova, Alexey A. Maschan, Michael A. Maschan
Dmitry Rogachev National Medical Research Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Contact: Dr. Anna A. Bogoyavlenskaya
Relapse, graft-versus-host disease (GvHD) and associated non-relapse mortality are the main obstacles to successful HSCT in children with leukemia. αβ T cell depletion was developed to prevent GvHD and improve immune reconstitution.
Patients and methods
A total of 89 children with AL (38AML, 51ALL, 36 female, 53 male, median age 8,7y) underwent allo-HSCT from haploidentical donor between 15.06.2012 and 19.07.2017. All the patients (pts) were in complete remission (CR1=43, CR2=34, CR>2=12). 64 pts received treosulfan-based conditioning, 25 – TBI-based (all ALL). Either melphalan (n=41), or thiophosphamide (n=31), or etoposide (n=16) were added as a second agent. Fludarabine was used in all pts. Two types of GVHD prophylaxis were used: Type1 (n=18): hATG 50 mg/kg and post-HSCT tacro/mtx, type2 (n=71): thymoglobulin (rATG) 5 mg/kg, rituximab 200 mg/m2 with either bortezomib on days +2, +5 (n=62), or tacrolimus (n=6), or without them (n=3). aβT-cell depletion with CliniMACS was used in all cases. The median dose of CD34+ cells was 8x106/kg, aβT cells dose was 16x103/kg. Median time of follow-up for survivors was 3 years (range, 1.3 to 6.3).
Five patients (5.6%) died before engraftment due to septic event. Primary engraftment was achieved in all evaluable pts (100%) with full donor chimerism, the median time to neutrophil and platelet recovery was 12 and 15 days. Among the whole cohort, the CI of GvHD grades II-IV and III-IV was 17.9% (95% CI:12-28) and 3.4% (95% CI:1-10), respectively. The CI for cGvHD was 19% (95% CI: 12.5-29). CI for aGvHD was significantly lower in a group with type 2 of GvHD prophylaxis: 11.2% (95% CI:6-22) vs 44% (95% CI:26-74), p=0.002. rATG was also effective in prevention of cGvHD: CI at 2 year after HSCT was 15% vs 33%, p=0.08. 3-year pTRM was 12.3% (95%CI: 7-21) and CI of relapse was 19.8% (95%CI: 13-31) without different between rATG and hATG. Three-year pEFS was 68% (95%CI:59-78), in AML pts 83% (95%CI:69-96), versus 57% (95%CI:43-70) in ALL, p=0.007, without difference between rATG and hATG. Among ALL pts, who received TBI-containing regimen, pEFS was 68% (95%CI:50-86), as compared to 46% (95%CI:27-65) among those conditioned without TBI, p=0.044 and pOS was 74% (95%CI:62-86). In the group with available immune reconstitution data (n=68) αβT cell recovery at day +30 was associated with a trend to decreased incidence of relapse, CI of relapse was 29% (95% CI:15-54) in those with αβ-T cell count below median vs 15 % (95% CI:6-38) in those with αβ-cell count above median, p=0.25 and decreased TRM: 16% (95% CI:6.5-39) among αβ T”low“ vs pTRM 0% among αβ T”high” (p=0.036). pEFS among αβ T”high” was 85% (+/-10) vs 55% (+/-14) among αβ T”low“, p=0,019, pOS 89% (+/-10) vs 59% (+/-20) respectively. Recovery of the NK and jd-T cell was not associated with improved survival.
We confirm that the depletion of αβT cells from haploidentical graft in combination with intensive conditioning regimen provides a high chance of long-term survival in a cohort of children with high-risk AL in remission, especially for AML pts. Our analysis suggests that early αβT cell recovery is associated with a relatively low non-relapse mortality and relapse rate.
Acute leukemia, αβ T cell depletion, haploidentical, GvHD prophylaxis, αβ T cell recovery.