ALBERT

Description: Introduction Relapse, graft-versus-host disease (GvHD) and GvHD-associated mortality are major obstacles to success of transplantation from unrelated and haploidentical donors in children with acute lymphoblastic leukemia. Future directions will focus on optimizing conditioning regimens and enhancing graft-versus-leukemia effect. Negative depletion of α/β(+) T cells and CD19+ B lymphocytes, which permits to maintain mature donor-derived natural killer cells and γδ(+) T cells in the graft may improve GvHD control, immune reconstitution and prevent the relapse. Patients and methods : A total of 67 pediatric patients with acute lymphoblastic leukemia (T-ALL- 26, B-ALL-41, 29 female, 38 male, median age 9,4 years, range 0,15-20) underwent allogeneic HSCT between May 2012 and May 2016. Forty two patients received haploidentical graft, 25 - a graft from matched unrelated donor. Disease status at transplant was CR1 in 19pts., CR2 in 35 pts. and CR〉2 13 pts. Transplantation in CR1 was performed according to risk stratification scheme in the current institutional ALL protocol.Fifty patients recieved treosulfan-based myeloablative preparative regimen (74%), TBI-based regimen was used in 17 patients (26%). Two regimens of GvHD prophylaxis were used: regimen 1 (n=28): ATG (horse, ATGAM) 50mg/kg, post-grafting immunosuppression consisted of short course Tacro/MTX (n=20) before day +30 or no post-transplant prophylaxis (n=8[ММ1] ); regimen2 (n=39): ATG (rabbit, thymoglobuline) 5mg/kg, rituximab 200mg/m2 (n=30), bortezomib (n=24) and post- transplant bortezomib (n= 19) or Tacro (n=19). All patients with TBI- based regimen received rabbit ATG. TCRαβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases according to manufacturer's recommendations. The median dose of CD34+ cells in transplant was 10 x106/kg (range 3,9-18,8), TCRα/β - 19x103/kg (range 0,2-300). Results Primary engraftment was achieved in 64 of 67 pts. (two patients died before engraftment), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Early (100 day) mortality was pTRM was 7,5% (95% CI: 0,3-17),2-year pTRM - 17% (95%CI: 9-30). The 3 early deaths included bacterial sepsis (n=2) and viral infections (n=1), seven late: viral infection in four pts. (ADV=2, ADV+CMV=1, CMV=1), bacterial sepsis in two pts. and rhinocerebral mucormycosis in 1 pt., all late deaths were associatedwith chronic GvHD and prolonged corticosteroid therapy. Cumulative incidence of acute graft-versus-host disease (GvHD) grades II - IV and III - IV was 23,9% (95% CI: 16-36), and 7,5% (95% CI: 3-17) respectively. CI of cGvHD was 22,9% (95% CI: 14-36). Regimen 2 was more effective in prevention of aGvHD II-IV: CI at 2 year after HSCT was 12,8% vs 35,7% in regimen 1, p=0,05 and in cGvHD 8,8% vs 35,7%, p=0,028. No correlation between graft composition, donor type in aGvHD and cGvHD was noted Cumulative incidence of relapse at 2 years was 32% (95%CI: 22-47). Two years pEFS (event=death or relapse) was 49,6% (95%CI: 36-63), 2-year pOS - 50% (95%CI: 40-67). In patients, who received TBI-based conditioning pEFS was 62% (95%CI: 37-86), as compared with treosulfan-based 46,5% (95%CI: 31-62), p=0,65. There was no significant difference in survival and relapse rate according leukemia subtype and donor type. Median time of follow-up for survivors was 2 years (range, 0,3 - 4). Discussion: We confirm that the depletion of TCR-alpha/beta and CD19 lymphocytes from the graft ensures high engraftment rate and acceptable transplant-related mortality in pediatric ALL patients. Viral infections and leukemia relapse await further improvement of control. All major outcomes were equivalent between transplantation from unrelated and haploidentical donor. Disclosures No relevant conflicts of interest to declare.

Description: Laberko et al report excellent survival outcomes for patients receiving TCRαβ/CD19-depleted hematopoietic stem cell transplantation (HSCT) for primary immunodeficiencies, demonstrating comparable results with mismatched related and matched unrelated donors.

Description: Introduction Relapse, graft-versus-host disease (GvHD) and associated non-relapse mortality are the main obstacles to successful hematopoietic stem cell transplantation in children with leukemia. αβ T cell depletion was developed to prevent GvHD and improve immune reconstitution in recipients of mismatched grafts. Most current protocols use rabbit anti-thymocyte globulin (ATG) as an essential component of preparative regimen to secure engraftment and GVHD control. In order to avoid damaging effects of circulating ATG on graft NK and gd T cells, we have replaced ATG with pharmacologic blockade of IL-6 and CD80/CD28 co-stimulation axis in our ongoing study. Patients and methods Major transplantation outcomes were compared between participants of the current prospective trial (ATG-) and a retrospective control group (ATG+). A total of 165 children with acute leukemia (67 AML, 98 ALL, 68 female, 97 male, median age 8,7 y) underwent allo HSCT between 01.11.2013 and 01.03.2018. Of them 134 - from haploidentical donor and 31 from unrelated donor. All pts were in complete remission (CR1=80, CR2=67, CR〉2=18). Ninety-two pts received treosulfan-based conditioning, 73 - TBI-based (all ALL). Either melphalan (n=46) or thiophosphamide (n=98) or etoposide (n=21) were added as a second agent. Fludarabine was used in all pts. Two types of GVHD prophylaxis were used: type 1 (ATG+), (n=98): thymoglobulin 5mg/kg, rituximab 200mg/m2 with either bortezomib on days +2, +5 (n=72) or tacro (n=9) or without any additional agents (n=17); Type 2 (ATG-) (n=67): tocilizumab at 8 mg/kg on day -1, bortezomib on day +2, +5 with abatacept at 10 mg/kg on day -1, +7, +14, +28 (n=63) or without added agent (n=4). αβ T cell depletion with CliniMACS was used in all cases. The median dose of CD34+ cells was 9x106/kg, αβ T cells - 16 x103/kg. Modified (CD45RA-depleted) donor lymphocyte infusions (DLI) were administered to 113 pts. Twenty-five patients received DLI on day 0 and 88 pts received DLI after engraftment. Median time of follow-up for survivors was 2 years (range, 0,3 - 4,5). Results Three patients died before engraftment due to septic event. Primary engraftment was achieved in 161 of 162 evaluable pts (99,3%), the median time to neutrophil and platelet recovery was 16 and 15 days. Among the whole cohort the cumulative incidence of acute graft-versus-host disease (GvHD) grades II - IV and III - IV was 11,5% (95% CI: 7,5-17,6) and 4,8% (95% CI: 2,5-9,5) respectively. The cumulative incidence of cGvHD was 10 % (95% CI: 6,3-15,9). The incidence of aGvHD and cGvHD was not different between ATG (+) and ATG (-). Among the whole cohort 2-year pTRM was 8% (95%CI: 4,8-13,5). pTRM was significantly lower among ATG (-) group - 1,5% (95%CI:0,2-10,4) versus 12,2% (95%CI:7,2-20,8) among ATG (+) group, p = 0,015. The cumulative incidence of relapse at 2 years was 21% (95%CI: 15,5-29), 24% (95%CI: 16-35), among ATG (+) and 19% (95%CI: 11-32), among ATG (-), p = 0,8. Two-year pEFS was 70% (95%CI: 62-77), 2-year pOS - 78% (95%CI: 71-85). Among patients, who received ATG (-) regimen, pEFS was 76% (95%CI: 68-89), as compared to 65% (95%CI: 56-75) among ATG (+), p=0,1 and pOS was 89% (95%CI: 81-97) versus 72% (95%CI: 63-81), p=0,032, respectively. αβ T cell recovery at day +30 was associated with a trend to decreased incidence of relapse, CI of relapse was 32% (95% CI:22 - 47) in those with αβ-T cell count 〈 median vs 18 % (95% CI: 11-32) in those with αβ-cell count 〉median, p=0,08. EFS among αβ T" high" was 81% (+/-10) vs 56% (+/-14) among αβ T"low", p=0,002. Discussion We confirm that the depletion of αβ T cells from the unrelated and haploidentical graft in combination with intensive conditioning regimen ensures high engraftment rate and low transplant-related mortality. Our analysis suggests that polyclonal ATG serotherapy is not an essential part of the transplant regimen in αβ T-depleted transplantation. Combined administration of tocilizumab and abatacept after αβ T cell-depleted grafting effectively prevents GVHD, does not compromise engraftment, appears to decrease non-relapse mortality and improve survival. Disclosures No relevant conflicts of interest to declare.