Haploidentical Stem Cell Transplantation in Children With Hematological Malignancies Using αβ+ T-Cell Receptor and CD19+ Cell Depleted Grafts: High CD56dim/CD56bright NK Cell Ratio Early Following Transplantation Is Associated With Lower Relapse Incidence and Better Outcome

Abstract

We prospectively analyzed outcomes of haploidentical hematopoietic stem cell transplantation using αβ+ T-cell receptor/CD19+ depleted grafts. Sixty-three transplantations were performed in 60 patients. Twenty-eight patients were diagnosed with acute lymphoblastic leukemia (ALL), 27 patients were diagnosed with acute myelogenous leukemia, and in eight other hematological malignancies were diagnosed. Twenty-three were in first complete remission (CR), 20 in second CR, 20 beyond second CR. Four patients developed graft failure. Median time to neutrophil and platelet recovery was 14 (range 9–25) and 10 days (range 7–30), respectively. The probability of non-relapse mortality (NRM) by day +100 after transplantation was 10 ± 4%. With a median follow-up of 28 months, the probability of relapse was 32 ± 6% and disease-free survival was 52 ± 6%. Immune reconstitution was leaded by NK cells. As such, a high CD56dim/CD56bright NK cell ratio early after transplantation was associated with better disease-free survival (DFS) (≥3.5; 77 ± 8% vs. <3.5; 28 ± 5%; p = 0.001) due to lower relapse incidence (≥3.5; 15 ± 7% vs. <3.5; 37 ± 9%; p = 0.04). T-cell reconstitution was delayed and associated with severe infections after transplant. Viral reactivation/disease and presence of venooclusive disease of liver in the non-caucasian population had a significant impact on NRM. αβ+ T-cell receptor/CD19+ cell-depleted haploidentical transplant is associated with good outcomes especially in patients in early phase of disease. A rapid expansion of “mature” natural killer cells early after transplantation resulted on lower probability of relapse, suggesting a graft vs. leukemia effect independent from graft-vs.-host reactions.

Blinatumomab in pediatric patients with relapsed/refractory B‐cell precursor acute lymphoblastic leukemia

“…Especially, a second haploidentical HSCT was associated with better relapse‐free survival in our cohort. Haploidentical HSCT has proven to be a highly efficient therapy especially for refractory malignant diseases 17‐20 . However, the small number of patients receiving a matched HSCT after blinatumomab does not enable a valid comparison between both HSCT subtypes.…”

“Ex‐vivo” T‐cell depletion in allogeneic hematopoietic stem cell transplantation: New clinical approaches for old challenges

“…Immune reconstitution in children receiving TCRαβ + depleted haploidentical transplant was characterized by early and fast NK‐cell recovery constituting major lymphocyte subpopulation in the early phase following transplantation 52 . After conditioning, blood high level of interleukin‐15 provides a favorable environment not only for mature donor NK‐cell infused but also for NK cells maturing from engrafted hematopoietic stem cells.…”

“…It has been previously reported using CD3 + CD19 + as TCD method that a high number of NK‐cells during early post‐transplant period protected form leukemia relapse 37 . Recently, the potential impact of CD56 dim and CD56 bright NK cells subpopulation on relapse incidence has been analyzed, resulting that the higher CD56 dim/ CD56 bright NK‐cell ratio the lower relapse incidence and better DFS 52 …”

“…Natural killer cells exert an antileukemic effect 68‐70 . As an association between NK‐cell recovery and transplant outcome has been observed, 52,69‐71 adoptive NK‐cell therapy has been proposed to overcome limitations associated with NK‐cell reconstitution after haploidentical transplant 66,70,71 . As such, this NK‐cell donor infusion has been explored in a pediatric phase II study.…”

Optimizing Allogeneic Grafts in Hematopoietic Stem Cell Transplantation

“…A longitudinal analysis after allo‐HSCT showed that the incidence of aGvHD was associated with a delayed expansion of the CD56high subset 38 . In addition, a high CD56dim/CD56high NK cell ratio early after transplantation was associated with better disease‐free survival (DFS, 77% vs 28%; P = .001) due to lower relapse incidence (15% vs 37%; P = .04) in the αβ+ TCR/CD19+‐depleted graft model 39 . These results suggest that the number and subsets of NK cells affect transplantation prognosis.…”