A Potent Thymic Function Is Associated with a Low Risk of Relapse In Leukemia Patients Treated with Haploidentical Stem Cell Transplantation

Abstract 1258

Hematopoietic Stem Cell Transplantation (HSCT) is an effective treatment for many malignant and non malignant diseases in children. Since less than 30% of the patients have an HLA identical related donor, alternative donor/sources of Hematopoietic Stem Cells need to be considered, such as unrelated bone marrow (BM) and Cord Blood (CB) donors or HLA-haploidentical related donors. However, these types of HSCT are associated with a significant delay in immune reconstitution that favors both a high incidence of opportunistic infection and, in the absence of an alloreactive, natural killer cell-mediated effect, disease relapse. Indeed, T-cell depletion of the allograft in the haploidentical setting or T-cell naivety in CB, as well as HLA-disparity and use of serotherapy before HSCT, contribute to this impaired immune reconstitution. In view of the role played by the thymus in immune reconstitution post-allogeneic HSCT, it would be informative to compare thymic-dependent immune reconstitution after these types of HSCT.

We have studied immune reconstitution and thymic function through signal joint (sj) and beta T cell Receptor Excision Circles (TREC) quantification in a group of 33 haplo-HSCT pediatric patients and in a group of 24 unrelated CB-HSCT. Patients were transplanted mainly for hematological malignancies (n=46, including 31 Acute Lymphocytic Leukemia and 9 Acute Myeloid Leukemia). All children received a myeloablative conditioning regimen, including the combination of total body irradiation and chemotherapy (n=33) or chemotherapy alone (n=24). In haplo-HSCT, no pharmacological immune-suppression was given after the allograft, while patients given CB-HSCT received cyclosporine-A and steroids as Graft vs. Host Disease (GvHD) prophylaxis. In haplo-HSCT patients the median number of CD34+ cells infused/kg was 20.7 × 10⁶ (range 8.7–41), while in patients given CB-HSCT the median number of nucleated cells infused/kg was 7.1) × 10⁷ (range 1.4–12.5). The only significant difference between the 2 groups was that haplo-HSCT patients were older (p=.0008) than CB-HSCT patients (median age being 7.7 and 3.4 yrs, range 3–17 and 0.75–16 yrs, respectively). Patients treated for an hematological malignancy had a significant lower pre-transplant TREC value (p = .0002 and .004 for sj and beta TREC respectively) than those affected by non-malignant diseases in both groups. Number of sj and betaTREC per 150 000 PBMC or absolute counts per μl of blood, showed a very similar thymic function in both groups despite the older age of haplo-HSCT patients. TREC levels were comparable to those found before transplantation starting from 6 months after HSCT. Cumulative incidence of acute or chronic GvHD was low in both groups, with no significant impact on thymic function.

In haplo-HSCT, but not in CB transplantation, patients treated for hematological malignancies (n=27) who relapsed (n=8) had a significantly lower level of thymic function (sjTREC) than those who did not relapse (n=19), before (p=0.03), after 3 (p=0.014) and 6 months (p=0.015) from the allograft. In this group of patients, relapse was not associated with age, conditioning regimen or number of CD34+ cells infused. In conclusion, we demonstrate the crucial importance of thymic function in the Graft-vs. Leukemia effect in the haplo-HSCT setting. Monitoring thymic function could be of predictive value in these patients.