Improvement of Survival By Use of New Tecniques of Manipulation after Haploidentical Hematopoietic Stem Cell Transplantation: Report of 230 Transplants in Paediatric Patients with Primary Immunodeficiencies and Oncological Diseases

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a consolidated therapeutic option for many malignant and nonmalignant diseases. The lack of HLA matched related donors (MRD) and HLA-matched unrelated donors (MUD) has, severely hampered the use of allo-HSCT. However, the advent of newer transplant strategies has resulted in a global increase in haplo-identical BMT.

Haploidentical hematopoietic stem cell transplantation (haplo HSCT) is a viable therapeutic option not only for malignant diseaseas but also for primary immunodeficiencies (PIDs).

Here we report the experience of the Pediatric BMT Unit of Brescia, the evolution and progress in transplantation techniques that have contributed to making haploidentical donors an alternative source of HSC in the absence of an HLA-compatible donor, overcoming one of the main limitations of this type of transplantation: the risk of GvHD. Indeed, the most important problem in isolated CD34+ transplantation for both sources (bone marrow and peripheral blood cells, PBSC) is the risk of delayed reconstitution or even no take. As a result, in recent years, an original graft manipulation technique has been developed in our Center; the positive selection of peripheral CD34+ stem cells enriched with the addback of a controlled number of donor CD3+ T lymphocytes (20-30 x10⁶ cells/kg recipient). The limitations of isolated selection of CD34+ stem cells in terms of immunological engraftment and reconstitution were overcome by adding a controlled number of CD3+T lymphocytes. This number of lymphocytes allows to mimic, even after PBSC infusion, the lymphocytic concentration of T cells in bone marrow, minimizing the risk of GvHD and ensuring prompt immunological reconstitution.

Since 1991 we performed 230 haploidentical HSCT; we focused on patients affected by Primary immunodeficiencies, a total of 86 patients, 56 with SCID and 30 patients with other Congenital Disorders. They have undergone 119 T depleted HSCT, among these, 7 transplants were carried out in utero.In 57% of cases, bone marrow HSC was infused, in 25% HSC from apheretic mobilization and in the remaining cases (18%) a co-infusion of bone marrow and apheretic HSCs was performed.

Recently our new techniques allowed to improve engraftment rate and to reduce incidence and severity of GVHD also in MUD HSCT. Analyzing our last four years, from January 2019 to July 2023 we retrospectively collected our data on haploidentical BMTs with CD34+ selection and CD3+ addback performed at our Centre for both malignant and non malignant diseases: 31 patients (18 MUD, 13 Haplo). Different conditioning were administered according to baseline diseases and international guidelines. Median Neutrofil engraftment was 18 days, mean platelet engraftment was 23 days. We didn't see any graft failure. Only one patient developed grade III acute GVHD, no patients developed grade IV aGVHD, only 1 patient developed chronic GVHD with cumulative incidence of aGVHD grade III-IV<10%.

The immunological exams revealed that in haplo cohort 20% reached 200 CD4+/mm³ and 1000 CD3+/mm³ cell counts on D+100, >50% on D+180, no significant differences between Haplo and MUD BMT.

Haploidentical transplantation using CD34+ selection/CD3+ addback/PT-Cy and serotherapy is feasible and safe, we had good engraftment rates, low rates of GVHD, especially high grade of acute GVHD. In addition, no invasive bacterial, fungal and viral infections were reported, with no life-threating infections or organ damage.

The continuous improvement of manipulation strategies has made excellent results possible not only in terms of GvHD control, but also in survival with an overall survival for the last transplanted patients almost 100%.

Porta:Jazz Pharmaceutical: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Biotest: Honoraria.