The results of allogeneic hematopoietic stem cell transplantation from HLA-haploidentical donor with post-transplant cyclophosphamide regimen in children

Summary

Hematopoietic stem cell transplantation (HSCT) is a commonly accepted treatment option for high-risk hematological and immunological patients. The selection and availability of a donor is crucial for the success of the treatment. The strategy of using stem cells of a HLA-haploidentical related donor (haplo-HSC) combined with using post-transplant cyclophosphamide has shown the possibility of controlling the graft-versus-host reaction while maintaining the efficacy of HSCT. The purpose of this study was to summarize the experience of haplo-HSCT transplantation of unmanipulated graft from related donors in children with hematological malignancies and immunological pathology with a modified post-transplant cyclophosphamide regimen (PY-CY).

Materials and methods

During the period from 2013 to 2019, 37 haplo-HSCTs were performed in 34 patients at the BMT department of Russian Children’s Clinical Hospital (RCCH) including: acute lymphoblastic leukemia (n=9), acute myeloid leukemia (n=13), juvenile myelomonocytic leukemia (n=7), high-grade lymphoma (n=1), severe combined immunodeficiency (SCID) (n=3), aplastic anemia (n=1). The average age of the patients was 3.5 years (6 month to 14 years). Stem cell sources were bone marrow (BMT, n=34); peripheral blood stem cells (PBSCs, n=3). Patients received a myeloablative regimen: busulfan-based (n=15), threosulfan-based (n=16), full-dose total body irradiation TBI 12 Gray (n=2); lower-intensity conditioning regimens (n=4). For GVHD prophylaxis, PT-CY was given 100 mg/kg on days +3, +4, with rituximab (n=25), calcineurin inhibitors, mycophenolate (n=28); tacrolimus and sirolimus (n=9), abatacept/tocilizumab (n=26).

Results

The median day for the neutrophil engraftment was 21 days. The risk of primary graft failure was 11%, and it was higher in 3/10 patients (30%) treated with busulfan, compared with 1/19 patients from threosulfan-treated group (5.2%). Of 28 patients, 8 relapsed after haplo-HSCT. Complete donor chimerism on day +30 was achieved in 79% patients (n=27). The following post-transplant complications occurred: oral mucositis: grade 1 (n=7), grade 2 (n=14), grade 3 (n=4); neutropenic enterocolitis grade 1 (n=8), grade 2 (n=18), grade 3 (n=5), grade 4 (n=2); toxic hepatitis (n=15), hemorrhagic cystitis (n=6), systemic inflammatory syndrome (n=8), polyneuropathy (n=2), TMA-HUS (n=2). Viremia: cytomegalovirus (n=8), herpes virus type 6 (n=4), adenovirus (n=4) were detected, followed by negative values within short terms. We have also observed acute GVHD with skin rash symptoms of grade 1 (n=5), grade 2 (n=15), grade 3 (n=5), grade 4 (n=2); GVHD with gastrointestinal manifestation of grade 1 (n=7), grade 2 (n=5), grade 3 (n=5), grade 4 (n=2); hepatic GVHD (n=4) of degree 3 of severity; chronic GVHD form (n=9). The transplant-related lethal outcome occurred in one patient with TMA (incidence of 2.9%). Patients with SCID who had respiratory insufficiency of 2^nd-3^rd degree before conditioning were improved and resolved their complications up to 45-60 days after HSCT. Relapse in children with hematological malignancies was 29% (8 of 28). Relapse-associated mortality was 21% (6 out of 28). Of 34 patients, 27 are currently alive (79%). Median follow-up has been 3.8 years (range 0.6 – 6 years).

Conclusion

Our experience shows that haplo-HSCT with post-transplant cyclophosphamide regimen is effective treatment for high-risk patients with acceptable toxicity and low transplant-associated mortality rate. Early control of infection and antivirus immune response stimulation are the issues to be resolved in further studies. It is still disputable whether threosulfan-based regimen is beneficial for engraftment. High incidence of GVHD requires administration of adaptive supportive care.

Keywords

Hematopoietic stem cell transplantation, HLA-haploidentical, post-transplant cyclophosphamide.