Evaluation of Infectious Complications after Haploidentical Stem Cell Transplantation in Adult Patients with Hematologic Malignancies

Introduction.

Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclophosphamide (PT-Cy) is being increasingly used in patients who lack a matched related or unrelated donor. It provides the opportunity for nearly all patients to benefit from hematopoietic stem cell transplantation when a matched donor is unavailable. However, while the use of PT-Cy has proven to be very effective to prevent graft-versus-host disease (GVHD) in the haplo setting, this effect may be associated with an enhanced and prolonged immunosuppression leading to a higher infectious related morbidity and mortality in those patients. Therefore, we performed this retrospective study to evaluate comprehensively the incidence and features of infectious complications in adult patients receiving PT-Cy haplo-SCT.

Patients and Methods.

Seventy-two consecutive adult patients who underwent haplo-SCT with PT-Cy between December 2012 and December 2016, in Saint-Antoine Hospital, Paris, France were included in this study. Graft was either bone marrow (BM, n=21) or peripheral blood stem cell (PBSC, n=51). All patients received PT-Cy 50 mg/Kg/d, either one (BM, n=20; PBSC, n=1) or two days (BM=1, PBSC, n=50), for GVHD prophylaxis. In addition all patients received cyclosporine A and mycophenolate mofetil and 60 patients (83%) received antithymocyte globuline. Conditioning regimens were reduced in 23 patients (32%), sequential in 27 (38%) and myeloablative (reduced toxicity) in 22 (30%). 42 recipients (58%) and 48 donors were CMV positive, whereas 66 donors and recipients (92%) were EBV positive. The HSCT comorbidity index (Sorror Score) was 0 in 29 patients (40%), 1 or 2 in patients 29 (40%) and ≥3 patientsin 14 (%20). Main transplant outcomes and cumulative incidence (CI) of bacterial, fungal and viral were evaluated.

Results.

Median age at transplantation was 48 (range, 15-72) years. 44 patients (61%) had myeloid malignancies and 28 patients (39%) had lymphoid malignancies. Disease risk index was low/intermediate in 42 patients (59%) and high/very-high in 30 patients (41%). Median dose of total nucleated cells was 3.61´108 (range, 1.16-11.86) cells/kg. Median follow-up was 23.3 (range, 4.7-48.9) months. The 2-years overall survival and progression free survival were respectively 60% and 40%. The 2-years CI of relapse was 18%. The CI of NRM was 16% at day 100, 31% at one year and 33% at 2-years. Neutrophil recovery was achieved at a median time of 17 (range: 12-88) days after haplo-SCT. The days CI of grade II-IV and grade 180III-IV acute GVHD were, respectively, 28% and 15%. The 2-years, CI of overall .and extensive chronic GVHD were, respectively, 31% and 12%

The CI of bacterial infections was 43% at day 100, 46% at one year and 48% at 2-years. 8 patients were admitted to intensive care unit for bacterial infections. The CI of fungal infections was 24% at day 100, 28% at one year and 28% at 2-years. Although the CI of cytomegalovirus (CMV) reactivation was 56% at day 100 and 60% at one and 2-years, only one patient presents a CMV disease (CMV retinitis). With a CI of Epstein Barr Virus (EBV) reactivation was 54% at day 100, 68% at one year and 72% at 2-years, only 2 patients developed an EBV related post-transplant lymphoproliferative disease (PTLD, 2-years CI: 2.8%). The CI of BK virus and severe BK virus cystitis were respectively 31% and 24% at day 100, and 33% and 25% at one and 2-years. Concerning Human Herpes Virus 6 reactivation, the CI was 65% at day 100, 67% at one year and 69% at 2-years. Finally, the CI of infectious-related mortality (IRM) was 13% at day 100, and 20% at one year and 2-years. Of note, type of graft and dose of Cy have no impact on IRM and CI of infections.

Conclusion.

In conclusion, this data shows that haplo-SCT is associated with a high incidence of infections, in particular viral reactivation, and that these complications occur mainly within the first 100 days after allo-SCT. However, beside BK virus cystitis, these complications remain manageable as highlighted by the low incidence of CMV disease and PTLD. The high incidence of severe BK virus cystitis remains a matter of concern and strategies must be developed to prevent this complication. Overall, the high incidence IRM, haplo-SCT appears to be an effective strategy in patients with a 2-years overall survival of 60%. Finally, further improvements are required to decrease the incidence of infectious complication and improve patients' outcome after haplo-SCT.