Reduced Dose of Post-Transplant Cyclophosphamide for HLA Haploidentical Peripheral Blood Stem Cell Transplantation

[Introduction]

Allogeneic hematopoietic stem cell transplantation (Allo-SCT) remains the only potentially curative therapy for patients with high-risk or chemo-refractory hematologic malignancies. Recently, various methods including post-transplant cyclophosphamide (PT-CY) showed the ability to overcome the HLA disparity barrier and haploidentical hematopoietic stem cell transplantation (haplo-SCT) have been becoming an attractive method of transplantation with less rejection or graft-versus-host disease (GVHD). There have been many reports that the outcomes of haplo-SCT are equivalent to those of matched related donors and matched unrelated donors. The standard dose of PT-CY is 50 mg/kg/day for 2 days. However, optimal dose of PT-CY has not been studied extensively. In this study, we performed a clinical study of reduced dose of PT-CY (40 mg/kg/day for 2 days) haplo-SCT for hematologic malignancies.

[Methods]

We included adult patients with hematologic malignancies who received haplo-SCT at Kurume university hospital, Kurume, Japan between Oct 2014 and March 2018. Myeloablative conditioning (MAC) regimen consisted of fludarabine (Flu) (30 mg/m² for 5 days), busulfan (BU) (3.2 mg/kg/day for 4 days) and total-body irradiation (TBI) 4Gy (Flu/BU4/TBI4Gy) or Flu (30 mg/m² for 3 days) and TBI 12Gy (Flu/TBI12Gy). Reduced-intensity conditioning (RIC) regimen consisted of Flu (30 mg/m² for 5 days), BU (3.2 mg/kg/day for 2 days) and TBI 4Gy (Flu/BU2/TBI4Gy). All patients were given PT-CY (40 mg/kg/day) on day +3 and day +4, followed by tacrolimus and mycophenolate mofetil (MMF) starting on day + 5 for GVHD prophylaxis. If there was no active GVHD, MMF was tapered off from day +30. Filgrastim 300 ug/m² was administered starting on day +5 and continuing until neutrophil engraftment was achieved. Donors were mobilized with filgrastim 400 ug/m² for 4 or 5 days, the peripheral blood stem cells were collected with one or two apheresis procedures. OS and PFS were calculated using the Kaplan-Meier method and the log-rank test was used for comparisons of Kaplan-Meier curves. Estimates of acute GVHD was calculated using death as the competing risk. P-values <0.05 were considered statistically significant.

[Results]

A total 15 patients with acute myeloid leukemia (AML, n=6), myelodysplastic syndrome (MDS, n=2), acute lymphoblastic leukemia (ALL, n=4), adult T-cell leukemia/lymphoma (ATLL, n=1) and malignant lymphoma (ML, n=2) were analyzed in this study. Patients median age was 54 years (range, 17 to 72); 9 patients were male, and 6 patients were female. Eight patients received MAC, 7 received RIC conditioning regimen. Disease status at transplantation was complete remission (CR) in 8 patients, non-CR in 7. The median CD34+ cell dose was 5.9 x 10⁶ /kg (range, 2.4 to 17.4). All 15 patients achieved a neutrophil engraftment in a median 15 days (range, 13 to 19). Grade II-IV and III-IV acute GVHD occurred in 46.7% (95% confidence interval [CI], 14.4-66.8) and in 13.3% (95% CI, 0-28.9) patients, respectively. At 2 years, overall survival (OS) and progression-free survival were 36.6% (95% CI, 13.0-60.9) and 32.0% (95% CI, 10.9-55.7), respectively. The 2-years OS of patients in CR before SCT was 50.0% (95% CI, 15.2-77.5) compared to 28.6% (95% CI, 4.1-61.2) not in CR (P=0.106). The causes of death were: disease progression (n = 3), infection (n = 3), acute GVHD (n = 2), and noninfectious pulmonary complications (n = 2). Among infectious complications, two were bacterial infections and one was BK virus-associated hemorrhagic cystitis.

[Conclusion]

Reduced dose of PT-CY HLA haploidentical peripheral blood stem cell transplantation resulted in acceptable rate and severity of acute GVHD. However, relapse and infection remain major problems after PT-CY haplo-SCT for hematologic malignancies.