Allogeneic stem cell transplantation offers potentially curative therapy for selected patients with hematopoietic malignancies or bone marrow failure states. Only 20–25% of transplantation candidates have compatible related donors, and thus the majority of patients require stem cells from unrelated individuals matching their human leukocyte antigen (HLA) genes. Unrelated donor transplantation (NMUDT) is associated with higher rate of acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) resulting in significant treatment related morbidity and mortality. Severe aGVHD (grade III/IV) occurs in 30–40% of patients and many of these patients eventually die from the complications. The incidence of cGVHD following unrelated transplantation was reported to occur up to 80%. Treatment-related mortality in the first 100–180 days post-transplant ranges from 30–60% depending on the patient/donor age, disease status at time of transplant and HLA mismatch. This compares to a treatment-related mortality of approximately 20–30% for patients receiving sibling-donor transplants. More aggressive conditioning including total body irradiation is believed to result in severe organ toxicities fueling subsequent GVHD in the NMUDT patients. In this study we evaluated chemotherapy only based preparative therapy (busulfan and fludarabine) and tacrolimus plus methotrexate as the GVHD prophylaxis. Also the donors and recipients were matched with strict HLA compatibility.
Thirty-five patients meeting eligibility criteria for NMUDT were prospectively enrolled. Diagnoses included:14 AML, 6 NHL, 6 MDS, 5 ALL, 2 MPD, 2 CML. The median age was 46 years (18-61); 20 males and 15 females. Preparative therapy consisted of Fludarabine (F) 30mg/m2 daily for 5 doses, Busulfan (Bu) 0.8mg/kg IV q6 hrs for 16 doses. All patients received stem cells from allele-matched unrelated donors; 7/8 (n=1), 8/10 (n=1), 9/10 (n= 7) or 10/10 (n= 26) at HLA A, B, C, DR and DQ. 9 patients received bone marrow and 26 patients received G-CSF mobilized peripherial blood stem cells. All patients received TAC (target 5–10 ug/L), MTX (5mg/m2 d1,3,6,11) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy.
The engraftment was documented as follows: ANC >1.0 median: day 12 (SD3.5), Plt >50×10e9/L median: day 16 (SD 7.2), Plt >100×10e9/L median: day 20 (SD 40.7). The frequent (>20%) toxicities included bone marrow suppression (grade 4 100%) mucositis (gr≥1 91%), enteritis (gr≥1 43%); elevated AST (gr 1 27%), elevated total bilirubin (gr 1 20%) and alkaline phosphatase (gr1 40%). Other significant toxicities (gr ≥3) included neutropenic fever (20%), bacteremia (11%), infections (including pneumonia, fungal pneumonia, CMV viremia) (26%), enteritis 6%, ARF 9%, rash 9%, respiratory failure 14%. The incidence of aGVHD (Gr II-IV) was 43%. The incidence of cGVHD was 60% (90% extensive cGVHD). The 100 day non-relapse mortality (NRM) was 9% (2 GVHD, 1 VOD). The late TRM (beyond 100 days) was 11% (3 GVHD, 1 infection). Cumulative relapse related mortality was 17% at 6 months, 26% at 9 months and 31% at 24 months. Overall mortality at 1 year was 44%. Overall survival is currently 40% with median follow-up of 4.4 years.
In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the busulfan/fludarabine preparative regimen is safe and resulting in reasonably low TRM and comparable GVHD rates. Disease relapse remains the most significant cause of death.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.