Effect of Donor on Outcomes after Myeloablative Conditioning with Daily IV Busulfan and Fludarabine (FLUBUP) +/− TBI with Thymoglobulin: Transplants from Mismatched Unrelated Donors (MMUD) Have Worse Survival Due to Higher Transplant-Related Mortality (TRM).
Authors: Russell James A. , Kmet Leanne , Savoie Mary Lynn , Bahlis Nizar J. , Chaudhry M. Ahsan , Quinlan Diana M. , Geddes Michelle , Turner A. Robert , Larratt Loree M. , Brown Christopher , Storek Jan , Stewart Douglas A. 
Published: October 2019

Historically myeloablative hematopietic stem cell transplants (SCT) from donors other than genotypically identical siblings (MRD) have had worse outcomes when the same conditioning and GVHD prevention is used. It is important to know if this is still the case when all patients receive better tolerated regimens, using i.v. rather than oral busulfan for example, and more aggressive GVHD prophyaxis. We have compared outcomes of pateints (pts) receiving myeloablative fludarabine/busulfan based conditioning (FLUBUP) between 05/99 and 05/05 according to donor. All pts received fludarabine 50mg/m2 on days -6 to -2 and IV busulfan (Busulfex, PDL Pharma) at a myeloablative dose of 3.2 mg/kg daily days -5 to -2 inclusive +/− TBI 200cGy × 2 on day -1 or 0. Prophylaxis for GVHD was cyclosporine A, methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Patients were divided into four groups depending on donor - MRD, genotypically mismatched family members (MMRD), unrelated donors matched for HLA-A, -B, C, DR & DQ (MUD) and MMUD. Of 40 MMUD 32 were mismatched for one antigen, 7 for 2 and one for 3 at least at the allelic level.

Baseline and transplant characteristics MRD MMRD MUD MMUD Number 201 22 81 40 Pt age (yrs) range/mean (SD) 18–66/45 (11.0) 19–63/44 (14.9) 16–61/40 (12.3) 19–64/40 (12.2) Donor age (yrs) range/mean (SD) 15–71/44 (11.1) 10–65/35 (19.1) 19–57/32 (8.5) 21–54/33 (8.2) Male pt % 63.7 54.6 58.0 65.0 Low risk (Acute leukemia CR1/2, CML CP1) % 41.8 54.6 55.6 32.5 TBI % (not risk factor for TRM) 23.9 31.8 42.0 47.5 Blood cell SCT % 87.6 90.9 43.2 65.0 Female to male SCT % 26.9 27.3 19.8 30.0 CMV+ve donor or recipient % 77.1 54.6 69.1 55.0 CD34+ cell dose/kg - range/median (IQR) 0.8–13.6/4.7(3.4–6.0) 2.0–10.3/4.1(3.3–6.9) 0.4–23.9/3.7(2.4–7.7) 0.9–17.7/5.0(3.0–7.0)

Five-year survival (OS) estimates (95% CI) were MRD 60% (52%–67%), MMRD 58% (34%–75%), MUD 57% (45%–67%), MMUD 38% (23%–53%). By Cox regression analysis MRD, MMRD and MUD SCT had similar outcomes and were combined for a more robust analysis. The hazard ratio for OS for MMUD vs all others was 2.03 (95% CI 1.31–3.16, p = 0.002). After adjusting for gender, risk group, patient age (continuous), donor age (continuous), TBI, stem cell source, female donor to male recipient, CMV status and CD34+ cell dose (continuous) the hazard ratio was 1.69 (1.04–2.74) (p = 0.03). The cumulative incidence of relapse mortality was silmiar across all 4 groups, the difference in outcome was mostly attributable to TRM. Thus the cumulative incidence of TRM at 3 years was 31.6% (17.5%–46.7%) for MMUD vs 14.5% (10.8%–18.8%) for all others. We conclude that the FLUBUP protocol +/− TBI with Thymoglobulin gives comparable OS for recipients of SCT from all donors apart from MMUD and patients should be advised of the increased risk when the latter donors are the only ones available.