Infection Is the Major Cause of Mortality after Nonmyeloablative Unrelated Bone Marrow Transplantation with Alemtuzumab, Fludarabine and Melphalan.
Authors: Carroll Michael P. , BuchBarker Diane , Schwartz Rowena , Agha Mounzer E. , Tompkins Cheryl , Baileys Kristen , O’Connell Kathleen , Donnenberg Albert D. , Yeager Andrew M. 
Published: April 2020

Abstract
Nonmyeloablative (NM) regimens for allogeneic (allo) hematopoietic cell transplantation (HCT) may be effective and associated with a low incidence of acute graft-versus-host disease (GVHD) in high-risk patients (pts) with hematologic malignancies. We report the results of NM bone marrow transplantation (BMT) from HLA-matched volunteer unrelated donors (VUDs) in 14 pts (median age 45 yr; range, 19–58 yr) with relapsed and/or refractory hematologic malignancies (1 ALL, 3 AML, 3 MDS/AML, 3 Hodgkin’s disease [HD], 2 multiple myeloma, 2 NHL). Thirteen pts had previous HCT: 10 autologous (auto), 1 related allo, 1 VUD, 1 auto and VUD. The NM regimen included alemtuzumab (20 mg/day x 5, days −8 through −4), fludarabine (30 mg/m2/day x 5, days −7 through −3) and melphalan (140 mg/m2 on day −2), as described by Kottaridis PD et al, Blood2000; 96: 2419 and Chakraverty R et al, Blood2002; 99: 1071. All pts received single-agent cyclosporine for prophylaxis of acute graft-versus-host disease (GVHD). Median doses of CD34+ and CD3+ cells were 2.79 (range, 1.35–4.87) x 106/kg and 2.8 (range, 1.99–6.39) x 107/kg, respectively. In 12 evaluable pts, median times to absolute neutrophils &gt;0.5 x 109/L and platelets &gt;20 x 109/L were 15 (range, 9–41) and 21 days (range, 15–41), respectively, after NMBMT. Two pts had primary graft failure (actuarial probability 16.4%; 95% confidence interval [CI], 0–37.6%). Two pts developed acute GVHD (1 grade I, 1 grade II) at 19 and 76 days, respectively, after NMBMT. The actuarial probability of all grades of acute GVHD is 16.1% (95% CI, 0–36.7%) and of grade II or greater GVHD is 9.1 % (95% CI, 0–26.2%). Two pts (1 with grade II acute GVHD) developed extensive chronic GVHD. Five pts developed cytomegalovirus (CMV) reactivation, for an actuarial probability of CMV reactivation of 58.5% (95% CI, 19.9–97.1%). One pt with CMV reactivation died with CMV infection at 122 days after NMBMT. Six pts died with other infections at a median of 74 days (range, 52–209) after NMBMT: 2 adenovirus (1 associated with graft failure), 2 toxoplasmosis, 1 Aspergillus (associated with graft failure), 1 Pseudomonas (associated with chronic GVHD). One pt died with pulmonary failure and chronic GVHD 267 days after NMBMT. Actuarial nonrelapse mortality (NRM) is 64.3% (95% CI, 35.5–93.1), and infection-associated mortality is 52.4% (95% CI 25.0–79.8%). Three pts (2 AML, 1 HD) relapsed at 181, 182 and 202 days, respectively, after NMBMT; actuarial relapse rate is 46.4% (95% CI, 26.4–66.4%). Three pts (1 ALL, 1 AML, 1 NHL) are alive without relapse at 164+, 184+ and 843+ days, respectively, after NMBMT; actuarial event-free survival (EFS) is 10.2% (95% CI, 0–28.8%). We conclude that opportunistic infection is the major cause of NRM after VUD NMBMT with a preparative regimen of alemtuzumab, fludarabine and melphalan and contributes significantly to the poor EFS in pts with relapsed/refractory hematologic malignancies thus treated. Efforts to improve immune reconstitution and infection prophylaxis after NMBMT with this regimen are warranted.