Pentostatin and Alemtuzumab: An Immunosuppressive Nonmyeloablative Preparative Regimen for Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).
Authors: Anwer Faiz , Carroll Michael P. , Green Myke R. , Cranmer Lee , Downey Leona , Garland Linda , Moini Katayoun , Persky Daniel O. , Swart Rachel , Yeager Andrew M. 
Published: October 2019

Abstract 4312

Introduction

Current nonmyeloablative and reduced-intensity preparative regimens for allogeneic (allo) PBSCT are associated with significant myelosuppression and neutropenia. We evaluated a novel, purely immunosuppressive preparative regimen of continuous-infusion pentostatin (PEN) plus alemtuzumab (ALEM) in patients (pts) undergoing related and unrelated allo PBSCT for high-risk hematological malignancies.

Patients and Methods

12 pts (median age, 58.5 yr; range, 23-69 yr; 7 male, 5 female) with high-risk, relapsed or refractory acute myelogenous leukemia (AML; 5 pts), Hodgkin's disease (HD; 2 pts), multiple myeloma (MM; 2 pts), chronic lymphocytic leukemia (CLL; 1 pt), low-grade non-Hodgkin's lymphoma (NHL; 1 pt) or myelodysplastic syndrome (1 pt) were enrolled on this study; 6 pts had failed previous autologous PBSCT. The median interval between most recent conventional chemotherapy and allo PBSCT was 3.5 months (range, 1.5-19.5 months). Pts received continuous-infusion PEN (12 mg/m2 over 72 hr, days -8 through -6) and ALEM (20 mg/day, days -5 through -1) followed by allo PBSCT from 8/8 HLA-matched related (3 pts) or unrelated (9 pts) donors. All pts received single-agent cyclosporine (CSP) for prophylaxis of acute graft-versus-host disease (GVHD).

Results

Median cell doses were 5.45 (range, 1.86-7.90) x 106 CD34+ cells/kg and 2.71 (range, 1.40-4.46) x 108 CD3+ cells/kg. Ten pts had asymptomatic transient elevations of AST and ALT (CTCAE grade 2-3) between days -6 and +21. No pts developed mucositis. Median duration of post-PBSCT hospitalization was 7 days (range, 3-62 days). The median nadir of the absolute neutrophil count (ANC) was 1.24 (range, 0.55–5.11) x 109/L at day +15, and the median nadir of the platelet count was 70 (range, 16-244) x 109/L at day -1. In contrast, the median nadir of the absolute lymphocyte count (ALC) was zero (range, 0-0.72) x 109/L at day -4. ALC remained low at day +28 (median, 0.09 × 109/L; range, 0.05-0.91 × 109/L) and increased by day +100 to a median of 0.34 × 109/L (range, 0.23-2.63 × 109/L). One pt developed grade 2 acute GVHD at day +21. No pts developed chronic GVHD. Evaluation of chimerism in bone marrow at day +28 showed that 3 pts had zero donor DNA and 9 pts had a median of 17% (range, 3-68%) donor DNA. At day +100, 2 of 8 evaluable pts (one with zero and one with 13% donor DNA at day +28) had zero donor DNA in bone marrow, and 6 pts had a median of 64% (range, 21.3-100%) donor DNA. Cumulative actuarial probability of sustained engraftment (defined as at least 50% donor DNA in bone marrow) is 53.4%. Doses of infused CD34+ cells or CD3+ cells were not statistically significantly different in pts with or without allogeneic engraftment (P=0.34, Mann-Whitney test). Three pts had asymptomatic reactivation of cytomegalovirus at 5, 11, and 35 days, respectively, after allo PBSCT. Two pts developed disseminated toxoplasmosis, which was fatal in 1 pt. One pt developed Mucor sinusitis and died with Enterococcus sepsis. One pt developed nonfatal Nocardia pneumonitis and sepsis at 175 days after allo PBSCT. Relapses occurred in 5 pts (1 AML, 1 CLL, 1 HD, 2 MM) at a median of 106 days (range, 28-360 days) after allo PBSCT; 1 of these pts had had engraftment failure and autologous hematopoietic recovery. The actuarial probability of relapse is 56.4%. Seven pts died at a median of 60 days (range, 44-347 days) after allo PBSCT: 1 relapse of HD, 2 infection (1 toxoplasmosis, 1 Enterococcus sepsis), 1 pulmonary hemorrhage with multiorgan failure, and 3 refractory acute GVHD that occurred following treatment of relapse with donor lymphocyte infusion (1 pt), withdrawal of CSP (1 pt) or second allo PBSCT (1 pt). Four subjects (2 AML, 1 HD, 1 NHL) are alive in remission at a median of 513 days (range, 267-787 days) after allo PBSCT. Actuarial probabilities of overall survival and event-free survival are 40.0% and 31.3%, respectively.

Conclusions

A preparative regimen of continuous-infusion PEN plus ALEM can allow engraftment of HLA-matched allogeneic PBSCs without significant myelosuppression. However, engraftment failure is greater after this purely immunosuppressive regimen than with standard nonmyeloablative or reduced-intensity regimens. Relapsed or refractory disease at time of allo PBSCT, the absence of cytoreduction with this preparative regimen, and potentially a decrease in graft-versus-tumor effect as a result of profound and prolonged immunosuppression are factors that contribute to the relapse rate observed in this study.

Disclosures:

Off Label Use: Pentostatin administered as a continuous infusion according to FDA IND #67,067.