Work

Rapid Immunosuppression Taper Following Reduced Intensity HCT From Related Donor Is Tolerable But Does Not Improve Outcomes of Advanced Hematologic Malignancies

Year: 2009

Type: article

Abstract: We have previously showed that, despite the significant reduction of transplant-related mortality (TRM) achieved by using reduced intensity conditioning (RIC), relapse continues to be a major cause of failure, especially in advanced-stage hematologic malignancies. In order to improve relapse-free survival in the setting of reduced intensity sibling donor transplants for advanced hematologic malignancies, our group has tested a modified Fludarabine/Busulfan RIC regimen (fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy) with a rapid post-transplant immunosuppression (IS) taper (start day 28, finish day 63) in a prospective single arm phase II study. The rapid taper was intended to facilitate a GVL effect that hopefully would translate into improved DFS. Patients without progression who did not develop GVHD by d100 received planned donor lymphocyte infusion (DLI) 5 × 107 CD3+/kg. 45 pts (median f/u 918d; range 100–1835d) have been treated between 8/2003- 2/2008. The median age was 56y (2–67y); 19 (42%) failed previous autologous HCT. Five patients received DLI. Forty patients received HSC from 6/6 HLA matched and 5 from 5/6 HLA matched related donors. Rapid tacrolimus taper reliably induced GVHD grade 2–4 in the study population (73 ± 6%) by day 100 at a median of 46d (range, 18–98d). Extensive chronic GVHD developed in 65±7% of patients. GVHD in this context was rarely fatal (7 GVHD-related deaths) resulting in 2-year NRM of 24 ± 7%. Outcomes were analyzed for the whole group and by stratification according to risk of relapse after non-myeloablative HSCTTabled 1Stratification of the Study Patients According to the Estimated Risk of Relapse After NMA HSCT (1).High/Standard-risk diseasen=28Low-risk diseasen=17AML (de novo)4Follicular lymphoma, low grade4AML (secondary)3MAntle cell lymphoma4AML (treatment-related)2DLBCL/t-DLBCL, CR3MDS6NHL/AITL, CR1CML-BC1MM, CR5Ph+ALL, CR21Hodgkin's disease, refractory4MM, refractory5t-DLBCL, refractory1CLL, refractory1(1)- Kahl,C., et al. Blood 2007; 110:7 2744-48. Open table in a new tab .The 2-year OS and PFS for all pts was 38±17% and 35±7% respectively, with superior PFS seen in low risk vs high/standard risk pts (52± 13% vs 26±8% p = 0.03). A higher cumulative incidence of progression in high/standard risk pts (63±9% vs 0%, p = 0.0001) accounted for most of the difference in survival. However, when compared to similar risk group pts in our prior trial (Levine, et al, BBMT 2003) that utilized identical conditioning, but a conventional IS taper, there were no differences in PFS for low risk (58% vs 50%, p = NS) or high risk pts (29% vs 23%, p = NS). TRM rates were similar in both trials (32% vs 24%, p = NS). Thus, while a rapid IS taper in this RIC setting induces GVHD that is usually non-lethal, the desired GVL effect did not manifest itself in terms of improvements in PFS for low or high risk pts. (1)- Kahl,C., et al. Blood 2007; 110:7 2744-48.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2008.12.019