Pre-Emptive T-Rapa Cell DLI for Therapy of High-Risk Lymphoma After Low-Intensity Allogeneic HCT

Abstract 471

Lymphoma progression remains an obstacle after allogeneic HCT, particularly after non-myeloablative conditioning in patients with high-risk histology (non-indolent; Kahl et al; Blood, 2007) and chemotherapy refractory disease (Bishop et al; Cancer, 2010). In murine models, rapamycin-resistant T cells favorably modulated the balance between GVHD, graft rejection, and GVT effects. To translate this, we conducted a multi-center phase II trial (NCT0074490) of T-Rapa cells infused as a pre-emptive DLI after low-intensity allogeneic HCT; here, we report overall outcome of patients with high-risk lymphoma diagnoses, many of whom were chemotherapy refractory. T-Rapa cells were manufactured by ex vivo culture of donor CD4⁺ T cells using CD3/CD28 co-stimulation and IL-4, IL-2, and rapamycin for 12-days (T-Rapa₁₂) or 6-days (T-Rapa₆), and administered (2.5 × 10⁷ cells/kg) at d14 post-HCT. Both populations of T-Rapa cells expressed a mixed Th2/Th1 phenotype with minimal T-Reg content. Patients (n=42) received outpatient-intensity chemotherapy (typically, EPOCH-FR) until CD4 count was < 200 cells/μl, and then received an HLA-matched sibling mobilized allograft and GVHD prophylaxis of cyclosporine plus short-course sirolimus (to d14 post-HCT); conditioning consisted of fludarabine (120 mg/m²) and cyclophosphamide (1200 mg/m²). Table I details the high-risk diagnoses, pre-treatment history (median of 4 prior regimens), remission status at time of HCT (7/42 [17%] in CR), and presence of chemotherapy refractory disease (stable or progressive disease to prior therapy: 23/42 pts, 55%). T-Rapa cell infusion was relatively safe, with no engraftment syndrome or d100 TRM; incidences of grade II-IV acute, late acute, and classical chronic GVHD were 17%, 34%, and 36%, respectively. Initial mixed donor/host chimerism converted to predominate donor chimerism after T-Rapa cell DLI (Table I). Overall median survival probability at 24 months post-HCT is 85.7% for patients with chemotherapy sensitive disease vs. 39.1% for patients with chemotherapy refractory disease (Fig. 1; p=0.0008). All deaths were due to progressive disease except for 2 infection-related deaths at days 162 and 359 post-HCT; all surviving patients are in CR. Survival was not statistically significantly influenced by DLI type (T-Rapa₁₂ vs. T-Rapa₆) or histology-type (NHL vs. HD). Pre-emptive DLI using donor T-Rapa cells after low-intensity conditioning is safe and very effective in patients with high-risk lymphoma diagnoses and chemotherapy sensitive disease; for such patients, future randomized trials should compare low-intensity T-Rapa cell therapy to other transplantation regimens. For patients with high-risk lymphoma diagnoses and chemotherapy-refractory disease, we are evaluating a modification to the current platform that incorporates high-dose sirolimus therapy.

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