Timely Use of Donor Lymphocyte Infusion (DLI) Improves Allogeneic Transplant Outcomes

Introduction: T-Cell depleted Allogeneic stem cell transplant using ATG or Alemtuzumab is associated with delayed immune reconstitution, increased risk of infections, increased chances of mixed chimerism and hence the risk of disease relapse. Role of donor lymphocyte infusion has been proven in treatment of relapse post SCT, but this retrospective analysis was undertaken to evaluate the efficacy, toxicity and long-term utility of DLI for management of mixed chimerism.

Methods: 157 patients (Group A) who received DLI were analysed for the indications, complications, risk of GVHD and outcomes on relapse rate, overall survival, non-relapse mortality after incremental DLI. This group was compared with 272 patients (Group B) who did not need DLI to compare relapse incidence. Data was collected using electronic/paper patient records, laboratory database and the transplant data base.

Results: Two groups were evenly balanced for demography [Group A: Median age: 53yr. (18-71); M/F:103/54. Group B: Median age: 51yr. (17-71); M/F: 171/101] but patients in group A had higher use of BM (20% vs 4%, p=0.001), sibling donor (52% vs 15%, p=0.001), RIC conditioning (80% vs 68%, p=0.005), CML/HD/Myeloma as underlying diagnosis (35% vs 11%, p=0.001), ATG or Alemtuzumab regimen (89% vs 60%, p=0.001) and lower chance of TBI conditioning (12% vs 33%, p=0.001). Thirty-one patients in group A had previous autoSCT (31, 20%) or alloSCT (4, 2.5%). Reasons for DLI was mixed chimerism (86, 55%), disease relapse (59, 38%), both (10, 6%) and not specified (2, 1%). The median time from SCT to DLI was 314 d (range: 63-6734) and the usual starting dose was 1x10^6/Kg CD3 positive cells (145/157, 92.4%). Initial dose did not vary with the indication for DLI. Median number of doses used was 2 (1-11) but 145 patients (94%) received a maximum of 3 doses. The median whole blood STR pre-DLI was 94% (5-100%) and CD3 STR was 55% (7-100%). Median post DLI CD3 STR was 99.5% (0-100%). CD3 chimerism increased to more than 90% in 102/137 cases with available data (75%), independent of previous ATG/alemtuzumab, TBI, intensity of conditioning or primary malignancy. Development of GVHD did not predict improvement in chimerism. aGVHD of any grade developed in 86/157 (55%) and 19 had grade 3+ aGVHD (12%). Frequency of organ involvement was skin (n=79), gut (n=23) and liver (n=13). cGVHD developed in 39/157 patients (25%) and it was moderate or severe in 21 cases (13.4%). Skin (n=22), mouth (n=25) and eyes (n=13) were commonly involved organs with cGVHD. Forty-six patients were treated for GVHD pre-DLI and GVHD developed in 55 patients post-DLI. GVHD developed in 29% cases post DLI without prior GVHD but in 50% cases with pre-DLI GVHD, manifestations were more severe after DLI (p=0.014). Severity of post-DLI GVHD did not correlate with the indication for therapy. 254 patients, including 96 receiving DLI are alive with median overall survival of 200mo (range:0.1-370) for the entire cohort (GroupA: 64mo, GroupB: 24mo, p<0.001). GVHD was responsible for mortality in 6 cases (4%). Incidence of relapse at 5 yr. was significantly lower at 15% in patients receiving DLI for mixed chimerism (95% CI: 7-24), 65 % in relapsed patients (95% CI: 52-73%) and 60% in patients with relapse and mixed chimerism (95% CI: 30-90%). Incidence of relapse at 5 yr. in GroupB was 23% (95% CI: 23-43%). Event free survival at 5 yr. was significantly better in patients receiving DLI (56%, 95% CL: 46-64% vs 43%, 95% CI: 37-50%; p=0.001). TRM at 5 years was 8% in GroupA and 30% in GroupB (p<0.001). Results of DLI are better if the treatment is delayed for 9-12 mo. post allograft.

Conclusion: Appropriate use of DLI to improve mixed chimerism is successful in 75% cases with maximum of three incremental doses of lymphocytes. There is a significant risk of developing GVHD and small risk of mortality but risk of relapse in patients receiving DLI is reduced to the same level as patients who have full chimerism. Development of GVHD is not necessary for restoration of CD3 chimerism. The analysis will expand upon the role of STR values at various time points, rate of increment and the impact on outcome measures.

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