Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes

Abstract

Background: Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton protocol of immunosuppression. New immunosuppressive strategies are required to improve long-term outcomes.

Materials and methods: Three subjects with unstable type 1 diabetes mellitus underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for 3 months and then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was more than 2 years. Comparison was with 16 historical subjects transplanted under the Miami version of the Edmonton protocol.

Results: Insulin independence was achieved in 2 of 3 alemtuzumab and 14 of 16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin-independence rates remained unchanged in the alemtuzumab group, but decreased from 14 of 16 (88%) to 6 of 16 (38%) in the historical group over 2 years. Insulin requirements increased in the historical group while remaining stable in the alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (P=NS). Further comparison of alemtuzumab versus historical groups, up to 24 months, demonstrated significantly better: Mixed meal stimulation index (24 months, 1.0+/-0.08 [n=3] vs. 0.5+/-0.06 pmol/mL [n=6], P<0.01), mixed meal peak C-peptide (24 months, 5.0+/-0.5 [n=3] vs. 3.1+/-0.3 nmol/mL [n=6], P<0.05), HbA1c (24 months, 5.4+/-0.15 [n=3] vs. 6.3+/-0.12 pmol/mL [n=10], P<0.01). Administration of alemtuzumab was well tolerated. There was no increased incidence of infections in alemtuzumab subjects despite profound, prolonged lymphocyte depletion.

Conclusions: Islet transplantation with alemtuzumab induction was well tolerated and resulted in improved short- and long-term outcomes. Further investigation is underway for validation.

Figure 1

Insulin Independence rates and Change in Insulin Requirements (A) demonstrate stability in Alemtuzumab group. By 24 months post infusion less than half of the Historical group remain insulin independent. HbA1c (B) is significantly better at 3 and 24 months post completion islet infusion in Alemtuzumab group (24 months 5.1±0.15 vs 6.3±0.12 % p<0.005). Results of routine protocol monitoring of Fasting Plasma Glucose (C) and C-peptide (D) up to 24 months post completion islet infusion demonstrate consistently better levels in the Alemtuzumab group, specifically normoglycemia compared to impaired fasting glucose levels in the Historical group.

Figure 2

Results of stimulation testing. Mixed Meal Peak C-peptide (A) and Stimulation Index (B) demonstrate significantly higher levels in the Alemtuzumab group (Peak C-peptide 24 months 1.67±0.17 nmol/L n=3 vs 1.17±0.10 nmol/L n=6 p<0.05, MMSI 24 months 1.0±0.08 n=3 vs 0.5±0.06 pmol/mL n=6, p<0.01). IVGTT Acute C-peptide Release (C) and MMTT C-peptide AUC (D), up to 24 months post completion islet infusion are consistently better in the Alemtuzumab group.

Figure 3

Hematological Effects of Alemtuzumab Induction. White blood cell count 0-150 days (A) and up to two years (B) and absolute lymphocyte count 0-150 days (C) and up to two years (D), following initial Alemtuzumab administration demonstrate profound long lasting depletion. Changes in subject 3 noted at 4-5 months post transplant coincide with change in immunosuppression (see text).