INNOVATION IN COMPOSITE TISSUE TRANSPLANTATION

V.S. Gorantla¹, G. Brandacher¹, S. Schneeberger², K. Azari¹, G.S. Wachtman¹, J.D. Keith¹, J.T. Shores¹, T.E. Starzl¹, J. Imbriglia¹, W.P.A. Lee^1
1Division Of Plastic And Reconstructive Surgery, UPMC, Pittsburgh/PA/UNITED STATES OF AMERICA, ²Division Of Plastic And Reconstructive Surgery, UPMC, Pittsburgh/UNITED STATES OF AMERICA

Body: INTRODUCTION: Over the past decade, 57 hand/forearm/arm transplants have been performed in 41 patients. Despite favorable graft survival and functional/immunologic outcomes, wider clinical application and benefits of these life-enhancing reconstructions is limited by the risks and morbidity of multiple, high dose immunosuppression. We present our early experience with 5 hand/forearm transplants performed under a novel cell based immunomodulatory protocol that differs from existing regimens in incorporating donor bone marrow (BM) infusion. We hypothesize that immunomodulation with donor BM cell based therapies can enable significant reduction of immunosuppression after upper extremity transplantation. METHODS: Patient #1: A 24 year-old Marine received a right hand transplant for a wrist-level amputation in March 2009, Patient #2: A 57 year-old Veteran with bilateral mid-forearm level amputations became the first US bilateral hand/forearm transplant recipient in May 2009. Patient #3: A 41 year-old mechanic received right above-elbow and left hand transplants in February 2010. All patients underwent thorough informed consent after exhaustive screening evaluation including comprehensive psychosocial assessment. Leukapheresis was performed at listing and cells cryopreserved. Upon identification of appropriate donors matched for limb size, skin color, tone and gender, patients received alemtuzumab (30mg) induction followed by tacrolimus monotherapy (0.2 mg/kg/day). Whole BM cells from 9 donor vertebral bodies were cryopreserved and infused on day 14. Comprehensive follow up included functional evaluation and immunomonitoring. RESULTS: Patient #1 is 12 months after transplant and reported one acute rejection (AR) of skin (POD 43, Banff Grade 2) that resolved with topical tacrolimus/clobetasol without further recurrence. Target troughs of tacrolimus are 6 - 8 ng/ml on 7.5 mg bid. Patient #2 is 10 months after transplant. He reported one AR episode of skin (POD 270, Banff Grade 2-3) that resolved with a steroid bolus and topical therapy. Tacrolimus trough levels are 8-12 ng/ml on 1.5 mg bid. He developed hyperglycemia post transplant that initially required insulin but is now managed on oral hypoglycemics with good glycemic control. Skin biopsies are negative for C4d. Immunomonitoring reveal insignificant donor specific antibodies (Luminex) adequate immunocompetence (Immuknow) and no chimerism. Both patients demonstrated sustained improvements in motor function (ROM, intrinsic return, grip/pinch strength) and sensory return (static/moving 2 PD, Semmes Weinstein, temperature and vibratory perception and stereognosis). Both patients undergo hand therapy for 3-6 hours 4-5 times per week. Advanced ultrasound imaging demonstrated patent vessels with no luminal occlusion. Patient #1 has returned to employment as an electrician. Patient #3 is 1 month post-transplant and recovering well. CONCLUSION: This is the first report of a novel cell based immunomodulatory therapy in upper limb transplantation. Implementation of such protocols could enhance the benefit to risk ratio by minimizing the number, dose and duration of drugs used, and in turn improve the safety and applicability of this reconstructive modality. Our early data suggest that the protocol is safe, efficacious and well tolerated and has allowed graft survival with low dose monotherapy. Rejection episodes are low grade and infrequent, with minimal complications. Longer-term follow up will provide greater insight into functional, immunologic and graft survival outcomes.

Disclosure: All authors have declared no conflicts of interest.