Sequential kidney and allogeneic hematopoietic stem cell transplantation
Authors: Alina D. Tanase, Ioanel Sinescu, Catalin Baston, Dorina Tacu, Liliana Domnisor, Laura Stefan, Adela Ranete, Lavinia Lipan, Oana Craciun, Ioan Manea, Horia Bumbea, Stefan O. Ciurea
Journal: American Journal of Hematology (2019)

Acute and chronic rejection represent a major challenge after solid organ transplantation,1, 2 with no significant changes in graft loss over the long-term.3 Induction of tolerance has been key to a successful transplantation of organs, and elimination of long-term immunosuppression.4-7 Hematopoietic stem cell transplantation (HSCT) from the same donor could be a potentially useful strategy to tolerize the new organ, in order to avoid life-long immunosuppression and chronic rejection. Previous work has focused on combining solid organ and hematopoietic stem cell transplants.8-13 However, with this approach only a minimal intensity conditioning regimen can be applied, most patients develop transient chimerism, and a proportion of patients need to be maintained on long-term immunosuppression. HSCT following solid organ transplantation has been successfully performed in primate models; however, no cases have been recorded in humans to date.14, 15 We used this sequential approach in a patient with multiple myeloma (MM) with end-stage renal disease (ESRD) on hemodialysis. Six months post solid organ transplant, the patient received an allogeneic HSCT performed with a personalized conditioning regimen, aiming to induce stable full donor chimerism, wean off immunosuppressive medications and ultimately achieve long-term tolerance of the transplanted organ. A 39-year-old woman was diagnosed with kappa light chain MM in January 2012 when she presented with acute renal failure (cr 6.8 mg/dL, BUN 127 mg/dL), hypercalcemia and proteinuria (3458 mg/24 hours), and was started on hemodialysis. Initial evaluation revealed 70% bone marrow plasmacytes, serum protein electophoresis (SPEP)/immunofixation (IFE) monoclonal kappa light chain restriction with low IgG levels (671 mg/dL) and normal IgA and IgM levels. At the time of diagnosis, the patient presented with IIIb International Staging System (ISS) stage. The patient started treatment in June 2012 with cyclophosphamide (Cy), bortezomid (Bor) and dexamethasone (D). All three drugs (CyBorD) (Bor 1.3 mg/m2 day1, 4, 8, 11, Cy 500 mg/m2 D1, 8, 15 and D 40 mg/day D1, 8, 15), were administered every 3 weeks, for a total of 6 courses. A repeat bone marrow biopsy perfomed after six courses showed complete remission (CR) with negative SPEP/IFE and urine protein electophoresis (UPEP)/IFE, and 2% plasma cells in the bone marrow aspirate. The patient received an autologous stem cell transplant in October 2013, conditioned with melphalan 200 mg/m2 as per standard of care, with cyclophosphamide and filgrastim-mobilized peripheral blood stem cell graft. After the autologous transplant, the creatinine remained persistently elevated (5-7 mg/dL) and the patient continued to require intermittent hemodialysis, which justified a kidney transplant. A kidney and allogeneic HSCT from the same HLA matched related donor (sister) was planned in a sequential fashion 4 to 6 months apart, starting with the kidney transplantation, followed by the hematopoietic transplant when patient would recover from surgery. Hemodialysis was planned at least twice weekly until the patient received the kidney transplant. Approximately 5 years post-autologous transplant, in October 2017, the patient underwent a living donor kidney transplant from her HLA matched sister. The patient received immunosuppression for kidney transplant with tacrolimus and mycophenolate mofetil (starting before the kidney transplantation on day −1 until day −2 of HSCT). The only immunosuppression after the HSCT was with tacrolimus. The post-transplant course was uncomplicated without graft failure/organ rejection, severe infections or graft-vs-host disease (GVHD). The patient tolerated the kidney transplant well without significant complications. Her creatinine returned to normal (0.9 mg/dL) by day +3 post-kidney transplantation. Tacrolimus was continued and maintained at low therapeutic level (5 ng/mL) throughout conditioning for hematopoietic transplant. In April 2018 the patient underwent a HSCT from the same HLA matched sibling donor conditioned with fludarabine 150 mg/m2 and melphalan 100 mg/m2. The GVHD prophylaxis included tacrolimus and “mini” methrotrexate. The patient remained in CR at the time of the HSCT and received 5.3 × 106 peripheral blood CD34 cells/kg on day 0 of HSCT. The tacrolimus goal post-HSCT was 10 ng/mL. The patient achieved marrow aplasia (WBC <500/mm3) on day −1. The post-transplant course was complicated by expected post-conditioning adverse effects, including oral mucositis (grade 4) requiring total parenteral nutrition, and on day +7 developed neutropenic fever with negative cultures. The patient engrafted neutrophils on day +24 and platelets on day +28, post-transplant. Day +90 post-transplant evaluation showed 100% donor chimerism, normal kappa/lambda ratio of 1.07, negative SPEP/UPEP/IFE without monoclonal spike, and bone marrow biopsy showed 1% plasma cells, normal cellularity, diploid cytogenetics. The 6-months post-transplant evaluation showed that multiple myeloma remained in CR. The patient did not develop any GVHD, and low-level viral reactivation, CMV and BKV viremia/viruria, which occurred on day 63 and 19 post-transplant, resolved without treatment. The immunosuppression (tacrolimus) was tapered slowly starting at 6 months and completely discontinued at 9 months post-transplant. A schematic representation of the sequential kidney-HSCT is depicted in Figure 1A. Here we describe the first case of sequential kidney - allogeneic HSCT, from the same donor, in a patient with multiple myeloma with ESRD, who previously underwent autologous HSCT in 2012. The patient received the allogeneic HSCT 6 months after the kidney transplant, and achieved normal kidney function soon after, 100% donor chimerism and long-term complete remission from her myeloma, without graft-vs-host disease (GVHD). Previous work focused on combined solid organ and hematopoietic stem cell transplants. However, logistics of this approach are challenging, primarily as solid organ transplantation cannot be performed during the period of cytopenia. Hence a very low intensity conditioning for allogeneic HSCT has been proposed,5, 9, 11 which usually results in transient mixed chimerism. Tolerance has been reported in many patients; however, some will develop chronic solid organ rejection.16 Establishing mixed hematopoietic chimerism to induce tolerance has been the key to increasing organ allograft survival.4-11 Depletion of T cells with or without ATG, decreasing numbers of NK cells, and administration of total lymphoid irradiation (TLI) have been previously studied in this setting.16-19 Clinical studies explored the use of non-myeloablative (NMA) conditioning to establish mixed donor chimerism for patients receiving combined hematopoietic and solid organ (kidney) transplantation.16-19 The combined solid organ - hematopoietic stem cell transplant is predominantly an immunosuppressive approach which might be associated with a faster engraftment for neutrophils and platelets,9 as compared with our sequential approach, in which a higher degree of myelopression is achieved (Figure 1B). Although the combined approach might allow early discontinuation of immunosuppression, it is associated with major challenges.17 In this setting, a more intense conditioning cannot be applied and most patients will reject the hematopoietic graft.9, 10, 13 Although some patients may remain tolerant to the donor graft, rejection of hematopoietic cells might predispose to late chronic rejection of the solid organ, while administration of donor lymphocyte infusion (DLI) early after HSCT to convert to full donor chimerism is usually associated with a high incidence of GVHD.17 Moreover, while mixed chimerism can be more likely obtained after HLA matched HSCT, in HLA mismatched transplantation there is a higher tendency to reject the donor cells.13, 18, 19 Our group has been interested in developing a sequential approach, which has several potential advantages. These include the possibility to use more intense conditioning to achieve reliable full donor chimerism, ability to take patients off immunosuppression within 1-year post-HSCT with very low likelihood of chronic solid organ rejection in this setting, and the possibility to use this approach in haploidentical donor transplants. A full donor chimerism is unlikely to be associated with graft loss with HLA mismatched grafts, which have a higher tendency of rejection due to more intense bidirectional alloreactive reactions present in this setting, compared with HLA matched donor grafts. In addition, better targeting the underlying disease in case of hematological malignancies, such as multiple myeloma, can be achieved. It remains to be seen if this approach will ultimately allow more patients to survive long-term. If successful, this will likely expand the use of HSCT after solid organ transplantation, which, to date, has not been achieved. In conclusion, with this proof-of-concept case, we have shown that sequential kidney and HSCT from the same HLA-matched donor is feasible, and may cure patients with myeloma and end-stage renal disease. This could potentially be applied to HLA half-matched (haploidentical) donor transplants using reduced fludarabine-melphalan-based conditioning and post-transplant cyclophosphamide-based GVHD prophylaxis, as previously reported by our group.20 Successful application of allogeneic HSCT will alleviate the need for life-long immunosuppression and might definitively mitigate chronic solid organ rejection, which in most cases, require re-transplantation or is associated with life-threatening complications. The authors are deeply thankful to both the kidney transplant and hematopoietic stem cell transplant teams for the excellent care of this patient. The authors have no significant conflict of interest to declare for this work. Authors did not receive financial support for this work. A.D.T. contributed with patient care, study design, manuscript writing; I.S, C.B., D.T., L.D., L.S, A.R., L.L., O.C., I.M., H.B., contributed with patient care; S.O.C contributed with study design, advised on management of the patient, wrote the manuscript. All authors reviewed and approved the manuscript.