Key Takeaways

  • Six patients with hematologic malignancies and end-stage renal failure underwent combined stem cell/kidney transplantation from haploidentical donors, with the goal of cultivating a curative graft-versus-malignancy effect and inducing immune tolerance of the transplanted kidney
  • Novel features of the pilot procedure were reduced-intensity conditioning and inclusion of post-transplant high-dose cyclophosphamide in the graft-versus-host-disease (GVHD) prophylactic regimen
  • No patient experienced grade 2 to 4 acute GVHD; at one year after transplantation one patient had moderate chronic GVHD that required immunosuppressive therapy
  • At the time of this report, with follow-up of 12 to 73 months, four patients were alive without rejection of the kidney or relapse of their hematologic disease

For patients with hematologic malignancies and end-stage renal disease, Massachusetts General Hospital doctors pioneered simultaneous hematopoietic cell transplantation (HCT) and kidney transplantation from the same donor, as described in Advances in Hematology. The goal is not just solid organ tolerance, but also durable full donor chimerism to cultivate a curative graft-versus-malignancy effect.

Published in Transplantation, a twenty-year follow-up of this approach showed continued efficacy in immunosuppression-free renal allograft survival and myeloma control. An important limitation to the procedure, though, was that donors had to be fully HLA-matched to the recipient.

Yi-Bin Chen, MD, director of the Bone Marrow Transplant Program at the Mass General Cancer Center, and Thomas R. Spitzer, MD, director emeritus of the Bone Marrow Transplant Center Program at the Mass General Cancer Center, and colleagues, are currently conducting ongoing trials of combined HCT/kidney transplantation from HLA-matched or haploidentical donors (those that are partially HLA-matched to the recipient). In Blood, they report on the first six recipients, demonstrating the feasibility of this approach.

Eligibility Criteria

Recipients were eligible for the trial if they were 18 to 70, had a hematologic malignancy and were receiving renal replacement therapy or had creatinine clearance ≤35 mL/minute. Donors were haploidentical first-degree relatives.

Transplantation Procedures

The first patient in the pilot study underwent a conditioning regimen of antithymocyte globulin (ATG), cyclophosphamide and total-body irradiation. Based on six-month outcomes described below, patients 2 and 3 had ATG replaced with fludarabine, and patients 4 to 6 received a lower cumulative dose of fludarabine and more intensive dialysis.

Kidney transplantation was performed according to standard techniques, and hematopoietic cells were infused immediately after revascularization of the kidney allograft. For graft-versus-host-disease (GVHD) prophylaxis, patients received post-transplantation high-dose cyclophosphamide (50 mg/kg per day IV on days 3 and 4), tacrolimus and mycophenolate mofetil.

Six-Month Outcomes

  • All recipients experienced successful donor neutrophil engraftment within the first 30 days
  • Patient 1, who received ATG in place of fludarabine, presented on day 24 with fever, fatigue and myalgias. Chimerism analysis confirmed loss of donor hematopoiesis; the patient subsequently recovered autologous-derived hematopoiesis. She was maintained on low-dose tacrolimus for prevention of kidney rejection
  • Patient 3, who had a diagnosis of non-Hodgkin's lymphoma, experienced grade 4 renal toxicity during the week after transplantation and required renal replacement therapy. One month after transplantation, he exhibited symptoms consistent with fludarabine neurotoxicity, from which he died on day 142
  • There were no cases of grade 2 to 4 acute GVHD

Longer-term Outcomes

  • One year after transplantation, all five surviving patients were free of disease (all had a diagnosis of multiple myeloma). Except for patient 1, all exhibited durable donor hematopoiesis

  • Patient 2 was found to have relapsed multiple myeloma three years after transplantation, and she died one year later

  • Patient 5 required continued low-dose tacrolimus and prednisone for moderate chronic GVHD. Patient 4 developed chronic GVHD at 18 months but did not require systemic immunosuppression

  • At the time of this report, four patients were alive and free of myeloma after follow-up that had lasted between 12 months (patient 6) and 73 months (patient 1)

Ethical Issues

When discussing whether a patient is a suitable candidate for simultaneous HCT/kidney transplantation, each discipline has its own perspective. The question is: What prognosis from an HCT standpoint justifies eligibility for a kidney transplant? Another consideration is that a staged approach (kidney transplantation first, then HCT from the same donor at a later date) may be safer but may miss a window of opportunity to cure the malignancy.

Nephrologists and their colleagues will continue to wrestle with these questions, but one thing is certain: this combination procedure has been a lifesaving therapy for patients with hematologic malignancy whose prognosis was dismal without transplantation.