There are few efficacious treatment options for patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma who have previously failed autologous stem cell transplant (ASCT) or who are ineligible for ASCT due to progressive disease. There are also limited options for patients with indolent lymphomas who have suffered multiple relapses. In both of these patient populations, there is a need for novel and ideally curative options.

Allogeneic hematopoietic cell transplantation has been studied in lymphoma, both in aggressive histologies

Studies support a potential for graft-versus-lymphoma (GVL) effect, though often at the cost of significant treatment-related morbidity and mortality. Complications often arise as a result of graft-versus-host disease (GVHD).

While rates of acute GVHD with reduced-intensity conditioning regimens may range relatively lower (10% to 20%), rates of extensive chronic GVHD range from 45% to 60%, even with human leukocyte antigen (HLA) matched donors.

Additionally, standard practice involves identifying a sibling who is an HLA-match, and if not available, searching for an unrelated donor, which can delay or even negate the possibility of transplant for such patients. The optimal scenario would be one in which GVL could be optimized while minimizing GVHD, and donors could be identified quickly.

Our pilot trial, to our knowledge, is the first of its type to investigate T cell receptor alpha/beta (TCRa/β)-depleted and CD19-depleted haploidentical stem cell grafts in relapsed/refractory lymphoma patients. We hypothesize that TCRa/β and CD19 depletion from haploidentical stem cell grafts in patients with relapsed/refractory lymphoma will lead to successful engraftment along with lower rates of acute and chronic GVHD than typically seen after matched donor transplantation in lymphoma patients, and ultimately a long lasting GVL effect.

TCRa/β cells and B cells are thought to be major players in mediation of GVHD. Selective removal of these cells from the transplanted graft would minimize GVHD, while still allowing for a meaningful GVL effect (from TCRγ/δ cells and other important mediating cell types).

First clinical experiences in TCRa/β-depleted and CD19-depleted PBSC grafts have been obtained in haploidentical transplantation with pediatric patients in Tübingen.

 All patients were at extremely high risk and had poor prognosis. They were pretreated with a reduced-intensity conditioning (RIC) regimen and received no post-transplantation immunosuppression. In these pilot patients, engraftment and immune reconstitution were rapid. No acute side-effects were noted. Similar small studies, primarily in pediatrics and conducted in Europe, have replicated similar data.

There is growing evidence that haploidentical donor transplants (primarily using post-transplant cyclophosphamide as immunosuppression) may be just as efficacious, if not more so, than matched unrelated donor transplants for adult patients with lymphoma.

Furthermore, in aggressive lymphomas, even data with matched 

 donor transplants is not highly promising,

 and the use of haploidentical donors is even more compelling and potentially associated with better disease control and less GVHD.

Additionally, haploidentical donors are typically readily available. In theory, virtually every patient has a potentially suitable haploidentical related donor—parent, sibling, or child&mdash;and thus a successful strategy for haploidentical donor transplantation may clearly be the solution for the ‘lacking donor’ problem.

Although preliminary data with TCRa/β - and CD19-depleted haploidentical graft transplantation is promising, any data with this type of graft manipulation in patients with lymphoma, while highly warranted, is lacking.

We have developed a novel clinical protocol including a new conditioning regimen. Our clinical cell processing laboratory at University of Wisconsin Hospital and Clinics has validated the depletion strategy being used for this study and is one of the first in the country capable of providing this for clinical use.

Our trial is open to patients with relapsed/refractory Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, mantle cell lymphoma, and T cell lymphoma. They will receive fludarabine/cyclophosphamide/ total nodal irradiation conditioning followed by transplantation of a haploidentical stem cell product that has undergone TCRa/β - and CD19-depletion

Although the primary endpoint for the study is engraftment of neutrophils and platelets by day 28, the incidence of acute and chronic GVHD and progression-free survival and overall survival are all included as secondary endpoints. Additionally, patients will have a detailed and highly sophisticated immunophentypic analysis by flow cytometry of peripheral blood lymphocytic populations at various time points after transplant to look for correlation to disease response, graft versus host disease, infection rates, and other potential side effects.

The study is now IRB approved and open to accrual with an IDE from the FDA. Please obtain more details at: https://clinicaltrials. gov/ct2/show/NCT02652468

If you have patients potentially eligible for this trial, please contact us at 608-263-1699 or vpkenkre@medicine.wisc.edu.

Chopra R, Goldstone AH, Pearce R, et al. Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. 

Doocey RT, Toze CL, Connors JM, et al. Allogeneic haematopoietic stem-cell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma.

Dann EJ, Daugherty CK, , and Larson RA. Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin's disease and non-Hodgkin's lymphoma. 

van Besien, K, Thall P, Korbling M, et al. Allogeneic transplantation for recurrent or refractory non-Hodgkin's lymphoma with poor prognostic features after conditioning with thiotepa, busulfan, and cyclophosphamide: experience in 44 consecutive patients. 

Ratanatharathorn V, Uberti J, Karanes C, et al. Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. 

Sarina B, Castagna L, Farina L, et al. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. 

Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

Peggs KS, Hunter A, Chopra R, et al. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. 

Alvarez I, Sureda A, Caballero MD, et al. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol. 

Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. 

Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. 

Rodriguez R, Nademanee A, Ruel N, et al. Comparison of reduced-intensity and conventional myeloablative regimens for allogeneic transplantation in non-Hodgkin's lymphoma. 

Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma. 

Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. 

Lang P, Teltschik HM, Feuchtinger T, et al. First clinical results with a-b+ T-cell depleted haplo-identical stem cells in children. Presented at: ASBMT 2000, Abstract 60.

Schumm M, , Bethge W, Vogel W, et al. Depletion of TcRab+ and CD19-positive cells from leukapheresis products with the CliniMACS device. Presented at: EBMT 2011, Abstract P1093.

Kanate AS, Musetti A, Kharfan-Dabaja MA, et al. Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. 

van Kampen, RJ, Canals C, Schouten HC, et al. Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. 

Thomson, KJ, Morris EC, Bloor A, et al, Favorable long-term survival after reduced-intensity allogeneic transplantation for multiple-relapse aggressive non-Hodgkin's lymphoma.

Rezvani AR, Norasetthada L, Gooley T, et al. Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. 

Burroughs, LM, O'Donnell PV, Sandmaier BM, et al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. 

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This pilot trial is the first of its type to investigate T cell receptor alpha/beta-depleted and CD19-depleted haploidentical stem cell grafts in relapsed/refractory lymphoma patients.

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