Novel Treatment Regimens for Refractory Hodgkin's Disease?

Joseph A. Sparano, MD

Disclosures

April 03, 2003

Question

A 42-year-old man was diagnosed 8 years ago with Hodgkin's disease (HD), nodular sclerosing type. He has had multiple relapses over the years. He underwent autologous bone marrow transplantation twice, once with BCNU, etoposide, cytarabine, and cyclophosphamide, and once with cyclophosphamide plus total body irradiation. He has also been treated with gemcitabine, vinorelbine, DVIP (dexamethasone, etoposide, ifosfamide, and cisplatin), ESHAP (etoposide, methylprednisolone, cytosine arabinoside, and cisplatin), and local radiotherapy. The patient is now showing an abdominal relapse. Are there any novel therapies that may be useful?

Response from Joseph A. Sparano, MD

This is a truly refractory case of HD. There is no magic bullet for this problem. Several approaches that have been investigated include radiolabeled antibodies directed at CD30 (which is expressed by Reed-Sternberg cells), nonmyeloablative transplants, and infusion of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes. If this patient has an HLA-identical sibling or if the tumor is EBV-positive, he might benefit from the latter 2 treatment options.

CD30 is an excellent target for immunotherapy of HD because it is overexpressed on Hodgkin and Reed-Sternberg cells. Borchmann and colleagues[1,2] developed a novel bispecific molecule consisting of F(ab') fragments derived from the murine anti-CD30 monoclonal antibody (MoAb) Ki-4 and the humanized CD64-specific MoAb H22. Patients with refractory CD30-positive HD who were treated with the molecule showed only transient side effects. Of the 10 patients evaluated, 1 demonstrated complete remission, 3 partial remission, and 4 stable disease.

EBV has also been detected in the Reed-Sternberg cells of approximately 50% of all cases of HD. Sun and colleagues[3] evaluated the safety, clinical effects, and immunologic effects of infusing allogeneic EBV-specific cytotoxic T lymphocytes (CTL) for patients with refractory EBV-positive malignancies, including EBV-positive HD. They reported 4 patients with EBV-related lymphoma who were treated with allogeneic EBV-specific CTL. Of interest, patients showed increased levels of EBV-specific CTL precursors post infusion, and no complications. Of the 2 organ transplant patients, 1 had refractory disease and has sustained a complete remission following the T-cell infusions. The second has also been disease-free since T-cell infusions, although the efficacy cannot be definitively attributed to CTL therapy because this patient received local radiation therapy prior to immunotherapy. One patient with HD received HLA 4/6 matched T cells from an unrelated donor and showed a decrease in the size of affected lymph nodes and resolution of B-symptoms post infusion. This approach might be reasonable should it be demonstrated that this patient's HD expressed EBV.

As a final possibility, the use of a nonmyeloablative fludarabine-based immunosuppressive regimen might be attempted. Carrella and colleagues[4] used this approach as a way to allow engraftment of HLA-sibling donors' mobilized stem cells and to induce a graft-vs-lymphoma effect for patients with advanced resistant HD (n = 10) and non-Hodgkin's lymphoma (n = 5). High-dose therapy with carmustine, etoposide, cytarabine, and melphalan was administered before and after initial infusion of hematopoietic stem cells. Of note, after mini-allografting, hematologic recovery was prompt, with 13 patients demonstrating 100% donor cell engraftment and 11 patients achieving complete remission after the combined procedure. Although this specific approach of transplant followed by nonmyeloablative therapy is unlikely to be feasible in this patient, he may be a candidate for the nonmyeloablative component of therapy.

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