Immunologic Manipulations To Treat
Hematologic Malignancies
Patients receiving chemotherapy or transplants for hematologic malignancies unfortunately are not always cured of their disease. Most regimens used are close to the dose limiting toxicity because of the side effects of these regimens. This suggests that simply giving more chemotherapy is not the solution to preventing relapse. More therapy is likely to result in more side effects. Likewise, the small increases in chemotherapy that are possible are unlikely to have significant effects since the remaining tumor cells are those that are the most resistant to chemotherapy. Thus, new approaches to preventing and/or treating are needed. We have been interested in using immunologic methods to address this problem. This type of approach makes sense because tumors that are resistant to chemotherapy are not necessarily resistant to immunologic therapy. Likewise, immunologic approaches usually have less toxicity than chemotherapy or radiotherapy approaches. The two major approaches being used at Hopkins now are the induction of autologous Graft-versus-Host disease and donor lymphocyte infusion. Although both are immunologic therapies the patients receiving these therapies are very different. Autologous Graft-versus-Host disease therapies are being used in patients receiving either autologous transplants or inpatients receiving intensive chemotherapy for acute lymphocytic leukemia. Donor lymphocyte infusions are being used to treat patients who have relapsed after an allogeneic bone marrow transplant.
Autologous GVHD
Autologous Graft-versus-Host disease sounds like a contradiction in terms. Graft-versus-Host disease is one of the major toxicities seen after allogeneic and unrelated donor transplants. For that reason, autologous transplants are considered much safer. However, patients developing Graft-versus-Host disease after an allogeneic transplant have a lower relapse rate. This effect of an allogeneic transplant is called Graft-versus-Leukemia effect. The lymphocyte recognizing the patient as foreign and causing Graft-versus-Host disease also recognizes the patient's tumor is foreign. Plus there is a significant killing of any remaining tumor cells. In the laboratory we found that we could trick a recovering immune system into recognizing a tumor as foreign after either autologous transplant or intensive chemotherapy. Experiments have shown that there is a significant survival advantage with killing of a tumor where autologous Graft-versus-Host disease could be induced. Autologous Graft-versus-Host disease is induced by giving low doses of a drug called Cyclosporine after the transplant. Early information suggests that patients receiving Cyclosporine after autologous BMT also have a clinical benefit. Today trials are taking place in patients with lymphoma, leukemia, myeloma, and breast cancer. Although all of these trials have been designed to try to define the best way of inducing autologous Graft-versus-Host disease, the results suggest that survival is better than would be expected without such therapy.
The clinical syndrome of autologous Graft-versus-Host disease is characterized by a mild skin rash. Involvement of other organs is rarely seen. In an attempt to increase the anti-tumor effect we are now using different cytokines (naturally produced chemicals within the body) to increase the recognition of tumor and tumor kill. There are several ongoing clinical trials including a randomized study in patients with sensitive non-Hodgkins lymphoma (i.e. responding to chemotherapy at the time of transplant) to induction or no induction of autologous Graft-versus-Host disease, and trials in patients with either relapsed or resistant hematologic tumors (lymphoma, myeloma, leukemia) using Cyclosporine, IL-2, and Interferon. Cyclosporine does have some side effects including kidney damage, high blood pressure, and on rare occasion can cause reversible neurologic problems. The side effects of Il-2 and Interferon include fever, fluid weight gain, slow count recovery, flu like symptoms, and reversible liver disease. There is also a trial looking at the use of Cyclosporine in patients receiving therapy for ALL. This trial examines whether patients who have achieved a remission with ALL can have a similar syndrome induced using low doses of Cyclosporine with their consolidation and maintenance chemotherapy. The hope of this trial is that an anti-tumor benefit can be achieved without the necessity of a marrow transplant.
Donor Leukocyte Infusion
Another therapy which uses the immune system to try to fight the tumor is donor lymphocyte infusions. Patients relapsing after an allogeneic marrow transplant have few treatment options. Several groups have found that transfusion of donor white cells into patients, especially those with relapse chronic myelogenous leukemia, is successful in reinducing a remission in these patients. Many of these patients have Graft-versus-Host disease induced by this type of treatment. The toxicity seen with donor lymphocyte infusion can be significant if either severe Graft-versus-Host disease or marrow toxicity from the lymphocyte infusions occurs. However, this toxicity is milder than that seen with attempts at second marrow transplants. Currently we are exploring the use of donor lymphocyte infusion in patients who have relapsed after transplant. The dose of lymphocytes given and the schedule is dependent on the disease which has relapsed. Patients with rapidly progressing tumors may first need to be treated with chemotherapy. Depending on the disease, multiple infusions of white cells may be tried until a remission or significant side effects are obtained. Some patients receiving this type of treatment require a second marrow transfusion (without a preparative regimen) because of low count.
Patients who have relapsed after an allogeneic transplant are eligible for this treatment. Patients transplanted at other centers may also be treated here, provided their donor is willing, the patient is in shape to undergo the treatment, and the patient did not have severe Graft-versus-Host disease with the transplant.
Immune Modulations for Patients Not Undergoing BMT
Johns Hopkins has been a pioneer in the treatment of ALL for many years. We choose therapy for patients based on clinical prognostic factors. In the treatment of ALL, we are currently focusing on ways of helping the patient's immune system fight the leukemic cells.
Johns Hopkins is also pioneering immune approaches for the treatment of Kaposi's sarcoma. | 
