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Radiolabeled-M195 Shows Promise in Myeloid Leukemias

Radiolabeled-M195 Shows Promise in Myeloid Leukemias

Radioimmunotherapy with an iodine 131-labeled monoclonal antibody shows promise in two applications in patients with myeloid leukemias: as cytoreductive therapy prior to bone marrow transplantation and for reduction of minimal residual disease, Dr. Joseph G. Jurcic said at the Fifth Conference on Radioimmunodetection and Radioimmunotherapy of Cancer.

Dr. Jurcic and his coworkers at Memorial Sloan-Kettering Cancer Center have used M195, a mouse monoclonal antibody reactive with the early myeloid surface antigen CD33. The antibody, labeled with iodine-131 has had significant activity against myeloid leukemias in previous clinical studies.

Studies have shown that about 20% of patients with relapsed or refractory lymphoid malignancies can be salvaged with allogeneic bone marrow transplant, Dr. Jurcic said. In an attempt to improve this response rate, the investigators combined iodidine-131-labeled M195 with a standard myeloablative pretransplant regimen of busulfan (Myleran) and cyclophosphamide (Cytoxan, Neosar).

Patients received escalating doses of iodine131-labeled antibody in three or four dose fractions at 2-day intervals, followed by chemotherapy and then transplantation with HLA-compatible, unmodified bone marrow, with cyclosporine (Sandimmune) and corticosteroid prophylaxis against graft-vs-host disease (GVHD).

So far, 19 patients have undergone this treatment. For 15 patients--10 with refractory or relapsed myelogenous leukemia and 5 with accelerated-phase or

blastic-phase chronic myelogenous leukemia--this was the first bone marrow transplant. Four additional patients underwent a second bone marrow transplant after a relapse. The patients received iodine-131 doses ranging from 120 to 225 mCi/m², with approximately 1,000 to 1,600 cGy delivered to the bone marrow.

The toxicity of iodidine-131-labeled M195 was low and appeared to add no adverse effects to the transplant, Dr. Jurcic said. One patient developed urticaria as a result of treatment. Engraftment occurred in all patients, with a median of 14 days to neutrophil recovery and 29 days to recovery of the platelet count. Seven patients developed acute GVHD, and two had chronic GVHD. Human antimouse antibodies developed in 6 of 16 patients in whom this could be evaluated, despite the use of myeloablative chemotherapy.

Complete remissions were documented in 14 of the 15 patients who had undergone bone marrow transplantation for the first time. However, three patients died as a consequence of infection or GVHD in the peritransplant period. With a median follow-up of 9 months, eight patients remain alive, and seven continue in remission for periods ranging from 2 to 28 months post-treatment. Four patients have had relapses.

Of the four patients who received a second bone marrow transplant, all achieved remission but all died due to complications of transplantation.

"From this trial, we can conclude that myeloablative doses of iodine-131 can safely be combined with a standard conditioning regimen prior to transplantation without any evidence of impairment of engraftment," Dr. Jurcic said. "Longer follow-up is needed, but these preliminary results are quite encouraging. This approach allows intensification of antileukemic therapy prior to transplantation."

Use in Relapsed APL

In a second trial, iodine-131-labeled M195 was used to treat minimal residual disease in patients with relapsed acute promyelocytic leukemia (APL). This patient group was chosen for study because they have a high rate of response to all-trans-retinoic acid. In addition, APL is associated with a specific cytogenetic abnormality that results in a novel fusion mRNA that can be detected by polymerase chain reaction (PCR), allowing the investigators to monitor residual disease with serial assays.

"Relapsed APL has a very poor prognosis, and many approaches have been tried," Dr. Jurcic said. "These patients have a median disease-free survival of less than 1 year, and often they relapse after only a few months."

Seven patients were treated in the present trial. The patients had relapsed after a first remission lasting a median of 9 months. Second remissions were induced with all-trans-retinoic acid, which was continued for an additional 30 days after the remission. Patients then received iodine-131-labeled M195 in divided doses totaling 50 mCi/m² (five patients) or 70 mCi/m² (two patients).

The maximum tolerated dose in this clinical setting appears to be 50 mCi/m2, Dr. Jurcic said. Repeated dosing was limited by HAMA formation, which occurred in five patients. All patients developed myelosuppression, but none required autologous bone marrow

rescue or granulocyte colony-stimulating factor (G-CSF, filgrastim; Neupogen).

Before treatment, six of the seven patients had PCR assays positive for minimal residual disease. Two of the six had a single negative PCR at 5 and 13 weeks post-treatment, but both relapsed. The median disease-free survival in these seven patients after all-trans-retinoic acid-induced remission has been 8 months, compared to a median of 3 months in a previous trial in which comparable patients were treated with all-trans-retinoic acid until relapse but radioimmunotherapy was not given.

After a median post-treatment follow-up of 25 months, four of the patients remain alive, with survival durations ranging from 5 to 34 months. In the previous trial, median overall survival was only 8 months.

"In this trial, we have seen that nonmyeloablative doses of iodine-131-labeled M195 can be given safely with modest hematologic toxicity and no extramedullary toxicity," Dr. Jurcic said. "The results of PCR and clinical outcomes suggest that this agent does have activity against minimal residual disease in APL, and further investigation of antibody-based therapy is warrented."

 
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