Radiolabeled-M195 Shows Promise in Myeloid Leukemias

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

Dr. Jurcic and his coworkers at Memorial Sloan-Kettering CancerCenter have used M195, a mouse monoclonal antibody reactive withthe early myeloid surface antigen CD33. The antibody, labeledwith iodine-131 has had significant activity against myeloid leukemiasin previous clinical studies.

Studies have shown that about 20% of patients with relapsed orrefractory lymphoid malignancies can be salvaged with allogeneicbone marrow transplant, Dr. Jurcic said. In an attempt to improvethis response rate, the investigators combined iodidine-131-labeledM195 with a standard myeloablative pretransplant regimen of busulfan(Myleran) and cyclophosphamide (Cytoxan, Neosar).

Patients received escalating doses of iodine131-labeled antibodyin three or four dose fractions at 2-day intervals, followed bychemotherapy and then transplantation with HLA-compatible, unmodifiedbone marrow, with cyclosporine (Sandimmune) and corticosteroidprophylaxis against graft-vs-host disease (GVHD).

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

blastic-phase chronic myelogenous leukemia--this was the firstbone marrow transplant. Four additional patients underwent a secondbone marrow transplant after a relapse. The patients receivediodine-131 doses ranging from 120 to 225 mCi/m², with approximately1,000 to 1,600 cGy delivered to the bone marrow.

The toxicity of iodidine-131-labeled M195 was low and appearedto add no adverse effects to the transplant, Dr. Jurcic said.One patient developed urticaria as a result of treatment. Engraftmentoccurred in all patients, with a median of 14 days to neutrophilrecovery and 29 days to recovery of the platelet count. Sevenpatients developed acute GVHD, and two had chronic GVHD. Humanantimouse antibodies developed in 6 of 16 patients in whom thiscould be evaluated, despite the use of myeloablative chemotherapy.

Complete remissions were documented in 14 of the 15 patients whohad undergone bone marrow transplantation for the first time.However, three patients died as a consequence of infection orGVHD in the peritransplant period. With a median follow-up of9 months, eight patients remain alive, and seven continue in remissionfor periods ranging from 2 to 28 months post-treatment. Four patientshave 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 dosesof iodine-131 can safely be combined with a standard conditioningregimen prior to transplantation without any evidence of impairmentof engraftment," Dr. Jurcic said. "Longer follow-upis needed, but these preliminary results are quite encouraging.This approach allows intensification of antileukemic therapy priorto transplantation."

Use in Relapsed APL

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

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

Seven patients were treated in the present trial. The patientshad relapsed after a first remission lasting a median of 9 months.Second remissions were induced with all-trans-retinoic acid, whichwas continued for an additional 30 days after the remission. Patientsthen received iodine-131-labeled M195 in divided doses totaling50 mCi/m² (five patients) or 70 mCi/m² (two patients).

The maximum tolerated dose in this clinical setting appears tobe 50 mCi/m2, Dr. Jurcic said. Repeated dosing was limited byHAMA formation, which occurred in five patients. All patientsdeveloped myelosuppression, but none required autologous bonemarrow

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

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

After a median post-treatment follow-up of 25 months, four ofthe patients remain alive, with survival durations ranging from5 to 34 months. In the previous trial, median overall survivalwas only 8 months.

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