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