PHILADELPHIASalvage therapy with the radiolabeled monoclonal
antibody tositumomab (Bexxar) produced durable complete remissions in
patients with multiply relapsed or refractory non-Hodgkin’s lymphoma (NHL) or
transformed indolent lymphoma when used as second-line therapy, and
first-line tositumomab produced 5-year progression-free survival of 58.9% in
patients with advanced follicular lymphoma.
Mark S. Kaminski, MD, who led the group that did the three
studies on which these conclusions are based, presented them as posters at
the 44th Annual Meeting of the American Society of Hematology (ASH abstracts
1381, 1382, and 1384). Dr. Kaminski is in the Department of Hematology and Oncology at the University of Michigan Medical Center, Ann Arbor.
Dr. Kaminski told ONI, "Tositumo-mab works in patients
who have had multiple treatments and are refractory to chemotherapy. We found
higher re-sponses to tositumomab than to the last prior chemotherapy in
resistant patients, which is quite unusual for second-line regimens.
Tositumomab worked in patients with low-grade lymphomas as well as in those
with transformed low-grade lymphomas."
He noted further that tositumomab "worked in patients who
were refractory to rituximab [Rituxan] and produced durable responses that
have continued now for at least 8 years in about 20% of patients, which is
something we have not seen in this population with any other treatment except
[As ONI went to press, the FDA’s Oncologic Drugs
Advisory Board met to review Bexxar, and voted in support of the efficacy of
Bexxar therapy in rituximab-refractory patients and chemotherapy-relapsed and
refractory, low-grade NHL, with or without transformation. A full report will
appear in next month’s issue of ONI.]
The follicular lymphoma study (abstract 1381) attracted the
most attention at the meeting, perhaps because it moved tositumomab into the
front-line setting. Responses to tositumomab salvage therapy for patients
with chemotherapy-relapsed or refractory low-grade NHL have been well
documented, and as Dr. Kaminski pointed out, treatments that are effective in
relapsed or refractory disease are typically even more effective when used as
initial therapy earlier in the disease course.
The standard method for giving tositu-momab in all of these
studies involves an initial "dose-metric dose" to determine dosage for the
individual patient, then the therapeutic dose a week later. Thyroid
protective agents are given beginning on day 1 and continuing until 14 days
after the last therapeutic dose.
To establish dose, patients are given 450 mg of unlabeled
tositumomab infused over 1 hour, then a 35-mg tracer dose of
iodine-131-labeled tositumomab, infused over 20 minutes. Total body radiation
counts are measured before treatment, then on days 2, 3, or 4, and finally on
day 6 or 7. For therapeutic dosing, the patient is given 450 mg of unlabeled
tositumomab followed by enough I-131-labeled tositumomab to deliver 75 cGy of
total body irradiation, based on data from the dosimetric test.
The phase II, single-center follicular lymphoma study
enrolled 76 patients with previously untreated stage III/IV low-grade NHL. Of
these, 69% had follicular small cell cleaved, 29% had follicular mixed cell,
and 2% had mantle cell lymphomas. Two thirds of patients had bone marrow
involvement, 31% had elevated baseline lactate dehydrogenase (LDH), and 43%
had bulky disease (larger than 5 cm). Median age was 49 year (range, 23 to 66
Of 76 patients, 72 (95%) had a confirmed response. "Median
duration has not been reached, but responses continued at 5 years in 61% of
patients. Of these, 57 (75%) had a confirmed complete response (CR), and 45
of these patients remain in CR at 30 to 66 months," Dr. Kaminski said.
Five-year progression-free survival for all patients is 58.9% at a median
follow-up of 49.3 months. Progression-free survival was significantly greater
in patients who had a complete remission.
Grade 4 hematologic toxicity occurred in 5% of patients, but
none required supportive care. No myelodysplastic syndromes had been seen at
a median follow-up of 2.6 years; 7% of patients required thyroid
Human antimouse antibodies (HAMA) against tositumomab were
seen in 63% of patients. "This is significantly higher than observed in
studies of previously treated patients, where the cumulative incidence is
about 10%," Dr. Kaminski said. The development of HAMA has been a concern
because of the possibility that such antibodies might reduce the efficacy of
the therapeutic antibody, cause anaphylactic reactions, or lead to misleading
results in immunoassays. Dr. Kaminski told ONI that such concerns now
appear overblown in light of the durable CRs seen in patients in his studies
and the relatively low toxicity.
"I would like to see a head-to-head randomized controlled
trial of tositumo-mab vs a chemotherapy/rituximab regimen as front-line
therapy," Dr. Kaminski commented.
Tositumomab produced a substantial number of durable complete
responses in patients with relapsed or refractory low-grade NHL who had
participated in five clinical trials that Dr. Kaminski retrospectively
analyzed (abstract 1382). The data included 250 patients, of whom 33% were
over age 60, two thirds had bulky disease, and 46% had bone marrow
involvement. Patients had a median of four prior regimens, and 28% had
transformed NHL. Seventy-nine percent had International Prognostic Index (IPI)
scores of 2 or greater, and 72% were refractory to previous regimens.
Tositumomab produced an overall response rate of 56% in these
multiply relapsed patients, with a median response duration of 13 months.
Thirty percent of patients had a complete response, with a median duration of
58.4 months. "To date, 70% of the patients who achieved a CR are alive and
remain in CR at up to 7.8+ years," Dr. Kaminski said.
Transformed Indolent Lymphomas
The third study in this group (abstract 1384) showed that
tositumomab can produce durable responses (defined as time to progression of
at least 12 months) in patients with transformed indolent lymphomas. Five
patients in this study remain in remission beyond 40 months, and the longest
is still in remission at 66 months after treatment.
"Histologic transformation of indolent lymphoma carries a
poor prognosis. There are few treatment options for these patients, virtually
all patients relapse and ultimately die either from lymphoma or from
complications of treatment," Dr. Kaminski said.
In general, he noted, treatment of relapsed disease results
in lower response rates and shorter duration of response with each successive
treatment attempt. "To date, no single therapy has shown a consistent
increase in durable response in patients with either recurrent or transformed
low-grade NHL. A single administration of tositumomab showed significant
efficacy and durable responses in patients with advanced-stage relapsed and
refractory low-grade NHL," he said.
Median of Four Prior Therapies
This retrospective report included 71 patients with
transformed low-grade NHL who had been enrolled on five tositumomab studies
since 1990. Median age was 59 years, and median time from diagnosis to study
entry was 74 months (range, 8 to 334 months). The median number of prior
therapies was four. In addition to transformed histology, 28% of patients had
bone marrow involvement, 70% had bulky disease, 57% had elevated LDH, and 52%
had IPI scores of 3 or worse.
Median follow-up after a single administration of tositumomab
was 19.4 months. Dr. Kaminski reported that the overall response rate was
39%, with a median duration of 21 months. A CR was achieved in 25% of
patients, with a median duration of 36.5 months. As might be expected, median
time to progression was much longer for patients who had a CR: 16.5 months vs
4.3 months for all patients.
An impressive point made in this poster was that CRs were
observed among patients with all types of poor-prognostic factors, including
14% of patients with IPI of 3 or greater, 25% of patients with bone marrow
involvement, and 24% of patients with four or more prior therapies. "These
results demonstrate that tositumomab is an effective therapy for patients
with transformed low-grade NHL," Dr. Kaminski said.