Initial studies used polyclonal antibodies,[
4] but the antibodies currently
used for radioimmunotherapy are
either monoclonal, murine, or human.[
2] The administration of a cold
antibody prior to the radiolabeled antibody
has been shown to improve
tumor-to-normal organ biodistribution
and deplete normal B cells.[5] The
antibodies used in I-131 tositumomab
and Y-90-labeled ibritumomab tiuxetan
to deliver radiation are murine in
origin. In Y-90-labeled ibritumomab
tiuxetan, the cold antibody used as a
predose is rituximab(Drug information on rituximab) (Rituxan), whereas
in I-131 tositumomab it is tositumomab.
Epratuzumab is an example
of a humanized antibody being used
for radioimmunotherapy.
At present, the two main radionucleotides
used in clinical radioimmunotherapy
are Y-90 and I-131.
Copper-67 (Cu-67) is also available
and has been used in a limited number
of studies. The I-131-labeled antibodies
are gamma emitters and can
be used for imaging and dosimetry.
Y-90-labeled antibodies are beta emitters
and cannot be used for imaging;
thus, indium-111 (In-111) is used for
tumor imaging and dosimetry as a
surrogate for Y-90. The differences
between these two agents that affect
their clinical use are outlined in Tables
1 and 2. The properties of these
radiolabels potentially could be used
to individualize therapy, but to date,
this strategy has not been studied.[2]
Clinical trials of anti-CD20 radioimmunotherapy
(I-131 tositumomab
and Y-90-labeled ibritumomab tiuxetan)
designed to assess efficacy and
safety were limited to patients with
relapsed disease, excellent bone marrow,
and normal organ function. Exclusion
criteria included central
nervous system lymphoma, human
immunodeficiency virus (HIV) infection
or HIV-related NHL or chronic
lymphoctic leukemia (CLL), pleural
or peritoneal fluid positive for lymphoma,
or known myelodysplasia.[1]
Ibritumomab Tiuxetan
CharacteristicsIbritumomab is a murine anti- CD20 antibody attached to tiuxetan, an MX-DTPA linker-chelator, to form Y-90-labeled ibritumomab tiuxetan. Ibritumomab is the murine parent of the anti-CD20 antibody from which the human chimeric antibody rituximab was engineered. In February 2002, it became the first radioimmunotherapy to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer. For dosimetry and tumor imaging, ibritumomab tiuxetan is reacted with In-11; for therapy, it is linked with Y-90. With the use of In-111-labeled ibritumomab tiuxetan, images of the tumor and normal organs are produced for dosimetry and biodistribution studies.[ 6] The therapeutic dose of Y-90- labeled ibritumomab tiuxetan is determined by the patient's weight and baseline platelet count. If the platelet count is normal, the recommended dose is 0.4 mCi/kg; if the platelet count is between 100 and 150,000 cells/mm3, the dose is 0.3 mCi/kg. For patients who weigh ≥ 80 kg, the dose is capped at 32 mCi. Patients are given rituximab at 250 mg/m2 and 5 mCi of In-111- labeled ibritumomab tiuxetan on day 1 followed by tumor imaging over the next few days. At least two to three images are required by the FDA to ensure normal biodistribution. On day 8, patients receive another dose of rituximab followed by Y-90- labeled ibritumomab tiuxetan.[5,7] The safety data accumulated from studies of Y-90-labeled ibritumomab tiuxetan have shown that myelosuppression is the most common side effect, with 27% to 30% of patients experiencing grade 4 neutropenia and about 10% experiencing grade 4 thrombocytopenia.[7] However, only 7.6% of patients were hospitalized with infections, and physicians need to be aware of the delayed nadir counts; unlike chemotherapy, platelet counts usually nadir about 7 to 9 weeks following therapy.[7,8] Clinical Trials
- Phase I Trials-Two phase I trials of Y-90-labeled ibritumomab tiuxetan were performed. The first trial used cold ibritumomab as the predose and enrolled patients with relapsed low- or intermediate-CD20-positive B-cell NHL.[5] Stem cells were harvested from the peripheral blood or marrow of all patients prior to treatment with Y-90-labeled ibritumomab tiuxetan. The overall response rate was 79%, with complete remissions in 36% and partial remissions in 43%. Two patients (both had received 50 mCi of Y-90-labeled ibritumomab tiuxetan) required reinfusion of stem cells. A comparison of two sets of In- 111-labeled ibritumomab tiuxetan images showed that predosing with cold antibody improved the biodistribution of Y-90-labeled ibritumomab tiuxetan. The second phase I study tested the use of rituximab rather than cold murine ibritumomab before administration of Y-90-labeled ibritumomab tiuxetan to determine the maximum tolerated dose of the radiolabeled an- tibody without stem cell support.[7] Rituximab was used to lower the risk of human antimurine antibody (HAMA) and to potentially add efficacy. A total of 51 previously treated patients were enrolled. The optimal rituximab dose was found to be 250 mg/m/2, although higher doses were not studied. Y-90-labeled ibritumomab tiuxetan doses ranged from 0.2 to 0.4 mCi/kg; no higher doses were used, given the risk of substantial myelosuppression and because stem cells were not collected prior to administration of the radiolabeled antibody. The overall response rate was 67%, and 26% achieved a complete remission. Patients with lowgrade NHL had a higher response rate (82%) than did patients with large-cell NHL (43%).
- Phase II Trials-A phase II trial using 0.3 mCi/kg of Y-90-labeled ibritumomab tiuxetan was conducted in 30 patients who were previously treated with chemotherapy and had low platelet counts (100,000 to 149,000 * 106/L). The overall response rate was 83%, with 43% achieving a complete remission. The most common toxicity was reversible myelosuppression.[9]
- Trials Comparing Ibritumomab Tiuxetan With Rituximab-In a pivotal study comparing the efficacy of Y-90-labeled ibritumomab tiuxetan vs rituximab, 143 patients with relapsed NHL and no prior rituximab therapy were randomized to receive the radiolabeled antibody or rituximab.[8] Patients received either 0.4 mCi/kg (maximum: 32 mCi) of Y-90 ibritumomab tiuxetan or rituximab at 375 mg/kg/wk * 4. Those randomized to Y-90 ibritumomab tiuxetan had an overall response rate of 80% and a complete remission rate of 30%, compared to 56% and 16%, respectively, in the rituximab arm. Another study tested the effect of Y-90-labeled ibritumomab tiuxetan after rituximab therapy had failed.[10] Among the 54 patients who were treated with the radiolabeled antibody at 0.4 mCi/kg, the overall response rate was 74%, with 15% achieving a complete remission.
Therapy After
RadioimmunotherapyUnfortunately, about 70% of patients will relapse after a single dose of Y-90 ibritumomab tiuxetan, requiring additional treatment. To address the question of tolerability of subsequent therapy, investigators studied 58 patients who had relapsed after treatment with 0.4 mCi/kg of Y-90 ibritumomab tiuxetan.[11] Peripheral stem cell collection was feasible in these patients, and all recipients of autologous transplantation achieved adequate engraftment. Growth factor support with chemotherapy was required in 28%, and two patients received reduced doses of chemotherapy because of persistent cytopenias. Safety
A report on the safety of Y-90- labeled ibritumomab tiuxetan in 349 patients treated in five studies[12] and followed for up to 4 years or until disease progression showed that the main toxicity was myelosuppression, with nadir counts occurring at 7 to 9 weeks for a duration of approximately 1 to 4 weeks. Patients with bone marrow involvement by NHL had a significantly greater incidence of grade 4 hematologic toxicity, and the greater the bone marrow involvement, the higher the incidence of grade 4 myelosuppression. Grade 1/2 infusion- related toxicities were associated with rituximab, and no further reactions were noted when Y-90- labeled ibritumomab tiuxetan was administered. Myelodysplasia or acute myelogenous leukemia was reported in 1% of patients after 8 to 34 months of therapy. However, all of these patients had received prior alkylating agents. The HAMA rate was less than 1%, compared to 8% to 10% for I-131 tositumomab. The clinical implications of a positive HAMA (and whether it will eventually resolve) are unclear at this time. Tositumomab Characteristics
Tositumomab is an IgG2a murine monoclonal antibody directed against CD20 that is radiolabeled with I-131 to form I-131 tositumomab. The FDA approved tositumomab/I-131 tositumomab in June 2003. As described previously, I-131 tositumomab can be used for dosimetry and treatment because it emits both gamma and beta radiation.[13] Dosimetry is used to calculate the therapeutic dose of I-131 tositumomab for each patient,[ 14] which varies with differences in body mass, tumor burden, metabolism, and renal excretion of I-131.[14-16] The therapeutic dose is administered within 7 to 14 days of the dosimetric dose and consists of 450 mg of tositumomab followed by a 20-minute infusion of the patientspecific dose of I-131 tositumomab. Because of the concentration of iodine in the thyroid, a saturated solution of potassium iodide(Drug information on potassium iodide) (SSKI, Lugol's solution) is started 1 day before tositumomab and is continued for 2 weeks after the therapeutic dose is given. The side effects of I-131 tositumomab[ 17] include a transient flu-like syndrome that may develop after infusion; toxicity during infusion is uncommon. The incidence of HAMA is about 10%. Reversible myelosuppression is the most common adverse event, with 16% of patients experiencing grade 4 neutropenia for a median duration of 11 days. The platelet count nadirs about 32 days after I-131 tositumomab administration, and approximately 2% of patients develop grade 4 thrombocytopenia for a median duration of 14 days. Similar to the experience with Y-90-labeled ibritumomab tiuxetan, patients with bone marrow involvement by NHL had a higher incidence of hematologic toxicity (21% vs 12% grade 4 neutropenia). In addition, patients previously treated with chemotherapy had a 21% incidence of grade 4 neutropenia, compared to 5% among those with no prior chemotherapy. Myelodysplasia has developed in a small number of patients treated with I-131 tositumomab.[18] However, all these patients had been previously treated with chemotherapy, and to date, no treated patients who did not receive prior chemotherapy have developed myelodysplastic syndrome.[ 19] Clinical Trials
- Phase I Trials-The phase I trial of I-131 tositumomab was designed to determine the dose that could be administered without stem cell support.[ 16,20,21] The dose-limiting toxicity was myelosuppression, and the maximum tolerated dose was 75 cGy to the whole body. A 475-mg dose of cold tositumomab was given before the dosimetric and therapeutic doses of the radiolabeled antibody. The overall response rate in this phase I/II trial was 71% (42/59) with a 34% (20/59) complete remission rate. Patients with low-grade or transformed NHL had an overall response rate of 83%, compared to 41% in those with intermediate-grade NHL. To address the concern about myelosuppression, another phase I trial was conducted in which I-131 tositumomab administration was followed by an infusion of stem cells.[22] A total of 43 patients were enrolled and their stem cells harvested before they received I-131 tositumomab. Of these patients, 19 were able to receive the therapeutic dose of I-131 tositumomab, followed 12 to 18 days later (after radioactivity ceased) by stem cell reinfusion. Neutrophil recovery occurred after a median of 23 days, and platelet recovery to 20,000 cells/mm3 after a median of 22 days. HAMA was detected in 16% of patients. The overall response rate was 95%, with 84% achieving a complete remission.
- Phase II Trials-A phase II trial was conducted in 47 patients with relapsed low-grade or transformed NHL. All patients had previously been treated with a median of four chemotherapy regimens.[23] Depending on their baseline platelet count, they were given either 75 cGy to the whole body (those with a platelet count > 150,000 cells/mm3) or 65 cGy (those with a platelet count between 100,000 and 150,000 cells/mm3). The overall response rate was 57%, and 32% achieved a complete remission. At last follow-up, six patients remained in complete remission for durations of 26.9+ to 33.8+ months. After the phase I trial of I-131 tositumomab followed by stem cell infusion, a phase II study that enrolled 25 patients was conducted using the same protocol.[24,25] The overall response rate was 86%, with a 76% complete remission rate. The study was then expanded to combine I-131 tositumomab with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) and etoposide(Drug information on etoposide) followed by autologous stem cell support.[26] This protocol demonstrated that the combination of radioimmunotherapy and chemotherapy could be safely administered to patients; estimated overall and progression-free survival rates at 2 years were 83% and 68%, respectively. A similar study performed in patients with mantle cell lymphoma showed a 91% tumor response rate, with overall and progression- free survival rates at 3 years of 93% and 61%, respectively.[27]
- I-131 Tositumomab Radioimmunotherapy vs Chemotherapy-A pivotal trial with I-131 tositumomab compared radioimmunotherapy to chemotherapy.[18] The trial was designed to compare the overall response rates associated with I-131 tositumomab and the last chemotherapy regimen the patient had received. The overall response rate was 65% for I-131 tositumomab, with a 17% complete remission rate, compared to 28% and 3%, respectively, for chemotherapy. A longer duration of response was seen in 78% of patients treated with I-131 tositumomab vs 22% of patients in the chemotherapy arm. The median duration of response for I-131 tositumomab was 6.5 months, compared with 3.4 months for chemotherapy. Another important finding in this study was that the overall response rate in patients with low-grade NHL was 81%, with 19% achieving a complete remission, compared to a 39% overall response rate and 13% complete remission rate in patients with transformed histology.
- I-131 Tositumomab vs Cold Tositumomab- A study comparing cold tositumomab to I-131 tositumomab in 78 patients with relapsed low-grade and transformed NHL demonstrated an overall response rate of 67% (33% complete remission) in the I-131 tositumomab arm, compared to 28% (8% complete remission) in the cold tositumomab arm.[28] The 19 patients with disease progression in the cold tositumomab arm were subsequently treated with I-131 tositumomab; 17 (89%) responded, with 42% achieving a complete remission.
- I-131 Tositumomab vs Rituximab- I-131 tositumomab has also been tested in patients previously exposed to rituximab. This is an important issue because many patients receive rituximab early in the course of their disease.[29] The study treated 38 patients, of which 88% were refractory to rituximab, 68% had received at least four prior chemotherapy regimens, and 32% had marrow involvement. Responses were achieved in 58% of patients, with a 21% complete remission rate. Among patients refractory to rituximab, the overall response rate was 57%, with a 14% complete remission rate.
- Other Studies of I-131 Tositumomab- Patients with transformed large-cell NHL who are not eligible for stem cell transplantation are difficult to cure. A retrospective study addressing this group analyzed 71 patients with transformed NHL treated with I-131 tositumomab.[30] Many of these patients had poor prognostic factors (International Prognostic Index of 3 in 52%, elevated lactate dehydrogenase in 57%, bulky disease in 70%). The overall response rate was 39%, with a 25% complete remission rate; five patients remain in remission beyond 40 months. The experience with re-treatment with I-131 tositumomab is limited. A report of 13 patients re-treated with I-131 tositumomab showed an overall response rate of 62% with a 31% complete remission rate.[31] None of the patients developed grade 4 hematologic toxicity. The only study that evaluated radioimmunotherapy in previously untreated patients was conducted by Kaminski et al.[32] This study enrolled 76 patients with advanced follicular lymphoma, of which 63% had bone marrow involvement by NHL. The overall response rate was 95%, with a 74% complete remission rate. The 5-year progression-free survival rate for all patients was 62.3%, and patients who achieved a complete remission had a longer progression-free survival. The major toxicities included HAMA in 63% of patients and hypothyroidism in 7%. To date, none of the patients have developed myelodysplastic syndrome. The high incidence of HAMA in this study (as opposed to a 10% incidence in studies with previously treated patients) is most likely related to the competency of the immune system in previously untreated patients. Whether the presence of HAMA has an impact on future treatment with I-131 tositumomab is unknown. It is possible that, with time, the HAMA response will disappear. Prior to FDA approval and outside of a formal clinical trial, a study enrolled 368 patients with relapsed lowgrade or transformed NHL in 53 community and academic sites.[33] The overall response rate was 58%, with 27% achieving a complete remission. The overall response rate among rituximab failures was 47%, with a 19% complete remission rate.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
