Annals of Oncology Advance Access published online on June 2, 2008
Annals of Oncology, doi:10.1093/annonc/mdn172
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Repeat treatment with iodine-131-rituximab is safe and effective in patients with relapsed indolent B-cell non-Hodgkin's lymphoma who had previously responded to iodine-131-rituximab
1 Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria
2 Department of Haematology, University of Western Australia, Fremantle Hospital, Fremantle
3 Department of Haematology and Medical Oncology, University of Melbourne, Victoria, Australia
* Correspondence to: Prof. J. F. Seymour, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne 3002, Victoria, Australia. Tel: +61-3-9656-1076; Fax: +61-3-9656-1408; E-mail: john.seymour{at}petermac.org
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Abstract |
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Background: Small series suggest retreatment of indolent lymphomas with murine anti-CD20 radioimmunotherapy is effective. The longer half-life of iodine-131 (131I)-rituximab may result in increased bone marrow exposure, with greater toxicity on repeat administration. We examined the effects of a second 131I-rituximab in patients with indolent lymphoma following relapse.
Patients and methods: We analyzed two institutional databases from January 2000 to July 2007 for retreatment with 131I-rituximab. The severity of cytopenia, development of myelodysplasia (MDS), acute myeloid leukemia (AML) and hypothyroidism was noted. We compared response duration and toxicity of the treatments.
Results: Fourteen of 16 patients responded with nine complete responses (CRs), with a median duration of 10.5 months in responders. Six of 13 reresponders had the same or a longer response and six more remain in complete response. The median event-free survival was not significantly different for the two treatments. There was no significant difference in the severity of myelosuppression. Four patients developed hypothyroidism with three requiring thyroxine. One patient developed AML, with no other cases of MDS. The actuarial progression-free survival rate at 12 months was 36%.
Conclusions: Repeat 131I-rituximab induces high response rates, some of which result in durable remissions in patients who had previously responded.
lymphoma, radioimmunotherapy, repeat
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introduction |
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Indolent B-cell non-Hodgkin lymphomas (NHL) are considered incurable diseases when disseminated, with a clinical course characterized by progressively shortening relapse and remission after sequential treatment with a variety of chemotherapeutic agents [1]. Anti-CD20 immunotherapy with rituximab and combination chemotherapy results in prolonged remission and improved survival [2] and prolonged maintenance rituximab improves both overall and event-free survival in the setting of relapsed disease [3, 4], but still without any evidence of cure, with all patients ultimately requiring additional treatments.
Radioimmunotherapy with an anti-CD20 mAb conjugated to a β-emitting radioisotope may overcome resistance by delivering radiation to antibody-binding tumor cells as well as neighboring tumor cells inaccessible to the antibody or with insufficient antigen expression. Indolent NHL cells are inherently radiosensitive, and the addition of a conjugated radioisotope improves response compared with the naked antibody alone [5]. The murine radiolabeled anti-CD20 antibody conjugated with iodine-131 (131I)-tositumomab (Bexxar; Corixa Corp., Seattle, WA) can achieve impressive overall response rates (ORRs) of 53%–65% in patients with relapsed or refractory low-grade NHL previously treated with chemotherapy both with [6] or without concurrent rituximab.
The results of a multicenter phase II trial of 131I-rituximab chimeric anti-CD20 antibody treatment of patients with relapsed or refractory indolent B-cell NHL were recently published, with an ORR of 76%, with 53% attaining a complete response (CR) or CR unconfirmed [7]. Radioiodination of the human/murine chimeric anti-CD20 mAb rituximab was intended to obviate induction of human anti-mouse antibodies (HAMA) and to allow repeat administration. While effective, there was no evidence of a plateau in event-free survival. Small series suggests retreatment with 131I-tositumomab or 90Y-ibritumomab tiuxetan is safe and effective [8, 9]. Humanized mAbs are cleared from the circulation at a slower rate than murine antibodies, thus prolonging radiation exposure and potentially increasing dose to normal tissue and increasing toxicity [10]. The longer half-life of the labeled rituximab may be expected to lead to greater normal marrow exposure and hence greater myelosuppression or cumulative hematologic toxicity on repeat exposure. We therefore examined the short- and long-term effects in these and other patients who have received a second treatment with 131I-rituximab following a relapse.
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patients and methods |
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This study was a retrospective analysis of data at two institutions of the safety and efficacy of retreatment with 131I-rituximab in patients with relapsed or refractory indolent CD20-positive B-cell NHL. All patients who had been treated with two or more episodes of 131I-rituximab from January 2000 to July 2007 were identified from the institutional databases.
All patients required an adequate bone marrow reserve, as demonstrated by neutrophils >1.5 x 109/l and platelets >100 x 109/l, although the specific extent of bone marrow involvement by NHL did not preclude treatment. Patients were routinely monitored with weekly full blood examination until 12 weeks posttherapy, or recovery from nadir levels, and thyroid function was routinely monitored at follow-up visits. Following treatment, the severity and duration of any cytopenia was noted, as was the development of myelodysplasia (MDS) and acute myeloid leukemia (AML), as well as elevated thyroid-stimulating hormone (TSH) and/or a low free thyroxine (T4). We set out to compare the response duration following first and second treatment and hematological toxicity. Neither HAMA nor human anti-chimeric antibodies was routinely measured in either hospital, although tracer whole-body dosimetry before radioimmunotherapy monitored biodistribution of 131I-rituximab in all patients.
In-house radioiodination of rituximab was undertaken at each institution with 131I-sodium iodide (Australian Radioisotopes and Industrials, Lucas Heights, New South Wales, Australia) using a chloramine-T method as described previously [10]. A tracer activity of 200 MBq 131I-rituximab was administered i.v. after a dose of 375 mg/m2 rituximab-unlabeled antibody. Within an hour, whole-body imaging and background scans were carried out and were repeated at 4 and 7 days under the same imaging conditions. The residence time of 131I-rituximab was calculated from whole-body gamma camera counts at these time points [10]. The radioimmunotherapeutic dose was administered 7–14 days later, after an additional 375 mg/m2 loading dose of unlabeled rituximab. The administered activity was estimated to deliver a whole-body radiation absorbed dose of 0.75 Gy. This prescribed radiation dose was on the basis of previous dose-escalation studies with 131I-tositumomab [11]. To minimize risk of hypothyroidism from free radioiodine, administration of Lugol's iodine was commenced 24 h before the tracer dosimetry study and continued for 14 days.
Responses to 131I-rituximab were classified according to standardized criteria [12]. Time to progression (TTP) or death was measured from the dosimetric dose to the first clinical or radiological evidence of relapse or death from any cause, respectively. Adverse events were recorded and graded according to the common terminology criteria for adverse events version 3.0. Weekly blood counts were taken and any grade 3/4 hematological toxicity and blood product transfusion was noted.
statistical methods
Time-to-event analyses were carried out according to the method of Kaplan and Meier and outcomes compared using the log-rank test. The length of time to blood count nadir values with each treatment was compared using the paired t-test. Analyses were carried out using the GraphPad Prism Program version 4.0 (Graphpad Software Inc, San Diego CA). All analyses were two sided, and P-values of <0.05 were considered to be significant.
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results |
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patients (table 1)
In the period of analysis, a total of XX patients had been treated with 131I-rituximab, and of these 16 patients who had received a second course of 131I-rituximab were identified. All patients had had a previous response >3 months to 131I-rituximab. All patients had undergone histological review before their first treatment and had no clinical evidence of transformation before their second treatment. Three quarters of the patients had follicular NHL, the majority of which had stage III or IV disease. Other than one patient who had a single week of treatment with oral chlorambucil and was unresponsive, no patient had any intervening treatment between doses of 131I-rituximab. Nine patients had received rituximab before both 131I-rituximab treatments, although none had received maintenance rituximab therapy. Five patients had received radiotherapy, and none had undergone previous autologous stem-cell transplantation.
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efficacy of second 131I-rituximab (table 2)
Fourteen of 16 (87.5%) patients responded, with nine (56%) achieving a CR, with a median duration of 10.5 months for all responding patients (Table 2). Four patients remain in an ongoing CR and two in ongoing PR with responses ranging from 5+ to 25+ months. Following the first 131I-rituximab, 11 of these patients had achieved a CR (68.8%), while the median TTP was 14 months (P = 0.96 compared with duration of second response). Six of 13 responders have had the same or longer duration of response following retreatment, and one patient has had a second response that is now 13 months greater than his initial response and ongoing. A further six patients remain in CR without having yet reached the same posttreatment duration time point as their first remission. Of the five patients with an initial response of <12 months, on retreatment four had a response that equaled or exceeded their initial remission duration (Figure 1).
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adverse effects
There were no grade 3/4 adverse reactions during retreatment infusion with 131I-rituximab, and in particular no anaphylaxis occurred. Hematological toxicity is summarized in Table 3. In all, 28.6% patients experienced grade 3/4 neutropenia, while 26.7% patients experienced grade 3/4 thrombocytopenia. However, there was no grade 3/4 anemia and only two patients required packed red blood cell transfusion, and no platelets were transfused. When hematological toxicity was compared with that seen after initial treatment, the degree of neutropenia was similar with a median absolute neutrophil nadir count of 1.6 x 109/l after the first treatment and 1.5 x 109/l after the second. In contrast, the median nadir platelet count was 68 x 109/l after initial treatment but was actually greater at 105 x 109/l after retreatment. There was no significant difference in the severity myelosuppression between courses for hemoglobin (P = 0.32), platelets (P = 0.13) or neutrophils (P = 0.32). The median time to both neutrophil and platelet nadirs was 6 weeks, for both lineages, for both treatments. The median time to platelet nadir values was also 6 weeks for both treatments. There were no infectious complications requiring hospital admission in either group.
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Of the 16 patients, 10 were assessable for the subsequent development of hypothyroidism; six patients were already on thyroxine replacement before their first 131I-rituximab treatment. Of the assessable patients, four have developed an elevated TSH following retreatment and three of these have required thyroxine supplementation. No cases of thyroid cancer have been reported.
A myelodysplastic syndrome later evolving to AML was diagnosed in one patient at 28 months following retreatment with 131I-rituximab. This patient had previously been treated with chlorambucil. There was a complex karyotype which included a monosomy 7 and deletion of 5q. In retrospect, this patient had a mild macrocytosis possibly consistent with an early MDS before the initial treatment with 131I-rituximab. No other cases of MDS or AML have been seen at this time point, with a median follow-up from first treatment of 41 months (range 20–96) and 22.5 months (range 3–72) from second treatment.
One patient has received a third 131I-rituximab treatment in conjunction with an autograft with BCNU, cytosine arabinoside, etoposide, melphalan conditioning 24 months after second 131I-rituximab, using previously stored stem cells. There was no delay in engraftment, and the patient remains in a PR with no evidence of MDS. Another patient has had an additional two treatments at 19 months and at 31 months after the second 131I-rituximab. The radiation dose of the third dose was reduced to 0.65 Gy due to thrombocytopenia and resulted in a CR. The fourth dose of 0.75 Gy was given as consolidation after immunochemotherapy which included rituximab. Neither of these treatments resulted in grade 3/4 hematological toxicity. The patient remains in a PR with no evidence of MDS.
survival
At the data analysis cut-off date, four (25%) of 16 patients had died, and the median survival has not been reached. The actuarial progression-free survival rate at 12 months for retreated patients was 36%. Three patients died as a result of progressive disease, while one died as a result of AML.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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A previous study using 131I-rituximab has shown similar efficacy to those reported using the radiolabeled murine antibodies 131I-tositumomab and 90Y-ibritumomab tiuxetan [13–15] without increased incidence of myelosuppression, despite a slower rate of clearance from the circulation. Currently, neither 131I-tositumomab nor 90Y-ibritumomab tiuxetan is commercially available in Australia. As radioiodination of rituximab is undertaken in-house, and the additional expense above the acquisition cost of the drug is modest, at around US $1000, this approach allows radioimmunotherapy to be available for patients with indolent B-cell lymphoma.
From our 16 retreated patients, an impressive 14 (87.5%) of our patients achieved a second response, and greater than half of all patients achieved a CR, confirming results with 131I-tositumomab retreatment. Encouragingly, the overall duration of responses (CR and PR) is not, thus far, statistically shorter with retreatment, although further follow-up is required. Indeed, six patients have had longer responses following retreatment, and a further six remain in an ongoing CR of a shorter duration. Long response durations have been observed previously with retreatment with the unlabeled antibody rituximab, while repeat treatment with 131I-tositumomab was studied in 32 patients in the context of a multicenter phase II clinical trial, with an ORR of 56% and 25% CR rate. The presence of HAMA was an exclusion factor in this study, and given the 10% rate of HAMA following a single dose of 131I-tositumomab [8, 11], retreatment with 131I-rituximab may be a therapeutic option in a larger population. A retrospective analysis from multiple centers in the United States of 18 patients receiving repeat treatment with 90Y-ibritumomab tiuxetan reported an ORR of 77%, although many responses were of short duration [9].
The hematologic toxicity of repeat radioimmunotherapy with 131I-rituximab using individualized dosimetry remains modest. Individualized dosimetric analysis in a standard prescribed whole-body radiation dose of 0.75 Gy [10, 16], as previously described, has demonstrated a median dose to red marrow of 1.9 Gy [17] less than the 2-Gy threshold for myelotoxicity. This is reflected in the mild myelosuppression encountered, with grade 4 neutropenia and thrombocytopenia occurring in only 21% of retreated patients. This was not associated with transfusion requirement in any patient, while the degree and duration of hematologic toxicity after retreatment was no statistically different from the first treatment. This would appear to confirm that serial radioimmunotherapy at the intervals we have used does not unduly reduce marrow reserve or impair subsequent treatments. Furthermore, two patients in our series received a total of three and four treatments without grade 3/4 hematological toxicity or the development of MDS to date.
The concern that radioimmunotherapy may predispose to MDS/AML and poor stem-cell mobilization has resulted in a reluctance for it to be used earlier in the disease course. Despite this risk, successful autologous transplantation in transformed follicular lymphoma previously treated with 131I-tositumomab has been reported [18]. Collection of autologous stem cells earlier in the disease course would avoid this possibility. Repeated cycles of chemotherapy and radiotherapy over many years are associated with an increased risk of MDS/AML, particularly in current treatment paradigms, when chemotherapy, radiotherapy to marrow-bearing areas and stem-cell transplantation are routine. Whether 131I-rituximab and other radioimmunotherapies contribute to the development of MDS therefore remains difficult to determine. In the case of 131I-tositumomab, the incidence rates of MDS and AML were consistent with those expected from the patients' pre-131I-tositumomab treatment regimens, with an annualized incidence of between 1.1% and 1.5% per year [19, 20]. In addition, no cases of MDS/AML have been reported in up to 6.7 years of follow-up in 76 previously untreated patients who received single-agent 131I-tositumomab as initial therapy.
Hypothyroidism is a known long-term potential consequence of iodine radioimmunotherapy, and a TSH should be checked at least annually indefinitely; however, there have been no cases of thyroid cancer seen.
Future possibilities for 131I-rituximab include use as an adjunct to autologous transplantation, which has been piloted at one of our centers, while future possibilities include planned retreatment and the use of ‘radiosensitising’ agents to improve response depth and remission duration.
Our results show retreatment with 131I-rituximab is an efficacious and safe option for patients who have responded previously to 131I-rituximab, with the duration of second or subsequent responses often exceeding the first response.
Received for publication December 15, 2007. Revision received March 18, 2008. Accepted for publication March 21, 2008.
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