Re-Treatment With I-131 Tositumomab in Patients With Non-Hodgkin's Lymphoma Who Had Previously Responded to I-131 Tositumomab
http://www.100md.com
《临床肿瘤学》
the University of Michigan Medical Center, Ann Arbor, MI
Christie Hospital, Manchester, UK
Rush-Presbyterian-St Luke's Medical Center, Chicago, IL
The New York Hospital-Cornell Medical Center, New York, NY
Stanford University Medical Center, Stanford, CA
Corixa Corporation, Seattle, WA
Johns Hopkins School of Medicine, Baltimore, MD
ABSTRACT
PURPOSE: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab.
PATIENTS AND METHODS: A prior response 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm3 or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days.
RESULTS: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia.
CONCLUSION: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.
INTRODUCTION
Low-grade (LG) and follicular non-Hodgkin's lymphomas (NHL) remain therapeutic challenges. They are usually regarded as incurable, and a variety of chemotherapeutic regimens have had little effect on long-term survival.1,2 Immunotherapeutic approaches to the treatment of NHL may afford enhanced targeting of therapy to malignant cells compared with conventional chemotherapy. When conjugated with a radiation-emitting radionuclide, a monoclonal antibody (MAb) may provide antitumor effects through multiple mechanisms of action.3
The B-cell–specific CD20 antigen is an attractive target for immunotherapy in NHL. It is expressed on more than 90% of all B-cell NHLs, and approximately 85% of NHLs are of B-cell origin.4-6 Unconjugated and conjugated anti-CD20 MAbs have become available. MAbs conjugated to radionuclides have been shown to improve response rates and, in some cases, time to progression in patients with NHL when compared with unconjugated antibodies.7,8
Tositumomab is a murine CD20 MAb that has been conjugated with iodine-131, yielding tositumomab and iodine I-131 tositumomab (BEXXAR Therapeutic Regimen; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA; "I-131 tositumomab" hereafter). It has been primarily studied in patients with LG, transformed LG, or follicular NHL whose disease had relapsed after, or was refractory to chemotherapy and/or immunotherapy. In 40 anti-CD20 antibody rituximab-relapsed/refractory patients (35 with no response or a response lasting < 6 months) who had also been heavily pretreated with chemotherapy, the overall response rate was 65% and complete response (CR) rate was 38%. The median duration of response was 25 months and was not reached for those with a CR with a median follow-up of 3.3 years.9 In studies in rituximab-naive, chemotherapy-relapsed/refractory patients, the aggregate overall response rate was 53%, and the CR rate was 29%, with a median duration of overall response of 13.2 months.12 Durable CRs (defined as progression-free survival > 12 months) were obtained in 23% of the patients, with a median duration of CR of 4.9 years.10
Patients enrolled on the I-131 tositumomab trials had previously undergone extensive treatments, and most or all conventional therapeutic options had been exhausted. This, together with the observation of long-lasting responses in a significant subset of patients treated with this agent raised the question of whether re-treatment with I-131 tositumomab after an initial response to I-131 tositumomab would be safe and effective at the time of disease progression. As part of a single-center phase I/II study,11,12 16 patients were re-treated when their disease progressed after a response to I-131 tositumomab, with a duration of at least 3 months. The overall response was 56%, and the CR was 31%. The present study was conducted to examine the safety and efficacy of re-treatment with radioimmunotherapy in a larger group of patients at multiple centers.
PATIENTS AND METHODS
Study Design and Objectives
This was a phase II, single-arm, open-label, multicenter study of the safety and efficacy of re-treatment with I-131 tositumomab in patients with LG, transformed LG, and follicular NHL who had responded previously to the same regimen. The primary end points of the study were confirmed overall response rate, confirmed CR rate, duration of response, and time to progression (TTP) or death. As a secondary end point, total body residence times of I-131 tositumomab after re-treatment and initial treatment were compared. The protocol was approved by the institutional review board or ethics committee at each of the five participating sites.
Patients
Patients at least 18 years of age with a histologically confirmed initial diagnosis of CD20-positive low-grade B-cell NHL with or without transformation were eligible. Patients were required to have achieved a partial response (PR), clinical CR (CCR), or CR of at least 3 months' duration following treatment with I-131 tositumomab in one of five I-131 tositumomab clinical trials; a Karnofsky performance status of 60%; and an anticipated survival of 3 months. Patients also had to have an absolute neutrophil count (ANC) more than 1,500 cells/mm3, a platelet count more than 100,000/mm3, and adequate renal and hepatic function. The presence of one or more lesions with size 2 x 2 cm on computed tomography scan was required. No more than 25% of the hematopoietic marrow space could be involved with lymphoma on bone marrow biopsy. Patients were excluded if pregnant or breast feeding, or if serum human antimurine antibody (HAMA) was present at any time following the initial treatment with I-131 tositumomab or at enrollment. Patients with known active infection with HIV, lymphoma of the CNS, or malignancies other than NHL during the previous 5 years (except for adequately treated skin and in situ cervical cancers) were excluded. Patients who progressed within 1 year of radiation in a field that had previously been irradiated or who were receiving other anticancer drugs or biologics were not eligible. Prior chemotherapy must have been discontinued 4 weeks (6 weeks for nitrosourea compounds) before enrollment. Systemic steroid treatment had to be discontinued 1 week before enrollment. Patients had to be able to provide written informed consent.
Treatment
Drug administration and dosimetry. Administration of I-131 tositumomab has been described previously.13,14 A dosimetric step and therapeutic step were given 7 to 14 days apart. Each step included a 1-hour infusion of 450 mg of unlabeled tositumomab before infusion of radiolabeled antibody. The radiolabeled portion of the therapeutic dose was adjusted according to the total-body residence time of the dosimetric dose calculated for each patient to give a target total-body dose (TBD) of 0.75 Gy for patients with baseline platelet counts greater than 150,000/mm3. Dose adjustments to 0.65 Gy were made for a platelet count of 100,000/mm3 to less than 150,000/mm3, and for obesity. The TBD was planned to be decreased by 0.20 Gy for patients who had received stem-cell transplantation. If a patient had experienced grade 4 thrombocytopenia or neutropenia for more than 7 days after the initial treatment with iodine I-131 tositumomab, the TBD was decreased by an additional 0.10 Gy. Administration of colony-stimulating factors was at the discretion of the investigator.
Outcome evaluations and measures. Baseline evaluations included a history, physical examination, bone marrow biopsy, and radiographic studies. Laboratory evaluation included a CBC with differential and platelet count, serum chemistries, thyroid function tests, and HAMA assessment. Serum samples were analyzed for HAMA using the individual assays of the clinical sites and by Covance Central Laboratory Services using the ImmuSTRIP (Immunomedics Inc, Morris Plains, NJ) ELISA for HAMA. Results from both HAMA assays were pooled, and a patient was classified as converting to HAMA positivity if either assay was positive. Weekly CBCs were obtained starting at week 3. Physical examinations, radiographic evaluations, laboratory studies, HAMA analysis (through week 25), and response evaluations were repeated at weeks 7, 13, and 25, and then every 26 weeks until disease progression, death, or until 2 years was reached. If the baseline bone marrow biopsy was positive for lymphoma, the bone marrow biopsy had to be repeated in those patients with a CR at the time the CR was documented, and then at the discretion of the investigator. Then long-term follow-up evaluations, including response assessments repeating all baseline radiographic evaluations for ongoing responders, vital status, secondary malignancies, thyroid-stimulating hormone (TSH), and thyroid medication usage, were performed every 6 months. Adverse events (AEs) and concomitant medication use were monitored throughout. A patient was considered to have developed hypothyroidism if a TSH level was elevated or if thyroid medication was initiated.
Tumor responses and durations of response. Measurable lesions were defined as any lesion 2 cm in both perpendicular diameters at baseline. A CR was a complete resolution of all disease-related radiologic abnormalities, and disappearance of all signs and symptoms related to the disease. A CCR was characterized as complete disappearance of all disease-related symptoms, but residual radiographic or palpable abnormality (eg, an unchanging lesion of 2 cm in diameter by radiographic evaluation or 1 cm by physical evaluation could be considered scar tissue), with the extent of disease unchanged or decreased on follow-up evaluations. A repeat bone marrow biopsy showing no evidence of lymphoma was required to document a CR or CCR if a bone marrow biopsy was positive for lymphoma at baseline. A PR was a reduction 50% in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. Stable disease was an increase of less than 25% and a decrease of less than 50% in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions present. Progressive disease was an increase of more than 25% from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion greater than 2 cm in diameter by radiographic evaluation or larger than 1 cm in diameter by physical examination. The response rates reported here had to be confirmed by two separate evaluations 4 weeks apart. Time to response was measured from the dosimetric dose to the first documented response; duration of response for patients with a PR, CR, or CCR was the time from the first documented response to the first documented progression; TTP or death (progression-free survival) was the time from the dosimetric dose to the first documented progression or to death.
AEs. AEs were recorded and graded according to the National Cancer Institute Common Toxicity Criteria (version 1.0). All AEs occurring from study entry to 12 weeks after the therapeutic dose or until alternative lymphoma therapy were recorded. After 12 weeks, only AEs that were considered possibly or probably related to study drug were recorded. All laboratory-derived hematologic AEs were classified as probably related to study drug. Duration of grade 3 or 4 hematologic toxicity was calculated from the last non–grade 3 or 4 laboratory value before grade 3 or 4 toxicity, to the first non–grade 3 or 4 laboratory value after grade 3 or 4 toxicity.
Statistical Analyses
The study was designed without a cap on the number of enrolled patients. The sample size of 32 patients allows the safety and efficacy incidence end points to be estimated with an SE no greater than 8.8%. Patients who received any portion of the study drug were included in the analyses (intent-to-treat). Patients who withdrew before disease progression or response were classified as having progressive disease. A significance level of .05 was set for all comparative analyses. Point estimates and exact two-sided 95% CIs for response rates were calculated using the binomial distribution. All duration data were analyzed with Kaplan-Meier censored data methods. SAS version 8.02 (SAS Institute, Cary, NC) was used to perform the analyses. For univariate subgroup analyses, the 2 test was used for comparing responses and complete responses; the log-rank test was used for comparing duration of response and of complete response. For multivariate analysis of response rate, the logistic regression model was used and for multivariate analysis of response duration the Cox proportional hazards model was used.
RESULTS
Patients
Between June 2, 1998, and April 11, 2002, 32 patients were enrolled. Data available through March 1, 2004, are presented. Twenty-eight patients completed the entire therapeutic regimen. One patient had an infusion reaction and did not complete the dosimetric dose. Following the dosimetric dose, one patient was found to be ineligible because of lack of prior response, and one patient was found to be HAMA-positive; neither patient received a therapeutic dose. One patient had an anaphylactoid reaction during the unlabeled antibody infusion preceding the radiolabeled part of the therapeutic dose and did not receive the radiolabeled dose. Twenty patients (62%) received a TBD of I-131 tositumomab of 0.75 Gy, seven (22%) received 0.65 Gy, and one (3%) received 0.55 Gy. The median I-131 activity administered was 86.1 mCi (range, 49.7 to 143.1 mCi). The median follow-up from the dosimetric dose was 35 months (range, 2 to 69 months).
Baseline characteristics of the patient population are listed in Table 1. The majority of patients had LG follicular NHL and stage III or IV disease at study entry, and half had bulky disease ( 5 cm). They had received a median of four previous treatments for NHL, which includes the first I-131 tositumomab treatment (range, one to 11 treatments). As listed in Table 2, the most common treatments included alkylkating-agent–containing regimens, followed by anthracycline-containing regimens in 66% and purine analog–containing regimens in 41% of patients. Rituximab was received by 22% of the patients. The median time from the initial therapy with I-131 tositumomab to re-treatment was 21 months (range, 7 to 73 months). With initial I-131 tositumomab therapy, 30 of 32 patients responded, with a median duration of response of 13.6 months, and 18 of 32 had a CR, with a median duration of CR of 14.5 months. Five patients received one or more intervening NHL therapies between their initial I-131 tositumomab treatment and re-treatment, two of whom did not complete the therapeutic dose. Three of these patients received fludarabine (two in combination with either cyclophosphamide or topotecan and one as a single agent), two received rituximab as a single agent, and one received single-agent doxorubicin.
Efficacy
Investigator-assessed responses to re-treatment are summarized in Table 3. Eighteen of 32 (56%) patients had a confirmed response, with a median duration of response of 15.2 months. Eight of 32 (25%) had a CR or CCR with a median duration of 35 months. Five of the 8 patients continue in CR with ongoing responses ranging from 22 to 69 months. The Kaplan-Meier estimates of TTP or death are shown in Figure 1 for all 32 patients and the eight patients who achieved a CR.
All 18 re-treatment responders had responded to their initial I-131 tositumomab treatments. The median duration of response was not significantly different between the initial therapy and re-treatment. For the 18 responders the median duration of response on re-treatment was 15.2 months (range, 3.8 to 66.7+ months), while the median duration of response on the initial treatment was 13.6 months (range, 3.3 to 57.4 months). However, 10 of the 18 re-responders had a longer response than after the first treatment, and five had responses that were at least 1.5 years longer (Fig 2).
An analysis of various potential factors that could influence outcome was performed for the subset of 28 patients who completed the therapeutic dose. These factors included: age ( 60 v > 60), sex, Ann Arbor stage (I/II v III/IV), tumor burden ( 500 g v > 500 g), bulky disease (< 5 cm v 5 cm), grade (low v transformed), baseline lactate dehydrogenase, bone marrow involvement, prior radiotherapy, number of prior therapies ( three v > three), CR to initial I-131 tositumomab, duration of response to initial I-131 tositumomab ( 12 months v > 12 months), and TBD (< 0.75 Gy v 0.75 Gy). None of these 13 factors were significant predictors (P > .05) of overall response or CR rates or durations of response in univariate or multivariate models.
Pharmacokinetics
The median total-body effective half-life was 65 hours (range, 40 to 95 hours). For each patient, the total body effective half-life of Iodine I-131 tositumomab after re-treatment was similar to that observed after the initial treatment. For 31 patients receiving a dosimetry dose of iodine I-131 tositumomab, the median total-body effective half-life was 65.2 hours, compared with 66.5 hours for the same patients after their initial dosimetric dose. The effective half-lives from the two studies had a correlation coefficient of 0.84.
Adverse Events
Eighty-six percent of nonhematologic AEs were grade 1 or 2. The most commonly reported AEs, regardless of relationship to study drug, were asthenia (53%), nausea (44%), headache (19%), and rash (19%). One patient experienced multiple grade 3 or 4 AEs related to sepsis (Pseudomonas) and pneumonia, typhlitis, neutropenia, and progressive non-Hodgkin's lymphoma, and five patients experienced a single grade 3 or 4 nonhematologic AE considered possibly or probably related to I-131 tositumomab, including fever (n = 1), anaphylactoid reaction (n = 1), postural hypotension (n = 2), and rash (n = 1). Thirteen (41%) of 32 and 12 (41%) of 29 patients had an AE possibly or probably related to study drug on the day of or the day following the dosimetric and the therapeutic dose, respectively. The most common AEs during the dosimetric infusion were nausea (19%), pruritus (16%), and headache (12%). During the therapeutic infusion, the most common AEs were nausea (21%) and asthenia (14%). Infusion-rate adjustments were made in two (6%) of 32 patients during the 1-hour planned infusion of tositumomab during the dosimetric dose. Both patients experienced grade 3 postural hypotension; the remainder of the therapeutic regimen was aborted in one patient, and the other patient received the remaining therapeutic dose without complications. One of 29 patients experienced an anaphylactoid reaction associated with the unlabeled tositumomab infusion during the therapeutic dose; the infusion was discontinued, and the radiolabeled dose was not given. Hematologic toxicity is detailed in Table 4 for the 28 patients completing the therapeutic dose. Fifty percent of patients experienced grade 3 or 4 neutropenia lasting a median of 26 days, 43% experienced grade 3 or 4 thrombocytopenia lasting a median of 30 days, and two patients experienced grade 3 or 4 anemia. Grade 4 neutropenia and thrombocytopenia were both documented in 21% of patients. Supportive care was administered to eight (25%) of 32 patients: RBC transfusions, 19%; platelet transfusions, 16%; granulocyte colony-stimulating factor, 12%; and erythropoietin, 3%.
When hematologic toxicity after re-treatment with I-131 tositumomab was compared with that seen after initial treatment, the degree of neutropenia and thrombocytopenia (nadir count) and the duration of grade 3 or 4 toxicity were similar. The median ANC nadir was 1,146 cells/mm3, and platelet nadir was 57,000/mm3 following initial treatment, compared with the median ANC nadir of 1,022 cells/mm3, and platelet nadir was 59,000/mm3 following re-treatment. The correlation between the initial and re-treatment neutrophil nadirs was 0.71; similarly, the correlation between the platelet nadirs was 0.75. The median duration of grade 3 or 4 neutropenia was 29 days after the initial treatment and 26 days after re-treatment; the median duration of grade 3 or 4 thrombocytopenia was 29 and 30 days, respectively. Sixteen (50%) of 32 patients experienced a total of 24 AEs that may have been related to infection, including 15 (54%) of 28 patients who received a therapeutic dose. Eight (50%) of the 16 patients with infection had grade 1 upper respiratory infections. The other eight patients had herpes simplex infection (three patients with cold sores), cellulites (one patient), infected skin lesion (one patient), grade 2 chest infection (one patient), pneumonia (one patient), and pneumonia and sepsis (one patient). The latter patient with separate episodes of pneumonia and sepsis was the only patient hospitalized with a documented infection. One other patient was hospitalized with neutropenic fever.
Twenty-six of the 32 patients were assessable for the development of hypothyroidism; four were unassessable because they had an elevated serum TSH level; one additional patient was taking thyroid medication before receiving I-131 tositumomab; and one patient had missing baseline data. Of the assessable patients, three (12%) had an elevated TSH level following treatment with I-131 tositumomab, and one additional patient initiated thyroid medication. The 2- and 4-year cumulative incidence rates for the development of hypothyroidism were 7.7% and 18.1%, respectively.
Thirty-one patients were assessable for the development of HAMA. One patient tested negative for HAMA before the dosimetric dose and then tested positive when retested immediately after the dosimetric dose was discontinued because of hypotension. Three (10%) of the assessable patients became HAMA positive. The median time to HAMA positivity was 12 days (range, 11 to 193 days).
Myelodysplastic Syndrome and Secondary Malignancies
Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) was diagnosed in five patients (four with MDS, one with AML) at approximately 8, 19, 25, 50, and 62 months after re-treatment, and approximately 6, 8, 9, 10, and 11 years after diagnosis and initial therapy, for an annualized incidence following re-treatment of 5.5% per year (95% CI, 2.3% to 13.1% per year). One of these patients had not received the therapeutic dose. Details of the numerous treatments these patients had received before and after re-treatment with I-131 tositumomab along with karyotypic analyses are presented in Table 5.
One of the patients diagnosed with MDS was also diagnosed with squamous cell lung cancer. One other patient (without MDS or AML) was diagnosed with cutaneous malignant melanoma.
Survival
As of the data analysis cutoff date, nine (28%) of 32 patients had died. The median duration of survival has not been reached. Five patients died as a result of progression of lymphoma. Two deaths were considered to be possibly related to study drug: one death from Pseudomonas sepsis (on day 48 of study treatment) and one death from AML (5.2 years after study treatment). Unrelated deaths included one patient who died from disseminated varciella zoster and fungemia (on day 133 of study treatment) and another patient who died as a result of complications from an allogeneic stem-cell transplantation following high-dose therapy to treat progressive disease (on day 284 of study treatment).
DISCUSSION
The impetus for this study was derived from two main observations. The first was that a single treatment cycle of I-131 tositumomab radioimmunotherapy has been shown to result in frequent and long-term responses lasting years in patients with multiply-relapsed or refractory LG, transformed LG, or follicular NHL.10,11 The second was from data derived from a single-center study in which patients who had initially responded to I-131 tositumomab were found to be able to respond again on re-treatment with I-131 tositumomab, and sometimes with longer durations of response.11,12 Because of the limited treatment options available to this patient population, it was believed important to confirm and extend these data in a larger group of patients in a multicenter trial.
With twice the number of patients in this current study, the results are strikingly similar in response rates and durations of response to that observed in the earlier single-center study. In both studies, slightly more than half of the patients achieved a second response, and approximately a quarter of the patients could attain a CR. Importantly, the CRs were durable for a median duration of CR of 35 months, and with five of eight patients continuing in CR from 1.8+ to 5.7+ years in the current study. Although the CR rate declined from 56% with initial treatment to 25% with re-treatment, the median duration of CR was longer with re-treatment (35 v 14.5 months for initial treatment). Encouragingly, the overall duration of responses (CR + PR) was not shorter with re-treatment, and indeed, 10 of the 18 re-treatment responders had longer responses, and five of these 10 had responses lasting 1.5 years (range, 1.5 to 3.9 years) or longer beyond that of their first response. The explanation for this finding is not clear as multiple factors that were analyzed (including degree and duration of initial I-131 tositumomab response, number of prior therapies, and tumor burden) did not predict which patients would achieve this favorable outcome. A similar phenomenon of longer response durations has been observed with re-treatment with the unlabeled antibody rituximab.15
Re-treatment with I-131 tositumomab did not appear to result in significantly increased toxicity over that normally seen with initial therapy with iodine I-131 tositumomab. The majority (86%) of nonhematologic AEs were grade 1 or 2. Infusion rate adjustments were required for only 6% of the dosimetric doses and 3% of the therapeutic doses, figures very similar to those during initial I-131 tositumomab therapy. Two patients, however, experienced grade 3 hypotension associated with the dosimetric infusion (which required discontinuation in one patient), and one patient experienced an anaphylactoid reaction associated with the therapeutic dose, which also required discontinuation of the infusion. Thus, re-treatment may require extra vigilance for infusion reactions.
Of patients who completed the therapeutic dose, 50% and 43% experienced grade 3 neutropenia and thrombocytopenia, respectively, and grade 4 neutropenia and thrombocytopenia each occurred in 21% of patients. In a subset analysis of 28 patients who received the full therapeutic dose, hematologic toxicity (degree and duration) after re-treatment was comparable to that after initial treatment, which suggests that the marrow reserve following radioimmunotherapy is not likely to compromise subsequent therapy.
Patients were followed long-term for assessment of HAMA, thyroid function, myelodysplasia, and secondary malignancies. The 10% rate of HAMA formation was similar to that observed after initial treatment with iodine I-131 tositumomab, though the time to developing HAMA positivity was rapid in two patients (11 and 12 days), as might be expected from a second exposure to a foreign protein. Three assessable patients developed elevated TSH levels at a median follow-up of 2.9 years, and one other patient initiated thyroid medication. Hypothyroidism is a known long-term consequence of iodine I-131 tositumomab therapy; thus, TSH should be monitored annually.
Repeated cycles of chemotherapy and radiotherapy throughout many years are known to be associated with an increased risk of myelodysplastic syndrome.16 Five patients in this study (16%) developed myelodysplasia (one patient had not received the therapeutic dose of I-131 tositumomab; one patient was also diagnosed with lung cancer; an additional patient was diagnosed with melanoma). All five patients with MDS/AML had received multiple courses of chemotherapy, radiation therapy to marrow-bearing areas, and even stem-cell transplantation (median, five therapies; range, two to eight therapies) over 6 to 11 years, in addition to their two courses of I-131 tositumomab. Thus, the contribution of I-131 tositumomab to the development of myelodysplasia is unclear. In an analysis of 995 heavily pretreated patients who received I-131 tositumomab, the incidence rates of MDS and AML were consistent with those expected from the patients' pre-I-131 tositumomab treatment regimens, with an annualized incidence of 1.5% per year based on investigator assessments and 1.1% per year based on an independent hematomorphologist's assessment.17 Furthermore, no cases of MDS or AML have been reported in up to 6.7 years of follow-up in 76 previously untreated patients who received single-agent I-131 tositumomab as initial therapy.18
In summary, the results of the current study suggest that re-treatment with I-131 tositumomab may be a potentially valuable therapeutic choice for patients who responded previously to therapy with I-131 tositumomab. Re-treatment with I-131 tositumomab appears to be relatively safe and effective and can result in durable responses in a subset of patients. Given these encouraging results, further studies of re-treatment with I-131 tositumomab have been designed and will include patients who prospectively enroll onto new clinical studies of I-131 tositumomab and have a duration of response of at least 6 months.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported by Corixa and GlaxoSmithKline, who have provided collaborative support and assistance to the authors for the research, writing, and production of this manuscript.
Presented in part as a poster at the 45th Annual Meeting and Exposition of the American Society of Hematology, San Diego, CA, December 6, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Christie Hospital, Manchester, UK
Rush-Presbyterian-St Luke's Medical Center, Chicago, IL
The New York Hospital-Cornell Medical Center, New York, NY
Stanford University Medical Center, Stanford, CA
Corixa Corporation, Seattle, WA
Johns Hopkins School of Medicine, Baltimore, MD
ABSTRACT
PURPOSE: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab.
PATIENTS AND METHODS: A prior response 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm3 or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days.
RESULTS: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia.
CONCLUSION: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.
INTRODUCTION
Low-grade (LG) and follicular non-Hodgkin's lymphomas (NHL) remain therapeutic challenges. They are usually regarded as incurable, and a variety of chemotherapeutic regimens have had little effect on long-term survival.1,2 Immunotherapeutic approaches to the treatment of NHL may afford enhanced targeting of therapy to malignant cells compared with conventional chemotherapy. When conjugated with a radiation-emitting radionuclide, a monoclonal antibody (MAb) may provide antitumor effects through multiple mechanisms of action.3
The B-cell–specific CD20 antigen is an attractive target for immunotherapy in NHL. It is expressed on more than 90% of all B-cell NHLs, and approximately 85% of NHLs are of B-cell origin.4-6 Unconjugated and conjugated anti-CD20 MAbs have become available. MAbs conjugated to radionuclides have been shown to improve response rates and, in some cases, time to progression in patients with NHL when compared with unconjugated antibodies.7,8
Tositumomab is a murine CD20 MAb that has been conjugated with iodine-131, yielding tositumomab and iodine I-131 tositumomab (BEXXAR Therapeutic Regimen; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA; "I-131 tositumomab" hereafter). It has been primarily studied in patients with LG, transformed LG, or follicular NHL whose disease had relapsed after, or was refractory to chemotherapy and/or immunotherapy. In 40 anti-CD20 antibody rituximab-relapsed/refractory patients (35 with no response or a response lasting < 6 months) who had also been heavily pretreated with chemotherapy, the overall response rate was 65% and complete response (CR) rate was 38%. The median duration of response was 25 months and was not reached for those with a CR with a median follow-up of 3.3 years.9 In studies in rituximab-naive, chemotherapy-relapsed/refractory patients, the aggregate overall response rate was 53%, and the CR rate was 29%, with a median duration of overall response of 13.2 months.12 Durable CRs (defined as progression-free survival > 12 months) were obtained in 23% of the patients, with a median duration of CR of 4.9 years.10
Patients enrolled on the I-131 tositumomab trials had previously undergone extensive treatments, and most or all conventional therapeutic options had been exhausted. This, together with the observation of long-lasting responses in a significant subset of patients treated with this agent raised the question of whether re-treatment with I-131 tositumomab after an initial response to I-131 tositumomab would be safe and effective at the time of disease progression. As part of a single-center phase I/II study,11,12 16 patients were re-treated when their disease progressed after a response to I-131 tositumomab, with a duration of at least 3 months. The overall response was 56%, and the CR was 31%. The present study was conducted to examine the safety and efficacy of re-treatment with radioimmunotherapy in a larger group of patients at multiple centers.
PATIENTS AND METHODS
Study Design and Objectives
This was a phase II, single-arm, open-label, multicenter study of the safety and efficacy of re-treatment with I-131 tositumomab in patients with LG, transformed LG, and follicular NHL who had responded previously to the same regimen. The primary end points of the study were confirmed overall response rate, confirmed CR rate, duration of response, and time to progression (TTP) or death. As a secondary end point, total body residence times of I-131 tositumomab after re-treatment and initial treatment were compared. The protocol was approved by the institutional review board or ethics committee at each of the five participating sites.
Patients
Patients at least 18 years of age with a histologically confirmed initial diagnosis of CD20-positive low-grade B-cell NHL with or without transformation were eligible. Patients were required to have achieved a partial response (PR), clinical CR (CCR), or CR of at least 3 months' duration following treatment with I-131 tositumomab in one of five I-131 tositumomab clinical trials; a Karnofsky performance status of 60%; and an anticipated survival of 3 months. Patients also had to have an absolute neutrophil count (ANC) more than 1,500 cells/mm3, a platelet count more than 100,000/mm3, and adequate renal and hepatic function. The presence of one or more lesions with size 2 x 2 cm on computed tomography scan was required. No more than 25% of the hematopoietic marrow space could be involved with lymphoma on bone marrow biopsy. Patients were excluded if pregnant or breast feeding, or if serum human antimurine antibody (HAMA) was present at any time following the initial treatment with I-131 tositumomab or at enrollment. Patients with known active infection with HIV, lymphoma of the CNS, or malignancies other than NHL during the previous 5 years (except for adequately treated skin and in situ cervical cancers) were excluded. Patients who progressed within 1 year of radiation in a field that had previously been irradiated or who were receiving other anticancer drugs or biologics were not eligible. Prior chemotherapy must have been discontinued 4 weeks (6 weeks for nitrosourea compounds) before enrollment. Systemic steroid treatment had to be discontinued 1 week before enrollment. Patients had to be able to provide written informed consent.
Treatment
Drug administration and dosimetry. Administration of I-131 tositumomab has been described previously.13,14 A dosimetric step and therapeutic step were given 7 to 14 days apart. Each step included a 1-hour infusion of 450 mg of unlabeled tositumomab before infusion of radiolabeled antibody. The radiolabeled portion of the therapeutic dose was adjusted according to the total-body residence time of the dosimetric dose calculated for each patient to give a target total-body dose (TBD) of 0.75 Gy for patients with baseline platelet counts greater than 150,000/mm3. Dose adjustments to 0.65 Gy were made for a platelet count of 100,000/mm3 to less than 150,000/mm3, and for obesity. The TBD was planned to be decreased by 0.20 Gy for patients who had received stem-cell transplantation. If a patient had experienced grade 4 thrombocytopenia or neutropenia for more than 7 days after the initial treatment with iodine I-131 tositumomab, the TBD was decreased by an additional 0.10 Gy. Administration of colony-stimulating factors was at the discretion of the investigator.
Outcome evaluations and measures. Baseline evaluations included a history, physical examination, bone marrow biopsy, and radiographic studies. Laboratory evaluation included a CBC with differential and platelet count, serum chemistries, thyroid function tests, and HAMA assessment. Serum samples were analyzed for HAMA using the individual assays of the clinical sites and by Covance Central Laboratory Services using the ImmuSTRIP (Immunomedics Inc, Morris Plains, NJ) ELISA for HAMA. Results from both HAMA assays were pooled, and a patient was classified as converting to HAMA positivity if either assay was positive. Weekly CBCs were obtained starting at week 3. Physical examinations, radiographic evaluations, laboratory studies, HAMA analysis (through week 25), and response evaluations were repeated at weeks 7, 13, and 25, and then every 26 weeks until disease progression, death, or until 2 years was reached. If the baseline bone marrow biopsy was positive for lymphoma, the bone marrow biopsy had to be repeated in those patients with a CR at the time the CR was documented, and then at the discretion of the investigator. Then long-term follow-up evaluations, including response assessments repeating all baseline radiographic evaluations for ongoing responders, vital status, secondary malignancies, thyroid-stimulating hormone (TSH), and thyroid medication usage, were performed every 6 months. Adverse events (AEs) and concomitant medication use were monitored throughout. A patient was considered to have developed hypothyroidism if a TSH level was elevated or if thyroid medication was initiated.
Tumor responses and durations of response. Measurable lesions were defined as any lesion 2 cm in both perpendicular diameters at baseline. A CR was a complete resolution of all disease-related radiologic abnormalities, and disappearance of all signs and symptoms related to the disease. A CCR was characterized as complete disappearance of all disease-related symptoms, but residual radiographic or palpable abnormality (eg, an unchanging lesion of 2 cm in diameter by radiographic evaluation or 1 cm by physical evaluation could be considered scar tissue), with the extent of disease unchanged or decreased on follow-up evaluations. A repeat bone marrow biopsy showing no evidence of lymphoma was required to document a CR or CCR if a bone marrow biopsy was positive for lymphoma at baseline. A PR was a reduction 50% in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. Stable disease was an increase of less than 25% and a decrease of less than 50% in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions present. Progressive disease was an increase of more than 25% from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion greater than 2 cm in diameter by radiographic evaluation or larger than 1 cm in diameter by physical examination. The response rates reported here had to be confirmed by two separate evaluations 4 weeks apart. Time to response was measured from the dosimetric dose to the first documented response; duration of response for patients with a PR, CR, or CCR was the time from the first documented response to the first documented progression; TTP or death (progression-free survival) was the time from the dosimetric dose to the first documented progression or to death.
AEs. AEs were recorded and graded according to the National Cancer Institute Common Toxicity Criteria (version 1.0). All AEs occurring from study entry to 12 weeks after the therapeutic dose or until alternative lymphoma therapy were recorded. After 12 weeks, only AEs that were considered possibly or probably related to study drug were recorded. All laboratory-derived hematologic AEs were classified as probably related to study drug. Duration of grade 3 or 4 hematologic toxicity was calculated from the last non–grade 3 or 4 laboratory value before grade 3 or 4 toxicity, to the first non–grade 3 or 4 laboratory value after grade 3 or 4 toxicity.
Statistical Analyses
The study was designed without a cap on the number of enrolled patients. The sample size of 32 patients allows the safety and efficacy incidence end points to be estimated with an SE no greater than 8.8%. Patients who received any portion of the study drug were included in the analyses (intent-to-treat). Patients who withdrew before disease progression or response were classified as having progressive disease. A significance level of .05 was set for all comparative analyses. Point estimates and exact two-sided 95% CIs for response rates were calculated using the binomial distribution. All duration data were analyzed with Kaplan-Meier censored data methods. SAS version 8.02 (SAS Institute, Cary, NC) was used to perform the analyses. For univariate subgroup analyses, the 2 test was used for comparing responses and complete responses; the log-rank test was used for comparing duration of response and of complete response. For multivariate analysis of response rate, the logistic regression model was used and for multivariate analysis of response duration the Cox proportional hazards model was used.
RESULTS
Patients
Between June 2, 1998, and April 11, 2002, 32 patients were enrolled. Data available through March 1, 2004, are presented. Twenty-eight patients completed the entire therapeutic regimen. One patient had an infusion reaction and did not complete the dosimetric dose. Following the dosimetric dose, one patient was found to be ineligible because of lack of prior response, and one patient was found to be HAMA-positive; neither patient received a therapeutic dose. One patient had an anaphylactoid reaction during the unlabeled antibody infusion preceding the radiolabeled part of the therapeutic dose and did not receive the radiolabeled dose. Twenty patients (62%) received a TBD of I-131 tositumomab of 0.75 Gy, seven (22%) received 0.65 Gy, and one (3%) received 0.55 Gy. The median I-131 activity administered was 86.1 mCi (range, 49.7 to 143.1 mCi). The median follow-up from the dosimetric dose was 35 months (range, 2 to 69 months).
Baseline characteristics of the patient population are listed in Table 1. The majority of patients had LG follicular NHL and stage III or IV disease at study entry, and half had bulky disease ( 5 cm). They had received a median of four previous treatments for NHL, which includes the first I-131 tositumomab treatment (range, one to 11 treatments). As listed in Table 2, the most common treatments included alkylkating-agent–containing regimens, followed by anthracycline-containing regimens in 66% and purine analog–containing regimens in 41% of patients. Rituximab was received by 22% of the patients. The median time from the initial therapy with I-131 tositumomab to re-treatment was 21 months (range, 7 to 73 months). With initial I-131 tositumomab therapy, 30 of 32 patients responded, with a median duration of response of 13.6 months, and 18 of 32 had a CR, with a median duration of CR of 14.5 months. Five patients received one or more intervening NHL therapies between their initial I-131 tositumomab treatment and re-treatment, two of whom did not complete the therapeutic dose. Three of these patients received fludarabine (two in combination with either cyclophosphamide or topotecan and one as a single agent), two received rituximab as a single agent, and one received single-agent doxorubicin.
Efficacy
Investigator-assessed responses to re-treatment are summarized in Table 3. Eighteen of 32 (56%) patients had a confirmed response, with a median duration of response of 15.2 months. Eight of 32 (25%) had a CR or CCR with a median duration of 35 months. Five of the 8 patients continue in CR with ongoing responses ranging from 22 to 69 months. The Kaplan-Meier estimates of TTP or death are shown in Figure 1 for all 32 patients and the eight patients who achieved a CR.
All 18 re-treatment responders had responded to their initial I-131 tositumomab treatments. The median duration of response was not significantly different between the initial therapy and re-treatment. For the 18 responders the median duration of response on re-treatment was 15.2 months (range, 3.8 to 66.7+ months), while the median duration of response on the initial treatment was 13.6 months (range, 3.3 to 57.4 months). However, 10 of the 18 re-responders had a longer response than after the first treatment, and five had responses that were at least 1.5 years longer (Fig 2).
An analysis of various potential factors that could influence outcome was performed for the subset of 28 patients who completed the therapeutic dose. These factors included: age ( 60 v > 60), sex, Ann Arbor stage (I/II v III/IV), tumor burden ( 500 g v > 500 g), bulky disease (< 5 cm v 5 cm), grade (low v transformed), baseline lactate dehydrogenase, bone marrow involvement, prior radiotherapy, number of prior therapies ( three v > three), CR to initial I-131 tositumomab, duration of response to initial I-131 tositumomab ( 12 months v > 12 months), and TBD (< 0.75 Gy v 0.75 Gy). None of these 13 factors were significant predictors (P > .05) of overall response or CR rates or durations of response in univariate or multivariate models.
Pharmacokinetics
The median total-body effective half-life was 65 hours (range, 40 to 95 hours). For each patient, the total body effective half-life of Iodine I-131 tositumomab after re-treatment was similar to that observed after the initial treatment. For 31 patients receiving a dosimetry dose of iodine I-131 tositumomab, the median total-body effective half-life was 65.2 hours, compared with 66.5 hours for the same patients after their initial dosimetric dose. The effective half-lives from the two studies had a correlation coefficient of 0.84.
Adverse Events
Eighty-six percent of nonhematologic AEs were grade 1 or 2. The most commonly reported AEs, regardless of relationship to study drug, were asthenia (53%), nausea (44%), headache (19%), and rash (19%). One patient experienced multiple grade 3 or 4 AEs related to sepsis (Pseudomonas) and pneumonia, typhlitis, neutropenia, and progressive non-Hodgkin's lymphoma, and five patients experienced a single grade 3 or 4 nonhematologic AE considered possibly or probably related to I-131 tositumomab, including fever (n = 1), anaphylactoid reaction (n = 1), postural hypotension (n = 2), and rash (n = 1). Thirteen (41%) of 32 and 12 (41%) of 29 patients had an AE possibly or probably related to study drug on the day of or the day following the dosimetric and the therapeutic dose, respectively. The most common AEs during the dosimetric infusion were nausea (19%), pruritus (16%), and headache (12%). During the therapeutic infusion, the most common AEs were nausea (21%) and asthenia (14%). Infusion-rate adjustments were made in two (6%) of 32 patients during the 1-hour planned infusion of tositumomab during the dosimetric dose. Both patients experienced grade 3 postural hypotension; the remainder of the therapeutic regimen was aborted in one patient, and the other patient received the remaining therapeutic dose without complications. One of 29 patients experienced an anaphylactoid reaction associated with the unlabeled tositumomab infusion during the therapeutic dose; the infusion was discontinued, and the radiolabeled dose was not given. Hematologic toxicity is detailed in Table 4 for the 28 patients completing the therapeutic dose. Fifty percent of patients experienced grade 3 or 4 neutropenia lasting a median of 26 days, 43% experienced grade 3 or 4 thrombocytopenia lasting a median of 30 days, and two patients experienced grade 3 or 4 anemia. Grade 4 neutropenia and thrombocytopenia were both documented in 21% of patients. Supportive care was administered to eight (25%) of 32 patients: RBC transfusions, 19%; platelet transfusions, 16%; granulocyte colony-stimulating factor, 12%; and erythropoietin, 3%.
When hematologic toxicity after re-treatment with I-131 tositumomab was compared with that seen after initial treatment, the degree of neutropenia and thrombocytopenia (nadir count) and the duration of grade 3 or 4 toxicity were similar. The median ANC nadir was 1,146 cells/mm3, and platelet nadir was 57,000/mm3 following initial treatment, compared with the median ANC nadir of 1,022 cells/mm3, and platelet nadir was 59,000/mm3 following re-treatment. The correlation between the initial and re-treatment neutrophil nadirs was 0.71; similarly, the correlation between the platelet nadirs was 0.75. The median duration of grade 3 or 4 neutropenia was 29 days after the initial treatment and 26 days after re-treatment; the median duration of grade 3 or 4 thrombocytopenia was 29 and 30 days, respectively. Sixteen (50%) of 32 patients experienced a total of 24 AEs that may have been related to infection, including 15 (54%) of 28 patients who received a therapeutic dose. Eight (50%) of the 16 patients with infection had grade 1 upper respiratory infections. The other eight patients had herpes simplex infection (three patients with cold sores), cellulites (one patient), infected skin lesion (one patient), grade 2 chest infection (one patient), pneumonia (one patient), and pneumonia and sepsis (one patient). The latter patient with separate episodes of pneumonia and sepsis was the only patient hospitalized with a documented infection. One other patient was hospitalized with neutropenic fever.
Twenty-six of the 32 patients were assessable for the development of hypothyroidism; four were unassessable because they had an elevated serum TSH level; one additional patient was taking thyroid medication before receiving I-131 tositumomab; and one patient had missing baseline data. Of the assessable patients, three (12%) had an elevated TSH level following treatment with I-131 tositumomab, and one additional patient initiated thyroid medication. The 2- and 4-year cumulative incidence rates for the development of hypothyroidism were 7.7% and 18.1%, respectively.
Thirty-one patients were assessable for the development of HAMA. One patient tested negative for HAMA before the dosimetric dose and then tested positive when retested immediately after the dosimetric dose was discontinued because of hypotension. Three (10%) of the assessable patients became HAMA positive. The median time to HAMA positivity was 12 days (range, 11 to 193 days).
Myelodysplastic Syndrome and Secondary Malignancies
Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) was diagnosed in five patients (four with MDS, one with AML) at approximately 8, 19, 25, 50, and 62 months after re-treatment, and approximately 6, 8, 9, 10, and 11 years after diagnosis and initial therapy, for an annualized incidence following re-treatment of 5.5% per year (95% CI, 2.3% to 13.1% per year). One of these patients had not received the therapeutic dose. Details of the numerous treatments these patients had received before and after re-treatment with I-131 tositumomab along with karyotypic analyses are presented in Table 5.
One of the patients diagnosed with MDS was also diagnosed with squamous cell lung cancer. One other patient (without MDS or AML) was diagnosed with cutaneous malignant melanoma.
Survival
As of the data analysis cutoff date, nine (28%) of 32 patients had died. The median duration of survival has not been reached. Five patients died as a result of progression of lymphoma. Two deaths were considered to be possibly related to study drug: one death from Pseudomonas sepsis (on day 48 of study treatment) and one death from AML (5.2 years after study treatment). Unrelated deaths included one patient who died from disseminated varciella zoster and fungemia (on day 133 of study treatment) and another patient who died as a result of complications from an allogeneic stem-cell transplantation following high-dose therapy to treat progressive disease (on day 284 of study treatment).
DISCUSSION
The impetus for this study was derived from two main observations. The first was that a single treatment cycle of I-131 tositumomab radioimmunotherapy has been shown to result in frequent and long-term responses lasting years in patients with multiply-relapsed or refractory LG, transformed LG, or follicular NHL.10,11 The second was from data derived from a single-center study in which patients who had initially responded to I-131 tositumomab were found to be able to respond again on re-treatment with I-131 tositumomab, and sometimes with longer durations of response.11,12 Because of the limited treatment options available to this patient population, it was believed important to confirm and extend these data in a larger group of patients in a multicenter trial.
With twice the number of patients in this current study, the results are strikingly similar in response rates and durations of response to that observed in the earlier single-center study. In both studies, slightly more than half of the patients achieved a second response, and approximately a quarter of the patients could attain a CR. Importantly, the CRs were durable for a median duration of CR of 35 months, and with five of eight patients continuing in CR from 1.8+ to 5.7+ years in the current study. Although the CR rate declined from 56% with initial treatment to 25% with re-treatment, the median duration of CR was longer with re-treatment (35 v 14.5 months for initial treatment). Encouragingly, the overall duration of responses (CR + PR) was not shorter with re-treatment, and indeed, 10 of the 18 re-treatment responders had longer responses, and five of these 10 had responses lasting 1.5 years (range, 1.5 to 3.9 years) or longer beyond that of their first response. The explanation for this finding is not clear as multiple factors that were analyzed (including degree and duration of initial I-131 tositumomab response, number of prior therapies, and tumor burden) did not predict which patients would achieve this favorable outcome. A similar phenomenon of longer response durations has been observed with re-treatment with the unlabeled antibody rituximab.15
Re-treatment with I-131 tositumomab did not appear to result in significantly increased toxicity over that normally seen with initial therapy with iodine I-131 tositumomab. The majority (86%) of nonhematologic AEs were grade 1 or 2. Infusion rate adjustments were required for only 6% of the dosimetric doses and 3% of the therapeutic doses, figures very similar to those during initial I-131 tositumomab therapy. Two patients, however, experienced grade 3 hypotension associated with the dosimetric infusion (which required discontinuation in one patient), and one patient experienced an anaphylactoid reaction associated with the therapeutic dose, which also required discontinuation of the infusion. Thus, re-treatment may require extra vigilance for infusion reactions.
Of patients who completed the therapeutic dose, 50% and 43% experienced grade 3 neutropenia and thrombocytopenia, respectively, and grade 4 neutropenia and thrombocytopenia each occurred in 21% of patients. In a subset analysis of 28 patients who received the full therapeutic dose, hematologic toxicity (degree and duration) after re-treatment was comparable to that after initial treatment, which suggests that the marrow reserve following radioimmunotherapy is not likely to compromise subsequent therapy.
Patients were followed long-term for assessment of HAMA, thyroid function, myelodysplasia, and secondary malignancies. The 10% rate of HAMA formation was similar to that observed after initial treatment with iodine I-131 tositumomab, though the time to developing HAMA positivity was rapid in two patients (11 and 12 days), as might be expected from a second exposure to a foreign protein. Three assessable patients developed elevated TSH levels at a median follow-up of 2.9 years, and one other patient initiated thyroid medication. Hypothyroidism is a known long-term consequence of iodine I-131 tositumomab therapy; thus, TSH should be monitored annually.
Repeated cycles of chemotherapy and radiotherapy throughout many years are known to be associated with an increased risk of myelodysplastic syndrome.16 Five patients in this study (16%) developed myelodysplasia (one patient had not received the therapeutic dose of I-131 tositumomab; one patient was also diagnosed with lung cancer; an additional patient was diagnosed with melanoma). All five patients with MDS/AML had received multiple courses of chemotherapy, radiation therapy to marrow-bearing areas, and even stem-cell transplantation (median, five therapies; range, two to eight therapies) over 6 to 11 years, in addition to their two courses of I-131 tositumomab. Thus, the contribution of I-131 tositumomab to the development of myelodysplasia is unclear. In an analysis of 995 heavily pretreated patients who received I-131 tositumomab, the incidence rates of MDS and AML were consistent with those expected from the patients' pre-I-131 tositumomab treatment regimens, with an annualized incidence of 1.5% per year based on investigator assessments and 1.1% per year based on an independent hematomorphologist's assessment.17 Furthermore, no cases of MDS or AML have been reported in up to 6.7 years of follow-up in 76 previously untreated patients who received single-agent I-131 tositumomab as initial therapy.18
In summary, the results of the current study suggest that re-treatment with I-131 tositumomab may be a potentially valuable therapeutic choice for patients who responded previously to therapy with I-131 tositumomab. Re-treatment with I-131 tositumomab appears to be relatively safe and effective and can result in durable responses in a subset of patients. Given these encouraging results, further studies of re-treatment with I-131 tositumomab have been designed and will include patients who prospectively enroll onto new clinical studies of I-131 tositumomab and have a duration of response of at least 6 months.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported by Corixa and GlaxoSmithKline, who have provided collaborative support and assistance to the authors for the research, writing, and production of this manuscript.
Presented in part as a poster at the 45th Annual Meeting and Exposition of the American Society of Hematology, San Diego, CA, December 6, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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