Tositumomab and Iodine-131 Tositumomab Produces Durable Complete Remissions in a Subset of Heavily Pretreated Patients With Low-Grade and Tr
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《临床肿瘤学》
the James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester
Memorial-Sloan-Kettering Cancer Center
Weill Medical College of Cornell University, New York, NY
University of Michigan Cancer Center, Ann Arbor, MI
Johns Hopkins School of Medicine, Baltimore, MD
Stanford University Medical Center, Stanford, CA
University of Nebraska Medical Center, Omaha, NE
Corixa Corporation, Seattle, WA
ABSTRACT
PURPOSE: This study is an integrated efficacy analysis of the five clinical trials of tositumomab and iodine-131 tositumomab in patients with relapsed or refractory low-grade, follicular, or transformed low-grade non-Hodgkin’s lymphoma (NHL) that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration.
PATIENTS AND METHODS: This integrated analysis included 250 patients. Patients received a single course of iodine-131 tositumomab. Responses were assessed by an independent panel of radiologists and oncologists.
RESULTS: Response rates in the five trials ranged from 47% to 68%; complete response rates ranged from 20% to 38%. With a median follow-up of 5.3 years, the 5-year progression-free survival was 17%. Eighty-one (32%) of 250 patients had a time to progression of 1 year (termed durable response population). For the durable response population, 44% had not progressed at 2.5 to 9.5 years and had a median duration of response of 45.8 months. The median duration of complete response was not reached. The durable response population had many poor prognostic characteristics, including bone marrow involvement (41%), bulky disease 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies and 36% had not responded to their most recent therapy.
CONCLUSION: The tositumomab and iodine-131 tositumomab therapeutic regimen produces high response rates in patients with relapsed or refractory low-grade, follicular, and transformed low-grade NHL, with a sizable subgroup of patients achieving long-term durable responses.
INTRODUCTION
Patients with low-grade non-Hodgkin’s lymphoma (NHL) are generally considered to be incurable, despite the sensitivity of the disease to initial therapy with radiation therapy, chemotherapy, or treatment with monoclonal antibodies (MAb). In addition, patients frequently demonstrate repetitive responsiveness at relapse to further treatment, although the number of responders and the duration of response both decrease each time.1,2 In general, overall survival is not believed to have changed materially over the past 40 years, even with increasingly aggressive therapies.2,3 However, a report suggesting that initial treatment with combination chemotherapy followed by a monoclonal antibody may improve survival has recently been presented.4
Outcomes from subsequent treatment regimens are significantly affected by the number of prior therapeutic attempts,1,5,6 response and duration of response to the prior therapy,1 transformation to a higher-grade histology,7,8 and prior therapy-induced damage to normal organs that may preclude the use of potentially effective doses of subsequent therapies. Patients die after disease transformation to a refractory aggressive lymphoma, organ failure due to infiltration with disease, or toxicities associated with therapy.1,5 Therefore, patients with multiple relapses of NHL represent a population in whom novel therapeutic approaches should be tested. The goals of such therapies should be twofold: to increase objective responses and to induce durable remissions.
The efficacy of anti-CD20 antibody therapy can be enhanced by the conjugation of the MAb with a beta-emitting radionuclide.9-11 Beta particle radiation can provide toxicity directly to the cell bound by the antibody and to neighboring tumor cells through cross-fire radiation. Cross-fire radiation can kill cells in the proximate environment that are not accessible to the MAb, that may not express CD20, and/or that may be resistant to the immune-mediated or direct apoptotic effects of the unlabeled antibody.12 Therapy with radioimmunoconjugates has had extensive clinical testing using murine anti-CD20 MAbs conjugated to either iodine-131 (iodine-131 tositumomab [BEXXAR; Corixa Corporation, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA]) or yttrium-90 (yttrium-90 ibritumomab tiuxetan [Zevalin; IDEC Pharmaceuticals, San Diego, CA]). Regimens employing one or the other radioimmunoconjugate have demonstrated therapeutic benefit for patients with low-grade and follicular lymphoma who had relapsed or whose disease became refractory following treatment with chemotherapy and/or immunotherapy.9-11,13-17
Tositumomab and iodine-131 tositumomab was introduced into clinical trials in 1990 for the treatment of relapsed or refractory low-grade and transformed low-grade NHL. Iodine-131 tositumomab provides for a dosimetric and a therapeutic dose. Details of the treatment regimen have been previously described.14,16,18
The current study evaluated iodine-131 tositumomab administered to 250 patients reported in five clinical trials in patients with relapsed and refractory low-grade, follicular, and transformed low-grade NHL.9,15-17,19,20 The demonstration that a significant subset of heavily pretreated patients with indolent lymphoma could achieve durable remissions with a single course of radioimmunotherapy prompted this report. Although the individual studies all demonstrate a subset of patients with durable responses, it is only in the pooling of these studies that the number of patients allows reasonably accurate long-term estimates and also allows the covariate analyses which are difficult to perform with limited data.
These patients also formed the accepted efficacy database that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration and thus also represent all of the iodine-131 tositumomab studies for whom the response and duration of response data have been independently reviewed by a blinded panel (see response criteria) and the US Food and Drug Administration. Preliminary results have been previously presented in abstract form.
PATIENTS AND METHODS
Patients
1990 to 2001, 250 patients with previously treated relapsed or refractory low-grade, follicular, or transformed low-grade NHL were enrolled in five clinical trials and received iodine-131 tositumomab. All patients provided written informed consent. Patients in these trials (Table 1) comprised the integrated efficacy (IE) population presented to the US Food and Drug Administration for product approval. Patients were at least 18 years old, and in four of the studies, had histologically confirmed diagnoses of CD20-positive low-grade NHL, according to the International Working Formulation A, B, or C,21 or low-grade NHL that had transformed to a higher-grade histology, including follicular large cell, diffuse large cell, or diffuse undifferentiated lymphoma.22 The fifth study, CP-97-012, allowed International Working Formulation D patients. All patients had previous treatment with at least one chemotherapy regimen. Generally, the previous chemotherapy regimens contained an anthracycline, an anthracenedione, or an alkylating agent, and the NHL had failed to respond to this treatment or had progressed following a response. Patients had to have an anticipated survival rates of more than 3 months, Karnofsky performance status of more than 60%, absolute granulocyte counts of more than 1,500 cells/mm3, platelet counts of more than 100,000/mm3, and serum creatinine levels of less than 1.5x the upper limit of normal (ULN), total bilirubin levels of less than 1.5x ULN, and AST less than 5x ULN.
All patients had bidimensionally measurable disease with at least one lesion 2 cm wide in 2 perpendicular diameters, as measured by computed tomography scans. Patients also had no more than 25% of their bone marrow occupied by NHL, as determined on a unilateral bone marrow biopsy (bilateral biopsies were performed if the unilateral biopsy had > 10% involvement). Involvement was defined by the percent of hematopoietic marrow space that was occupied by NHL and not by the percent of total cells that were involved. Patients were excluded if they had previously been treated with nonhuman antibodies or radioimmunotherapy. Other exclusion criteria were previous or current investigational drug use; cytotoxic therapy, radiation therapy, or immunosuppressive drugs within the 4 weeks preceding study entry (6 weeks for nitrosourea therapy); evidence of obstructive hydronephrosis; active infection requiring intravenous antibiotics; or class III or IV heart disease defined by the New York Heart Association criteria. Patients also were excluded from the study for disease progression within the last 1 year in a field previously irradiated with more than 0.35 Gy, a prior malignancy other than lymphoma (with the exception of cervical carcinoma-in-situ or adequately treated skin cancer) unless the patient had been disease-free for 5 years, and pregnancy. Patients defined as having refractory disease had to have been treated with at least two prior regimens, and to either have not responded to the most recent therapy or to have had response duration of 6 months.
Drug preparation, dosimetry, and administration of iodine-131 tositumomab has been previously described.15,16,18 Following the phase I/II study, the total body dose (TBD) of radiation was standardized to 0.75 Gy and was attenuated to 0.65 Gy for patients with a baseline platelet count of 100,000 to 150,000/mm3. For obese patients, dosage was based on 137% of lean body mass. To block uptake of iodine-131 by the thyroid gland, patients were treated with a saturated solution of potassium iodide, Lugol’s solution, or potassium iodide tablets beginning at least 24 hours before the dosimetric dose and continuing for 14 days after the therapeutic dose.
Initially, patients were hospitalized in isolation for the therapeutic dose until emission decreased to 5 mrem/h, which generally occurred within 3 to 4 days.16 Subsequent revision of the Nuclear Regulatory Commission guidelines allowed most patients to be treated as outpatients, discharged within 4 hours of receiving the therapeutic dose.
Response Criteria
Response was assessed by physical examination and computed tomography scans at weeks 7 and 13, every 3 months for 2 years, and then every 6 months until disease progression or death. A complete response (CR) was defined as complete disappearance of all disease-related physical or radiologic abnormalities and all signs and symptoms related to disease. A clinical CR (CCR) was characterized as a complete disappearance of all disease-related symptoms, but residual radiographic or palpable abnormality remained (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. Patients who had demonstrable lymphoma in baseline bone marrow were required to have a repeat biopsy to demonstrate the absence of lymphoma for a designation of CR or CCR. A partial response (PR) was defined as a 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, without the appearance of new lesions. Stable disease was defined as no decrease of more than 50% or no increase of more than 25% in the sum of the products of the longest perpendicular diameters of measurable lesions, and the absence of any detectible new lesions. Progressive disease was defined as a more than 25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions, or the appearance of new lesions measuring more than 2 cm in diameter by radiographic evaluation or more than 1 cm in diameter by physical examination. The notation of CR includes patients with a documented CCR or CR. All responses required confirmation by a repeat evaluation at least 4 weeks after the initial documentation. Review of each reported tumor response was performed by one of two independent review teams, each consisting of an oncologist and a radiologist who were not involved in the clinical trials, known as the MIRROR (Masked Independent Randomized Radiology and Oncology Review) panel. Members were blinded to investigator assessment.
The MIRROR panel reviews were conducted routinely for all patients in studies RIT-II-002, RIT-II-004, and CP-97-012, and for patients in studies RIT-I-000 and RIT-II-001 who had an investigator-assessed durable response (ie, progression-free survival of at least 12 months). Analyses of response rates were based on the MIRROR panel assessments. Investigators continued to follow patients using the above criteria. The investigator-assessed durations were used to supplement the MIRROR panel durations for all MIRROR panel-assessed responders who continued in response at their last MIRROR panel assessment.
Statistical Analysis
Integrated analyses (data cutoff, March 2004) were performed using data from patients with low-grade and transformed low-grade NHL from the phase I/II study and all patients receiving iodine-131 tositumomab in the other studies. All statistical tests of treatment and subgroup differences were two-sided and set with a significance level of .05. P values and CIs were presented without adjustment for multiple comparisons, multiple outcomes, or multiple looks. Duration of response was calculated from the date of first documented response. Progression-free survival (PFS) was calculated from the date of start of the treatment program. The end point for PFS was progression or death. Patients who had not progressed or died were censored at the time of their last assessment. Patients withdrawing from the study for reasons other than progression or death were censored at the time of withdrawal. Duration of response and PFS were analyzed according to Kaplan-Meier methodology. Exploratory univariate analyses of factors contributing to the overall response (OR) and CR rates used the 2 test with Yates’ correction for categories with two subgroups. The log-rank test was used for duration of response analyses. The following variables were included in the univariate analyses: sex, age, Ann Arbor stage, time from NHL diagnosis ( 4 years or > 4 years), tumor burden ( 500 or > 500 g), bulky disease (< 5 or 5 cm), disease transformation (yes or no), histology (follicular, other), lactate dehydrogenase (LDH) level, bone marrow involvement, prior radiotherapy, modified International Prognostic Index (IPI) score ( 2 or 3), number of prior chemotherapy regimens (1 to 3, 4), response to last chemotherapy, response to last rituximab, and TBD (< 0.75 or 0.75 Gy). Multivariate stepwise logistic regression and multivariate stepwise proportional hazard models included all variables identified as significant on univariate analysis.
RESULTS
Integrated Summary of Efficacy Population
Demographics for the 250 patients are listed in Table 2. Patients had been treated with a median of four prior therapies (range, one to 13), and 50% of patients did not respond to their last treatment regimen (chemotherapy or rituximab). Forty patients were from study CP-97-012, which evaluated response in rituximab relapsed/refractory patients. The rate of nonresponse to the last rituximab-containing regimen was 60% (24 of 40 patients). The other 210 patients in the integrated efficacy population did not receive rituximab. Response data were available for 208 of these 210 patients. The rate of nonresponse to last chemotherapy was 49% (101 of 208 patients).
For the entire population, the median follow-up time from the administration of the dosimetric dose was 41.5 months (range, 0.2 to 133.1 months). The OR and CR rates were 56% and 30%, respectively (Table 3). The response rates in each of the five clinical trials ranged from 47% to 68%. Complete response rates ranged from 20% to 38%. Parameters predictive of a lower OR rate, as assessed by univariate analyses, were older age, high tumor burden, bulky disease, transformed histology, nonfollicular histology, elevated LDH, increased IPI score, prior radiotherapy, prior anthracycline-containing regimen, no response to last chemotherapy, and TBD of radiation less than 0.75 Gy. Parameters predictive of a lower response that remained statistically significant in multivariate analyses included nonfollicular histology (odds ratio = 0.41; P = .009), elevated LDH (odds ratio = 0.40; P = .002), and prior radiotherapy (odds ratio = 0.39; P = .003). Parameters predictive of a lower frequency of CR as assessed by univariate analyses were older age, high tumor burden, bulky disease, nonfollicular histology, elevated LDH, increased IPI score, no response to last chemotherapy, and having been treated with less than 0.75 Gy TBD of radiation. In multivariate analyses, the predictors for failing to achieve a CR that remained significant included absence of response to last chemotherapy (odds ratio = 0.28; P < .001), elevated LDH (odds ratio = 0.34; P = .002), and bulky disease (odds ratio = 0.35; P = .009). Multivariate analysis of parameters associated with a shorter duration of response were elevated LDH (relative risk [RR] = 1.7; P = .003), patient age older than 65 years (RR = 1.6; P = .032), and no response to last chemotherapy (RR = 1.5; P = .018).
Progression-free survival for all patients is shown in Figure 1. There is no universally accepted definition of what constitutes a long-term durable response. However, there was a sharp decline in the proportion of patients without disease progression in the first year, and the slope of the PFS curve seems to change at about 1 year. At about that time, a subpopulation of patients emerged who seemed to have derived long-term benefit from treatment with iodine-131 tositumomab. That subpopulation of patients with durable responses was observed in each of the five studies, including in patients enrolled onto the initial phase I trial (RIT-I-000).
More specifically, 81 (32%) of 250 patients had a PFS of 1 year or longer, validated by the MIRROR panel. This is the group we have defined as having durable responses. However, 58 patients (23%) had a PFS of longer than 18 months and 53 patients (21%) actually had a PFS of 2 years. Beyond 2 years, the relapse rate was approximately 10% per person-year, or one relapse per 10 person-years. A durable response population was observed consistently within all five clinical trials (Fig 2) and was not unique to certain trials. Of note, 9% to 20% of the patients on each of the five clinical trials have not experienced diseased progression, with a median follow-up of 5.3 years. Overall, 17% of the original treated population is predicted to be alive and disease-free by Kaplan-Meier analysis at 5 years. The longest duration of response could obviously be noted in the original phase I/II clinical trial RIT-I-000, in which 38% of the patients had a PFS of longer than 1 year, with five patients remaining in remission between 8.0 years and 10.2 years. The differences in the response rates and relative percentages of durable responders in each of these trials probably reflects variations in the number of prior therapies administered and patients’ responses to their most recent therapy within each study.
Of the 81 durable responders, 62 patients (77%) had a CR by MIRROR panel assessments and 19 (23%) had a PR (Table 4). The median duration of OR was 45.8 months with a median follow-up of 61.2 months (range, 15.5 to 133.1 months). The median duration of response was not reached for those patients who achieved a CR. Forty-four percent remain in PFS ranging from 2.7 to 10.2 years (Fig 3A).
Table 5 compares the prognostic characteristics for the 81 patients in the durable response population (PFS of 12 months) with the 169 patients in the integrated efficacy population who had a PFS of less than 12 months. Patients in the durable response population had multiple poor prognostic characteristics: 43% had been treated with at least four prior therapies (12% had received only one prior therapy), 36% had not responded to their last treatment, and 64% had disease that was refractory (no response or duration of response < 6 months) to their last treatment regimen. Other poor prognostic characteristics included stage IV disease (63%), transformed disease (23%), bulky disease (49%), and an IPI score of 3 (24%). However, factors, such as the number of prior therapies ( four), refractory disease, elevated LDH, bulky disease, and high IPI score were observed less often in the durable response population than in patients in the integrated efficacy population.
In a subgroup analysis for the durable response population, the duration of response to iodine-131 tositumomab was compared with the duration of response to each patient’s last prior therapy. Of the 81 patients, 77 (95%) had a longer response (defined as 1 month) to iodine-131 tositumomab. Only two patients had a longer response to their last prior therapy. Two patients had equivalent response durations. In addition, the duration of response was not affected by whether patients had responded to the last regimen they received (Fig 3B).
DISCUSSION
Considering the incurability of low-grade NHL with standard low-dose or high-dose chemotherapy regimens, the evaluation of promising new therapies that might prolong remission and survival in this patient population is an important endeavor. Rituximab has had a major impact on the treatment of patients with indolent lymphoma. Treatment of heavily pretreated patient populations with four weekly doses of rituximab resulted in overall and complete response rates of 48% and 6%, respectively.23 These numbers will vary somewhat depending on the response criteria being utilized; however, the median time to progression was approximately 1 year and there was no evidence of a plateau on the time to progression curve.
The inherent radiosensitivity of NHL and the known efficacy of therapy with anti-CD20 antibodies make low-grade NHL ideally suited for the development of radioimmunotherapy regimens. CD20 is expressed in high density on more than 90% of B-cell NHL.24,25 It is expressed on pre-B and mature B cells, but not on early precursors, stem cells, or plasma cells.24,25 Furthermore, it is not shed and is minimally internalized on binding of the MAb,26 and it elicits antibody-dependent27 and complement-mediated cytotoxicity and apoptosis.28 The radionuclide iodine-131 can be covalently conjugated to the MAb without significant dehalogenation, and the energy and path-length are sufficient for significant cytotoxicity.
An integrated efficacy database of 250 patients with long-term follow-up, beginning from the time that clinical development of iodine-131 tositumomab began in 1990, is available for analysis. This is the same database that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration. The patients were heavily pretreated. Patients had been treated with a median of four prior chemotherapy or immunotherapy regimens (range, one to 13 regimens), and 50% of patients had not responded to their most recent treatment. Many had other poor prognostic characteristics, such as bulky and transformed disease and high IPI scores. Despite this, OR and CR rates of 56% and 30%, respectively, were achieved following a single therapeutic dose of iodine-131 tositumomab. The purpose of this article was not to focus on the toxicity and safety profiles of iodine-131 tositumomab, because they have been reported previously.9,15-17,19,20 Acute toxicities relate to generally well-tolerated myelosuppression and long-term toxicities have included human antimurine antibodies and hypothyroidism; by far, the most important toxicity is myelodysplasia, which has been recently analyzed in detail.29 The authors confirmed an annualized incidence of 1.1%/year of treatment-related myelodysplastic syndrome or treatment-related acute myeloid leukemia, which they concluded was consistent with that expected on the basis of the patients’ prior chemotherapy for NHL.
Although there is no universally accepted definition of what constitutes a long-term durable response, an analysis was undertaken of the subpopulation of patients who had a PFS of 1 year (32% of patients), because the slope of the PFS curve changed at about 1 year. Within this durable response population, 77% achieved a CR and 23% a PR. All but one patient who had a PR relapsed within 20 months, confirming that induction of a CR is key to attainment of a long-term durable response. The PFS for patients who had achieved a CR was not reached, with a median follow-up of 5.1 years (range, 1.3 to 11.1 years). Moreover, 53 patients (21%) actually had a PFS of 2 years and 17% of the original treated population is predicted to be alive and disease-free by Kaplan-Meier analysis at 5 years. No treatment modality, other than stem-cell transplantation, has been shown to offer such long-term durable responses in similar heavily pretreated patients.30,31
Recently, Wiseman and Witzig32 published a comparable analysis for the 211 patients treated with ibritumomab tiuxetin radioimmunotherapy. The potential differences in clinical activity between iodine-131–based and yttrium-90–based agents and/or the regimens used may have important therapeutic implications. The comparative efficacy and safety of iodine-131 tositumomab versus yttrium-90 ibritumomab tiuxetan, as well as a comparison of iodine-131 tositumomab versus rituximab, are planned for multicenter, randomized, comparative trials.
For the durable response population, the duration of response after treatment with iodine-131 tositumomab was longer in 77 patients (95%) compared with the duration of response after their last prior therapy. This denotes a reversal of the anticipated decrement in rate and duration of response expected with successive chemotherapy regimens used to treat patients with relapsed and refractory low-grade NHL.1,5
Durable responses obviate the need for repetitive cycles of chemotherapy and eliminate the associated toxicity from cytotoxic regimens, as well as the need for and cost of supportive care measures to ameliorate associated toxicities. In this study, iodine-131 tositumomab therapy for relapsed and refractory low-grade, follicular, and transformed low-grade NHL resulted in long-term durable responses and a significant clinical benefit for a subset of patients.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors 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 discription 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, in the conduct of the research reported in this article.
This original manuscript has not been previously published.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Memorial-Sloan-Kettering Cancer Center
Weill Medical College of Cornell University, New York, NY
University of Michigan Cancer Center, Ann Arbor, MI
Johns Hopkins School of Medicine, Baltimore, MD
Stanford University Medical Center, Stanford, CA
University of Nebraska Medical Center, Omaha, NE
Corixa Corporation, Seattle, WA
ABSTRACT
PURPOSE: This study is an integrated efficacy analysis of the five clinical trials of tositumomab and iodine-131 tositumomab in patients with relapsed or refractory low-grade, follicular, or transformed low-grade non-Hodgkin’s lymphoma (NHL) that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration.
PATIENTS AND METHODS: This integrated analysis included 250 patients. Patients received a single course of iodine-131 tositumomab. Responses were assessed by an independent panel of radiologists and oncologists.
RESULTS: Response rates in the five trials ranged from 47% to 68%; complete response rates ranged from 20% to 38%. With a median follow-up of 5.3 years, the 5-year progression-free survival was 17%. Eighty-one (32%) of 250 patients had a time to progression of 1 year (termed durable response population). For the durable response population, 44% had not progressed at 2.5 to 9.5 years and had a median duration of response of 45.8 months. The median duration of complete response was not reached. The durable response population had many poor prognostic characteristics, including bone marrow involvement (41%), bulky disease 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies and 36% had not responded to their most recent therapy.
CONCLUSION: The tositumomab and iodine-131 tositumomab therapeutic regimen produces high response rates in patients with relapsed or refractory low-grade, follicular, and transformed low-grade NHL, with a sizable subgroup of patients achieving long-term durable responses.
INTRODUCTION
Patients with low-grade non-Hodgkin’s lymphoma (NHL) are generally considered to be incurable, despite the sensitivity of the disease to initial therapy with radiation therapy, chemotherapy, or treatment with monoclonal antibodies (MAb). In addition, patients frequently demonstrate repetitive responsiveness at relapse to further treatment, although the number of responders and the duration of response both decrease each time.1,2 In general, overall survival is not believed to have changed materially over the past 40 years, even with increasingly aggressive therapies.2,3 However, a report suggesting that initial treatment with combination chemotherapy followed by a monoclonal antibody may improve survival has recently been presented.4
Outcomes from subsequent treatment regimens are significantly affected by the number of prior therapeutic attempts,1,5,6 response and duration of response to the prior therapy,1 transformation to a higher-grade histology,7,8 and prior therapy-induced damage to normal organs that may preclude the use of potentially effective doses of subsequent therapies. Patients die after disease transformation to a refractory aggressive lymphoma, organ failure due to infiltration with disease, or toxicities associated with therapy.1,5 Therefore, patients with multiple relapses of NHL represent a population in whom novel therapeutic approaches should be tested. The goals of such therapies should be twofold: to increase objective responses and to induce durable remissions.
The efficacy of anti-CD20 antibody therapy can be enhanced by the conjugation of the MAb with a beta-emitting radionuclide.9-11 Beta particle radiation can provide toxicity directly to the cell bound by the antibody and to neighboring tumor cells through cross-fire radiation. Cross-fire radiation can kill cells in the proximate environment that are not accessible to the MAb, that may not express CD20, and/or that may be resistant to the immune-mediated or direct apoptotic effects of the unlabeled antibody.12 Therapy with radioimmunoconjugates has had extensive clinical testing using murine anti-CD20 MAbs conjugated to either iodine-131 (iodine-131 tositumomab [BEXXAR; Corixa Corporation, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA]) or yttrium-90 (yttrium-90 ibritumomab tiuxetan [Zevalin; IDEC Pharmaceuticals, San Diego, CA]). Regimens employing one or the other radioimmunoconjugate have demonstrated therapeutic benefit for patients with low-grade and follicular lymphoma who had relapsed or whose disease became refractory following treatment with chemotherapy and/or immunotherapy.9-11,13-17
Tositumomab and iodine-131 tositumomab was introduced into clinical trials in 1990 for the treatment of relapsed or refractory low-grade and transformed low-grade NHL. Iodine-131 tositumomab provides for a dosimetric and a therapeutic dose. Details of the treatment regimen have been previously described.14,16,18
The current study evaluated iodine-131 tositumomab administered to 250 patients reported in five clinical trials in patients with relapsed and refractory low-grade, follicular, and transformed low-grade NHL.9,15-17,19,20 The demonstration that a significant subset of heavily pretreated patients with indolent lymphoma could achieve durable remissions with a single course of radioimmunotherapy prompted this report. Although the individual studies all demonstrate a subset of patients with durable responses, it is only in the pooling of these studies that the number of patients allows reasonably accurate long-term estimates and also allows the covariate analyses which are difficult to perform with limited data.
These patients also formed the accepted efficacy database that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration and thus also represent all of the iodine-131 tositumomab studies for whom the response and duration of response data have been independently reviewed by a blinded panel (see response criteria) and the US Food and Drug Administration. Preliminary results have been previously presented in abstract form.
PATIENTS AND METHODS
Patients
1990 to 2001, 250 patients with previously treated relapsed or refractory low-grade, follicular, or transformed low-grade NHL were enrolled in five clinical trials and received iodine-131 tositumomab. All patients provided written informed consent. Patients in these trials (Table 1) comprised the integrated efficacy (IE) population presented to the US Food and Drug Administration for product approval. Patients were at least 18 years old, and in four of the studies, had histologically confirmed diagnoses of CD20-positive low-grade NHL, according to the International Working Formulation A, B, or C,21 or low-grade NHL that had transformed to a higher-grade histology, including follicular large cell, diffuse large cell, or diffuse undifferentiated lymphoma.22 The fifth study, CP-97-012, allowed International Working Formulation D patients. All patients had previous treatment with at least one chemotherapy regimen. Generally, the previous chemotherapy regimens contained an anthracycline, an anthracenedione, or an alkylating agent, and the NHL had failed to respond to this treatment or had progressed following a response. Patients had to have an anticipated survival rates of more than 3 months, Karnofsky performance status of more than 60%, absolute granulocyte counts of more than 1,500 cells/mm3, platelet counts of more than 100,000/mm3, and serum creatinine levels of less than 1.5x the upper limit of normal (ULN), total bilirubin levels of less than 1.5x ULN, and AST less than 5x ULN.
All patients had bidimensionally measurable disease with at least one lesion 2 cm wide in 2 perpendicular diameters, as measured by computed tomography scans. Patients also had no more than 25% of their bone marrow occupied by NHL, as determined on a unilateral bone marrow biopsy (bilateral biopsies were performed if the unilateral biopsy had > 10% involvement). Involvement was defined by the percent of hematopoietic marrow space that was occupied by NHL and not by the percent of total cells that were involved. Patients were excluded if they had previously been treated with nonhuman antibodies or radioimmunotherapy. Other exclusion criteria were previous or current investigational drug use; cytotoxic therapy, radiation therapy, or immunosuppressive drugs within the 4 weeks preceding study entry (6 weeks for nitrosourea therapy); evidence of obstructive hydronephrosis; active infection requiring intravenous antibiotics; or class III or IV heart disease defined by the New York Heart Association criteria. Patients also were excluded from the study for disease progression within the last 1 year in a field previously irradiated with more than 0.35 Gy, a prior malignancy other than lymphoma (with the exception of cervical carcinoma-in-situ or adequately treated skin cancer) unless the patient had been disease-free for 5 years, and pregnancy. Patients defined as having refractory disease had to have been treated with at least two prior regimens, and to either have not responded to the most recent therapy or to have had response duration of 6 months.
Drug preparation, dosimetry, and administration of iodine-131 tositumomab has been previously described.15,16,18 Following the phase I/II study, the total body dose (TBD) of radiation was standardized to 0.75 Gy and was attenuated to 0.65 Gy for patients with a baseline platelet count of 100,000 to 150,000/mm3. For obese patients, dosage was based on 137% of lean body mass. To block uptake of iodine-131 by the thyroid gland, patients were treated with a saturated solution of potassium iodide, Lugol’s solution, or potassium iodide tablets beginning at least 24 hours before the dosimetric dose and continuing for 14 days after the therapeutic dose.
Initially, patients were hospitalized in isolation for the therapeutic dose until emission decreased to 5 mrem/h, which generally occurred within 3 to 4 days.16 Subsequent revision of the Nuclear Regulatory Commission guidelines allowed most patients to be treated as outpatients, discharged within 4 hours of receiving the therapeutic dose.
Response Criteria
Response was assessed by physical examination and computed tomography scans at weeks 7 and 13, every 3 months for 2 years, and then every 6 months until disease progression or death. A complete response (CR) was defined as complete disappearance of all disease-related physical or radiologic abnormalities and all signs and symptoms related to disease. A clinical CR (CCR) was characterized as a complete disappearance of all disease-related symptoms, but residual radiographic or palpable abnormality remained (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. Patients who had demonstrable lymphoma in baseline bone marrow were required to have a repeat biopsy to demonstrate the absence of lymphoma for a designation of CR or CCR. A partial response (PR) was defined as a 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, without the appearance of new lesions. Stable disease was defined as no decrease of more than 50% or no increase of more than 25% in the sum of the products of the longest perpendicular diameters of measurable lesions, and the absence of any detectible new lesions. Progressive disease was defined as a more than 25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions, or the appearance of new lesions measuring more than 2 cm in diameter by radiographic evaluation or more than 1 cm in diameter by physical examination. The notation of CR includes patients with a documented CCR or CR. All responses required confirmation by a repeat evaluation at least 4 weeks after the initial documentation. Review of each reported tumor response was performed by one of two independent review teams, each consisting of an oncologist and a radiologist who were not involved in the clinical trials, known as the MIRROR (Masked Independent Randomized Radiology and Oncology Review) panel. Members were blinded to investigator assessment.
The MIRROR panel reviews were conducted routinely for all patients in studies RIT-II-002, RIT-II-004, and CP-97-012, and for patients in studies RIT-I-000 and RIT-II-001 who had an investigator-assessed durable response (ie, progression-free survival of at least 12 months). Analyses of response rates were based on the MIRROR panel assessments. Investigators continued to follow patients using the above criteria. The investigator-assessed durations were used to supplement the MIRROR panel durations for all MIRROR panel-assessed responders who continued in response at their last MIRROR panel assessment.
Statistical Analysis
Integrated analyses (data cutoff, March 2004) were performed using data from patients with low-grade and transformed low-grade NHL from the phase I/II study and all patients receiving iodine-131 tositumomab in the other studies. All statistical tests of treatment and subgroup differences were two-sided and set with a significance level of .05. P values and CIs were presented without adjustment for multiple comparisons, multiple outcomes, or multiple looks. Duration of response was calculated from the date of first documented response. Progression-free survival (PFS) was calculated from the date of start of the treatment program. The end point for PFS was progression or death. Patients who had not progressed or died were censored at the time of their last assessment. Patients withdrawing from the study for reasons other than progression or death were censored at the time of withdrawal. Duration of response and PFS were analyzed according to Kaplan-Meier methodology. Exploratory univariate analyses of factors contributing to the overall response (OR) and CR rates used the 2 test with Yates’ correction for categories with two subgroups. The log-rank test was used for duration of response analyses. The following variables were included in the univariate analyses: sex, age, Ann Arbor stage, time from NHL diagnosis ( 4 years or > 4 years), tumor burden ( 500 or > 500 g), bulky disease (< 5 or 5 cm), disease transformation (yes or no), histology (follicular, other), lactate dehydrogenase (LDH) level, bone marrow involvement, prior radiotherapy, modified International Prognostic Index (IPI) score ( 2 or 3), number of prior chemotherapy regimens (1 to 3, 4), response to last chemotherapy, response to last rituximab, and TBD (< 0.75 or 0.75 Gy). Multivariate stepwise logistic regression and multivariate stepwise proportional hazard models included all variables identified as significant on univariate analysis.
RESULTS
Integrated Summary of Efficacy Population
Demographics for the 250 patients are listed in Table 2. Patients had been treated with a median of four prior therapies (range, one to 13), and 50% of patients did not respond to their last treatment regimen (chemotherapy or rituximab). Forty patients were from study CP-97-012, which evaluated response in rituximab relapsed/refractory patients. The rate of nonresponse to the last rituximab-containing regimen was 60% (24 of 40 patients). The other 210 patients in the integrated efficacy population did not receive rituximab. Response data were available for 208 of these 210 patients. The rate of nonresponse to last chemotherapy was 49% (101 of 208 patients).
For the entire population, the median follow-up time from the administration of the dosimetric dose was 41.5 months (range, 0.2 to 133.1 months). The OR and CR rates were 56% and 30%, respectively (Table 3). The response rates in each of the five clinical trials ranged from 47% to 68%. Complete response rates ranged from 20% to 38%. Parameters predictive of a lower OR rate, as assessed by univariate analyses, were older age, high tumor burden, bulky disease, transformed histology, nonfollicular histology, elevated LDH, increased IPI score, prior radiotherapy, prior anthracycline-containing regimen, no response to last chemotherapy, and TBD of radiation less than 0.75 Gy. Parameters predictive of a lower response that remained statistically significant in multivariate analyses included nonfollicular histology (odds ratio = 0.41; P = .009), elevated LDH (odds ratio = 0.40; P = .002), and prior radiotherapy (odds ratio = 0.39; P = .003). Parameters predictive of a lower frequency of CR as assessed by univariate analyses were older age, high tumor burden, bulky disease, nonfollicular histology, elevated LDH, increased IPI score, no response to last chemotherapy, and having been treated with less than 0.75 Gy TBD of radiation. In multivariate analyses, the predictors for failing to achieve a CR that remained significant included absence of response to last chemotherapy (odds ratio = 0.28; P < .001), elevated LDH (odds ratio = 0.34; P = .002), and bulky disease (odds ratio = 0.35; P = .009). Multivariate analysis of parameters associated with a shorter duration of response were elevated LDH (relative risk [RR] = 1.7; P = .003), patient age older than 65 years (RR = 1.6; P = .032), and no response to last chemotherapy (RR = 1.5; P = .018).
Progression-free survival for all patients is shown in Figure 1. There is no universally accepted definition of what constitutes a long-term durable response. However, there was a sharp decline in the proportion of patients without disease progression in the first year, and the slope of the PFS curve seems to change at about 1 year. At about that time, a subpopulation of patients emerged who seemed to have derived long-term benefit from treatment with iodine-131 tositumomab. That subpopulation of patients with durable responses was observed in each of the five studies, including in patients enrolled onto the initial phase I trial (RIT-I-000).
More specifically, 81 (32%) of 250 patients had a PFS of 1 year or longer, validated by the MIRROR panel. This is the group we have defined as having durable responses. However, 58 patients (23%) had a PFS of longer than 18 months and 53 patients (21%) actually had a PFS of 2 years. Beyond 2 years, the relapse rate was approximately 10% per person-year, or one relapse per 10 person-years. A durable response population was observed consistently within all five clinical trials (Fig 2) and was not unique to certain trials. Of note, 9% to 20% of the patients on each of the five clinical trials have not experienced diseased progression, with a median follow-up of 5.3 years. Overall, 17% of the original treated population is predicted to be alive and disease-free by Kaplan-Meier analysis at 5 years. The longest duration of response could obviously be noted in the original phase I/II clinical trial RIT-I-000, in which 38% of the patients had a PFS of longer than 1 year, with five patients remaining in remission between 8.0 years and 10.2 years. The differences in the response rates and relative percentages of durable responders in each of these trials probably reflects variations in the number of prior therapies administered and patients’ responses to their most recent therapy within each study.
Of the 81 durable responders, 62 patients (77%) had a CR by MIRROR panel assessments and 19 (23%) had a PR (Table 4). The median duration of OR was 45.8 months with a median follow-up of 61.2 months (range, 15.5 to 133.1 months). The median duration of response was not reached for those patients who achieved a CR. Forty-four percent remain in PFS ranging from 2.7 to 10.2 years (Fig 3A).
Table 5 compares the prognostic characteristics for the 81 patients in the durable response population (PFS of 12 months) with the 169 patients in the integrated efficacy population who had a PFS of less than 12 months. Patients in the durable response population had multiple poor prognostic characteristics: 43% had been treated with at least four prior therapies (12% had received only one prior therapy), 36% had not responded to their last treatment, and 64% had disease that was refractory (no response or duration of response < 6 months) to their last treatment regimen. Other poor prognostic characteristics included stage IV disease (63%), transformed disease (23%), bulky disease (49%), and an IPI score of 3 (24%). However, factors, such as the number of prior therapies ( four), refractory disease, elevated LDH, bulky disease, and high IPI score were observed less often in the durable response population than in patients in the integrated efficacy population.
In a subgroup analysis for the durable response population, the duration of response to iodine-131 tositumomab was compared with the duration of response to each patient’s last prior therapy. Of the 81 patients, 77 (95%) had a longer response (defined as 1 month) to iodine-131 tositumomab. Only two patients had a longer response to their last prior therapy. Two patients had equivalent response durations. In addition, the duration of response was not affected by whether patients had responded to the last regimen they received (Fig 3B).
DISCUSSION
Considering the incurability of low-grade NHL with standard low-dose or high-dose chemotherapy regimens, the evaluation of promising new therapies that might prolong remission and survival in this patient population is an important endeavor. Rituximab has had a major impact on the treatment of patients with indolent lymphoma. Treatment of heavily pretreated patient populations with four weekly doses of rituximab resulted in overall and complete response rates of 48% and 6%, respectively.23 These numbers will vary somewhat depending on the response criteria being utilized; however, the median time to progression was approximately 1 year and there was no evidence of a plateau on the time to progression curve.
The inherent radiosensitivity of NHL and the known efficacy of therapy with anti-CD20 antibodies make low-grade NHL ideally suited for the development of radioimmunotherapy regimens. CD20 is expressed in high density on more than 90% of B-cell NHL.24,25 It is expressed on pre-B and mature B cells, but not on early precursors, stem cells, or plasma cells.24,25 Furthermore, it is not shed and is minimally internalized on binding of the MAb,26 and it elicits antibody-dependent27 and complement-mediated cytotoxicity and apoptosis.28 The radionuclide iodine-131 can be covalently conjugated to the MAb without significant dehalogenation, and the energy and path-length are sufficient for significant cytotoxicity.
An integrated efficacy database of 250 patients with long-term follow-up, beginning from the time that clinical development of iodine-131 tositumomab began in 1990, is available for analysis. This is the same database that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration. The patients were heavily pretreated. Patients had been treated with a median of four prior chemotherapy or immunotherapy regimens (range, one to 13 regimens), and 50% of patients had not responded to their most recent treatment. Many had other poor prognostic characteristics, such as bulky and transformed disease and high IPI scores. Despite this, OR and CR rates of 56% and 30%, respectively, were achieved following a single therapeutic dose of iodine-131 tositumomab. The purpose of this article was not to focus on the toxicity and safety profiles of iodine-131 tositumomab, because they have been reported previously.9,15-17,19,20 Acute toxicities relate to generally well-tolerated myelosuppression and long-term toxicities have included human antimurine antibodies and hypothyroidism; by far, the most important toxicity is myelodysplasia, which has been recently analyzed in detail.29 The authors confirmed an annualized incidence of 1.1%/year of treatment-related myelodysplastic syndrome or treatment-related acute myeloid leukemia, which they concluded was consistent with that expected on the basis of the patients’ prior chemotherapy for NHL.
Although there is no universally accepted definition of what constitutes a long-term durable response, an analysis was undertaken of the subpopulation of patients who had a PFS of 1 year (32% of patients), because the slope of the PFS curve changed at about 1 year. Within this durable response population, 77% achieved a CR and 23% a PR. All but one patient who had a PR relapsed within 20 months, confirming that induction of a CR is key to attainment of a long-term durable response. The PFS for patients who had achieved a CR was not reached, with a median follow-up of 5.1 years (range, 1.3 to 11.1 years). Moreover, 53 patients (21%) actually had a PFS of 2 years and 17% of the original treated population is predicted to be alive and disease-free by Kaplan-Meier analysis at 5 years. No treatment modality, other than stem-cell transplantation, has been shown to offer such long-term durable responses in similar heavily pretreated patients.30,31
Recently, Wiseman and Witzig32 published a comparable analysis for the 211 patients treated with ibritumomab tiuxetin radioimmunotherapy. The potential differences in clinical activity between iodine-131–based and yttrium-90–based agents and/or the regimens used may have important therapeutic implications. The comparative efficacy and safety of iodine-131 tositumomab versus yttrium-90 ibritumomab tiuxetan, as well as a comparison of iodine-131 tositumomab versus rituximab, are planned for multicenter, randomized, comparative trials.
For the durable response population, the duration of response after treatment with iodine-131 tositumomab was longer in 77 patients (95%) compared with the duration of response after their last prior therapy. This denotes a reversal of the anticipated decrement in rate and duration of response expected with successive chemotherapy regimens used to treat patients with relapsed and refractory low-grade NHL.1,5
Durable responses obviate the need for repetitive cycles of chemotherapy and eliminate the associated toxicity from cytotoxic regimens, as well as the need for and cost of supportive care measures to ameliorate associated toxicities. In this study, iodine-131 tositumomab therapy for relapsed and refractory low-grade, follicular, and transformed low-grade NHL resulted in long-term durable responses and a significant clinical benefit for a subset of patients.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors 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 discription 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, in the conduct of the research reported in this article.
This original manuscript has not been previously published.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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