Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan

Authors

  • Thomas E. Witzig MD,

    Corresponding author
    1. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota
    • Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905
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    • Fax: (507) 266-9277

    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Arturo Molina MD, MS,

    1. Department of Global Medical Affairs, Biogen Idec, San Diego, California
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    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Leo I. Gordon MD,

    1. Department of Medicine, Division of Hematology/Oncology, Northwestern University, Chicago, Illinois
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  • Christos Emmanouilides MD,

    1. Division of Hematology/Oncology, University of California, Los Angeles, California
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  • Russell J. Schilder MD,

    1. Department of Medical Oncology, Fox Chase Comprehensive Cancer Center, Philadelphia, Pennsylvania
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    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Ian W. Flinn MD,

    1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland
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    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Mohamed Darif PhD,

    1. Department of Global Medical Affairs, Biogen Idec, San Diego, California
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    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Roger Macklis MD,

    1. Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio
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    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Katie Vo PharmD,

    1. Department of Global Medical Affairs, Biogen Idec, San Diego, California
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    • Drs. A. Molina, M. Darif, and K. Vo are employees of Biogen Idec. Dr. R.J. Schilder is a member of the speakers' bureau for Biogen Idec. Dr. I.W. Flinn has received grant support and Dr. R. Macklis has received honoraria and research support from Biogen Idec. Dr. T.E. Witzig has received grant support from Biogen and has participated on their advisory board

  • Gregory A. Wiseman MD

    1. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota
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  • Presented in part at the 2004 Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 3-7, 2004, Atlanta, Georgia.

Abstract

BACKGROUND.

Radioimmunotherapy with radiolabeled monoclonal antibodies to CD20 produces a high response rate in patients with recurring non-Hodgkin lymphoma (NHL), but the durability of those remissions is not well defined.

METHODS.

Data on patients with recurring NHL treated with yttrium Y 90 ibritumomab tiuxetan in 4 clinical trials were reviewed to identify patients with a long-term response, defined as a time to progression of 12 months or longer.

RESULTS.

Long-term responses were seen in 37% (78/211) of patients. At a median follow-up of 53.5 months (range, 12.7–88.9) the median duration of response was 28.1 months and the median time to progression was 29.3 months. A third of these patients had been treated with at least 3 previous therapies, and 37% of them had not responded to their last therapy. The findings in patients with follicular lymphoma (n = 59) were similar to those in the overall population of long-term responders. The estimated overall survival at 5 years was 53% for all patients treated with 90Y ibritumomab tiuxetan and 81% for long-term responders.

CONCLUSIONS.

A single dose of 90Y ibritumomab tiuxetan can produce durable responses and prolonged overall survival in a substantial number of patients in whom previous therapies have failed. Cancer 2007. © 2007 American Cancer Society.

Radioimmunotherapy (RIT) involves the use of monoclonal antibodies labeled with a radioactive nuclide for therapeutic intent. Two RIT agents have been approved by the US Food and Drug Administration for the treatment of recurring or refractory CD20+ non-Hodgkin lymphoma (NHL)—yttrium Y 90 ibritumomab tiuxetan (Biogen Idec, Cambridge, Mass) and iodine I 131 tositumomab (GlaxoSmithKline, Research Triangle Park, NC). Both agents target the B-cell CD20 antigen, which is present on more than 90% of B-cell NHL tumors.1 The chelation of the 90Y radionuclide results in the delivery of cytotoxic radiation to nearby cells in addition to those to which the antibody has bound.2 The β emissions of 90Y have a maximum energy of 2.3 MeV3, 4 and their mean path length in soft tissue is 5 mm (100–200 cell diameters). The ibritumomab tiuxetan regimen also includes the unlabeled antibody rituximab, which is given before the radiolabeled antibody to saturate CD20 binding sites on B cells in the peripheral blood and spleen and thereby improve the biodistribution of the radiolabeled antibody.5

The overall response (OR) rates in clinical trials of the ibritumomab tiuxetan regimen in patients with recurring or refractory NHL have been 73% to 83%.6–10 In 1 of these trials, a randomized study that compared the ibritumomab tiuxetan regimen with rituximab monotherapy, the OR and complete response (CR) rates were higher with the radioimmunoconjugate.6 The primary toxicity of the ibritumomab tiuxetan regimen is transient and reversible myelosuppression.11

Data from the 4 registration trials of the ibritumomab tiuxetan regimen show a high OR rate in patients with recurring or refractory B-cell NHL.7, 8, 12, 13 To determine the durability of these responses and to characterize the role of patient and disease factors in patients with a long-term response (LTR), we evaluated data on the patients in the 4 registration trials in whom the time to progression (TTP) after treatment with the ibritumomab tiuxetan regimen was 12 months or longer.

MATERIALS AND METHODS

Study Population

In all, 211 patients were treated in 4 clinical trials at 30 centers in the United States—a Phase I-II dose-finding trial in patients with indolent and aggressive NHL, a Phase II trial of reduced-dose 90Y ibritumomab tiuxetan in patients with mild thrombocytopenia, a randomized Phase III trial that compared the ibritumomab tiuxetan regimen with rituximab monotherapy, and a Phase III trial in patients with rituximab-refractory NHL. The eligibility criteria for these studies have been described.6, 8–10

Ibritumomab Tiuxetan Regimen

On Day 1 the patients were given an infusion of rituximab 250 mg/m2 followed within 4 hours by an intravenous injection of indium 111 ibritumomab tiuxetan 5 mCi for imaging. On Days 7, 8, or 9 they were given another infusion of rituximab 250 mg/m2 followed by an intravenous injection of 90Y ibritumomab tiuxetan given over 10 minutes. The dose of 90Y ibritumomab tiuxetan was 0.2 to 0.4 mCi/kg, to a maximum total dose of 32 mCi.

Efficacy and Safety Measures

The primary efficacy measures were CR, CR unconfirmed (CRu), partial response, TTP, and duration of response (DR). Both the protocol-defined criteria and the International Workshop Response Criteria were used to assess responses. A TTP of at least 12 months after treatment with 90Y ibritumomab tiuxetan was considered an LTR. The DR and TTP were determined in all patients with an LTR and in those with a CR/CRu; the DR in patients with an ongoing response was also calculated. All adverse events, along with other measures of safety, that occurred in the treatment period (from the first dose of rituximab to 12 weeks after the dose of 90Y ibritumomab tiuxetan) and in the initial follow-up period (up to 4 years after the start of treatment) were evaluated and have been reported.11 Information on disease progression and survival is collected every 6 months.

Statistical Analysis

Pretreatment characteristics and prognostic factors in the entire population, patients with LTR, and patients without LTR were described by using summary statistics from univariate analysis. Patient characteristics were compared between groups by using the Fisher exact 2-tailed test, with P < .05 considered significant. Time-to-event variables (DR, TTP, and overall survival) were analyzed by using the Kaplan-Meier method.14 Time to progression was calculated as the time from the first infusion of rituximab (Day 1) to the time of disease progression; DR was calculated as the time from the first observation of a response to the time of disease progression. A stepwise logistic regression model was used for an exploratory multivariate analysis of the effect of pretreatment factors on predicting the patients in whom there would be an LTR. In this stepwise selection a .10 significance level determined whether a factor entered into and remained in the model. The multivariate analysis model of the LTR outcome included CR/CRu status, sex, age (≤60 vs >60 years), number of previous therapies (<3 vs ≥3), histology type (follicular vs other), disease bulk (<5 vs ≥5 cm), bone marrow involvement (presence vs absence), splenomegaly (presence vs absence), hepatomegaly (presence vs absence), number of extra nodal sites (1 vs >1), and resistance to last chemotherapy (yes vs no). The odds ratios and their 95% confidence intervals (CIs) were estimated for the factors that were retained in the final model.

RESULTS

Patient Characteristics

Characteristics of the 211 patients in the 4 clinical trials are shown in Table 1. There were LTRs in 78 (37%) of 211 patients. The number and percentage of patients with an LTR differed by study—22 patients (43%) in the Phase I-II dose-finding trial,9 14 patients (47%) in the Phase II trial of reduced-dose 90Y ibritumomab tiuxetan,10 31 patients (42%) in the randomized Phase III trial,6 and 11 patients (19%) in the Phase II trial in rituximab-refractory NHL.8 The median age of these 78 patients was 58 years (range, 24–80), 44% were older than 60 years, and 55% were men (see Table 1). Most of them (76%) had follicular lymphoma, and 41% had marrow involvement. They had been treated with a median of 2 previous regimens (range, 1–7), with 59% having been treated with 2 or more and 33% having been treated with 3 or more. The disease appeared to be resistant to therapeutic intervention in a substantial number of patients, with 37% having not responded to their last therapy. There was bulky disease (≥5 cm) in 30% of the patients with an LTR and in 72% of these without an LTR (P < .001). Eighty-three percent of patients with an LTR had stage III or IV disease compared with 92% of patients without an LTR (P = .13). The median DR with the last therapy before 90Y ibritumomab tiuxetan in patients with an LTR was 12 months. The percentages of patients with bulky disease, with more than 2 previous therapies, and with disease that was resistant to their last therapy were lower in the patients with an LTR than in those without an LTR (all P < .01). There were LTRs in 59 (39%) of the 153 patients with follicular lymphoma, and the patient and disease characteristics in them were similar to those in the overall population of patients with LTRs (see Table 1).

Table 1. Patient Characteristics
CharacteristicAll patients N = 211Patients with long-term responsePatients without long-term response n = 133
All histologies n = 78Follicular lymphoma n = 59
  1. LDH indicates lactate dehydrogenase.

Age, y, median (range)58 (24–85)58 (24–80)59 (34–79)58 (29–85)
>60 years old44%44%48%44%
Men55%55%51%56%
Follicular lymphoma73%76%71%
Bone marrow involvement45%41%41%47%
No. of previous regimens, median (range)2 (1–9)2 (1–7)2 (1–7)2 (1–9)
≥2 previous regimens70%59%58%77%
≥3 previous regimens44%33%34%50%
No response to last therapy52%37%36%60%
Bulky disease (≥5 cm)56%30%31%72%
Stage III or IV disease89%83%86%92%
Elevated LDH level6.6%5.1%5.1%7.5%

The stepwise multivariate logistic regression analysis used to determine prognostic factors for an LTR showed that CR/CRu, nonbulky disease, and stage I or II disease at initial presentation were significant predictors (Table 2). The achievement of a CR/CRu was a strong positive predictor of an LTR, with an odds ratio of 7.0 (95% CI, 3.4–14.5). Bulky disease was a negative predictor of an LTR. Stage I or II NHL was a significant positive predictor of an LTR, but, because only 24 patients had stage I or II disease, it was considered a less important factor. Alternatively, older age (>60 years) and elevated lactate dehydrogenase (LDH) level, among other characteristics, did not significantly impact the likelihood of achieving an LTR with 90Y ibritumomab tiuxetan.

Table 2. Predictors of Long-Term Response in Multivariate Analysis
PredictorAdjusted odds ratio 95% confidence intervalP
Complete response (confirmed or unconfirmed)7.0 (3.4–14.5)<.001
Nonbulky disease (<5 cm)4.2 (2.2–8.6)<.001
Stage I or II disease at time of radioimmunotherapy4.1 (1.3–13.0).02

Durability of Responses in Patients With LTRs

At a median follow-up of 53.5 months (range, 12.7–88.9) the median DR in the 78 patients with an LTR was 28.1 months (range, 10.5–86.6+) and the median TTP was 29.3 months (range, 12.1–87.8+) (Table 3). In 29% of these patients the DR was at least 72 months (Fig. 1) and the TTP was at least 73 months.

Figure 1.

Duration of response in patients with long-term responses and in the intent-to-treat population. Information on duration of response was not available in 50 patients in the intent-to-treat population.

Table 3. Durations of Response in Patients With Long-Term Responses
 All histologies n = 78Follicular lymphoma n = 59
  • CR/Cru indicates complete response or complete response unconfirmed.

  • *

    There were ongoing responses at the time of analysis in 23 patients, 21 of whom had follicular non-Hodgkin lymphoma.

Duration of follow-up, median (range)49.8 m (12.7–88.9)54.9 m (12.7–88.9)
Patients with CR/CRu65%64%
Duration of response, median (range)
All patients28.1 m (10.5–86.6+)29.4 m (10.5–86.6+)
Patients with CR/CRu29.4 m (10.8–86.6+)29.8 m (11.2–86.6+)
Patients with ongoing responses*62.0 m (48–87+)60.3 m (48–87+)
Time to progression, median (range)
All patients29.3 m (12.1–87.8+)30.9 m (12.1–87.8+)
Patients with CR/CRu30.9 m (12.1–87.8+)31.1 m (12.1–87.8+)

Durability of Responses by Histology and Response to Previous Therapy

The DR, TTP, and CR/CRu rates in patients with follicular lymphoma in whom there were LTRs were similar to those in the overall population of patients with LTRs (see Table 3). The median TTP in patients who had responded to their last therapy was 26.1 months and in those who had not responded to their last therapy was 28.3 months (P = .98) (Fig. 2A). In addition, there were no significant differences in the median TTP among patients with LTRs on the basis of previous exposure to rituximab (P = .54), disease bulk (P = .69), CR/CRu status (P = .62), or disease histology (P = .12) (Fig. 2B–E). This suggests that, whereas some factors such as resistance to previous therapies, bulky disease, and achievement of a PR (instead of a CR) may indicate a lower probability of attaining a LTR, these factors do not compromise the durability of the responses to 90Y ibritumomab tiuxetan if indeed an LTR is achieved.

Figure 2.

Time to progression in patients with long-term responses, by patient and disease characteristics. (A) Response to last previous therapy (n = 75 [information on response to last therapy was not available in 3 patients]). (B) Previous exposure to rituximab. (C) Disease bulk before treatment. (D) Response status. (E) Disease histology.

Overall Survival

Median overall survival in all 211 patients was 49.3 months. Overall survival was 52 months or longer in 82% of the patients with LTRs (Figure 3), and median survival has not been reached. In contrast, median overall survival in patients without an LTR was 34.6 months. The estimated 5-year overall survival was 53.0% for all patients and 80.6% for patients with LTRs.

Figure 3.

Overall survival in 78 patients with long-term responses.

Durability of Responses in Patients With CR/CRu and Ongoing Responses

There was a CR/CRu in 51 (65%) of the 78 patients with LTRs. The median DR in these patients was 29.4 months (range, 10.8–86.6+), and the median TTP was 30.9 months (range, 12.1–87.8+) (see Table 3). At the time of this analysis, the disease had not experienced recurrence in 23 patients, 21 of whom had follicular lymphoma. The median DR in these 23 patients was 62 months (range, 48–87+) (see Table 3).

DISCUSSION

Treating recurring or refractory NHL with a single dose of RIT in an outpatient setting produces a high OR rate of approximately 80%. In this long-term follow-up study in 211 patients treated with 90Y ibritumomab tiuxetan in registration trials there was a TTP of 12 months or longer in 37% of patients. Predicting the patients in whom RIT will produce an LTR is difficult. For example, the patients in this study in whom there were LTRs had been treated with a median of 2 previous therapies, and more than 80% of them had stage III or IV disease. Close to half of them were older than 60 years, a third of them had been treated with 3 or more previous therapies, and more than a third of them had not responded to their last therapy. The only pretreatment characteristics that predicted an LTR with RIT were nonbulky disease (<5 cm) and stage I or II disease.

Whether the patient had responded to his or her last previous therapy had no effect on the likelihood of an LTR with the ibritumomab tiuxetan regimen, nor did patient age or the number of previous therapies. It is important to note that the best predictor of an LTR to RIT was a CR/CRu. These findings are comparable to those in a recent report by Fisher et al.15 who reviewed data on 250 patients with recurring or refractory low-grade or transformed NHL who had been treated with a single dose of 131I tositumomab. The OR in these 250 patients was 56% (CR rate of 30%), with a median DR of 12.9 months (range, 10.6–17.3). In that report LTRs were referred to as durable responses (also defined as a TTP ≥12 months) and were achieved in 81 (32%) of 250 patients, comparable to the LTR rate of 37% in our study. They also found that the patients with a durable response were more likely to have had a CR (77% vs 8%, respectively) and low-bulk disease (51% vs 31%, respectively) than those without a durable response. Other characteristics that were predictive of a durable response with 131I tositumomab treatment were sensitivity to the last therapy, history of <3 previous therapies, follicular histology, normal LDH level, and modified International Prognostic Index (IPI) score ≤2. In a study of 131I tositumomab in patients with previously untreated follicular NHL by Kaminski et al.16 the only patients with extended remissions were those who had a CR.

These findings are important for the design of future trials. Patients with bulky NHL may benefit from tumor debulking before treatment with RIT, and patients who have a response but have residual disease may benefit from additional treatment aimed at converting a partial response to a CR. In the trials that are analyzed in this report, neither treatment before the RIT nor after the RIT to convert a partial response to a CR was permitted. It is now time to build on the very high response rates and excellent safety profile with single-agent RIT by incorporating other treatments along with functional imaging, such as positron emission tomography, into clinical practice, with the goal of producing CRs. This approach would be expected to produce very long responses in a higher percentage of patients than in this analysis. Indeed, several ongoing studies are evaluating the safety and efficacy of frontline treatment with RIT in combination with other therapies.

Shipley et al.17 reported that the ibritumomab tiuxetan regimen is active and well tolerated as frontline consolidation therapy for follicular NHL, and Emmanouilides et al.18 reported higher response rates and more durable responses with the ibritumomab tiuxetan regimen when it is used earlier in the course of treatment. In a small study in patients with low-grade follicular lymphoma, frontline therapy with 90Y ibritumomab tiuxetan followed by rituximab maintenance therapy produced responses in all 8 patients.19 External beam radiation has been shown to be effective in treating sites that recur after RIT.20 Whether treating bulky tumor sites with external beam radiation before or after RIT can increase the response rates or the duration of response remains to be studied.

This study also shows the excellent overall survival in this population of patients with LTRs (see Fig. 3). It has been shown that chemotherapy, transplantation,21, 22 and retreatment with RIT23 can all be effective in patients in whom there is recurrence after RIT. Radioimmunotherapy is clearly an effective therapy that should be used early in patients with recurring disease rather than only after all other options have been expended.

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