|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.00.9217 on September 26 2005 © 2005 American Society of Clinical Oncology. Tositumomab and Iodine-131 Tositumomab Produces Durable Complete Remissions in a Subset of Heavily Pretreated Patients With Low-Grade and Transformed Non-Hodgkin’s LymphomasFrom 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 Address reprint requests to Richard I. Fisher, MD, University of Rochester School of Medicine, James P. Wilmot Cancer Center, 601 Elmwood Ave, Box 704, Rochester, NY 14642; e-mail: richard_fisher{at}urmc.rochester.edu
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 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.
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 From 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
Response Criteria 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 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).
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 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.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
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.
1. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986 2. Fisher RI: Overview of non-Hodgkin’s lymphoma: Biology, staging, and treatment. Semin Oncol 30:3-9, 2003[Medline] 3. Horning SJ: Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol 20:75-88, 1993[Medline] 4. Fisher R, LeBlanc M, Press OW, et al: New treatment options have changed the natural history of follicular lymphoma. Blood 104:168a, 2004 (abstr 168)
5. Johnson PW, Rohatiner AZ, Whelan JS, et al: Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13:140-147, 1995
6. Bierman PJ, Vose JM, Anderson JR, et al: High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin’s lymphoma. J Clin Oncol 15:445-450, 1997 7. Acker B, Hoppe RT, Colby TV, et al: Histologic conversion in the non-Hodgkin’s lymphomas. J Clin Oncol 1:11-16, 1983[Abstract] 8. Bastion Y, Sebban C, Berger F, et al: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15:1587-1594, 1997[Abstract]
9. Davis TA, Kaminski MS, Leonard JP, et al: The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin Cancer Res 10:7792-7798, 2004
10. Witzig TE, Flinn IW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262-3269, 2002
11. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20:2453-2463, 2002
12. Nourigat C, Badger CC, Bernstein ID: Treatment of lymphoma with radiolabeled antibody: Elimination of tumor cells lacking target antigen. J Natl Cancer Inst 82:47-50, 1990
13. Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma with [131 I] anti-B1 (Anti-CD20) antibody. N Engl J Med 329:459-465, 1993
14. Kaminski MS, Zasadny KR, Francis IR, et al: Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 14:1974-1981, 1996
15. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 19:3918-3928, 2001
16. Vose JM, Wahl RL, Saleh M, et al: Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 18:1316-1323, 2000
17. Horning SJ, Younes A, Jain V, et al: Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 23:712-719, 2005 18. Wahl RL, Kroll S, Zasadny KR: Patient-specific whole-body dosimetry: Principles and a simplified method for clinical implementation. J Nucl Med 39:14S-20S, 1998
19. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with iodine I31 tositumomab for relapsed or refractory B-cell non-Hodgkin’s lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000
20. Davies AJ, Rohatiner AZ, Howell S, et al: Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 22:1469-1479, 2004 21. The Non-Hodgkin’s Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135, 1982[CrossRef][Medline] 22. Zelenetz AD, Saleh M, Vose J, et al: Patients with transformed low grade lymphoma attain durable responses following outpatient radioimmunotherapy with tositumomab and iodine I 131 tositumomab (Bexxar). Blood 100:357a, 2002 (abstr 1384) 23. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract] 24. Stashenko P, Nadler LM, Hardy R, et al: Characterization of a human B lymphocyte-specific antigen. J Immunol 125:1678-1685, 1980[Abstract]
25. Anderson KC, Bates MP, Slaughenhoupt BL, et al: Expression of human B cell-associated antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 63:1424-1433, 1984
26. Press OW, Howell-Clark J, Anderson S, et al: Retention of B-cell-specific monoclonal antibodies by human lymphoma cells. Blood 83:1390-1397, 1994 27. Tedder TF, Forsgren A, Boyd AW, et al: Antibodies reactive with the B1 molecule inhibit cell cycle progression but not activation of human B lymphocytes. Eur J Immunol 16:881-887, 1986[Medline]
28. Shan D, Ledbetter JA, Press OW: Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91:1644-1652, 1998
29. Bennett JM, Kaminski MS, Leonard JP, et al: Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab. Blood 105:4576-4582, 2005
30. Schouten HC, Bierman PJ, Vaughan WP, et al: Autologous bone marrow transplantation in follicular non-Hodgkin’s lymphoma before and after histologic transformation. Blood 74:2579-2584, 1989
31. Freedman AS, Ritz J, Neuberg D, et al: Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin’s lymphoma. Blood 77:2524-2529, 1991 32. Wiseman GA, Witzig TE: Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-Cell non-Hodgkin’s lymphoma. Cancer Biother Radiopharm 20:185-188, 2005[CrossRef][Medline] Submitted January 6, 2005; accepted July 5, 2005. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
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 (
