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Originally published as JCO Early Release 10.1200/JCO.2006.09.2882 on August 20 2007 © 2007 American Society of Clinical Oncology. Treatment-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Patients Treated With Ibritumomab Tiuxetan Radioimmunotherapy
From the Roswell Park Cancer Institute, Buffalo, NY; University of California, Los Angeles; Biogen Idec, San Diego, CA; Mayo Clinic, Rochester, MN; and Northwestern University, Chicago, IL Address reprint requests to Myron S. Czuczman, MD, Roswell Park Cancer Institute, Elm & Carlton St, Buffalo, NY 14263; e-mail: Myron.Czuczman{at}RoswellPark.org
Purpose To investigate the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after treatment with ibritumomab tiuxetan radioimmunotherapy. Patients and Methods Analysis of the incidence of t-MDS and t-AML in 746 patients with non-Hodgkin's lymphoma (NHL) treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Results Nineteen patients (2.5%) developed t-MDS or t-AML at a median follow-up of 4.4 years (range, 0 to 9.3). These malignancies were diagnosed at a median of 5.6 years (range, 1.4 to 13.9) after the diagnosis of NHL and 1.9 years (range, 0.4 to 6.3) after radioimmunotherapy. The annualized rates were 0.3% per year after the diagnosis of NHL and 0.7% per year after treatment. Most patients with t-MDS or t-AML had multiple cytogenetic aberrations, commonly on chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. Conclusion Analysis of data from patients in registration and compassionate-use trials suggests that the annualized incidences of t-MDS and t-AML are consistent with that expected in patients with NHL who have had extensive previous chemotherapy treatment and do not appear to be increased after treatment with the ibritumomab tiuxetan regimen. Cytogenetic testing before treatment with radioimmunotherapy may identify existing chromosomal abnormalities in previously treated patients, particularly those who have been treated with alkylating agents and purine nucleoside analogs and would be at higher risk for t-MDS or t-AML.
Conventional therapies for disseminated indolent non-Hodgkin's lymphoma (NHL), with the possible exception of rituximab monotherapy, are associated with a risk of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML).1,2 It has been estimated that 10% to 30% of all cases of AML are secondary to therapeutic interventions.3 This association is of special concern because patients with t-MDS or t-AML generally respond poorly to treatment and median survival after diagnosis is shorter than 1 year.4,5 The clinical and cytogenetic presentation of t-MDS or t-AML is distinct from that of cases with no relation to treatment.1 Complex karyotypes are observed in a high percentage of patients, including abnormalities that involve chromosome 5 or 7, recurring balanced rearrangements, and other clonal abnormalities.6-8 Secondary MDS or AML typically occur after extensive exposure to alkylating agents, and it has also been reported after treatment with fludarabine and anthracyclines.9-13 Cytogenetic abnormalities that are associated with DNA-damaging agents and treatment-related myeloid leukemias can occur after treatment with fludarabine-based regimens, but the risk of t-MDS or t-AML appears to be greater in patients treated with a combination of alkylating agents and purine nucleoside analogs than in those treated with purine nucleoside analogs alone.9,10,14,15 The crude incidence of t-MDS and t-AML has been reported to range from 0% to 12% with conventional-dose chemotherapy or radiotherapy, and the actuarial incidence may reach as high as 17% at 15 years after diagnosis of the primary malignancy.11,16-22 Armitage and colleagues1 reviewed the literature and found a crude incidence of between 0% and 12% across studies in patients with NHL who were treated with high-dose chemotherapy with autologous stem-cell transplantation. They suggest that 5 to 10 years after transplantation the cumulative incidence is likely to be 5% to 10%. The annualized incidence of t-MDS and t-AML after long-term treatment with alkylating agents has been estimated to be 1% to 1.5% per year between 2 years and 9 years after the initiation of chemotherapy.11
Radioimmunotherapy with yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin; Biogen Idec, Cambridge, MA) is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory NHL.23 Ibritumomab tiuxetan consists of a murine immunoglobulin-1 The purpose of this study was to determine the risk of t-MDS or t-AML after treatment with the ibritumomab tiuxetan regimen in patients in registration and compassionate-use trials. Possible risk factors and chromosomal abnormalities were also evaluated to clarify any possible relation between the occurrence of t-MDS or t-AML and treatment with the ibritumomab tiuxetan regimen.
In this integrated analysis, we evaluated data from 746 patients who were treated with 90Y ibritumomab tiuxetan in four registration trials and a compassionate-use study that were conducted between 1996 and 2002. The registration trials were a dose-finding phase I-II trial in patients with indolent and aggressive NHL,25,29 a phase II trial of reduced-dose 90Y ibritumomab tiuxetan in patients with mild thrombocytopenia,27 a randomized phase III trial that compared the ibritumomab tiuxetan regimen with rituximab,28 and a single-arm trial in patients with rituximab-refractory NHL.26 Patients were eligible for the registration trials if they had histologically confirmed, bidimensionally measurable relapsed or refractory CD20-positive B-cell NHL. The following characteristics were also required: age  18 years, bone marrow involvement less than 25%, acceptable hematologic status (absolute neutrophil count > 1.5 x 109/L; platelet count 100 x 109/L to 149 x 109/L [trial in patients with mild thrombocytopenia] or 150 x 109/L), acceptable hepatic and renal function (serum creatinine level  176 µmol/L [20 mg/L] and total bilirubin level 34 µmol/L [20 mg/L]), expected survival of at least 3 months, and WHO performance status of 0, 1, or 2. The exclusion criteria included previous myeloablative therapy, irradiation of more than 25% of the active marrow, and hypocellular bone marrow ( 15% cellularity or marked reduction in bone marrow precursors). There was no limitation on the number of previous therapies or number of relapses. The same eligibility criteria were used in the compassionate-use study (N = 535), but some exemptions to the criteria were made on a case by case basis. The studies were sponsored by Biogen Idec (San Diego, CA) and were approved by the institutional review boards of the study sites. All patients were required to provide written informed consent in accordance with the Declaration of Helsinki.
Ibritumomab Tiuxetan Treatment
Reporting of t-MDS and t-AML
Statistical Analysis Univariate analyses were performed by using the Fisher's exact test to assess the association of t-MDS and t-AML with pretreatment characteristics listed in Table 1. Exploratory multivariate analyses of the effects of pretreatment factors on the time to t-MDS or t-AML were made by using a stepwise Cox regression model.33 The stepwise selection used a .15 significance level for a factor to enter into the model and .05 for it to remain in the model. The selection was made by using data from all the studies and from the registration trials only.
Patient Characteristics Pretreatment characteristics of the patients in the registration and compassionate-use trials are presented in Table 2. Patients had several NHL histologies: follicular (66%), small lymphocytic (9%), transformed (16%), and other or unknown (9%). They had been treated with several previous therapies (median of three; four in 42% of patients). Their treatment history included a variety of antilymphoma therapies, with rituximab, anthracyclines and anthracenediones, alkylating agent–based regimens, and purine nucleoside analogs being the most common. The pretreatment characteristics of the patients in the registration trials and in the compassionate-use trial were generally similar. Advanced disease was more common in the patients in the registration trials than in those in the compassionate-use trial, and previous treatment with rituximab was more common in the patients in the compassionate-use trial, which is likely related to the fact that only one of the registration trials was in patients with rituximab-refractory disease.
Incidence of t-MDS and t-AML in the Registration and Compassionate-Use Trials At a median follow-up of 4.4 years (range, 0 to 9.3 years), 19 cases of t-MDS or t-AML had been reported. The crude incidence was 2.5% across all trials (Table 3) and ranged from 1.5% to 6.7% in the individual trials. The median time from the diagnosis of NHL to the diagnosis of MDS or AML was 5.6 years (range, 1.4 to 13.9 years), and the median time from treatment with the ibritumomab tiuxetan regimen to the diagnosis of MDS or AML was 1.9 years (range, 0.4 to 6.3 years). The annualized rates of MDS and AML were 0.3% (95% CI, 0.2% to 0.4%) per year after the diagnosis of NHL and 0.7% (95% CI, 0.4% to 0.9%) per year after treatment with the ibritumomab tiuxetan regimen (Table 3).
Demographics and disease characteristics in the 19 patients in the registration and compassionate-use trials in whom t-MDS or t-AML developed and in the 727 in whom it did not develop are presented in Table 1. There were two statistically significant differences in risk factors between patients with and without t-MDS or t-AML: follicular histology (90% v 66%; P = .046) and previous treatment with a purine nucleoside analog (53% v 29%; P = .038). Fludarabine was used as the purine nucleoside analog treatment in all 10 patients with t-MDS or t-AML who had received prior therapy with a purine nucleoside analog. Cox multivariate regression analysis found that previous treatment with a purine nucleoside analog was a significant risk factor for t-MDS or t-AML (hazard ratio, 3.5; 95% CI, 1.4 to 8.8; P = .006) adjusting for bone marrow involvement that was also significant. The cumulative incidence of t-MDS and t-AML after treatment with the ibritumomab tiuxetan regimen in all patients and in the patients in registration trials is shown in Figure 1. The cumulative incidences at 2 and 5 years were 1.9% and 4.3%, respectively, in the patients in the registration trials and 1.4% and 2.5%, respectively, in all patients (Table 4).
Patients with t-MDS or t-AML in whom cytogenetic analysis was performed had complex karyotypes with several chromosomal abnormalities (Table 5).9,34 The specimens from 13 of 19 patients in whom cytogenetic data were available had abnormalities on chromosome 5, chromosome 7, or both. All 17 patients with t-MDS or t-AML in whom treatment history was available had been treated with alkylating agent–based regimens or fludarabine, 12 had been treated with cyclophosphamide, doxorubicin, vincristine, and prednisone or cyclophosphamide, vincristine, and prednisone, and 10 had been treated with fludarabine.
Radioimmunotherapy is beginning to play a more prominent role in the treatment of NHL, even as treatment patterns shift from nonspecific cytotoxic agents to targeted cell-specific agents.35 There is growing evidence of greater benefits with the earlier use of 90Y ibritumomab tiuxetan, including its use after first relapse, which results in higher response rates and longer durations of response.36 Studies have shown that 90Y ibritumomab tiuxetan has promising activity when it is used as first-line therapy, either in combination with short-course chemotherapy37 or as a single-agent followed by rituximab maintenance therapy.38 The efficacy of 90Y ibritumomab tiuxetan in the treatment of aggressive lymphomas, such as mantle-cell lymphoma, is also being investigated.39 With this increasing and earlier use of radioimmunotherapy, it is important to know what risks are associated with this therapy, including the risk of developing t-MDS and t-AML. The crude incidence of secondary MDS and AML in five studies of 90Y ibritumomab tiuxetan was 2.5%, which falls in the incidence range of 0% to 12% that has been reported with conventional-dose chemotherapy and radiotherapy.11,16-22 The annualized rate, 0.7% per year, is within the annualized rate of 1.0% to 1.5% reported after long-term treatment with alkylating agents.11 In our study, the crude incidence (5.2% v 1.5%) and the annualized incidence (1.0% per year v 0.4% per year) were higher in the registration trials than in the compassionate-use trial. This may be due to different reporting methods in the two types of trials because reporting of adverse events was less strictly controlled in the compassionate-use trial. Alternatively, the difference may be due to differences in the patient populations or to differences in the lengths of follow-up. However, it is important to note that even the higher rate seen in the registration trials is within the range reported for conventional-dose chemotherapy and radiotherapy,11,16-22 and high-dose chemotherapy with autologous stem-cell transplantation.1 Consistent with the findings in our study, a masked independent review of specimens of bone marrow and peripheral blood from 985 patients with relapsed or refractory lymphoma treated with iodine 131 (131I) tositumomab found that the crude and annualized incidences of t-MDS and t-AML were 2.3% and 1.1% (Table 4), respectively.34 The median follow-up in these patients, who had extensive previous treatment (median of three cytotoxic regimens), was relatively short at 2.0 years. However, at a median follow-up of 5.1 years there were no reports of secondary leukemia with 131I tositumomab in the 76 treatment-naive patients,40 suggesting that t-MDS and t-AML resulted from previous treatments and not from radioimmunotherapy. A potential risk factor for developing t-MDS or t-AML after treatment with 90Y ibritumomab tiuxetan was prior exposure to nucleoside purine analogs. A significantly higher percentage of patients with t-MDS or t-AML had previously received purine nucleoside analog–containing regimens compared with patients in whom these secondary malignancies did not develop (59% v 29%; P = .013) and multivariate regression analysis indicated that previous exposure to a purine nucleoside analog was a significant risk factor for t-MDS and t-AML (P = .006). Indeed the crude rate seen in our study is in the range of that reported in a recent prospective trial in 202 patients with stage IV indolent lymphoma in which eight cases of MDS that occurred at 2 to 5 years after treatment with fludarabine, mitoxantrone, and dexamethasone (FND) with or without rituximab were reported (Table 4).9 The only treatment that had been used in four of these eight patients was six to eight cycles of FND with or without rituximab; the four other patients had been treated with other agents, including alkylating agents, either as their first regimen or as part of salvage therapy. All eight of these cases were characterized by complex cytogenetic abnormalities, including aberrations of chromosome 7 in six of eight patients, three of whom had been treated with only FND plus rituximab. Conversely, a large study of patients (n = 2,014) with chronic lymphocytic leukemia or hairy cell leukemia who were treated with nucleoside analogs found a very low crude incidences of MDS and leukemia (0.06% and 0.22%), suggesting that nucleoside treatment is not associated with these secondary malignancies.41 In our study, of those who received nucleoside analogs, 5% developed t-MDS or t-AML. It is possible that the increased risk seen with nucleoside therapy is impacted by other factors such as previous or concomitant chemotherapeutics.9,10,14,15 Given the fact that a study of 131I tositumomab in patients with NHL also found an association between previous fludarabine therapy and the incidence of t-MDS and t-AML (relative risk, 3.08; P = .011),34 further investigation of this relationship is warranted. In our study, all patients in whom t-MDS or t-AML developed and in whom cytogenetic data were available had significant chromosomal abnormalities, nearly all with at least two deletions, rearrangements, duplications, or other clonal abnormalities each. The most frequent cytogenetic changes involved chromosomes 5 and 7, which have been associated with previous chemotherapy or radiotherapy in as many as 76% to 90% of cases.6,7 Complete or partial deletions of chromosome 5 or 7 are particularly common in patients with t-MDS or t-AML who have been treated with alkylating agents, although such deletions have also been observed after treatment with FND.4,9 There was no clear pattern of chromosomal abnormality among the 10 patients in our trial who were treated with previous fludarabine therapy and who developed t-MDS or t-AML that distinguished them from the remaining nine patients who developed t-MDS or t-AML but who had not been treated with fludarabine. Because all of the patients in whom t-MDS or t-AML developed after the administration of the ibritumomab tiuxetan regimen had been previously treated with agents that are associated with t-MDS and t-AML, it is possible that these abnormalities are the result of cumulative damage rather than of damage that was solely because of the ibritumomab tiuxetan regimen. This is supported by the extent and type of cytogenetic morphologic changes in the patients in whom t-MDS or t-AML developed and their similarity to the findings in previous analyses. An early case study of ibritumomab tiuxetan in an 80-year-old patient, however, suggested a possible relation between secondary AML with 11q23 abnormality and treatment with radioimmunotherapy, and highlighted the need for further investigation.42 On the basis of this observation, many subsequent clinical trials of the ibritumomab tiuxetan regimen were amended to require pretreatment cytogenetic studies in bone marrow specimens. Nonetheless, the currently available data do not suggest a direct association between treatment with the ibritumomab tiuxetan regimen and a higher incidence of secondary MDS and AML. The incidences of t-MDS and t-AML are similar to those expected on the basis of the patient's history of treatment for NHL. Longer follow-up, however, is necessary to further support this observation.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Mohamed Darif, Biogen Idec; Stephen Revell, Biogen Idec; Katie Vo, Biogen Idec; Arturo Molina, Biogen Idec Leadership: N/A Consultant: Myron S. Czuczman, Biogen Idec Stock: Mohamed Darif, Biogen Idec; Stephen Revell, Biogen Idec; Katie Vo, Biogen Idec; Arturo Molina, Biogen Idec Honoraria: Myron S. Czuczman, Biogen Idec; Leo I. Gordon, Sherring AG, Genentech, Pharmocyclics Research Funds: Myron S. Czuczman, Biogen Idec; Christos Emmanouilides, IDEC; Thomas E. Witzig, Biogen Idec; Leo I. Gordon, Pharmocyclics, Biogen Idec Testimony: N/A Other: N/A
Conception and design: Myron S. Czuczman, Christos Emmanouilides, Leo I. Gordon, Arturo Molina Financial support: Arturo Molina Provision of study materials or patients: Myron S. Czuczman, Christos Emmanouilides, Thomas E. Witzig Collection and assembly of data: Myron S. Czuczman, Christos Emmanouilides, Stephen Revell, Arturo Molina Data analysis and interpretation: Myron S. Czuczman, Mohamed Darif, Leo I. Gordon, Stephen Revell, Katie Vo, Arturo Molina Manuscript writing: Myron S. Czuczman, Mohamed Darif, Thomas E. Witzig, Stephen Revell, Katie Vo, Arturo Molina Final approval of manuscript: Myron S. Czuczman, Christos Emmanouilides, Mohamed Darif, Thomas E. Witzig, Leo I. Gordon, Stephen Revell, Katie Vo, Arturo Molina
published online ahead of print at www.jco.org on August 20, 2007. Presented in part in poster format at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002; and abstract format at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Sweetenham JW, Dicke K, Arcaroli J, et al: Efficacy and safety of yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin) therapy with rituximab maintenance in patients with untreated low-grade follicular lymphoma. Blood 104:720a, 2004 (abstr 2633) 39. Younes A, Pro B, Rodriguez MA, et al: Activity of yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin) in 22 patients with relapsed and refractory mantle cell lymphoma (MCL). Blood 106:689a-690a, 2005 (abstr 2452) 40. Kaminski MS, Tuck M, Estes J, et al: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441-449, 2005 41. Cheson BD, Vena DA, Barrett J, et al: Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 17:2454-2460, 1999 42. Nabhan C, Peterson LA, Kent SA, et al: Secondary acute myelogenous leukemia with MLL gene rearrangement following radioimmunotherapy (RAIT) for non-Hodgkin's lymphoma. Leuk Lymphoma 43:2145-2149, 2002[CrossRef][Medline] Submitted December 29, 2006; accepted June 20, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
monoclonal antibody to CD20, ibritumomab, covalently linked to tiuxetan, which chelates indium-111 for imaging and 90Y for therapy. 90Y ibritumomab tiuxetan is well tolerated,
