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Journal of Clinical Oncology, Vol 26, No 27 (September 20), 2008: pp. 4518-4519 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.8177
Non-Hodgkin's Lymphoma in Patients With Glioma Treated With TemozolomideUniversitair Ziekenhuis Brussel, Brussels, Belgium
Ospedale Regionale Umberto Parini, Aosta, Italy
ZiekenhuisNetwerk Antwerpen Middelheim, Antwerp, Belgium
University of Virginia, Charlottesville, VA To the Editor: Temozolomide (Temodal; Schering-Plough Labo NV, Heist-op-den-Berg, Belgium) is a DNA-alkylating drug that is registered for the treatment of patients with newly diagnosed glioblastoma and recurrent gliomas.1 Sensitivity to temozolomide is correlated with the hypermethylation of the O6-alkylguanine-DNA-alkyltransferase promoter in glioma cells (which leads to an absence of the AGAT DNA repair protein that repairs the O6-methylguanine adduct created by temozolomide).2 Temozolomide is most often prescribed as a 5 of 28 days regimen at a dose of 150 to 200 mg/m2 every 28 days. Alternatively, temozolomide can be administered by extended daily dosing, resulting in an up to 210% higher dose density over a period of 28 days (eg, 7 of 14 days at a dose of 150 mg/m2, 21 of 28 days at a dose of 100 mg/m2, or 6 of 8 weeks at a dose of 75 mg/m2).3-5 Such regimens more profoundly deplete AGAT activity in peripheral blood mononuclear cells and may improve the antitumor activity.6 Daily dosing for 6 weeks during radiation therapy has become part of standard care for newly diagnosed glioblastoma, and the 21 of 28 days regimen is under study in two large randomized phase III trials for newly diagnosed low-grade glioma (European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada protocol 22033-26033) and glioblastoma (Radiation Therapy Oncology Group/ European Organisation for Research and Treatment of Cancer protocol 26052-22053). The 5 of 28 days temozolomide regimen has remarkable low acute toxicity (< 10% thrombocytopenia and neutropenia), no cumulative toxicity, and has not been associated with an increased incidence of secondary malignancies, such as treatment-related myelodysplastic syndrome or acute leukemia7,8 or cases of aplastic anemia.9,10 The short life expectancy of patients with glioblastoma and recurrent gliomas might, however, have obscured observations of such delayed adverse effects that have a peak incidence between 5 and 10 years after exposure to the mutagenic alkylating chemotherapy. In contrast to the 5 of 28 days regimen, extended dose-dense regimens have been associated with a high incidence (50% to 100%) of treatment-related lymphopenia in a number of phase II trials, resulting in a state of immunosuppression with an increased incidence of opportunistic infections and possibly also immunosuppression-related neoplasms, such as Kaposi's sarcoma.11,12 During the past year we have become aware of three patients with glioma treated with temozolomide who subsequently developed a malignant lymphoma. The first case concerns a 53-year-old Italian woman with a 10-year history of low-grade oligodendroglioma diagnosed in 1998. After the initial diagnosis, she was treated with three cycles of procarbazine, lomustine, and vincristine. After the patient experienced disease progression in January 2006, a second surgery was performed, and the diagnosis of transformation to an anaplastic oligodendroglioma was established. She was treated with one cycle of neoadjuvant temozolomide (5 of 28 days at a dose of 150 mg/m2) followed by radiotherapy (54 Gy) with concomitant temozolomide (75 mg/m2/d x 42 days) and five cycles of adjuvant temozolomide (5 of 28 days at a dose of 150 mg/m2). Seven months after the end of temozolomide therapy, she was diagnosed with a diffuse large B-cell lymphoma of the neck. The patient was treated with cyclophosphamide, doxorubicin, vincristine, and prednisone. Both her diffuse large B-cell lymphoma and glioma were in remission in January 2008. The second case concerns a Belgian male patient who, in 1998 at the age of 48 years, was diagnosed with a low-grade oligoastrocytoma that could be partially resected. In September 2003, transformation to an anaplastic oligoastrocytoma was diagnosed, for which he underwent radiation therapy (60 Gy). In April 2005, a first recurrence was treated with 5 of 28 days temozolomide. Because of progressive disease, treatment was stopped after two cycles, and the patient received cetuximab in a phase II trial. Because of further disease progression, temozolomide was reintroduced in August 2005 and administered on a 21 of 28 days regimen (at a daily dose of 100 mg/m2). The patient had a regression of his glioma and improvement in his neurologic condition and continued temozolomide for 25 uninterrupted treatment cycles. In August 2008, a plasmablastic diffuse large B-cell lymphoma of the stomach was diagnosed. Temozolomide was stopped and the patient received treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, to which he responded favorably. In November 2008, progression of his glioma was diagnosed, for which he underwent re-irradiation. The third case concerns a 48-year-old man who was diagnosed with a low-grade oligodendroglioma (1p/19q deleted) in January 2005. The tumor demonstrated modest shrinkage in response to 12 cycles of protracted low-dose temozolomide (75 mg/m2/d, 21 of 28 days).13 However, the patient developed odynophagia and cervical lymphadenopathy; tonsillectomy revealed a malignant tissue consistent with mucosa-associated lymphoid tissue lymphoma. The patient was treated with two cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone because of concern for aggressive disease. In March 2006, he was diagnosed with disseminated, progressive disease, involving the lung, liver, pelvis, and CNS. On progression, he was treated with and responded well to rituximab and methotrexate for CNS symptoms (eg, diplopia). Having responded well to CNS therapy, he was then treated with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for systemic disease. Unfortunately, despite two cycles of R-ICE, imaging revealed progressive disease. In light of progressive disease, altered mental status, and multiple complications owing to chemotherapy, including pancytopenias, recurrent GI bleeding, and chronic diarrhea, active treatment was stopped. The patient died in August 2006. Excess risk of non-Hodgkin's lymphoma has been observed after treatment for Hodgkin's disease (the cause for this is not well understood) and also in immunosuppressed organ transplant recipients and patients with HIV. Temozolomide has a strong mutagenic potential on mouse bone marrow cells in vivo,14 and patients who are treated with dose-dense extended dosing regimens of temozolomide for an extended period of time might present with particular risk for secondary malignancy because of treatment-associated immunosuppression and a high cumulative dose of a potentially carcinogenic alkylating drug. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Bart Neyns, Schering-Plough (C) Stock Ownership: None Honoraria: Bart Neyns, Schering-Plough Research Funding: Bart Neyns, Schering-Plough Expert Testimony: None Other Remuneration: Bart Neyns, Schering-Plough REFERENCES
1. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 2. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 3. Neyns B, Chaskis C, Joosens E, et al: A multicenter cohort study of dose-dense temozolomide (21 of 28 days) for the treatment of recurrent anaplastic astrocytoma or oligoastrocytoma. Cancer Invest 26:269-277, 2008[CrossRef][Medline] 4. Wick A, Felsberg J, Steinbach JP, et al: Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25:3357-3361, 2007 5. Brandes AA, Tosoni A, Cavallo G, et al: Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: Phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO). Br J Cancer 95:1155-1160, 2006[CrossRef][Medline] 6. Tolcher AW, Gerson SL, Denis L, et al: Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004-1011, 2003[CrossRef][Medline] 7. Noronha V, Berliner N, Ballen KK, et al: Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: Case study and review of the literature. Neuro Oncol 8:280-283, 2006 8. Su YW, Chang MC, Chiang MF, et al: Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma. J Neurooncol 71:315-318, 2005[CrossRef][Medline] 9. Jalali R, Singh P, Menon H, et al: Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide. J Neurooncol 85:105-107, 2007[CrossRef][Medline] 10. Villano JL, Collins CA, Manasanch EE, et al: Aplastic anaemia in patient with glioblastoma multiforme treated with temozolomide. Lancet Oncol 7:436-438, 2006[CrossRef][Medline] 11. Tosoni A, Cavallo G, Ermani M, et al: Is protracted low-dose temozolomide feasible in glioma patients? Neurology 66:427-429, 2006 12. Ganière V, Christen G, Bally F, et al: Listeria brain abscess, Pneumocystis pneumonia and Kaposi's sarcoma after temozolomide. Nat Clin Pract Oncol 3:339-343, 2006[CrossRef][Medline] 13. Pouratian N, Gasco J, Sherman JH, et al: Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas. J Neurooncol 82:281-288, 2007[CrossRef][Medline] 14. Geiger H, Schleimer D, Nattamai KJ, et al: Mutagenic potential of temozolomide in bone marrow cells in vivo. Blood 107:3010-3011, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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