Correspondence
An EBV-Positive Lymphoproliferative Disorder after Therapy with Alemtuzumab
N Engl J Med 2003; 349:2570-2572December 25, 2003
- Article
To the Editor:
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against CD52, a glycosylated peptide antigen that is expressed on normal lymphocytes and highly expressed on chronic lymphocytic leukemia cells. It has been shown to have clinically significant activity in T-cell chronic lymphocytic leukemia. The primary treatment-related adverse event that has been reported is the development of opportunistic infections secondary to the T-cell immunodeficiency.1
We report a case of an Epstein–Barr virus (EBV)–positive lymphoproliferative disorder occurring after the use of alemtuzumab. An 80-year-old woman had received the diagnosis of CD4-positive T-cell chronic lymphocytic leukemia eight years previously. There was a gradual increase in the lymphocyte count until September 2001, when her white-cell count reached 87,400 per cubic millimeter. She was treated initially with chlorambucil, followed by oral cyclophosphamide, with minimal response. In May 2002, because of progression of the disease, she was treated with 25 mg of fludarabine per square meter of body-surface area per day for one cycle, with no response. In June 2002, cytomegalovirus retinitis with bilateral visual loss developed. On June 3, 2002, the patient began receiving alemtuzumab and had a good response. The last dose was given in early April 2003. In mid-April, she noticed enlargement and soreness of the right parotid gland, with no fever, adenopathy, weight loss, or night sweats. A computed tomographic scan showed marked thickening of the parotid gland. She received antibiotics, without improvement; fine-needle aspiration of the mass was performed twice but did not lead to a conclusive diagnosis. The patient was referred to the Mayo Clinic and subsequently underwent a right-sided extended radical parotidectomy. Pathological examination showed a mass, 6.0 by 3.5 cm, that had ulcerated through the skin and that had the features of diffuse large B-cell lymphoma. In situ hybridization for EBV RNA was strongly positive.
EBV infections and EBV-positive lymphoproliferative disorders are well recognized in immunosuppressed patients, such as those with congenital or acquired immunodeficiency disorders, post-transplantation lymphoproliferative disorders, or autoimmune disorders managed with methotrexate or other therapies. In addition, purine nucleoside analogues, such as fludarabine and cladribine, have recently been linked to the development of EBV-positive lymphoproliferative disorders.2 In two of the reported cases, the patients also received a short course of therapy with alemtuzumab. Alemtuzumab used as a single agent has not previously been reported to be linked with EBV-positive lymphoproliferative disorders. Caution should be exercised when this agent is used alone or in combination with other therapies known to induce T-cell immunodeficiency.
2 ReferencesIrene M. Ghobrial, M.D.
Mayo Clinic, Rochester, MN 55905
ghobrial.irene@mayo. edu Larry A. Otteman, M.D.
McFarland Clinic, Ames, IA 50010William L. White, M.D.
Mayo Clinic, Rochester, MN 559051
Rai KR ,Freter CE ,Mercier RJ , et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 2002;20:3891-3897
CrossRef | Web of Science | Medline2
Abruzzo LV ,Rosales CM ,Medeiros LJ , et al. Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms. Am J Surg Pathol 2002;26:630-636
CrossRef | Web of Science | Medline
Author/Editor Response
The above letter was referred to ILEX Pharmaceuticals, the manufacturer of alemtuzumab, which offers the following reply:
To the Editor: The treatment of T-cell chronic lymphocytic leukemia is challenging. This disease generally does not respond well to treatment, and as a result, the prognosis for patients is poor. The observation that alemtuzumab shows clinically significant activity in this hard-to-treat disease continues to give hope to patients with refractory leukemias.1,2 This is affirmed by the case report presented by Dr. Ghobrial and colleagues.
As Dr. Ghobrial and colleagues mention, infections are frequently observed in patients with long-lasting hematologic dysfunction, such as T-cell chronic lymphocytic leukemia. Opportunistic infections associated with the use of alemtuzumab have generally been predictable, manageable, and reversible.3 The alemtuzumab package insert specifically recommends the use of anti-infective prophylaxis to minimize the risks. Typically, patients who have infections despite prophylaxis have been successfully treated when appropriately monitored.
In the case described by Dr. Ghobrial and colleagues, the patient was an 80-year-old woman who did not have a response to several prior treatments, including chlorambucil, cyclophosphamide, and fludarabine. All these chemotherapy agents are myelosuppressive and highly immunosuppressive.4 The fact that cytomegalovirus retinitis developed after the patient had received these agents suggests that she was already immunosuppressed, before alemtuzumab was administered. In addition, lymphocytes in persons older than 79 years of age are more likely to undergo spontaneous, EBV-related lymphoblastoid transformation than are lymphocytes in younger persons.5
Multiple risk factors predisposed this patient to this type of infection. Consequently, the EBV-related lymphoproliferative disorder in this case cannot be solely attributed to any single agent. We agree with Dr. Ghobrial and colleagues that caution should be exercised when immunosuppressed patients are treated.
5 ReferencesDavid A. Rizzieri, M.D.
Duke University Medical Center, Durham, NC 27710Steve Weitman, M.D., Ph.D.
Dana M. Vaughn, Ph.D.
ILEX Pharmaceuticals, San Antonio, TX 782291
Keating MJ ,Flinn I ,Jain V , et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554-3561
CrossRef | Web of Science | Medline2
Rai KR ,Freter CE ,Mercier RJ , et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 2002;20:3891-3897
CrossRef | Web of Science | Medline3
Lundin J ,Hagberg H ,Repp R , et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sézary syndrome. Blood 2003;101:4267-4272
CrossRef | Web of Science | Medline4
Lazzarino M ,Orlandi E ,Baldanti F , et al. The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders. Br J Haematol 1999;107:877-882
CrossRef | Web of Science | Medline5
Rangan SRS ,Armatis P . Enhanced frequency of spontaneous B cell lines from Epstein-Barr virus (EBV) seropositive donors 80 years and older. Exp Gerontol 1991;26:541-547
CrossRef | Web of Science | Medline
- Citing Articles (12)
Citing Articles
1
Naoki Hosen, Hiroyoshi Ichihara, Atsuko Mugitani, Yasutaka Aoyama, Yuki Fukuda, Satoshi Kishida, Yoshikazu Matsuoka, Hiroko Nakajima, Manabu Kawakami, Tamotsu Yamagami, Shigeo Fuji, Hiroya Tamaki, Takafumi Nakao, Sumiyuki Nishida, Akihiro Tsuboi, Shinsuke Iida, Masayuki Hino, Yoshihiro Oka, Yusuke Oji, Haruo Sugiyama. (2011) CD48 as a novel molecular target for antibody therapy in multiple myeloma. British Journal of Haematologyno-no
CrossRef2
F. A. H. Cooles, G. H. Jackson, G. Menon, J. D. Isaacs. (2011) Epstein-Barr virus-driven lymphoproliferative disorder post-CAMPATH-1H (alemtuzumab) in refractory polymyositis. Rheumatology 50:4, 810-812
CrossRef3
G Meyers, R T Maziarz. (2010) Is it time for a change? The case for early application of unrelated allo-SCT for severe aplastic anemia. Bone Marrow Transplantation 45:10, 1479-1488
CrossRef4
Katja C. Weisel, Eckhart Weidmann, Ioannis Anagnostopoulos, Lothar Kanz, Antonio Pezzutto, Marion Subklewe. (2008) Epstein–Barr virus-associated B-cell lymphoma secondary to FCD-C therapy in patients with peripheral T-cell lymphoma. International Journal of Hematology 88:4, 434-440
CrossRef5
H. C. Kluin-Nelemans, J. L. Coenen, J. E. Boers, G. W. van Imhoff, S. Rosati. (2008) EBV-positive immunodeficiency lymphoma after alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. Blood 112:4, 1039-1041
CrossRef6
A. Y. Peleg, S. Husain, E. J. Kwak, F. P. Silveira, M. Ndirangu, J. Tran, K. A. Shutt, R. Shapiro, N. Thai, K. Abu-Elmagd, K. R. McCurry, A. Marcos, D. L. Paterson. (2007) Opportunistic Infections in 547 Organ Transplant Recipients Receiving Alemtuzumab, a Humanized Monoclonal CD-52 Antibody. Clinical Infectious Diseases 44:2, 204-212
CrossRef7
C Cameron Yin, Dan Jones. (2006) Molecular approaches towards characterization, monitoring and targeting of viral-associated hematological malignancies. Expert Review of Molecular Diagnostics 6:6, 831-841
CrossRef8
Ann Janssens, Mario Berth, Pascale De Paepe, Bruno Verhasselt, Nadine Van Roy, Lucien Noens, Jan Philippé, Fritz Offner. (2006) EBV negative Richter's syndrome from a coexistent clone after salvage treatment with alemtuzumab in a CLL patient. American Journal of Hematology 81:9, 706-712
CrossRef9
Janice MY Brown. (2005) Exogenous administration of immunomodulatory therapies in hematopoietic cell transplantation: an infectious diseases perspective. Current Opinion in Infectious Diseases 18:4, 352-358
CrossRef10
Christine G. Parks, Glinda S. Cooper, Lori L. Hudson, Mary Anne Dooley, Edward L. Treadwell, E. W. St.Clair, Gary S. Gilkeson, Janardan P. Pandey. (2005) Association of Epstein-Barr virus with systemic lupus erythematosus: Effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype. Arthritis & Rheumatism 52:4, 1148-1159
CrossRef11
D.S. Nath, R. Kandaswamy, R. Gruessner, D.E.R. Sutherland, D.L. Dunn, A. Humar. (2005) Fungal Infections in Transplant Recipients Receiving Alemtuzumab. Transplantation Proceedings 37:2, 934-936
CrossRef12
Farhad Ravandi, Susan O’Brien. (2005) Alemtuzumab. Expert Review of Anticancer Therapy 5:1, 39-51
CrossRef
