Remission of a Refractory, Anaplastic Large-Cell Lymphoma after Treatment with Daclizumab
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《新英格兰医药杂志》
To the Editor: A 37-year-old woman who delivered her first child in June 2002 presented in September 2002 with an axillary mass, a fever, and chills. A biopsy revealed an anaplastic large-cell lymphoma of the T-cell type, positive for the hybrid protein ALK, with cytoplasmic as well as nuclear staining associated with the t(2;5) translocation.1 The tumor involved the mediastinal and left axillary nodes and the skin. The patient was treated with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone but had progressive disease in the central nervous system, as confirmed by radiology, and cells that were positive for ALK in the cerebrospinal fluid. She was then treated according to the German protocol NHL-BFM 90 (vincristine, doxorubicin, prednisone, cyclophosphamide, dexamethasone, etoposide, ifosfamide, cytarabine, methotrexate, and vindesine), after which she had no evidence of disease outside the central nervous system.
Before craniospinal radiotherapy could begin, the patient was admitted to the hospital owing to fever and thoracic pain associated with breathing. A computed tomographic scan of the thorax showed enlarged thoracic nodes. An acute abdomen developed, and a laparotomy was performed, revealing an enlarged liver and enlarged mesenteric nodes. After the laparotomy, the patient had to be intubated owing to respiratory distress. She had enlarged lymph nodes, a very high titer of soluble interleukin-2 receptor alpha (89,000 kU per liter), and in the blood, a small fraction of large CD2 cells and strongly CD30-positive cells. This condition was interpreted as being due only to progressive disease. After the administration of steroids, vincristine, and epoprostenol, the patient was extubated. She received five weekly infusions of vinblastine and had some initial clinical improvement, but then the disease progressed clinically, with recurrence of fever and night sweats. On the day of the last infusion of vinblastine, cytologic examination of the cerebrospinal fluid showed CD30-positive malignant cells.
The patient was offered treatment with the anti-CD25 antibody daclizumab (Zenapax, Hoffmann–La Roche). This treatment was suggested on the basis of her high titer of soluble interleukin-2 receptor alpha, a report that anaplastic large-cell lymphomas are CD25-positive,2 and a report about the use of the parental mouse antibody of daclizumab for adult T-cell leukemia.3 She received four weekly infusions; the first was at a dose of 62 mg (1 mg per kilogram of body weight) and the others were at a dose of 75 mg. The soluble interleukin-2 receptor alpha level fell overnight from 66,000 to 1200 kU per liter (normal range, <700 kU per milliliter) but normalized only after eight months. The patient remains in clinical remission 12 months after the start of therapy.
The therapeutic success of daclizumab in this case of a chemorefractory disease is noteworthy, but the fact that the patient had central nervous system involvement that responded to treatment with a systemically administered antibody is also an interesting clinical observation, indicating a high sensitivity to the treatment. Several mechanisms of action of daclizumab have been suggested, such as direct induction of apoptosis, antibody-dependent cytotoxicity, and interleukin-2 deprivation,4 but the possibility that daclizumab may have immunoregulatory effects that are of therapeutic value in the treatment of cancer cannot be ruled out.5
Ola Lindén, M.D., Ph.D.
Lund University Hospital
221 85 Lund, Sweden
References
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Delsol G, Al Saati T, Gatter KC, et al. Coexpression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas: diagnostic value in so-called malignant histiocytosis. Am J Pathol 1988;130:59-70
Waldmann TA. Anti-IL-2 receptor monoclonal antibody (anti-Tac) treatment of T-cell lymphoma. Important Adv Oncol 1994:131-41.
Phillips KE, Herring B, Wilson LA, et al. IL-2Ralpha-directed monoclonal antibodies provide effective therapy in a murine model of adult T-cell leukemia by a mechanism other than blockade of IL-2/IL-2Ralpha interaction. Cancer Res 2000;60:6977-6984.
Nicholl M, Lodge A, Brown I, Sugg SL. Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells. J Pediatr Surg 2004;39:941-946.
Before craniospinal radiotherapy could begin, the patient was admitted to the hospital owing to fever and thoracic pain associated with breathing. A computed tomographic scan of the thorax showed enlarged thoracic nodes. An acute abdomen developed, and a laparotomy was performed, revealing an enlarged liver and enlarged mesenteric nodes. After the laparotomy, the patient had to be intubated owing to respiratory distress. She had enlarged lymph nodes, a very high titer of soluble interleukin-2 receptor alpha (89,000 kU per liter), and in the blood, a small fraction of large CD2 cells and strongly CD30-positive cells. This condition was interpreted as being due only to progressive disease. After the administration of steroids, vincristine, and epoprostenol, the patient was extubated. She received five weekly infusions of vinblastine and had some initial clinical improvement, but then the disease progressed clinically, with recurrence of fever and night sweats. On the day of the last infusion of vinblastine, cytologic examination of the cerebrospinal fluid showed CD30-positive malignant cells.
The patient was offered treatment with the anti-CD25 antibody daclizumab (Zenapax, Hoffmann–La Roche). This treatment was suggested on the basis of her high titer of soluble interleukin-2 receptor alpha, a report that anaplastic large-cell lymphomas are CD25-positive,2 and a report about the use of the parental mouse antibody of daclizumab for adult T-cell leukemia.3 She received four weekly infusions; the first was at a dose of 62 mg (1 mg per kilogram of body weight) and the others were at a dose of 75 mg. The soluble interleukin-2 receptor alpha level fell overnight from 66,000 to 1200 kU per liter (normal range, <700 kU per milliliter) but normalized only after eight months. The patient remains in clinical remission 12 months after the start of therapy.
The therapeutic success of daclizumab in this case of a chemorefractory disease is noteworthy, but the fact that the patient had central nervous system involvement that responded to treatment with a systemically administered antibody is also an interesting clinical observation, indicating a high sensitivity to the treatment. Several mechanisms of action of daclizumab have been suggested, such as direct induction of apoptosis, antibody-dependent cytotoxicity, and interleukin-2 deprivation,4 but the possibility that daclizumab may have immunoregulatory effects that are of therapeutic value in the treatment of cancer cannot be ruled out.5
Ola Lindén, M.D., Ph.D.
Lund University Hospital
221 85 Lund, Sweden
References
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Delsol G, Al Saati T, Gatter KC, et al. Coexpression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas: diagnostic value in so-called malignant histiocytosis. Am J Pathol 1988;130:59-70
Waldmann TA. Anti-IL-2 receptor monoclonal antibody (anti-Tac) treatment of T-cell lymphoma. Important Adv Oncol 1994:131-41.
Phillips KE, Herring B, Wilson LA, et al. IL-2Ralpha-directed monoclonal antibodies provide effective therapy in a murine model of adult T-cell leukemia by a mechanism other than blockade of IL-2/IL-2Ralpha interaction. Cancer Res 2000;60:6977-6984.
Nicholl M, Lodge A, Brown I, Sugg SL. Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells. J Pediatr Surg 2004;39:941-946.