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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4490-4492 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.9114
Anaplastic Large Cell Lymphoma in Leukemic Transformation: Successful Treatment by TransplantationDepartment of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
Department of Internal Medicine, National Taiwan University Hospital; and the Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan A 35-year-old woman presented with a 3-week history of night sweats and progressive generalized lymphadenopathy unresponsive to one course of oral antibiotics. She was then admitted to our institution. On admission, lymphadenopathy was observed over the bilateral neck, axilla, and inguinal area, but hepatosplenomegaly was not present. CBC showed: hemoglobin, 13.8 g/dL; WBC, 76,050/µL with 15.5% granulocytes, 3.25% monocytes, 2.5% lymphocytes, and 79.25% atypical lymphocytes; and platelets, 179 K/µL. Atypical lymphocytes were small to medium in size with cleaved nuclei. Some cells exhibited cytoplasmic granules (Fig 1A, x400; Fig 1B, x1,000). Atypical cells in peripheral blood were subjected to fluorescent flow-cytometry (Beckman Coulter) and found to be positive for human leukocyte antigen-DR (HLA-DR), CD2, CD3, CD7, and CD4, and negative for CD19, CD8, CD56, CD16, and CD25. Increased level of serum lactate dehydrogenase (857 U/L; normal < 460 U/L) and C-reactive protein (14.29 mg/dL; normal < 0.8 mg/dL) were the main biochemical abnormalities. Computed tomography scan revealed diffuse enlarged lymph nodes at the bilateral neck and axillary regions, mediastinum, para-aortic areas, celiac trunk, superior mesenteric artery, and mesenteric root. A neck lymph node biopsy was performed. The lymph node biopsy sample stained with hematoxylin and eosin stain revealed severe effacement of the architecture by homogenous lymphoid cells (Fig 2A, x40). These cells posed clear cytoplasm and hyperchromatic nuclei (Fig 2B, x200). The immunohistochemical stains demonstrated positive CD30 and anaplastic large cell lymphoma (ALCL) kinase (ALK) expression (Figs 2C and 2D, respectively; x100). Bone marrow pathology showed no evidence of lymphoma involvement. Cytogenetic analyses of the lymph node and peripheral blood confirmed the presence of t(2;5) (p23;q35) as well as t(X;14) (q24;q24) (Fig 3). ALCL with leukemic transformation was diagnosed. Induction chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) was administered. The response was poor and the peripheral leukocyte count remained high. Salvage chemotherapy according to the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Munster 90 "AA" protocol (methotrexate, ifosfamide, etoposide, cytarabine, and dexamethasone) was administered with improvement of clinical status, including reductions in peripheral leukocytosis and peripheral lymphadenopathy. The patient then received chemotherapy with etoposide, methylprednisolone, cytarabine, and cisplatin. Peripheral blood stem cells (PBSCs) were mobilized after intermediate-dose cyclophosphamide (4 g/m2 on day 1) and were harvested and submitted for CD34-positive cell selection (CliniMACS; Miltenyi Biotech, Bergisch Gladbach, Germany). Postselection nucleated cells totaled 3.20 x 106/kg body weight with total CD34-positive cells approximating 3.05 x 106/kg body weight. Dose-positive nucleated cell purity increased from 0.49% to 95.17% (2.3 log elevation). The percentage of CD3-positive cells decreased from 10.65% to 0.0135% (2.9 log reduction). Less than 1 month after stem cell harvest, however, her disease progressed with new enlarged lymph nodes appearing over the bilateral neck and left inguinal area. Nonetheless, her peripheral WBC count was not elevated. On treatment with BOMES chemotherapy (BCNU, vincristine, methotrexate, etoposide, and methylprednisolone), a complete remission was obtained again. Then, she received high-dose conditioning with regimen of BEAM (BCNU, etoposide, cytarabine, and melphalan), and CD34-positive selected autologous PBSC transplantation was done subsequently. The course of transplantation proceeded without major complications. Her absolute neutrophil count exceeded 500/µL on day 13 and 1,000/µL on day 16 post-transplantation. Her platelet count exceeded 20 K/µL on day 12 and 50 K/µL on day 43 post-transplantation. She remains disease free at present, 30 months after autologous PBSC transplantation.
ALCL, originally described in 1985,1,2 is a T-cell lymphoma. ALCL cells are CD30/Ki-1 positive. The majority of ALCL patients are also positive for the ALK protein. The chromosomal translocation t(2;5) occurs in approximately three fourths of these patients.2 This lymphoma was designated as high grade in nature by the Working Formulation classification.3 ALCL accounts for 2% to 8% of adult non-Hodgkin's lymphomas and 20% to 50% of childhood lymphomas.2,4 The majority of ALCL patients present with advanced stage III to IV disease, often associated with extranodal infiltrates and involvement of the bone marrow.4-6 Although lymphoma cells have been observed in peripheral blood in several studies by morphological examination or molecular analysis,7,8 the presence of a frank leukemic phase was rare. Because such presentations are uncommon in ALCL, their clinical nature and prognostic significance are not well understood and effective treatment strategies have not been identified. In 2003, three cases were reported and another nine cases were reviewed that had previously been described in the literature.9 Nine of these 12 patients had leukemic disease at initial diagnosis. These patients exhibited either a poor response to therapy or an early relapse, suggesting that the leukemic component of ALCL was a clinicopathological entity with an unfavorable prognosis and requiring more aggressive therapy. The response of our patient to standard chemotherapy was poor. Although salvage chemotherapy resulted in remission, this remission was short-lived and the patient relapsed quickly. Intensive therapy was therefore indicated. In our patient, salvage chemotherapy after disease relapse led to complete remission, indicating that the lymphoma cells were still chemotherapy sensitive. Therefore, high-dose chemotherapy with autologous PBSC transplantation rescue was selected for our patient. Because she had previously undergone a leukemic phase, the possibility that lymphoma cells contaminated the harvested peripheral stem cells was of concern. CD34-positive cell selection has proved to be an effective strategy for enrichment of CD34-positive cells and reduction of contamination of the autograft by tumor cells.10 In our patient, who would certainly have relapsed without administration of high-dose chemotherapy in accordance with the course of her disease, high-dose chemotherapy with CD34-positive selected autologous PBSC transplantation led to a sustained remission. To our knowledge, this report is the first to describe the successful treatment of leukemic ALCL with such a strategy. A leukemic phase of ALCL is unusual and associated with poor prognosis. A strategy involving intensive treatment indicated. Based on the present report, CD34-positive–selected autologous stem-cell transplantation should prove effective for such patients providing the lymphoma cells remain chemotherapy sensitive. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Desol G, Ralfkiaer E, Stein H, et al: Anaplastic large cell lymphoma, in Jaffe ES, Harns NL, Stein H, et al (eds): Lyon, France, IARC Press, 2001, pp 230-235 2. Stein H, Foss HD, Durkop H, et al: CD30(+) anaplastic large cell lymphoma: A review of its histopathologic, genetic, and clinical features. Blood 96:3681-3695, 2000 3. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage: The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49:2112-2135, 1982[CrossRef][Medline] 4. Stein H, Mason DY, Gerdes J, et al: The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 66:848-858, 1985 5. Brugieres L, Deley MC, Pacquement H, et al: CD30(+) anaplastic large-cell lymphoma in children: Analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92:3591-3598, 1998 6. Tilly H, Gaulard P, Lepage E, et al: Primary anaplastic large-cell lymphoma in adults: Clinical presentation, immunophenotype, and outcome. Blood 90:3727-3734, 1997 7. Greer JP, Kinney MC, Collins RD, et al: Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. J Clin Oncol 9:539-547, 1991[Abstract] 8. Chhanabhai M, Britten C, Klasa R, et al: T(2;5) positive lymphoma with peripheral blood involvement. Leuk Lymphoma 28:415-422, 1998[Medline] 9. Onciu M, Behm FG, Raimondi SC, et al: ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis: Report of three cases and review of the literature. Am J Clin Pathol 120:617-625, 2003[CrossRef][Medline] 10. Despres D, Flohr T, Uppenkamp M, et al: CD34+ cell enrichment for autologous peripheral blood stem cell transplantation by use of the CliniMACs device. J Hematotherapy & Stem Cell Res 9:557-564, 2000[CrossRef][Medline]
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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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