Methods

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Patients were required to have a histologic diagnosis of Langerhans-cell histiocytosis and measurable disease. 2-Chlorodeoxyadenosine was supplied by Ortho Biotech and was administered every 28 to 35 days until maximum response or prohibitive toxicity. A complete response was defined as the absence of disease as proven by physical examination and imaging studies. Skin lesions did not require repeat biopsy to document histologic resolution. A partial response was defined as a reduction by more than 50% of all measurable disease for more than 1 month. Any response less than partial was designated as no response. Standard criteria of the Eastern Cooperative Oncology Group were used for the evaluation of toxicity [7].

Results

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Patient 1

A 33-year-old woman presented at age 15 years with polyuria and polydipsia from diabetes insipidus and later developed vesiculopustular lesions of her gingiva, scalp, and vagina that were histologically confirmed as Langerhans-cell histiocytosis. High-dose steroids induced a brief, partial response. After delivering a normal infant by cesarean section, she developed painful vaginal ulcers that were treated with irradiation. The cutaneous lesions were treated with vinblastine, which initially achieved a partial response; later, however, the lesions became refractory. Oral VP-16, vincristine, cyclophosphamide, and methotrexate were administered without benefit.

When first treated with 2-CdA, she had numerous 3- to 4-mm vesiculopustular lesions and shallow ulcers of her scalp, buccal mucosa, vagina, and external auditory canals (Figure 1). Her medications were intranasal desmopressin, 0.1 mL twice a day, and synthroid replacement. Before treatment, she had normal liver function test results, a leukocyte count of 5.5 x 10⁹/L with a normal differential, a hemoglobin concentration of 123 g/L, and a platelet count of 202 x 10⁹/L. The marrow was normocellular, and computed tomographic (CT) scans of the abdomen and bone survey were normal. She was assessed as having "good-risk" disease [8] (stage II as designated by Lavin and Osband [9]). Four courses of 2-CdA at 0.7 mg/kg of body weight per course given over 7 days by continuous intravenous infusion were administered. The second 2-CdA course was delayed by dermatomal herpes zoster and was later complicated by transient grade 3 neutropenia (absolute neutrophil count, <0.5 to 1.0 x 10⁹/L). The patient achieved a complete response after treatment and has remained in unmaintained complete remission for more than 23 months. Follow-up blood counts showed a leukocyte count of 4.3 x 10⁹/L with a normal differential, a hemoglobin concentration of 118 g/L, and a platelet count of 149 x 10⁹/L.

View larger version (80K): [in this window] [in a new window]   Figure 1. Langerhans-cell histiocytosis lesions of the scalp (A), skin (B), and gingiva (C) in patient 1 before administration of 2-CdA therapy.

During each course of 2-CdA, blood monocytes completely disappeared. The median absolute monocyte count before treatment was 0.28 x 10⁹/L (range, 0.09 to 0.38 x 10⁹/L); after 48 hours of 2-CdA treatment, the count was 0.09 x 10⁹/L (range, 0.05 to 0.38 x 10⁹/L). On day 7, the monocyte count was 0.0 x 10⁹/L during all four courses. A peripheral blood immunophenotypic analysis done after the second 2-CdA course showed a CD4 cell count of 137 cells/mL and a CD8 cell count of 76 cells/mL (CD4/CD8 ratio, 1.61). After three courses of 2-CdA, the CD4 cell count was 175 cells/mL and the CD8 cell count was 464 cells/mL (CD4/CD8 ratio, 0.38). Six months after the fourth course of 2-CdA, the CD4 count was 202 cells/mL, and the CD8 cell count was 307 cells/mL (CD4/CD8 ratio, 0.66).

After treatment, the patient became pregnant and delivered a normal 5 1/2-pound baby girl by cesarean section. Twelve months postpartum, she remains free of disease.

Patient 2

A 57-year-old man presented with a 2-year history of erythematous patches and scattered papular lesions involving his scalp, external auditory canals, axillae, and scrotal areas without associated lymphadenopathy or hepatosplenomegaly (Figure 2). He received a brief course of high-dose prednisone without response. Biopsy specimens of these skin lesions confirmed Langerhans-cell histiocytosis and showed positivity for the S-100 protein immunohistochemical stain. Intracytoplasmic Birbeck granules were identified on electron microscopy. Before treatment, the leukocyte count was 3.1 x 10⁹/L, the absolute neutrophil count was 1.3 x 10⁹/L, the hemoglobin concentration was 146 g/L, and the platelet count was 147 x 10 (⁹/L). The bone marrow, chest radiograph, bone scan, bone survey, and CT scan of the abdomen were all normal. He was staged as "poor risk" because of the neutropenia [8] (Lavin and Osband's stage III [9]).

View larger version (122K): [in this window] [in a new window]   Figure 2. The scalp of patient 2 before treatment (A) and the inguinal cutaneous lesions of patient 2 before and after treatment (B and C, respectively).

Two courses of 2-CdA at 0.7 mg/kg per course given over 7 days by continuous intravenous infusion were administered. The second course was delayed because of protracted grade 3 neutropenia and mild thrombocytopenia. Three months after the last course of 2-CdA, all lesions resolved. The patient has remained in complete remission for more than 15 months (Figure 2). On follow-up, the leukocyte count was 2.6 x 10⁹/L, the absolute neutrophil count was 0.8 x 10⁹/L, the hemoglobin concentration was 134 g/L, and the platelet count was 100 x 10⁹/L.

Patient 3

A 51-year-old woman had a 10-year history of cutaneous involvement by Langerhans-cell histiocytosis. She had extensive nonpruritic erythematous papular lesions involving her face, chest, extremities, and perineum. A partial response lasting 3 months was achieved after a course of vinblastine. At relapse the patient was retreated with vinblastine, which induced a second brief, partial response. Later, psoralen plus ultraviolet A exposure were administered without benefit. Because of symptomatic and progressive cutaneous lesions, the patient was treated with 2-CdA at 0.7 mg/kg per course, given over 5 days by 2-hour intravenous infusions. She was assessed as having "good-risk" disease because of the absence of organ dysfunction [8] (Lavin and Osband's stage II [9]).

The patient developed transient grade 3 neutropenia within 1 week of completing the course of 2-CdA therapy that fully resolved by week 2. One month after her first course of 2-CdA, her symptoms and skin lesions improved, and a complete clinical remission was achieved at 2 months. She received a second course of 2-CdA without complications, and her skin biopsy-confirmed complete remission has continued for more than 5 months.

Discussion

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Langerhans cells are found in various tissues and belong to a class of dendritic histiocytes, the major function of which is antigen presentation to lymphocytes. These cells and the histiocytes of the mononuclear-phagocyte system are derived from marrow stem cells. However, tissue macrophages can proliferate independently of marrow stimulation [10]. 2-Chlorodeoxyadenosine, an antimetabolite that is uniquely able to destroy resting and dividing cells with equal efficacy [11] and is potently toxic to monocytes [5], offers advantages in treating monocyte-derived neoplasms and chronic inflammatory conditions.

All three patients achieved complete remissions after 2-CdA therapy. Patient 1, refractory to vinblastine and other single-agent chemotherapeutic agents, remains in a long-lasting complete remission after four courses of 2-CdA. Patient 2, refractory to high-dose steroids, achieved a durable, unmaintained complete remission after two courses of 2-CdA. Patient 3, previously responsive to vinblastine, achieved a complete remission after a single course of 2-CdA.

Therapy in patient 1 was complicated by reversible myelosuppression and dermatomal herpes zoster. At 6 months, there appeared to be CD4 and CD8 lymphocyte subset recovery was seen that was similar to the tendency reported in hairy cell leukemia [12]. In patient 2, protracted myelosuppression was the principal toxicity of 2-CdA therapy, but CD4 and CD8 lymphocyte subsets were not measured. In patient 3, therapy was complicated only by transient, asymptomatic neutropenia.

The activity of 2-CdA against monocytes was not predicted from congenital adenosine deaminase deficiency, in which there is only an absence or immunologic incompetence of lymphocytes without monocytopenia. Additionally, 2'-deoxycoformycin, a tight-binding inhibitor of adenosine deaminase that in some ways simulates the situation of severe combined immunodeficiency disease and has a similar spectrum of activity against lymphoid malignancies as that of 2-CdA, is not toxic toward monocytes [13]. The mechanism of response to 2-CdA in Langerhans-cell histiocytosis has not been elucidated but may involve direct cytotoxicity to monocytes or the putative Langerhans cell, or may be mediated through its T-cell immunosuppressive effects [12].

The potential activity of 2-CdA in the treatment of histiocytic diseases is encouraging and warrants further investigation in Langerhans-cell histiocytosis, especially in patients with pulmonary involvement for which glucocorticoids represent the primary treatment, in the hemophagocytic syndromes, and in the malignant histiocytosis syndromes. In addition, the marked vulnerability of monocytes to 2-CdA in vitro and the 2-CdA-induced monocytopenia observed in patients with rheumatoid arthritis [5] suggests that 2-CdA may offer a novel approach to the treatment of chronic inflammatory and autoimmune diseases in which abnormal monocyte localization or action is present. For example, in patients with progressive multiple sclerosis, which is believed to be an autoimmune disorder, 2-CdA appeared to favorably alter the patients' clinical course [14].