• © 2005 by American Society of Clinical Oncology

Unusual Leukemia Presentations

CASE 3. Type I IgG_λ Cryoglobulinemia Associated With Chronic Lymphocytic Leukemia

A 55-year-old man presented with a 14-year history of an intermittent truncal rash and pruritus associated with sweating from exertion. For 2 years he had noted pruritus and erythema mainly in the hands and feet, occurring on exposure to cool weather and resolving promptly on warming. There was no history of Raynaud's phenomenon. He also complained of dark purple discoloration of the ears (left, Fig 1; right, Fig 2) when exposed to cold. There were no systemic symptoms except for mild fatigue. Physical examination revealed bilateral 0.5- to 1.5-cm rubbery, nontender, mobile lymph nodes in the cervical, axillary, and inguinal areas. Purpura and 5-mm ulcers were noted on the auricles. The WBC count was 10.6 × 10⁹ cells/L, with 88% lymphocytes, hemoglobin 13.5 g/dL, and platelet count 138 × 10⁹ cells/L. A bone marrow biopsy showed nodular infiltration with small lymphocytes. Flow cytometry revealed clonal lymphocytes coexpressing CD5, CD20, CD23, and immunoglobulin G gamma (IgGλ). Fluorescence in situ hybridization demonstrated trisomy 12. Serum and urine protein electrophoresis was remarkable for a small globulin band, characterized as an IgGλ monoclonal protein by immunofixation electrophoresis; Bence Jones protein was not detectable. The IgGλ precipitated at cold temperature. The serum IgG concentration was 566 mg/dL; IgA, 34 mg/dL; IgM, 14 mg/dL; creatinine, 1.1 mg/dL; and blood urea nitrogen, 19 mg/dL. Total hemolytic complement ranged between 2% and 5%. The urinalysis was unremarkable. Computed axial tomography demonstrated multiple lymph nodes measuring 1 to 2 cm in diameter in the abdomen, pelvis, and groins. As the patient was reluctant to start treatment, therapy was not given until 15 months after diagnosis when he enrolled in a phase II trial of combined fludarabine and rituximab therapy.² He received his first cycle of fludarabine 30 mg/m²/d for 4 days, and rituximab 375 mg/m² on day 5, in conjunction with allopurinol 300 mg daily. One week after chemotherapy, the patient presented with an erythematous, pruritic rash over most of his body. A punch biopsy revealed leukocytoclastic vasculitis, which was attributed to allopurinol. Chemotherapy and allopurinol were suspended, and the rash gradually resolved. Two months after receiving fludarabine and rituximab, the patient reported a marked decrease in his cold-related symptoms. On physical examination, the peripheral lymphadenopathy was less prominent. Five additional cycles of fludarabine were given monthly, without adverse effects. Twenty-two months after treatment, he noted occasional pruritus of his hands and feet on exposure to the cold, but no other symptoms. He had no palpable lymphadenopathy, and minimal discoloration of his ears. The WBC was 3.8 × 10⁹ cells/L, of which 54% were lymphocytes. The chronic lymphocytic leukemia (CLL) clone persisted on marrow biopsy, flow cytometry, and fluorescence in situ hybridization analysis. His IgG_λ cryoglobulin was intermittently detectable; the serum IgG concentration was 641 mg/dL.

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Fig 1.

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Fig 2.

Type I cryoglobulinemia is only rarely associated with CLL. In one series of 86 patients with cryoglobulinemia, only three had CLL, and six had well-differentiated lymphocytic lymphoma (WDLL). None of these nine patients had type I disease.¹ In a series of 13 patients with CLL or WDLL and glomerulonephritis, only one had type I cryoglobulinemia.³ Three additional cases of glomerulonephritis secondary to IgG cryoglobulinemia in the setting of CLL have been previously published.^3–5 Our report describes the fifth case of type I cryoglobulinemia related to CLL. All four previously reported patients had IgG_κ cryoglobulinemia and glomerulonephritis associated with their CLL.^3–5 In contrast, our patient had an IgG_λ paraprotein and cryoglobulinemic symptoms limited to the skin, without renal involvement. In three previous patients,^3–5 manifestations of cryoglobulinemia occurred years after the initial diagnosis of CLL/WDLL. Only one patient had been previously treated for his lymphoproliferative disorder.⁵ When his cryoglobulinemia appeared, reintroduction of chlorambucil led to resolution of the lymphocytosis and a decrease in proteinuria.⁵ Cryoglobulinemic manifestations improved in two additional patients treated with alkylator-based therapy.^3,4 Our patient presented with CLL and cutaneous manifestations. He was treated with fludarabine and rituximab,^2,6 which produced an excellent hematologic response and sustained remission of his symptoms of cryoglobulinemia.