Successful response to rituximab in a patient with pure red cell aplasia complicating chronic lymphocytic leukaemia.

Abstract

Rituximab is a chimaeric human antibody directed against the CD20 antigen expressed on normal and malignant B lymphocytes. It is therefore used to treat patients with follicular non-Hodgkin's lymphoma and, less frequently, other lymphoproliferative diseases such as chronic lymphocytic leukaemia (CLL), large cell lymphoma, mantle cell lymphoma, Waldenström's macroglobulinaemia and post-transplant lymphoproliferative diseases. Recently, rituximab has also been used to treat different autoimmune diseases refractory to conventional treatment with immunosuppressive drugs, i.e., autoimmune haemolytic anaemia (Ahrens et al, 2001; Zecca et al, 2001), immune thrombocytopenia (Faurschou et al, 2001), cold agglutinin disease (Bauduer, 2001) and polyneuropathy related to IgM antibodies either isolated or complicating lymphoproliferative disease. The usefulness of rituximab as a treatment of other immunological diseases such as pure red cell aplasia (PRCA) has rarely been reported (Zecca et al, 2001). We report a patient with CLL who developed PRCA without response to cyclosporin A but who was successfully treated with rituximab. On a search of the Medline database (1995–2001, key words: pure red cell aplasia, chronic lymphocytic leukaemia, rituximab), no other similar cases were found. A 58-year-old man was admitted to our hospital in August 1994 because of fatigue and lymphadenopathy. Cervical, axillary and inguinal examination revealed lymph nodes 2 cm in diameter, hepatomegaly and splenomegaly 4 cm below the costal margins, and skin and mucosal paleness. The main haematological parameters were: haemoglobin 5·2 g/dl, reticulocytes 0%, white blood cell count 7·9 × 109/l (9% neutrophils, 90% lymphocytes, 1% monocytes) and platelet count 96 × 109/l. The lymphocytes showed a weak expression of surface immunoglobulin (sIg) and were positive to CD19, CD20, CD79a, CD23 and CD5, and negative to CD79b. Bone marrow biopsy revealed a diffuse pattern of infiltration by mature lymphocytes without red cell precursors. Conventional cytogenetic study of peripheral blood was normal. Serological search for parvovirus B19 infection (IgG and IgM) was negative. Diagnosis of CLL in stage C(IV) with associated PRCA was performed. Treatment with prednisolone (1 mg/kg/d, p.o., for 4 d consecutively every month), chlorambucil (0·25 mg/kg/d, p.o., for 4 d consecutive every month) and cyclosporin A (3 mg/kg/12 h, p.o.) was administered and complete resolution of PRCA was observed in 12 months. This treatment was stopped in February 1996. The patient remained well without any treatment until November 1998 when he developed a submandibular lymphadenopathy 3 cm in diameter. Fifteen percent of prolymphocytes were observed in peripheral blood and there was diffuse infiltration by mature lymphocytes and prolymphocytes on bone marrow biopsy. Diagnosis of prolymphocytic transformation of CLL was performed and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy every 3 weeks for six cycles was given, with good response. In April 2001, the haemoglobin level decreased from 12·0 g/dl to 6·0 g/dl and the reticulocyte count was again 0%. A bone marrow study showed a diffuse pattern of mature lymphocyte infiltration as well as absence of erythroid precursors. Serological study for parvovirus B19 was again negative. Cyclosporin A (3 mg/kg/12 h, p.o.) was administered for 2 months without haematological improvement. Rituximab (375 mg/m2 i.v. every 7 d for 4 weeks) was administered. Minor chills during the first infusion were observed but no other side-effects were present on subsequent doses. The patient was monitored weekly for haematological parameters (haemoglobin level, reticulocyte count) and for any packed red cell transfusion requirements. The last transfusion was in July 2001 and in August 2001 the haemoglobin level was 12·0 g/dl, and the reticulocyte count 100 × 109/l. Six months after rituximab administration, the patient remains well with a stable haemoglobin level of 12·0 g/dl. On the other hand, CLL remains stable (normal physical examination and white blood cell count 7·8 × 109/l with 40% neutrophils, 56% lymphocytes and 4% monocytes, and platelet count 126 × 109/l). PRCA is associated with CLL in 0·5% of the cases and its pathogenesis is unknown. The response to rituximab in this case of PRCA associated with CLL and refractory to cyclosporin A suggests that this chimaeric antibody could be an alternative to immunosuppressive drugs (such as prednisone and cyclosporin A), other immunomodulating agents or immunoglobulins for the control of PRCA, complicating or not, CLL. Although other antibody-mediated haematological disorders (immunothrombocytopenia, autoimmune haemolytic anaemia, chronic cold agglutinin disease)(Ahrens et al, 2001; Bauduer, 2001; Berentsen et al, 2001; Faurschou et al, 2001; Zaja et al, 2001; Zecca et al, 2001) have been successfully treated with rituximab, to our knowledge no cases of PRCA associated with CLL have been referred. This case adds to the evidence that rituximab may be a good alternative therapy to conventional drugs for the treatment of immune-mediated haematological disorders, including PRCA, and encourages further clinical investigations. This work is supported in part by grants FIS 99/1053 (Fondo de Investigaciones Sanitarias) and FIJC P/EF 01 (Fundación Internacional José Carreras para la Lucha Contra la Leucemia).