Haematologica 2002; 87:(07)ELT33
[Medline] [prev] [index] [next]

Inefficacy of rituximab in a case of low grade non-Hodgkin's lymphoma with cryoglobulinemia
D. Baronciani, E. Angelucci, J.Gaziev, G. Visani
Department of Haematology, Pesaro Hospital, Italy

Rituximab (Mabthera®; Roche) is a anti CD20 monoclonal antibody that has demonstrated activity in relapsed/refractory low grade lymphomas of B cell origin.1 Because of its anti panB activity it was supposed to be effective in Waldenstrom macroglobulinemia as well as Cold agglutinin disease or Cryoglobulinemia.2 This has been reported in few cases with a clinical benefit after the treatment. Here we present a case of a low grade B cell non HodgKin lymphoma associated with refractory type II Cryoglobulinemia who unexpectedly worsened after treatment with Rituximab.

A 59-years old woman presented to our hospital in February 2000 for hepatic lesions revealed on ultrasound examination and diagnosed as chronic lymphoproliferative disease type Immunocytoma . She was previously diagnosed as type II mixed Cryoglobulinemia (monoclonal IgM /K and policlonal IgG) since 1993 and was treated with plasmapheresis, steroids, chlorambucil, cyclophosphamide and interferon without sustained clinical response. The clinical picture was periodically characterized by purpura, arthralgia and symptoms related to peripheral neuropathy; she was also on treatment for severe hypertension due to a previous glomerulonephritis. On admission laboratory tests showed: hemoglobin 13.7 g/dL, white blood cell (WBC) count 7,800/µL, platelet count 232,000/µL; IgG level 768 mg/dL (normal values 751-1560), IgM 62 mg/dL (46-304), K chains 672 mg/dL (629-1350 ), C4 titer 2,2 mg /dL (16-38 ), Waaler-Rose titer 1/5120 (1/80 ), Rheumatoid test 59 U/mL (<20),cryoglobulins positive (absent ), HCV antibodies negative. Bone marrow analysis was negative for lymphoma localization. A cyclic monthly treatment with corticosteroids and chlorambucil was started without substantial variation of the clinical conditions, except for development of moderate anemia (Hb 10-9.5 g/dL). A restaging was performed in January 2001. A new liver biopsy of the lesions confirmed the diagnosis of low grade non Hodgkin lymphoma, variety Immunocytoma according to Real classification. The Immuno-histochemical test on biopsy samples showed CD20 positivity. In March 2001 she developed an anasarcatic state and was admitted to the Kidney Unit. She received diuretics, packed red blood cell tranfusions and 5 plasma exchanges with some clinical improvement. In May 2001 a new bone marrow evaluation showed decreased cellularity with lymphocytosis and VDJ rearrangment. Laboratory test showed a decreased level of IgG (164 mg/dL) and IgM (27 mg/dL). We decided for a treatment with Rituximab (375 mg/mq iv/weekly for 4 weeks ) in order to control disease progression; concomitantly steroids (8 mg/day methylprednisolone) were administered. The first infusion was well tollerated. One week later she presented again with diffuse oedemas and increase of the purpuric lesions. Rituximab was not performed and steroid treatment was increased to 20 mg/day together with diuretics. Renal function was normal. Following this therapy her clinical conditions improved. On May 31th she received the second dose of Rituximab without problems. On June 6th she presented again with oedemas and purpura; for the first time she developed renal impairment (BUN 171 mg/dL, creatinine 2,6mg/dL). She was hospitalized in the Kidney Unit and treated with 4 plasma-exchanges, high dose steroids and cyclophosphamide. Patient was discharged 3 weeks later in good conditions with improved kidney function tests. In July 2001 she presented to the Kidney Unit with high fever, confusional state, shock and respiratory distress; death occurred in few hours due to septic shock with multiorgan failure. In this patient we wondered whether immunotherapy with Rituximab had resulted in disease progression. Because Rituximab is a anti CD20 IgG antibody and in the pathogenesis of the mixed cryoglobulinemia IgG-IgM immonocomplexes formation plays an important role, a possible role of the drug in promoting the cryoprecipitation could be postulated. Even if there are no data supporting the hypothesis that Rituximab promotes cryoprecipitation, also in the case reported by Zaja et al.3 a thrombosis of the retinal arterial was observed in a patient with type II mixed cryoglobulinemia after a Rituximab second infusion; the drug was withdrawn for safety even if the patient presented some improvement of the disease.
Clinical benefit after Rituximab therapy in patients with Cold Agglutinin Disease and cryoglobulins has also been reported elsewhere.4 Rituximab therapy may be an ncouraging strategy also in this field but particular caution must be done and specific protocols must be studied in this setting.

References

  1. Mc Laughlin P, Grillo-Lopez A, Link B, Levy R, Czuczman M, Williams M, Bence-Bruckler I, White C, Cabanillas F, Jain V, Ho A, Lister J, Wey K, Shen D, Dallaire B : Rituximab chimeric anti-CD 20 monoclonal antibody therapy for relapsed indolent lymphoma; half of patients respond to a four dose treatment program. J Clin Oncol 1998; 16: 2825.
  2. Lee EJ, Kueck B. Rituxan in the treatment of cold agglutinin disease. Blood 1998; 92; 3490-1.
  3. Zaja F, Russo D, Fuga G, Patriarca F, Ermacora A, Baccarani M. Rituximab for the treatment of type II mixed cryoglobulinemia. Haematologica 1999; 84:1157-8.
  4. Layos N, Van Den Neste E, Jost E, Deneys V, Scheiff JM, Ferrant A. Remission of severe cold agglutinin disease after Rituximab therapy. Leukemia 2001;15:187-8.