Autoimmune complications following purine analog therapy
- Jeffrey Zonder, MD
Jeffrey Zonder, MD
- Professor of Medicine and Oncology
- Barbara Ann Karmanos Cancer Institute
- Wayne State University School of Medicine
- Charles A Schiffer, MD
Charles A Schiffer, MD
- Professor of Medicine and Oncology
- Barbara Ann Karmanos Cancer Institute
- Wayne State University School of Medicine
Purine analogs have long been an important part of the treatment of hematologic malignancies. The adenosine analogue fludarabine remains perhaps the most widely used agent to treat chronic lymphocytic leukemia (CLL). Multiple cases of autoimmune hemolytic anemia (AIHA) [1-5] as well as autoimmune thrombocytopenia [6-10], apparently triggered by treatment with fludarabine treatment, have been reported.
Autoimmune hemolytic anemia and immune thrombocytopenia (ITP) following the use of purine analogs (ie, fludarabine, cladribine, pentostatin) will be reviewed here. Infectious complications following purine analog therapy are discussed separately. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Purine analogs'.)
The clinical features, pathogenesis, diagnosis, and treatment of de novo autoimmune hemolytic anemia and de novo immune thrombocytopenia (ITP) are discussed separately. (See "Warm autoimmune hemolytic anemia: Clinical features and diagnosis" and "Pathogenesis of autoimmune hemolytic anemia: Warm agglutinins and drugs" and "Warm autoimmune hemolytic anemia: Treatment" and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis".)
AUTOIMMUNITY IN CLL
As many as one-third of patients with chronic lymphocytic leukemia (CLL) may develop AIHA over the course of their illness unrelated to treatment modality , although most series suggest a rate in the range of 4 to 10 percent [12,13]. This background incidence of AIHA, particularly in patients with advanced stage CLL , makes the frequency of AIHA caused by fludarabine difficult to estimate. (See "Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia", section on 'Laboratory abnormalities'.)
Patients with CLL also have an increased incidence of immune-mediated (autoimmune) thrombocytopenia (AITP). The exact incidence of AITP in CLL is unknown, but it is thought to be somewhat lower than that of AIHA .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Tertian G, Cartron J, Bayle C, et al. Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia. Hematol Cell Ther 1996; 38:359.
- Tsiara S, Christou L, Konstantinidou P, et al. Severe autoimmune hemolytic anemia following fludarabine therapy in a patient with chronic lymphocytic leukemia. Am J Hematol 1997; 54:342.
- Longo G, Gandini G, Ferrara L, et al. Fludarabine and autoimmune hemolytic anemia in chronic lymphocytic leukemia. Eur J Haematol 1997; 59:124.
- Taha HM, Narasihman P, Venkatesh L, et al. Fludarabine-related hemolytic anemia in chronic lymphocytic leukemia and lymphoproliferative disorders. Am J Hematol 1998; 59:316.
- Gonzalez H, Leblond V, Azar N, et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther 1998; 40:113.
- Hegde UP, Wilson WH, White T, Cheson BD. Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Blood 2002; 100:2260.
- Leach M, Parsons RM, Reilly JT, Winfield DA. Autoimmune thrombocytopenia: a complication of fludarabine therapy in lymphoproliferative disorders. Clin Lab Haematol 2000; 22:175.
- Bay JO, Fouassier M, Béal D, et al. Autoimmune thrombocytopenia after six cycles of fludarabine phosphate in a patient with chronic lymphocytic leukemia. Hematol Cell Ther 1997; 39:209.
- Churn M, Clough V. Autoimmune thrombocytopenia associated with the first cycle of fludarabine therapy in the treatment of relapsed non-Hodgkin's lymphoma. Clin Oncol (R Coll Radiol) 2001; 13:273.
- Usman M, Adil SN, Sajid R, Khurshid M. Fludarabine induced immune thrombocytopenia in a patient with CD5 positive B cell chronic lymphocytic leukemia. J Pak Med Assoc 2003; 53:496.
- Bergsagel DE. The chronic leukemias: a review of disease manifestations and the aims of therapy. Can Med Assoc J 1967; 96:1615.
- Dührsen U, Augener W, Zwingers T, Brittinger G. Spectrum and frequency of autoimmune derangements in lymphoproliferative disorders: analysis of 637 cases and comparison with myeloproliferative diseases. Br J Haematol 1987; 67:235.
- Mauro FR, Foa R, Cerretti R, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000; 95:2786.
- Hamblin T. Autoimmune Disease and Its Management in Chronic Lymphocytic Leukemia. In: Chronic Lymphoid Leukemias, Cheson B (Ed), Marcel Dekker, New York 2001. p.435.
- Borthakur G, O'Brien S, Wierda WG, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab--incidence and predictors. Br J Haematol 2007; 136:800.
- Weiss RB, Freiman J, Kweder SL, et al. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol 1998; 16:1885.
- Citores MJ, Castejon R, Villarreal M, et al. CD154 expression triggered by purine analogues in vitro: Correlation with treatment response and autoimmune events in chronic lymphocytic leukemia. Exp Hematol 2010; 38:165.
- Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 2001; 98:2319.
- Dearden C, Wade R, Else M, et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 2008; 111:1820.
- Chasty RC, Myint H, Oscier DG, et al. Autoimmune haemolysis in patients with B-CLL treated with chlorodeoxyadenosine (CDA). Leuk Lymphoma 1998; 29:391.
- Robak T, Błasińska-Morawiec M, Krykowski E, et al. Autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia treated with 2-chlorodeoxyadenosine (cladribine). Eur J Haematol 1997; 58:109.
- Fleischman RA, Croy D. Acute onset of severe autoimmune hemolytic anemia after treatment with 2-chlorodeoxyadenosine for chronic lymphocytic leukemia. Am J Hematol 1995; 48:293.
- Robak T, Boński JZ, Kasznicki M, et al. Re-treatment with cladribine-based regimens in relapsed patients with B-cell chronic lymphocytic leukemia. Efficacy and toxicity in comparison with previous treatment. Eur J Haematol 2002; 69:27.
- Tetreault SA, Saven A. Delayed onset of autoimmune hemolytic anemia complicating cladribine therapy for Waldenström macroglobulinemia. Leuk Lymphoma 2000; 37:125.
- Aslan DL, Peterson BA, Long-Tsai M, Eastlund T. Early-onset autoimmune hemolytic anemia after cladribine therapy for Waldenström's macroglobulinemia. Transfusion 2006; 46:90.
- Byrd JC, Hertler AA, Weiss RB, et al. Fatal recurrence of autoimmune hemolytic anemia following pentostatin therapy in a patient with a history of fludarabine-associated hemolytic anemia. Ann Oncol 1995; 6:300.
- Zaucha JM, Hałaburda K, Ciepłuch H, Hellmann A. 2-Chlorodeoxyadenosine treatment of patients with chronic lymphocytic leukaemia associated with autoimmune haemolysis. Acta Haematol Pol 1994; 25:119.
- Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol 1995; 91:341.
- Orchard J, Bolam S, Myint H, et al. In patients with lymphoid tumours recovering from the autoimmune complications of fludarabine, relapse may be triggered by conventional chemotherapy. Br J Haematol 1998; 102:1112.
- Dighiero G. Adverse and beneficial immunological effects of purine nucleoside analogues. Hematol Cell Ther 1996; 38 Suppl 2:S75.
- Peller S, Kaufman S. Decreased CD45RA T cells in B-cell chronic lymphatic leukemia patients: correlation with disease stage. Blood 1991; 78:1569.
- Fagiolo E, Toriani-Terenzi C. Th1 and Th2 cytokine modulation by IL-10/IL-12 imbalance in autoimmune haemolytic anaemia (AIHA). Autoimmunity 2002; 35:39.
- Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol 1998; 25:80.
- Tosti S, Caruso R, D'Adamo F, et al. Severe autoimmune hemolytic anemia in a patient with chronic lymphocytic leukemia responsive to fludarabine-based treatment. Ann Hematol 1992; 65:238.
- Juliusson G, Elmhorn-Rosenborg A, Liliemark J. Response to 2-chlorodeoxyadenosine in patients with B-cell chronic lymphocytic leukemia resistant to fludarabine. N Engl J Med 1992; 327:1056.
- Piro LD, Carrera CJ, Beutler E, Carson DA. 2-Chlorodeoxyadenosine: an effective new agent for the treatment of chronic lymphocytic leukemia. Blood 1988; 72:1069.
- Trapè G, Fianchi L, Lai M, et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for refractory hemolytic anemia in patients with lymphoproliferative disorders. Haematologica 2003; 88:223.
- Paydas S, Yavuz S, Disel U, et al. Successful rituximab therapy for hemolytic anemia associated with relapsed splenic marginal zone lymphoma with leukemic phase. Leuk Lymphoma 2003; 44:2165.
- Hofer S, Hunziker S, Dirnhofer S, Ludwig C. Rituximab effective in a patient with refractory autoimmune haemolytic anaemia and CD20-negative multiple myeloma. Br J Haematol 2003; 122:690.
- Paydas S. Fludarabine-induced hemolytic anemia: successful treatment by rituximab. Hematol J 2004; 5:81.
- Shvidel L, Shtalrid M, Berrebi A. Intractable autoimmune hemolytic anemia in B cell chronic lymphocytic leukemia resolved by Rituximab. Leuk Lymphoma 2004; 45:1493.
- Chemnitz J, Draube A, Diehl V, Wolf J. Successful treatment of steroid and cyclophosphamide-resistant hemolysis in chronic lymphocytic leukemia with rituximab. Am J Hematol 2002; 69:232.
- Iannitto E, Ammatuna E, Marino C, et al. Sustained response of refractory chronic lymphocytic leukemia in progression complicated by acute hemolitic anemia to anti-CD20 monoclonal antibody. Blood 2002; 99:1096.
- Gupta N, Kavuru S, Patel D, et al. Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia. Leukemia 2002; 16:2092.
- Kaufman M, Limaye SA, Driscoll N, et al. A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma 2009; 50:892.
- Mo CC, Njuguna N, Beum PV, et al. Rapid clearance of rituximab may contribute to the continued high incidence of autoimmune hematologic complications of chemoimmunotherapy for chronic lymphocytic leukemia. Haematologica 2013; 98:1259.
- Karlsson C, Hansson L, Celsing F, Lundin J. Treatment of severe refractory autoimmune hemolytic anemia in B-cell chronic lymphocytic leukemia with alemtuzumab (humanized CD52 monoclonal antibody). Leukemia 2007; 21:511.
- Lundin J, Karlsson C, Celsing F. Alemtuzumab therapy for severe autoimmune hemolysis in a patient with B-cell chronic lymphocytic leukemia. Med Oncol 2006; 23:137.
- Rodon P, Breton P, Courouble G. Treatment of pure red cell aplasia and autoimmune haemolytic anaemia in chronic lymphocytic leukaemia with Campath-1H. Eur J Haematol 2003; 70:319.
- Cavazzini F, Lista E, Quaglia FM, et al. Response to ibrutinib of refractory life-threatening autoimmune hemolytic anemia occurring in a relapsed chronic lymphocytic leukemia patient with 17p deletion. Leuk Lymphoma 2016; 57:2685.
- Rogers KA, Ruppert AS, Bingman A, et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia 2016; 30:346.
- Bussel JB, Cunningham-Rundles C, Abraham C. Intravenous treatment of autoimmune hemolytic anemia with very high dose gammaglobulin. Vox Sang 1986; 51:264.
- Majer RV, Hyde RD. High-dose intravenous immunoglobulin in the treatment of autoimmune haemolytic anaemia. Clin Lab Haematol 1988; 10:391.
- Björkholm M. Intravenous immunoglobulin treatment in cytopenic haematological disorders. J Intern Med 1993; 234:119.
- Bastion Y, Coiffier B, Dumontet C, et al. Severe autoimmune hemolytic anemia in two patients treated with fludarabine for chronic lymphocytic leukemia. Ann Oncol 1992; 3:171.
- Ford CD, Asch J, Pulsipher M, Petersen FB. Successful reduced-intensity allogeneic transplantation utilizing a fludarabine-based preparative regimen in a patient with chronic lymphocytic leukaemia and a history of fludarabine-associated autoimmune haemolytic anaemia. Br J Haematol 2004; 126:623.
- Del Poeta G, Del Principe MI, Consalvo MA, et al. The addition of rituximab to fludarabine improves clinical outcome in untreated patients with ZAP-70-negative chronic lymphocytic leukemia. Cancer 2005; 104:2743.
- O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 2001; 19:1414.
- Wierda W, O'Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4070.
- Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4079.
- Lewis FB, Schwartz RS, Dameshek W. X-radiation and alkylating agents as possible "trigger" mechanisms in the autoimmune complications of malignant lymphophroliferative disease. Clin Exp Immunol 1966; 1:3.
- Seipelt G, Böhme A, Koschmieder S, Hoelzer D. Effective treatment with rituximab in a patient with refractory prolymphocytoid transformed B-chronic lymphocytic leukemia and Evans syndrome. Ann Hematol 2001; 80:170.
- Wells T, Kovacs MJ. Autoimmune thrombocytopenia due to chronic lymphocytic leukemia treated with fludarabine. Ann Pharmacother 2003; 37:671.
- Stern SC, Shah S, Costello C. Probable autoimmune neutropenia induced by fludarabine treatment for chronic lymphocytic leukaemia. Br J Haematol 1999; 106:836.
- Roberts L, Lucas G, Green L, et al. Autoimmune neutropenia following therapy for chronic lymphocytic leukaemia: a report of three cases. Br J Haematol 2007; 136:348.
- AUTOIMMUNITY IN CLL
- AUTOIMMUNE HEMOLYTIC ANEMIA
- AIHA after fludarabine
- AIHA after cladribine or pentostatin
- Risk factors
- - Development of a positive Coombs test
- - Prior episode of FA-AIHA
- TREATMENT OF FA-AIHA
- Initial steps
- Poorly responsive disease
- - Immunosuppression
- - Chemotherapy
- - Cladribine
- - Rituximab
- - Alemtuzumab
- - Ibrutinib
- - Intravenous immune globulin
- Retreatment with fludarabine or other chemotherapy
- AUTOIMMUNE THROMBOCYTOPENIA
- AUTOIMMUNE NEUTROPENIA
- SUMMARY AND RECOMMENDATIONS