Immune Thrombocytopenia and CLL
Abstract & Commentary
By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Immune thrombocytopenia is a problematic but poorly characterized complication of chronic lymphocytic leukemia. The authors propose a definition for immune thrombocytopenia in CLL that included a 50% drop in platelet count and adequate marrow megakaryocytes in the absence of chemotherapy or other causes. Among 1278 CLL patients followed in several Italian centers, 64 (5%) met criteria for immune thrombocytopenia. Fourteen were found at diagnosis, and 50 in follow-up. Immune thrombocytopenia patients had a worse prognosis, possibly mediated by a strong association of immune thrombocytopenia with unmutated immunoglobulin heavy chain.
Source: C. Visco, et al. Blood. 2008. vol. 111: 1110-1116.
Autoimmune hematologic disorders are uncommon but clinically problematic complications of chronic lymphocytic leukemia (CLL). The spectrum of immune disorders includes autoimmune hemolytic anemia, pure red blood cell aplasia, and immune thrombocytopenia. Immunosuppression therapy with agents such as cyclosporine, steroids, or rituximab is often used to combat immune complications, rather than aggressive CLL treatment, emphasizing the importance of recognition.
Immune mediated thrombocytopenia has been reported in about 2-3% of patients having CLL.1 Diagnosis criteria and prognostic relevance of immune thrombocytopenia in CLL remains poorly characterized. Thrombocytopenia in CLL typically signifies more advanced disease and thus a low platelet count is a critical component of staging and treatment. Although clinically recognized by an unexpected rapid fall in platelets and adequate marrow megakaryocytes, diagnostic criteria for immune thrombocytopenia are lacking.
The authors analyzed 1278 consecutive patients diagnosed with CLL at 3 Italian institutions. The median age was 67 years, 85% had Rai stages 0, 1 or 2, and median follow-up was 5 years. Diagnostic criteria for immune thrombocytopenia required a 50% or greater decline in platelets below 100 x 109/L over a period of less than 2 weeks in the absence of cytotoxic therapy or any other cause for new onset thrombocytopenia. Patients were not included if they had significant splenomegaly or any decrease in marrow megakaryocytes. For patients having Rai stage 3 or 4 CLL where marrow megakaryocyte determination was difficult, the diagnosis required a lack of response to platelet transfusion or response to high dose IV immunoglobulin in less than 1 week. Sixty-four patients (5%) met criteria for IT; 14 of these presented at diagnosis (1% of total) and the remaining 50 developed immune thrombocytopenia at a median of 17 months after presentation. The majority of patients (75%) had previously been treated for CLL when immune thrombocytopenia was diagnosed. Ten immune thrombocytopenia patients had concurrent or prior autoimmune hemolytic anemia. Autoimmune hemolytic anemia was much more common in patients with immune thrombocytopenia (Evans Syndrome) than in those without (P < 0.001). The adverse prognostic markers of unmutated IgVh gene and ZAP-70 were significantly associated with developing immune thrombocytopenia.
Immune thrombocytopenia was treated using a variety of interventions when the platelet count fell below 20 to 30 x 109/L or bleeding in the presence of a platelet count below 50 x 109/L. Four patients died of refractory immune thrombocytopenia. Among the 64 immune thrombocytopenia patients, 87% received treatment. Complete and partial responses occurred in 37% and 21%, respectively after first line treatment.
Unadjusted survival analysis showed that the 14 patients presenting with immune thrombocytopenia had inferior survival (five died), having similar outcomes to Rai Stage IV patients. The development of immune thrombocytopenia was also associated with worse survival (P = .004) although the effect was mitigated when adding a full panel of biologic and clinical variables.
Commentary
Visco and colleagues provide important data characterizing immune thrombocytopenia in CLL. An important accomplishment is developing diagnostic criteria for immune thrombocytopenia. They document a "prevalence" of 5% among 1278 patients which was higher than other reports of 2-3%. However, since they followed patients in time, they actually quantify prevalence at diagnosis of approximately 1% and incidence during follow-up of an additional 4%. Although not validated, criteria will be useful in confirming these data in other populations and could be used as a guideline for clinicians entertaining immune thrombocytopenia.
Previous data suggested that immune thrombocytopenia did not confer an adverse prognosis;2 however, small sample size limited robust estimates of effect size. The authors suggest immune thrombocytopenia may confer a worse prognosis. This was based upon a subset analysis of a small number of immune thrombocytopenia at presentation (N = 14) and in another subset analysis of immune thrombocytopenia occurring within 24 months of diagnosis or treatment refractory. As noted by the authors, immunosuppressive therapy for immune thrombocytopenia could have led to complications that worsened outcome. Most likely, the increase in mortality was related to worse biologic features among immune thrombocytopenia patients. The lack of mutation in the variable region immunoglobulin heavy chain (VH) genes has emerged as a powerful predictor or progression and impaired survival.3 Unmutated IgVH and immune thrombocytopenia showed a strong correlation, as this group previously suggested.4 The finding is intriguing and certainly explains much of the adverse prognosis. Since mutational status of the IgVH is not widely available, finding immune thrombocytopenia may alert the clinician to a high risk of an unmutated IgVH and/or a worse prognosis. This also raises questions if unmutated IgVH predisposes to the pathogenesis of immune thrombocytopenia in CLL.
Because therapies for immune thrombocytopenia were at the physicians' discretion, limited insight can be garnered as to the optimal therapeutic approach. The complete and partial response rate of around 50% indicates treatments remains suboptimal.
References
1. Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol. 1998;25:80-97.
2. Kyasa MJ, et al. Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003;74:1-8.
3. Krober A, et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410-1416.
4. Visco C, et al: Un-mutated IgVH in chronic lymphocytic leukemia is associated with a higher risk of immune thrombocytopenia. Leukemia. 2007;21:1092-1093.
Immune thrombocytopenia is a problematic but poorly characterized complication of chronic lymphocytic leukemia. The authors propose a definition for immune thrombocytopenia in CLL that included a 50% drop in platelet count and adequate marrow megakaryocytes in the absence of chemotherapy or other causes.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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