Cyclosporine for Cytopenias in Chronic Lymphocytic Leukemia
Cyclosporine for Cytopenias in Chronic Lymphocytic Leukemia
Abstract & Commentary
Synopsis: This report deals with the use of Cyclosporin A in 31 CLL patients with autoimmune anemia or thrombocytopenia. A response was seen in 69% of patients with anemia and 66% of patients with thrombocytopenia. They also were durable with a median duration of 10 months and occurred after a median of 3 weeks. Previous treatment with steroids, immune globulin (IVIG), or splenectomy did not affect the likelihood of a response to CsA. The most important toxicity was renal insufficiency, occurring in 19% of patients.
Source: Cortes J, et al. Cancer. 2001;92:2016-2022.The management of chronic lymphocytic leukemia (CLL) can be complicated by autoimmune thrombocytopenia (ITP) and hemolytic anemia (AIHA). For those patients resistant to steroids, cyclosporin A (CsA) has provided encouraging data in case reports and small series. Cortes and associates therefore studied 31 CLL patients whose cytopenias were felt to be immune-mediated. All but 3 of the patients had received antileukemic therapy, with 15 patients exposed to 2 or more regimens. Anemia (hemoglobin < 11) was present in 52% and thrombocytopenia (platelets < 100) was observed in 94% of patients when CsA was started. The cytopenia was associated with fludarabine in 17 cases (55%).
A response was seen in 11 of 16 (69%) patients with anemia and 19 of 29 (66%) patients with thrombocytopenia. The responses were characterized as excellent in 9 anemic patients (hemoglobin rise > 3 to at least 12 g/dL) and 12 thrombocytopenic patients (platelet rise > 50 to at least 150 ´ 109/L). They were also durable with a median duration of 10 months and occurred after a median of 3 weeks. Previous treatment with steroids, immune globulin (IVIG), or splenectomy did not affect the likelihood of a response to CsA. CsA was effective in 76% of fludarabine-associated cytopenias and 57% of the patients without fludarabine exposure. The most important toxicity was renal insufficiency, occurring in 19% of patients.
Comment by Kenneth W. Kotz, MD
Cortes et al present what is likely the largest study of CsA for autoimmune cytopenias in CLL. AIHA is the most common hematologic autoimmune disease in CLL, occurring in 10-25% of patients, with ITP occurring in 2-5% and pure red cell aplasia being relatively rare.1,2 Interestingly, the association of nonhematologic autoimmune disease and CLL may be overstated due to reporting biases and errors in study design.1,3
Diagnosing AIHA and monitoring response to therapy can be complicated by the multifactorial nature of the anemia in CLL, including therapy-related myelosuppression, marrow infiltration, and hypersplenism. Once diagnosed, the standard therapy is prednisone, usually started at 1 mg/kg daily. Responses occur as soon as 3 days or up to 3 weeks. IVIG has been recommended for patients not responding after 7-10 days,1 but Diehl and colleagues point out that responses to IVIG are limited and may be best for those patients requiring a rapid result.1 CsA has been recommended as second-line therapy for AIHA while reserving splenectomy for those patients with ongoing hemolysis.1,4 Surprisingly, the data supporting the use of splenectomy for AIHA in CLL are relatively sparse.1,3,4 Nevertheless, either CsA or splenectomy could be used in selected patients as second-line therapy.
Diagnosing ITP in CLL can be complicated by myelosuppression, marrow infiltration, or hypersplenism. Of the 31 patients enrolled, 29 had thrombocytopenia perhaps reflecting the cutoff used (platelets < 100) and the imprecise eligibility requirements ("suspected immune etiology"). Treatment of ITP in CLL starts with prednisone 1 mg/kg daily. Cortes et al report ITP responds to CsA 66% of the time. They also reference articles showing similar or better response rates to splenectomy. The choice of second-line therapy for ITP in CLL could probably be individualized.
Oncologists unaccustomed to using CsA should remember that the several available brands are not bioequivalent (although they are all spelled "cyclosporine" in the PDR). The drug should be given twice a day with the CsA level drawn right before the morning dose. Be aware that CsA levels can be measured by different assays that are in general use. Also, CsA is associated with thrombotic microangiopathy that might be confused with progressive autoimmune cytopenias. Hypertension can be managed with diltiazem, but calcium channel blockers can interfere with CsA metabolism, as does grapefruit (and grapefruit juice), which should be avoided. Remember to check for the multiple drug interactions, watch the renal function carefully, and watch for hypomagnesemia. Starting doses in the literature range from 5-8 mg/kd/d although Cortes et al used "300 mg p.o. daily" which would best be given as 150 mg every 12 hours.1,4
The AIHA in CLL is related to polyclonal antibodies rather than the malignant clone itself.4 Therefore, one theory holds that AIHA occurs in CLL as the progressive immune dysregulation allows re-expression of normally suppressed auto-reactive T cells.1,3 This may explain the association of immune complications and purine analogs, which cause prolonged lymphopenia mainly affecting T cells. It has been recommended that CLL patients recovering from fludarabine-associated AIHA not be rechallenged due to life-threatening recurrence of the hemolysis.3,4 Because fludarabine has also been associated with ITP,3 it is interesting that Cortes et al re-treated 3 fludarabine-associated ITP patients and report that subsequent cycles had improved platelet nadirs with CsA. Nevertheless, extreme caution should be taken when considering reexposure to fludarabine after any autoimmune complication.
Several reports, referenced by Cortes et al, have described antileukemic responses during treatment with CsA. By design, concurrent chemotherapy was not administered with CsA in this study. Amazingly, there were 6 responses which included a sustained (8+ months) reduction in the leukocyte count in 1 patient and transient but major improvement in measurable lymphadenopathy in 2 patients. Although treating physicians should be aware of this phenomenon, the benefit is modest in degree and duration, and standard anti-CLL therapy should be instituted concurrently if appropriate. Perhaps elucidating the mechanism of action will translate into newer therapeutic approaches.
References
1. Diehl L, et al. Semin Oncol. 1998;25:80-97.
2. Keating M. Semin Oncol. 1999;26:107-114.
3. Hambin T. Autoimmune Disease and its Management in Chronic Lymphoid Leukemias. In: Cheson B, ed. Chronic Lymphoid Leukemias. New York, NY: Marcell Dekker; 2001:435-458.
4. Dighiero G. CLL. The Cutting Edge. 1998;3:2-4.
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