3. What is new and Conclusion
The manifestations of CLL are excessive proliferation and aggregation of clonal B lymphocytes in peripheral blood, bone marrow, lymphaden, and spleen. Clonal B lymphocytes are similar to mature lymphocytes in morphology. However, these cells possess abnormal immune expression and dysregulated cell functioning. Furthermore, despite having the typical immunophenotypes of clonal B lymphocytes (CD5+, CD10-, CD19+, FMC7-, CD23+, CD43+/- and CCND1-), the cells are considered abnormal. In the 1980s, the ability to assess genomic sequences for markers of disease facilitated a significant breakthrough in CCL diagnosis and therapy. Combination treatment using fludarabine and cyclophosphamide (FC) has become the basic recommendation which is stated in the NCCN guidelines. 2, 3 But CLL remains an incurable hematologic malignant disease.
CLL can cause various complications, especially infection and autoimmune diseases. Globally, the incidence of autoimmune diseases is approximately 10-25% and often affects the blood system. The most common autoimmune diseases are autoimmune cytopenias (AIC), developed in 4-7% of CLL patients. Among these cases, pure erythrocyte aplastic anemia (PRCA ) is a rare disorder that is often seen in the terminal stage of disease in fludarabine-treated patients.4, 5PRCA may be related to immune dysfunction induced by immune inhibitors, but this remains to be elucidated. Immune-mediated hypocytosis occurs frequently in CLL, but only two cases have reported CLL with secondary pancytopenia.6, 7 The pathogenesis of CLL-related AIC is associated with T lymphocyte dysfunction, clonally proliferating B lymphocyte antigen presentation, and autoantibody production by normal residual B lymphocytes.8, 9 Previous studies have shown that these antibodies directly inhibited erythropoiesis and thrombocytopoiesis.10, 11 Additionally, CLL-related AIC can easily be confused with CLL progression, chemotherapy-related marrow suppression, myelodysplastic syndrome, and acute arrest of hemopoiesis. Immunohistochemical analyses and the assessment of the recovery period after treatment provide key strategies to differentiate and diagnose these diseases.
Lad et al12 reported that dysfunctional T lymphocytes in CLL, especially at the late stage, may explain the pathogenesis of CLL-associated AIC. Therefore, although no direct evidence has shown that CLL patients have a significant tendency to develop auto-immune disorders, the correlation between CLL and non-hematological autoimmunity should not be ignored. In the current case report, the increased frequency of inhibitory T lymphocytes was indicative of immunologic derangement in the patient. Further, these data suggest that the induction of autoantibodies and T lymphocyte dysfunction may play important roles in our case. CsA, an immunomodulator, can regulate T lymphocyte function and suppress the release of lymphokines such as IL-2, IL-4, TNF, and IFN from antigen-activated T lymphocytes. We further explored how CsA regulates immunologic derangement in CLL patients and whether CsA can facilitate complete remission. Previously, a study of 31 cases where CsA treatment was used to treat CLL-related AIC confirmed its effectiveness. In that study, 19 of 29 (66%) thrombocytopenic patients and 11 of 16 (69%) anemic patients were remitted following treatment. Additionally, a reduction of tumor load and lymph nodes was observed in some patients.13 Zhao et al14 suggested that CsA can regulate the immune micro-environment, recover T lymphocyte function, inhibit auto-antibodies, eliminate tumor cells, and reduce tumor cell escape. These mechanisms may be the methods by which CsA sustained remitted CLL and exerted synergistic effects in leukemia therapy. However, the underlying mechanism of CsA in CLL cell lines remains unknown. Furthermore, any evidence for the treatment of CLL-related autoimmune disease using CsA treatment is mostly found in cases reports. Together, data in the literature highlight the urgent need for the assessment of CsA in a large-scale, sufficiently powered experimental setting. Additionally, after the reduction of tumor load in CLL, the ability of CsA to regulate marrow immune-environment and exert synergistic anti-tumor effects need to be further explored.
In conclusion, we reported a CLL patient with related pancytopenia who showed an obvious and complete remission of the disease after CsA treatment. These findings provide new insights into CLL treatment and help to inform future studies.