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.