Effective Treatment of Aplastic Anemia Secondary to Chemoradiotherapy Using Cyclosporine A
Aplastic anemia (AA) is a severe bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow. It can be classified into congenital and acquired forms, with the majority of acquired cases being idiopathic. In idiopathic AA, the immune system mistakenly attacks hematopoietic stem cells and their microenvironment, leading to impaired blood cell production. However, AA can also occur secondary to chemoradiotherapy, a common treatment modality for malignant tumors. While most patients recover from chemotherapy-induced cytopenia within 1 to 2 months after cessation of treatment, some individuals fail to recover even after 3 months of therapy-free intervals. These patients are diagnosed with AA and face significant challenges, including severe infections, bleeding, and the inability to continue planned chemoradiotherapy, which may result in relapse of the primary tumor. The increasing use of bone marrow suppression therapies in cancer treatment has led to a rise in therapy-related AA. Despite this, there are no established guidelines or consensus on managing this condition. This study explores the efficacy and safety of cyclosporine A (CsA) in treating AA secondary to chemoradiotherapy.
The study included patients who met specific criteria: (1) a clear diagnosis of malignant tumor with no prior hematologic abnormalities; (2) persistent cytopenia in at least one lineage for at least 3 months after stopping chemoradiotherapy; (3) a confirmed diagnosis of AA based on bone marrow smear, biopsy, chromosome analysis, and gene profiling; (4) severe cytopenia, defined as hemoglobin (HGB) <90 g/L, absolute neutrophil count (ANC) <0.5 × 10^9/L, or platelet count (PLT) <20 × 10^9/L; and (5) stable tumor status with an expected survival of more than 6 months. All patients received CsA at a dose of 3–5 mg/kg/day for at least 6 months, with a target blood concentration of 100–200 ng/mL. Blood transfusions were permitted, but hematopoietic growth factors, including eltrombopag, were not used during the study period. Efficacy was evaluated according to international guidelines, and patients were followed up for at least 1 year.
Twenty-five patients were included in the final analysis. The cohort consisted of 8 males and 17 females, with a median age of 58 years (range: 25–76 years). The primary malignancies included cervical cancer (5 cases), ovarian cancer (4 cases), colorectal cancer (4 cases), urinary tumors (4 cases), breast cancer (3 cases), lung cancer (2 cases), thymic carcinoma (1 case), tongue cancer (1 case), and nasopharyngeal carcinoma (1 case). The median number of chemotherapy cycles was 3 (range: 1–8 cycles), and the median radiotherapy dosage was 45 Gy (range: 25–60 Gy). All patients had previously received supportive treatments such as granulocyte-colony stimulating factor (G-CSF), erythropoietin (EPO), thrombopoietin (TPO), interleukin-11 (IL-11), or eltrombopag for 4 to 12 weeks without improvement. The diagnosis of AA was made at a median of 4 months (range: 3–5 months) after the last chemoradiotherapy session. Seven patients had single-lineage cytopenia, four had bi-lineage cytopenia, and 14 had tri-lineage cytopenia. Baseline blood counts showed an average HGB of 95 ± 27 g/L, ANC of 2.0 ± 1.9 × 10^9/L, and PLT count of 18 ± 17 × 10^9/L.
Patients were treated with CsA for a median duration of 12 months (range: 6–24 months) and followed up for a median of 14 months (range: 8–40 months). The CsA concentration was maintained within the target range of 100–200 ng/mL throughout the treatment period. After 3 months of CsA therapy, the complete response (CR) rate was 16% (4/25), the partial response (PR) rate was 36% (9/25), and the overall response rate (ORR) was 52% (13/25). At 6 months, the CR, PR, and ORR increased to 24% (6/25), 40% (10/25), and 64% (16/25), respectively. By the end of the follow-up period, the CR, PR, and ORR further improved to 36% (9/25), 44% (11/25), and 80% (20/25), respectively. The average HGB increased to 100 ± 20 g/L, ANC to 2.3 ± 1.0 × 10^9/L, and PLT count to 92 ± 81 × 10^9/L. Fifteen patients had their CD4/CD8+ ratios measured before and after CsA treatment, showing values of 1.05 ± 1.20 and 1.62 ± 2.05, respectively (P = 0.263).
The side effects of CsA were generally mild and manageable. One patient (4%) experienced elevated creatinine levels, four (16%) had mild gingival hyperplasia, three (12%) had mild bilirubin elevation, and three (12%) reported gastrointestinal discomfort. All patients maintained stable tumor status during the follow-up period. Notably, two patients who achieved CR with CsA were able to resume additional chemotherapy courses without significant complications. One patient with breast cancer received four additional chemotherapy cycles after 1 year of CsA treatment, while another with kidney cancer underwent two cytotoxic consolidation chemotherapies after 8 months of CsA. CsA was temporarily discontinued during these chemotherapy periods.
The study highlights the importance of careful patient selection and diagnostic workup to exclude transient myelosuppression and other causes of cytopenia. All patients had normal blood counts before chemoradiotherapy, and AA was confirmed at least 3 months after treatment cessation. The underlying mechanisms of secondary AA may involve immune-mediated destruction of hematopoietic stem cells triggered by chemoradiotherapy, similar to primary AA. However, due to the small sample size, it was challenging to identify specific risk factors such as age, tumor type, or chemoradiotherapy dosage and cycles. The cohort had a higher proportion of females (8 males vs. 17 females), but no significant differences in response rates were observed based on baseline characteristics.
CsA is an immunosuppressive agent commonly used in primary AA, where it modulates Treg cells and reduces immune surveillance. However, its use in cancer patients is limited due to concerns about tumor progression and the risk of lymphoproliferative disorders. In this study, CsA was administered to patients with stable tumor status and severe cytopenia that hindered further anti-tumor therapy. The response rates were higher than those typically observed in primary AA, possibly due to the shorter duration and less severe nature of secondary AA in this cohort. Adverse events were comparable to those reported in primary AA, including elevated creatinine, bilirubin, and mild gingival hyperplasia, but most were managed with dose adjustments.
During the follow-up period, no tumor progression was observed, and two patients successfully resumed chemotherapy after achieving hematological remission with CsA. This suggests that CsA may provide a window of opportunity for patients to continue anti-tumor therapy, which would otherwise be impossible due to severe cytopenia. However, long-term follow-up with a larger patient cohort is needed to confirm these findings and assess the potential risks of tumor progression associated with CsA.
In conclusion, this study demonstrates that CsA is an effective and safe treatment option for patients with AA secondary to chemoradiotherapy. The high response rates and manageable side effects make it a viable alternative for patients who fail to recover from cytopenia with supportive therapies alone. While the study’s sample size and follow-up duration are limited, the results provide valuable insights for managing this challenging condition and underscore the need for further research to establish standardized treatment guidelines.
doi.org/10.1097/CM9.0000000000001365
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