Determinants of Relapse and Treatment-Free Survival Following Splenectomy in Patients with Immune Cytopenias

Background:

Splenectomy has historically been a treatment option for patients with immune cytopenia not responding to standard treatment. Despite being a highly effective treatment option, current guidelines recommend this strategy as a third-line treatment. There is a need for more evidence regarding predictive response factors that could help adequately select the ideal candidate for splenectomy, its effectiveness, and related complications. The study aims to identify factors associated with relapse in patients diagnosed with immune cytopenia who have undergone splenectomy.

Methods:

Retrospective cohort study including patients with immune cytopenia, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES), who underwent splenectomy between January 1990 and March 2023 in a tertiary referral center in Mexico City. Response criteria were based on the 2019 American Society of Hematology guidelines for ITP and the 2020 First International Consensus Meeting for AIHA. We defined early surgical complications as those occurring in the first 30 days from splenectomy; a durable response after splenectomy was described as lasting one year or more.

Results:

With a median follow-up of 100 months (interquartile range [IQR] 55.6 - 141.7 months), 173 patients were analyzed: 70% were female, 83% had primary ITP, 10% AIHA, and 7% ES. Only 15% had secondary autoimmune cytopenia: 4% systemic lupus erythematosus, 4% antiphospholipid antibody syndrome (APS), and 4% both; 3% had other autoimmune diseases; one (0.5%) patient had common variable immunodeficiency (CVI). Before splenectomy, all the patients received corticosteroids as first-line treatment, 13% rituximab, and 10% thrombopoietin receptor analogs (TPO-RA). Splenectomy was performed as the second-line treatment (2L) in 43% of the cases and as a third or later line of therapy (>2L) in 57%. When analyzing periods, there is a decline in the frequency of splenectomy as 2L: 62% from 1990-2010, 48% from 2011-2015, and 33% from 2016-2023. The median time from diagnosis to splenectomy was 6.3 months (IQR 2.6 - 19.9 months), 10.9 months (IQR 3.7 - 30.9 months), and 16.5 months (IQR 3.5 - 49.5 months) in the respective periods. The global response rate after splenectomy was 97.7%: complete response in 91.9%, partial response in 5.8%, and durable responses in 77.5%. The relapse rate after splenectomy was 32.0%, significantly lower in patients undergoing splenectomy as 2L vs. >2L: 20.0% vs. 40.8% (p<0.001). The relapse rate after splenectomy was the same in the different periods (p = 0.244). The number of patients free of a new line treatment after splenectomy at 100 months was significantly higher in patients undergoing splenectomy as 2L vs. >2L: 82.7% vs. 65.3% (p=0.014). When analyzing factors associated with relapse requiring a new line of treatment, splenectomy as the 2L (HR 0.403; 95% CI 0.206-0.788, p = 0.008) and post-splenectomy thrombocytosis (HR 0.301; 95% CI 0.144-0.6, p = 0.001) were associated with higher treatment-free survival in the multivariate analysis (See Table 1 and Figure 1).

The rate of early surgical complications was 14%: severe infections (8.7%), bleeding (5.2%), and thrombosis (3.5%). Late surgical complications occurred in 8%: thrombosis (5.8%), infections (2.9%), and bleeding (2.3%). Five patients (3%) died during the follow-up period: 3 related to thrombocytopenia, one to splenectomy (abdominal sepsis in a patient with CVI), and one due to prostate adenocarcinoma. The use of TPO-RA before splenectomy and the diagnosis of APS were associated with post-surgical thrombosis in the multivariate analysis: OR 6.8 (95% CI 1.9 - 23.5, p = 0.002) and OR 4.3 (95% CI 1 - 17.8, p = 0.044), respectively.

Conclusions:

At our center, splenectomy is frequently employed as a very early 2L treatment. However, this tendency has diminished due to improved access to new drugs. Interestingly, splenectomy as 2L vs. >2L is associated with better outcomes which contrast with current recommendations. In a center where splenectomy is frequently performed, the procedure is associated with a reasonable rate of complications. In patients with immune cytopenia, splenectomy as a second-line treatment is a valid, effective, relatively safe, and cost-effective option, particularly in low-income areas with limited access to new therapies.