Background: Acquired aplastic anemia (AA) is characterized by an aplastic bone marrow and pancytopenia. Adult patients with AA can be treated with immunosuppressive treatment (IST) consisting of ATGAM in combination with cyclosporin (CsA) or with an allogeneic hematopoietic stem cell transplantation (alloSCT). Patients <40 years with an HLA-identical sibling preferentially receive an alloSCT. Other patients are treated with IST as 1st line treatment. IST leads to transfusion independency in the majority of patients but it can take up to 6 months before this response occurs. Some patients need long-term treatment with CsA to maintain this response and durable efficacy is hampered by relapsing aplasia or the development of MDS, AML or PNH. While graft versus host disease and relapse-free survival (GRFS) is used as a favorable composite outcome after alloSCT, a widely accepted measurement for treatment success after IST is missing.
Aims: In this study we examined Transplant, Treatment and Transfusion-free survival (TTT-free survival) as a relevant clinical outcome after standard IST with ATGAM and CsA in AA adult patients. We determined the 5-year TTT-free survival after standard IST in patients ≤40 years and >40 years.
Methods: The Dutch Adult Aplastic Anemia Registry started in 2014 and contains detailed data of all consecutive AA patients who have been treated with ATGAM-based therapy in the participating hospitals, offering a unique possibility to evaluate real-life long-term efficacy and safety of 1st line IST treatment in AA. To determine TTT-free survival, a multistate model (MSM) was developed, to take into account that patients can have transient periods of treatment success and failure. Patients started in the dynamic state treatment & transfusion at time of the start of ATGAM. This state also included all other (2nd line) non-alloSCT treatments (for example Eltrombopag, Rabbit-ATG or Danazol). Other dynamic states patients could enter and leave during follow-up were treatment & no transfusion, transfusion & no treatment and no treatment & no transfusion (considered as TTT-free survival). Absorbing states, accessible from all dynamic states, were death, alloSCT for AA, treatment for MDS/AML and treatment for PNH.
Results: ATGAM with CsA as 1st line treatment was started in 117 patients (median age 54 years, range 18-79). Overall survival after 5 year is 77% (95% Confidence Interval (95%CI) 67-86%) Figure 1 shows the results of the MSM. After 5 years, the TTT-free survival was 42% (95%CI: 33-55%) for the total cohort. 19% (95%CI: 12-31%) of the patients was transfusion independent but still needed medication at this time (mainly CsA or Eltrombopag). 15% (95%CI: 10-23%) had received an alloSCT as 2nd line treatment for AA, 5% (95%CI: 2-13%) had started treatment for MDS/AML and 2% (95%CI: 0-11%) had started treatment with complement inhibition for PNH. 5-year TTT-free survival was 60% (95%CI:44-82%) in patients aged ≤40 years (n=36), but only 33% (95%CI: 23-49%) in patients aged >40 years (n=81).
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Summary/Conclusion: TTT-free survival can be used to evaluate treatment success after IST in AA patients, allowing achievement, loss and recovery of response. We showed that 5-year TTT-free survival is superior in patients ≤40 years compared to patients >40 years. This MSM can be used to predict outcomes in AA patients receiving IST and can help in the decision whether and when to offer a patient an alloSCT.