Clinical Spectrum, Evolution and Management of Autoimmune Cytopenia Associated with Angioimmunoblastic T-Cell Lymphoma: A Retrospective, Multicenter Study

Introduction

Angioimmunoblastic T-cell lymphomas (AITL) are frequently associated with immune system activation such as hypergammaglobulinemia, positive direct antiglobulin test, anti-smooth muscle antibodies and clinical autoimmunity. Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) have been reported, but to date, there is no specific study focusing on autoimmune cytopenia (AIC) in AITL. We sought to determine the clinical characteristics, evolution and response to treatment of AITL presenting with autoimmune cytopenia, including ITP, AIHA, auto-immune neutropenia (AIN) and pure red cell aplasia (PRCA) in a large cohort of patients from the multicentric T-cell lymphoma consortium (TENOMIC).

Patients and methods

We conducted a retrospective, multicenter study of patients diagnosed with AITL between 2001 and 2015 and presenting with at least one AIC (i.e. AHAI and/or ITP and/or AIN and/or PRCA, defined according to the international criteria). Patients were retrospectively selected from a cohort of 293 patients with AITL from a multicentric T-cell lymphoma consortium (TENOMIC). Medical charts were collected using a standardized from. Patients with AIC were matched for age and sex to control patients (5/1 ratio) diagnosed with AITL without AIC from the cohort.

Results

28 patients were included, with a mean age of 63 years (range 39 - 83), and 50% were females. There were 41 AIC (AIHA, n=21 (including 5 cold agglutinin diseases), ITP, n=12, PRCA, n=7, AIN, n=1). Among them, 17 patients had only one AIC, 7 had both ITP and AIHA (Evan's syndrome) and 4 had PCRA associated with another AIC. One hundred and thirty six control patients were included (mean age 64 years (range 35 - 84), 49% female). Clinical characteristics of AITL at diagnosis showed more stage IV disease in AIC patients versus control patients (86% vs 66%, P= 0.0442), as well as more bone marrow (71% vs 34%, P=0.0005) and splenic (61% vs 19%, P< 0.0001) involvement. Immune activation markers such as anti-smooth muscle antibodies (71% vs 0.9%, P< 0.0001), gammaglobulins titers (27 g/l vs 18 g/l, P= 0.0019), and EBV replication (89% vs 61%, P= 0.0232), were significantly increased in AIC patients versus control patients. AIC were mainly concomitant with AITL diagnosis (83%). Only 2 patients had AIC before AITL diagnosis (2 and 8 months), and 4 patients developed AIC during the disease course (median 14 months (8 - 114)). Mean hemoglobin level at AIHA and PRCA diagnosis were 7.1 g/dl and 5.3 g/dl, and red blood cell transfusions were required in 52% and 86% of patients, respectively. Mean platelet count was 35 x 10⁹/L at ITP diagnosis, and 42% of patients had bleeding manifestations, although no life threatening bleeding manifestation was observed. First line treatments of AIC included corticosteroids (88%), chemotherapy for AITL (71%), intravenous immunoglobulin (27%), or other treatments (12%), and were effective in all patients except for two patients who presented with refractory ITP. Ten patients had a relapse of AIC (5 ITP, 4 AIHA, 3 PRCA) with a median time to relapse of 4 months (1 - 18)). All AIC relapses were associated with AITL relapse. Only 3 patients had active AIC while AITL was considered in remission, including one patient who developed ITP after autologous stem cell transplantation. Sixty-four percent versus 66% of patients experienced AITL relapse in AIC and control group, respectively (P=1). Median overall survival (OS) and median progression free survival (PFS) were 77 and 12 months in the AIC group, and 41 and 12 months in the control group, respectively (P=ns).

Conclusion

In summary, AITL associated with AIC had more advanced disease with increased immune activation compared to our control group, although it did not impact OS and PFS. AIC were mainly inaugural and responded well to chemotherapy. Interestingly, all AIC relapses were associated with AITL relapse. These findings are of interest for management of AITL patients presenting with AIC.