A Retrospective Analysis on Prognostic Factors of Angioimmunoblastic T-Cell Lymphoma: a Multicenter Cooperative Study In Japan

Angioimmunoblastic T-cell lymphoma (AITL) is one of the major types of peripheral T-cell lymphoma (PTCL), with T follicular helper cells (TFH) reported to be the normal counterpart cell type. The disease generally presents with poor prognosis following conventional chemotherapy treatments. Furthermore, existing prognostic factors or predictive models for non-Hodgkin lymphoma are not useful in the prognostification of AITL. Identification of novel prognostic factors is therefore vital. Unfortunately, the number of studies using a large cohort of patients with AITL has so far been limited.

To elucidate the clinicopathological characteristics of AITL in Japan, we retrospectively analyzed 213 patients who were diagnosed with AITL between January 1990 and September 2008 from 31 participating hospitals. Patients with AITL were eligible for analysis only if their diagnosis was confirmed by histopathological and immunohistochemical criteria in accordance with the WHO classification. For immunohistochemical analysis, we evaluated CD10, CXCL13, PD-1 and EBER-ISH in addition to routine immunostaining. Clinical data was retrospectively collected from case reports. Patients received treatment for AITL according to the respective institutional protocols. Overall survival (OS) and progression free survival (PFS) were analyzed by using the log-rank test, and results expressed as Kaplan-Meier plots. Cox proportional hazard regression analysis with OS and PFS was performed to identify potential independent prognostic factors. This study was approved by the institutional review board of participating hospitals and complied with the provisions of the Declaration of Helsinki.

The median patient age was 67 years (range: 34–89 years), with 74% of patients older than 60 years. The female:male ratio was 1:1.8. Ninety percent of patients displayed Stage III or IV disease, and 23% of patients involved more than 1 extranodal site. B-symptoms and bone marrow involvement were present in 60% and 30% of patients, respectively. Laboratory findings showed anemia (male: Hb <13.0 g/dl, female: Hb <11.0 g/dl) in 61% of patients, a positive Coombs test in 47%, hypergammaglobulinemia (IgG >1700 mg/dl) in 54%, IgA >400 mg/dl in 37%, and elevated serum LDH levels in 75% of patients, respectively. According to the international prognostic index (IPI) and prognostic index for PTCL-NOS (PIT) score, patients were categorized as follows; IPI: Low (L), 10% (22/199); Low-intermediate (LI), 20% (39/199); High-intermediate (HI), 39% (77/199); and High (H), 31% (61/199), respectively, and PIT: Group1 (G1), 4% (8/201); Group2 (G2), 19% (38/201); Group3, 42% (85/201); and Group4, 35% (70/201), respectively. In terms of the initial series of treatments, 84% of patients received anthracycline-based chemotherapies. With a median follow-up duration of 42 months in surviving patients, 3-year OS and PFS were 54% and 39%, respectively. IPI was predictive for OS (3-years OS: L, 84%; LI, 65%; HI, 54%; H, 38%; Log-rank test, p<0.001), however, PIT was less predictive than IPI according to the distribution of the number of patients and survival in each group (3-years OS: G1, 88%; G2, 65%; G3, 57%; G4, 42%; Log-rank, p=0.014). Immunohistochemical staining revealed positivity for CD10 in 31% (40/130), EBER-ISH in 68% (108/160), CXCL13 in 92% (76/83), and PD-1 in 61% of patients (51/83), respectively. Multivariate analysis revealed total protein (TP) (<6.5 g/dl), {hazard ratio (HR), 2.12; 95% confidence interval (CI), 1.20–3.72; p=0.010}, IgA (>400 mg/dl) (HR, 2.00; 95% CI, 1.19–3.34; p=0.009), anemia (male, Hb <13.0 g/dl; female, Hb <11.0 g/dl) (HR, 1.95; 95% CI, 1.11–3.52; p=0.020), CRP (>1.0 mg/dl) (HR, 1.84; 95% CI, 1.05–3.35; p=0.033), and performance status (>2) (HR, 1.73; 95% CI, 1.03–2.92; p=0.040) were identified as significant prognostic factors for OS. IgA (HR, 1.94; 95% CI, 1.25–2.98; p=0.003), and anemia (HR, 1.65; 95% CI, 1.03–2.66; p=0.036) were significant prognostic factors for PFS.

Prognosis of patients with AITL in Japan is poor. Although IPI was useful in prognostification of AITL, other factors including those not adopted in IPI, such as IgA, anemia, TP and CRP, significantly affected the prognosis in this analysis. Further validation studies of these criteria should be performed.

Naoe:Chugai Pharmaceutical Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.,Ltd.: Research Funding; Dainippon Sumitomo Pharma Co.,Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Kinoshita:Chugai Pharmaceutical Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.,Ltd.: Research Funding.