Management of Double/Triple Hit Early Stage Diffuse Large B-Cell Lymphoma With Radiation Therapy

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The role of consolidative radiation therapy (RT) after R-CHOP in early stage Diffuse Large B-Cell Lymphoma (DLBCL) remains controversial. Further, recent research has identified double-hit (DHL) and triple-hit (THL) as aggressive subtypes of this disease, but the role of RT has not been well defined in these cases. We evaluated the outcome of patients treated with systemic therapy followed by consolidative RT vs. those treated with systemic therapy alone with a focus on DHL and THL. A total of 209 lesions treated in 188 patients with early stage DLBCL were identified for retrospective analysis. These patients were treated in a single institution, from February 1998 to December 2014. Details of clinical characteristics, treatments, outcomes, and molecular profiles were extracted from clinical chart review and radiologic examinations. A total of 141 lesions were treated with RT (67%). Outcomes including time to relapse (TTR) and overall survival (OS) were estimated with Kaplan-Meier rates. Univariate (UVA) and multivariate (MVA) Cox proportional hazard ratios (HR) were used to assess the effect of patient, tumor, and other predictive factors. The median age was 60 years (range: 20-90), the majority were male (n = 105; 56%) and white (n = 167; 89%). Stages of disease were 1A (n = 87; 46%), 1B (n = 5; 3%), 2A (n = 73; 39%), and 2B (n = 23; 12%). Seventy-five (40%) patients had germinal center B-cell subtype. 27 (14%) were identified as DHL (7 typical and 20 atypical), and 10 (5%) were identified as THL (3 typical and 7 atypical). In those treated with chemotherapy (CT) alone, the median number of CT cycles was 6 (range: 1-10), and in patients treated with CT and RT it was 4 (range: 0-8, P<0.001). Median follow-up from treatment completion was 33 months (0.3-204 months). Median RT dose was 36 Gy (20-54 Gy). A total of 40 patients (21%) were known to be dead at last analysis. The receipt of RT was significant on MVA for the TTR with a HR 0.38 (0.20 -0.71; P = 0.002) with a trend for OS on MVA (P = 0.08). TTR at 36 months was 46% and 83% in patients treated without and with RT (P<0.0001). MVA demonstrated significance for OS in THL vs. DHL with a HR 6.1 (1.6-22.8, P = 0.01), and THL vs. none with a HR 4.5 (1.4-12.9, P = 0.02). MVA demonstrated significance for TTR in THL vs. none HR 6.6 (1.4-30.7, P = 0.05). TTR and OS rates at 36 months were 80%/83%, 47%/72%, and 17%/44% in patients without analyzed genetic aberrations, DHL, and THL (P < 0.0001 and P = 0.0002), respectively. DHL and THL patients treated with R-CHOP benefited significantly from consolidative RT with a 36 month TTR rate of 64% and 11% in patients treated with and without RT, respectively (P = 0.04). The receipt of RT and DHL/THL status were the only factors that correlated with TTR on MVA. DHL and THL status correlated with worse OS, and consolidative RT may offer a significant benefit to this cohort of patients. Early identification of these patients for more aggressive treatment utilization may lead to improved outcomes.