Survival Outcomes for High Risk Primary Refractory and Relapsed Large B-Cell Lymphoma (LBCL) within the Veterans Health Administration (VHA)

Introduction:

Even in the Rituxan era, patients with primary refractory or relapsed LBCL have poor outcomes. The standard of care for these patients is salvage therapy (ST) as second-line treatment followed by high dose therapy with autologous stem cell transplant (ASCT) in chemosensitive patients with an estimated 30-40% of ST responders deemed eligible to undergo transplant (PMID: 28774879). Currently, chimeric antigen receptor (CAR) T-cell therapy is the standard of care for high risk LBCL (high International Prognostic Index (IPI), HIT status) who do not respond to ST and have manageable safety profiles and high efficacy. Promising CAR T data is also emerging for early chemotherapy failure and as alternative second-line therapy (PMID: 35314842). The purpose of this study is to analyze the treatment patterns and survival outcomes of primary refractory and relapsed population of LBCL within the VHA.

Methods:

This is a retrospective chart review of 5199 randomly selected patients with an ICD code for lymphoma treated within the VHA between 01/01/2011 and 12/31/2019. Data abstractors included patients with LBCL who completed first-line chemotherapy treatment and had documented post-treatment scans (PET, CT). We defined primary refractory as either stable disease (SD) or progressive disease (PD) based on post-treatment scans and relapsed disease as recurrence of disease within 12 months of post treatment scans. Median overall survival (OS) was calculated using the Wilcoxon-Mann-Whitney test.

Results:

A total of 2288 patients met inclusion criteria who received or completed treatment at the VHA. Baseline characteristics are outlined in Table 1. From our analysis, 299 (13.1%) of patients were primary refractory. Median age was 68.9 years and 97% were male. European Cooperative Oncology Group (ECOG) was 0-2 (81.3%). Stage at diagnosis was III-IV (83.9%). Most patients had an IPI score ≥3 (85%). Germinal center B-Cell (GCB) accounted for 48.2% while Activated B-Cell (ABC) was 24.4%. Gene rearrangement was present in 26% of the patients with available data. Of the 119 (63.9%) patients who received second line treatment, only 19 (6.4%) were able to receive high dose chemotherapy and underwent an ASCT and only 3 (1%) of patients received CAR T-cell therapy. One year and two year overall survival was 47.8% and 24.7% respectively. Median OS for this population was 11.0 months.

There were 105 (4.6%) relapsed patients in our cohort. Median age was 64.7 years and 96.2% were male. ECOG was 0-2 (85.7%). Stage at diagnosis was III-IV at 84.8%. Most patients had an IPI score ≥3 (80%). GCB accounted for 37.1% while ABC was 35.2%. Gene rearrangement was present for 20% of the patients with available data. In this group, 16 (15.2%) of patients received high dose chemotherapy and ASCT and only 3 (2.9%) received CAR T-cell therapy. One year and two year overall survival was 72% and 41% respectively. Median OS for this population was 21.3 months.

1403 (61%) of patients had complete response (CR) with a 1 and 2 year survival rate of 97 % and 93 % respectively and median OS of 69.3 months.

Conclusion:

This is one of largest data sets studying the rate of primary refractory and relapsed LBCL in the VHA and shows that more than two-thirds of these patients have high risk disease. Furthermore, a significant portion of these veterans did not receive second-line therapy including ASCT as compared to previously reported real world and clinical trial data. It is possible that our patient populations had higher rates of chemoresistance, were deemed ineligible for transplant due to age or performance status, or had higher comorbidities. Emerging data on newer antibodies and CAR T-cell therapy for early chemotherapy failure or second-line therapy might be a more appropriate option for our veteran population. In conclusion, CAR T-Cell therapy will likely replace the treatment paradigm for primary refractory or relapsed disease for early treatment failures in patients with LBCL.