Prognostic Factors Other Than Age Drive the Risk of Disease Progression in Adults with Burkitt Lymphoma Treated with DA-EPOCH-R
Authors: Lakhotia Rahul , Dunleavy Kieron , Abramson Jeremy S. , Link Brian K. , Powell Bayard L. , Melani Christopher , Lucas Andrea Nicole , Steinberg Seth M. , Friedberg Jonathan W. , Kahl Brad S. , Little Richard F. , Bartlett Nancy L. , Fanale Michelle A. , Noy Ariela , Wilson Wyndham H. , Roschewski Mark 
Published: November 2021

Abstract
Introduction
Adults with Burkitt lymphoma (BL) are at risk for both early toxic death and disease progression. Age is associated with a poor prognosis with highly dose-intensive regimens, but it is unclear if this is driven by disease biology or treatment intolerance. We previously reported that survival for adult BL patients treated with DA-EPOCH-R were poorest with CNS, bone marrow (BM) and/or peripheral blood (PB) involvement, but age was not prognostic (Roschewski et al J Clin Oncol 2020). A retrospective study of patients treated with standard regimens outside of clinical trials identified the Burkitt Lymphoma International Prognostic Index (BL-IPI) which stratified patients into risk categories based on 4 variables: age ≥40y, ECOG ≥2, serum LDH &gt;3x ULN, and CNS involvement (Olszewski J Clin Oncol 2021). We analyzed the prognostic utility of BL-IPI to predict time to progression (TTP) and event-free survival (EFS) for adult patients with BL treated on a prospective multicenter study of risk-adapted DA-EPOCH-R.
Methods
NCI 9177 was a multicenter study that included pts ≥ age 18 with any HIV status. Treatment was risk-adapted based on LDH, ECOG status, stage, and largest tumor lesion. Low-risk patients received 3 cycles of DA-EPOCH-RR and high-risk patients received 6 cycles of DA-EPOCH-R with either IT chemo prophylaxis or extended IT treatment for active CNS disease. Event-free survival (EFS) was calculated from study entry until progression, last documentation of active disease, death, or last follow-up. Time to progression (TTP) was calculated from study entry until date of progression. Kaplan-Meier estimation and log-tank tests were used to determine the prognostic utility of the BL-IPI including individual factors. Receiver operating characteristic curves were plotted to determine the c-index which measures the predictive ability of a survival model.
Results
113 patients were enrolled including 31 (27%) low-risk, 55 (49%) intermediate-risk, and 27 (24%) high-risk by BL-IPI. With a median follow up of living patients of 3.3y, the 5-year TTP for pts with high-risk BL-IPI was 78.3% (95% CI: 55-90) compared to 95.2% (95% CI: 88-98)(p=0.022) for pts with low/intermediate IPI (Figure 1A). Pts with high-risk BL-IPI had a lower 5-year EFS of 66.7% (95% CI: 46-81) compared to 94.2% (95% CI: 83-98) for intermediate-risk and 83.6% (95% CI: 65-93) for low-risk, respectively (p=0.004)(Table 1). Pts aged ≥40y had a similar 5-year TTP and EFS of 93.6% (95% CI: 84-98) versus 88.4% (95% CI: 74-95)(p=0.32) and 86.7% (95% CI: 76-93) versus 81.1% (95% CI: 66-90)(p=0.50) compared to pts under 40y. Pts with ECOG PS ≥2 had a worse 5-year TTP and EFS of 76.5% (95% CI: 49-90) versus 94.4% (95% CI: 87-98)(p=0.01) and 61.9% (95% CI: 38-79) versus 89.8% (95% CI: 81-95)(p=0.0004) compared to pts with ECOG PS &lt;2. Pts with serum LDH 3x ULN also had worse 5-year TTP and EFS of 77.3% (95% CI: 54-90) versus 95.2% (95% CI: 88-98)(p=0.008) and 65.4% (95% CI: 44-80) versus 90.4% (95% CI: 82-95)(p=0.001) compared to pts without serum LDH &gt; 3x ULN. Pts with CNS involvement had worse 5-year TTP and EFS of 62.5% (95% CI: 23-86) versus 93.9% (95% CI: 87-97)(p=0.002) and 45.5% (95% CI: 17-71) versus 88.8% (95% CI: 81-94)(p=0.0001) compared to pts without CNS involvement. Nineteen (70%) pts high-risk by BL-IPI had CNS/BM/PB involvement while 8 (30%) had no CNS/BM/PB involvement. Ten (12%) pts with low/intermediate-risk by BL-IPI had CNS/BM/PB involvement and 76 (88%) had no CNS/BM/PB involvement. Pts without involvement of CNS/BM/PB had an excellent prognosis across BL-IPI groups with 5-year TTP of 97.3% (95% CI: 90-99) for low/intermediate-risk by BL-IPI and 100% for high-risk by BL-IPI. Patient with CNS/BM/PB involvement had 5-year TTP of 80.0% (95% CI: 41-95) for low/intermediate-risk by BL-IPI and 66.7% (95% CI: 38-85) for high-risk by BL-IPI (global p=0.006)(Figure 1B). Compared to BL-IPI (C-index 0.62 p=0.13), CNS/BM/PB involvement had better discrimination between prognostic groups (C-index 0.76, p=0.0005).
Conclusion
Patients with low-or intermediate risk BL-IPI scores had an excellent 5-year TTP and EFS of 95% and 94% in NCI 9177. Age is not prognostic with DA-EPOCH-R but CNS/BM/PB involvement is prognostic across BL-IPI groups. Future studies in adults with BL should focus on high-risk disease including younger patients.
Figure 1 Figure 1.

Disclosures
Dunleavy: Gebmab: Honoraria; Beigene: Honoraria; Morphosys: Honoraria; Bayer: Honoraria; Pharmacyclics: Honoraria; Genetech: Honoraria; Idec: Honoraria. Abramson: C4 Therapeutics: Consultancy; Allogene Therapeutics: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Link: MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis, Jannsen: Research Funding. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC . Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.