Andrew M. Evens, DO, MSc from Robert Wood Johnson University Hospital and Rutgers Cancer Institute of New Jersey discusses the ASH 2020 abstract – 705 The Burkitt Lymphoma International Prognostic Index (BL-IPI).
Context:
BL is a rare, high-grade lymphoma of B cells that is mostly studied in limited sample size trials. Historical meanings of “low-risk BL” vary between studies, using lactate dehydrogenase (LDH) arbitrary cutoffs, and defining a small desirable subset, leaving >80-90% of patients (pts) in an undifferentiated category of “high-risk.” A validated prognostic index would help to compare the populations of the sample and better identify pts of good prognosis for which reduced therapy will be acceptable relative to a community of bad prognosis in need of new approaches. A simplified prognostic model for BL applicable to different clinical settings around the world was developed and validated here.
Methodology:
From a broad real-world proof cohort of US adults treated for BL in 2009-2018, we extracted the BL-IPI (Evens A, Blood 2020). The primary outcome was Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring. For age, LDH (normalized to local upper limit standard, ULN), hemoglobin (Hgb), and albumin, we first defined the best prognostic cutoffs. By forward stepwise selection into Cox regression, independent risk factors were determined from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ⇠2, advanced stage (3/4), the involvement of >1 extranodal site, bone marrow, central nervous system (CNS), LDH, Hgb, and albumin values. Multiple imputation derivation models were used to reduce bias from missing data and reported hazard ratios (HR) with a 95% confidence interval (CI). The BL-IPI classes, identified by survival curve inspection, were compared using the log-rank trend test. In an external retrospective dataset of BL pts handled simultaneously in centers in the United Kingdom, Scandinavia, Canada, and Australia, we validated the performance of the BL-IPI.
Outcomes:
The characteristics of derivation pts (N= 633) and validation cohorts (N= 457) are shown in the table below. As optimal prognostic cutoffs, age >40 years (yr), LDH >3xULN, Hgb <11.5 g/dL, and albumin <3.5 g/dL were calculated. Inferior PFS was correlated with age >40 years, PS ⇠2, stage 3/4, the involvement of marrow, CNS, LDH >3xULN, low Hgb, and low albumin in univariate studies. LDH > 3xULN, PS ⇠2, and CNS involvement were selected as 4 independent prognostic factors in the multivariate model age ⇠40 yr; the model was not improved by the addition point. The model was simplified to three classes of 0 (low risk; 18 percent of pts), 1 (intermediate risk; 36 percent of pts; HR=3.14; 95 percent CI, 1.61-6.14) or 2-4 variables (high risk; 46 percent of pts; HR=6.52; 95 percent CI, 3.48-12.20; Fig A) with 3-yr PFS of 92 percent, 72 percent, and 53 percent respectively (P<.001, Fig. B); the median PFS was only obtained in the high-risk group (46 months, 95 percent CI, 19-53). The overall survival prognosis of BL-IPI was similar (OS, P<.001; Fig. C).
The BL-IPI also discriminated against subgroups with 3 yr PFS of 87 percent, 71 percent, and 52 percent, respectively (P<.001; Fig. D), and OS of 95 percent, 75 percent, and 57 percent, respectively (P<.001; Fig. E), among pts with stage III/IV (historically categorized as ‘high-risk’ and constituting 78 percent of all pts in the cohort). Furthermore, in the subcohort treated with rituximab (3 yr PFS: 92 percent, 73 percent, and 55 percent, respectively, P<.001) and in pts treated with specific regimens, BL-IPI was prognostic irrespective of HIV status: CODOX-M/IVAC±R (3 yr PFS: 88 percent, 67 percent, 61 percent, respectively, P=.004), DA-EPOCH-R (3 yr PFS, 87 percent, 73 percent, 51 percent, respectively, P<.001), or h
Fewer pts had CNS participation in the international validation cohort; the rest obtained CODOX-M/IVAC+R, and PFS/OS estimates were higher at 3 years. The categories of BL-IPI were identical in size (low-risk 15%, intermediate-risk 35%, high-risk 50%) and similar risk discrimination (Harrell’s C=.65 in both datasets). PFS at 3 years was 96%, 82%, and 63%, respectively (P<.001; Fig. F), and OS was 99%, 85%, and 64%, respectively (P<.001; Fig. G). BL-IPI remained prognostic in the validation population in the subsets receiving rituximab (P<.001) and in the advanced phase (P<.001).
Findings:
BL-IPI is a new, BL-specific prognostic index that has been validated to allow for simpler stratification and risk distribution comparisons in geographically diverse cohorts. The index identified a low-risk category with PFS >90-95 percent, which could target potential care de-escalation strategies. Conversely, with currently accessible immunochemotherapy, just around 55-60 percent of the pts in the high-risk community achieved a cure.