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Real-world CNS outcomes in Burkitt lymphoma
The median time from diagnosis to CNS recurrence was 5.8 months (IQR, 4.3-7.6). Thirty-four CNS recurrences (87%) occurred during the first year of follow-up and 32 (82%) involved the CNS alone, without systemic disease. Thirty- seven (95%) patients with CNS recurrence had stage 4 dis- ease at initial diagnosis, and the only one with early-stage BL had CNS progression during treatment with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The location of the CNS recurrence was only the leptomeninges in 52% of cases, only parenchyma in 22%, both compartments in 19%, and unspecified in 7%.
Prior to CNS recurrence, 81% of patients had received rit- uximab, 97% had received intrathecal chemotherapy, and 44% had received HDMTX. Of note, 22 patients (56%) did not attain a complete response before progression in the CNS, and 18 of those had residual/recurrent disease limited only to the CNS. Following the CNS recurrence, 77% of patients received salvage treatment: systemic chemothera- py (64%), intrathecal chemotherapy (8%), or radiation (5%). Only five (13%) achieved a second complete response and the median survival after CNS recurrence was 2.8 months (range, 2.0-4.2) (Online Supplementary Figure S2B). All five survivors received HDMTX-based salvage therapy. Four of them had received first-line DA-EPOCH-R, one underwent consolidative autologous stem cell trans- plantation, and one received an allogeneic stem cell trans- plant.
Analysis of the cumulative incidence of CNS recurrence was conducted in the subcohort of 570 patients who received one of the NCCN-recommended first-line regi- mens: CODOX-M/IVAC, hyperCVAD/MA, or DA- EPOCH-R. The cumulative incidence of CNS recurrence in this subcohort was 6% [4-8] at 1 year (Figure 3A). In uni- variate analysis, the strongest associations we observed were between CNS recurrence and stage 4 disease (Figure 3B), baseline CNS involvement (Figure 3C), and testicular involvement, this last being very rare (Table 2). Other sig- nificant factors included HIV infection, poor PS, ≥2 extra- nodal sites, LDH level >3xULN, and bone marrow involve- ment (Online Supplementary Figure S3). In a two-variable model, stage 4 disease (adjusted SHR=7.68 [1.01-58.40], P=0.049) and baseline CNS involvement (adjusted SHR=4.04 [2.08-7.87], P<0.001) were cumulatively associat- ed with CNS recurrence. Due to the limited number of events, we did not explore more complex multivariate models. Achievement of complete response after first-line therapy was associated with a lower risk of CNS recurrence (SHR=0.30 [0.15-0.57], P<0.001), whereas receipt of ritux- imab was not (SHR=1.51 [0.36-6.39], P=0.58).
Central nervous system recurrence according to first-line treatment regimen
We examined the risk of CNS recurrence according to first-line treatment regimen, comparing regimens that con- tain high-dose, CNS-penetrant systemic agents (CODOX- M/IVAC or hyperCVAD/MA; n=389) with DA-EPOCH-R (n=181). There was no significant difference between these two groups in the prevalence of baseline CNS involvement (P=0.93), stage 4 disease (P=0.79), LDH level >3xULN (P=0.31), ≥2 extranodal sites (P=0.27), or testicular involve- ment (P=0.20). However, patients selected for DA- EPOCH-R were older (median age 54 vs. 44 years; P<0.001), and more likely to have poor PS (30% vs. 18%; P=0.002), HIV infection (33% vs. 20%; P<0.001), or low
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B
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Figure 3. Cumulative incidence of central nervous system recurrence. (A-C) The cumulative incidence of central nervous system (CNS) recurrence in: (A) all patients (n=570) who received chemotherapy with CODOX-M/IVAC, hyperCVAD/MA, or DA-EPOCH-R; (B) stratified by disease stage; and (C) strati- fied by the presence of baseline CNS involvement at diagnosis. Shaded areas indicate 95% confidence interval bands; P values are from univariate competing risk models; estimates at 3 years are presented.
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