Page 168 - 2021_07-Haematologica-web

A.S. Zayac et al.
Table 2. Risk factors for central nervous system recurrence in Burkitt lymphoma.
Cumulative incidence at 3 years
Variable With Without SHR
% 95%CI % 95%CI
Univariate model
95%CI P
(0.47-1.79) 0.80
(0.38-1.95) 0.72 (0.78-3.13) 0.20
Age ≥40 years 6 Age ≥60 years 5 Female sex 9 HIV infection 11 Stage 4 9 B symptoms 7 ECOG PS 2-4 11 Hemoglobin <11.5 g/dL 9 Albumin <3.5 g/dL 9 LDH > ULN 7 LDH >3x ULN 10 LDH >5x ULN 10 ≥2 extranodal sites 9
Involvement at diagnosis:
CNS 18 Bone marrow 9 Intestine 5 Liver 8 Pancreas 9 Pleura/peritoneum 5 Kidney/adrenal 4 Testisa 26 Uterus/ovarya 8 Female breasta 8
(4-9) 7
(2-11) 7 (5-14) 6 (6-17) 5 (6-12) 1 (4-11) 6 (6-17) 5 (6-14) 4 (5-13) 5 (5-10) 6 (6-14) 4 (6-16) 5 (6-14) 4
(11-26) 4 (6-14) 5 (2-11) 7 (3-16) 6 (2-24) 6 (2-11) 7 (1-12) 7 (6-52) 5 (1-31) 9 (1-29) 9
(4-11) 0.92
(5-9) 0.86 (4-8) 1.57 (3-8) 2.04 (0-3) 13.47 (4-9) 1.25 (3-7) 2.31 (2-7) 2.54 (3-8) 1.84 (2-11) 1.48 (3-7) 2.30 (3-8) 2.04 (2-7) 2.13
(2-6) 5.73 (3-7) 2.14 (5-9) 0.74 (4-9) 1.30 (4-9) 1.31 (5-9) 0.76 (5-9) 0.61 (3-8) 5.93 (5-15) 0.97 (5-15) 0.90
(1.05-4.00)
(1.83-98.9)
(0.65-2.40) 0.50
0.036 0.011
(1.14-4.67)
(1.26-5.11)
(0.92-3.66) 0.08 (0.62-3.55) 0.38
0.019 0.009
(1.17-4.50) (1.05-3.97) (1.09-4.16)
(2.98-11.0)
(1.09-4.17)
(0.29-1.88) 0.52 (0.54-3.14) 0.55 (0.32-5.30) 0.70 (0.27-2.15) 0.60 (0.15-2.58) 0.51
0.016 0.036 0.027
<0.001 0.026
(1.74-20.2)
(0.13-7.35) 0.97 (0.11-7.22) 0.92
0.004
aMen or women only, as pertinent. 95% CI: 95% confidence interval; CNS: central nervous system; ECOG PS: Eastern Cooperative Oncology Group performance status; HIV: human immunodeficiency virus; LDH: lactate dehydrogenase; SHR: subhazard ratio; ULN: upper limit of normal.
albumin concentration (48% vs. 34%; P<0.001) (Online Supplementary Table S2).
The 3-year risk of CNS recurrence was significantly lower after CODOX-M/IVAC (4% [2-8]) or hyperCVAD/MA (3% [1-6]) than after DA-EPOCH-R (13% [8-18]; SHR=3.57 [1.83-6.97]; P<0.001) (Figure 4A and B). Furthermore, recurrences involved the CNS more frequent- ly after DA-EPOCH-R (40%) than after the other two regi- mens (16%, P<0.001). The risk was higher regardless of baseline CNS involvement (Pinteraction=0.99) (Figure 4C and D), age (Pinteraction=0.94), PS (Pinteraction=0.12), or HIV status (Pinteraction=0.86) (Online Supplementary Figure S4A-F). Among patients with baseline CNS involvement receiving DA-EPOCH-R, the 3- year incidence of CNS recurrence reached 35% [20-51%]. The risk did not differ significantly between patients treat- ed with CODOX-M/IVAC or hyperCVAD/MA within any subset. The increased risk of CNS recurrence after DA- EPOCH-R persisted adjusting for age, PS, stage 4 disease, HIV positivity, baseline CNS involvement, and testicular involvement (adjusted SHR=4.38 [2.16-8.87], P<0.001).
All patients with CNS recurrence after DA-EPOCH-R treatment had received intrathecal chemotherapy during their initial therapy with a median of six (IQR, 5-12) doses of methotrexate and a median of four (IQR, 0-5) doses of cytarabine, but strict adherence to the protocol-defined schedule was reported in only 57% of this subgroup. CNS recurrence after DA-EPOCH-R treatment was lep- tomeningeal in 63%, intraparenchymal in 25%, and in both compartments in 12% of cases. Seven patients (6 with base- line leptomeningeal disease) received prophylactic HDMTX (± cytarabine) upon completion of DA-EPOCH-R,
but BL recurred in five, including three with a CNS recur- rence. Among all patients receiving DA-EPOCH-R, factors significantly associated with CNS recurrence included base- line CNS involvement (SHR=5.97 [2.59-13.79]; P<0.001), marrow involvement (SHR=2.57 [1.07-6.14]; P=0.034), LDH level >3xULN (SHR=2.53 [1.08-5.94]; P=0.033), and ≥2 extranodal sites (SHR=3.29 [1.28-8.44]; P=0.013). However, adjusting for baseline CNS involvement, no other variable retained statistical significance.
DIscussion
In this large, multi-institutional dataset of patients with BL treated with contemporary immunochemotherapy regi- mens, CNS involvement at diagnosis was an independent prognostic factor for PFS and OS, and a strong predictor of subsequent CNS recurrence. CNS recurrences developed early and almost exclusively in stage 4 BL. No patient with stage 1 or 2 disease experienced a CNS recurrence after treat- ment with NCCN-recommended regimens. The risk of CNS recurrence was significantly lower with regimens con- taining high-dose systemic CNS-penetrating agents. However, we observed that among patients with baseline CNS involvement who were treated with DA-EPOCH-R, intrathecal therapy was frequently (in 55%) not adminis- tered according to the schedule in the published protocol, which may have contributed to the high observed incidence of CNS recurrence (35%). Our results have important impli- cations for the management of BL in clinical practice, given the rarity of the disease and the paucity of randomized trials.
1938
haematologica | 2021; 106(7)