Clinical outcomes of newly diagnosed primary central nervous system lymphoma treated with zanubrutinib-based combination therapy

Table 1 Baseline data of the patients with primary central nervous system lymphoma

Characteristic	N = 19
Age, yr	57 (27–81)
Sex, n (%)
Male	9 (47.4)
Female	10 (52.6)
ECOG-PS ≥ 2, n (%)	5 (26.3)
Invasion of deep intracranial areas, n (%)	16 (84.2)
High CSF protein concentration (> 450 mg/L), n (%)	11 (68.75)1
High LDH serum concentration (> 250 U/L), n (%)	1 (5.3)
IELSG risk score, n (%)
Low	3 (18.75)1
Intermediate	12 (75)1
High	1 (6.25)1
Follow-up time (mo)	14.7 (3.9–30)

¹Three patients refused lumbar puncture for personal reasons.

ECOG-PS: Eastern Cooperative Oncology Group performance score; CSF: Cerebrospinal fluid; LDH: Lactate dehydrogenase; IELSG: International Extranodal Lymphoma Study Group.

Table 2 Baseline tumor genomic characteristics of the patients with primary central nervous system lymphoma

Patient	ID	COO Subtype	Best response (mo)	MYDBB	CD79B	Ki-67	Cyclin D1	Other IHC results
p973624	1	Non-GCB	CR (22.2)1	L265P	Y196D	> 90%+	NA	CD20(+++), CD79a(+++), CD3(−), CD5(−), CD21(−), CD23(−), Bcl6(>90%+), MUM1(>90%+), FOXP1(>90%+), Bcl2(60%+), c-Myc(40%+), CD30(−), ALK(ALK1)(−), CD138(−), P53(+), c-Met(−), PD-L1(22C3)(30%+)
p968283	2	GCB	CR (23)1	NA	NA	100%+	−	CD43(−), CD20(+++), CD3(−), CD79a(+++), CD5(−), CD23(−), CD10(95%+), CD21(−), CD30(−), ALK(ALK1)(−), Bcl6(90%+), CD138(−), MUM1(65%+), Bcl2(50%+), c-Myc(20%+), GFAP(−), Olig2(−)
p955842	3	Non-GCB	SD (6.0)	NA	NA	70%+	−	LCA(+++), OCT-2(+++), CD20(+++), CD19(+++), CD10(−), Bcl6(70%+), MUM1(40%+), CD3(−), CD5(+), ALK(ALK1)(-), CD23(−), CD21(−), CD30(−), CD138(−), Bcl2(++), TdT(−), GECT1(+), FOXP1(+++), c-Myc(80%+), c-Met(−), P53(+++), GFAP(−), CK(−), EMA(−)
p241574	4	Non-GCB	CR (27.5)1	NA	K159Q, V223R	90%+	−	LCA(++), CD79a(++), CD43(−), CD20(+), CD3(−), CD5(−), CD23(−), CD10(−), CD21(−), CD30(−), ALK(ALK1)(−), Bcl6(90%++), CD138(−), MUM1(70%+), Bcl2(50%+), TdT(−), GECT1(30%+), FOXP1(+), c-Myc(70%+), c-Met(+), LMP-1(−), EBNA2(−), P53(+), PD-L1(22C3)(90%+)
p939668	5	Non-GCB	PR (28.5)1	NA	NA	NA	NA	NA
p932230	6	GCB	CR (29.5)1	S219C	NA	98%+	NA	CD20(+++), CD79a(+++), CD3(−), CD5(−), ALK(ALK1)(−), CD21(−), CD23(−), Bcl6(90%+), MUM1(20%+), CD10(100%+), CK(−), Vimentin(−), EMA(−), S100(−), GFAP(−), Bcl2(80%+), GECT1(35%+), FOXP1(80%+), c-Myc(45%+), C-MET(50%+), P53(4%+), PD-L1(22C3)(10%+)
p929763	7	Non-GCB	CR (18.8)	L265P	C.553-2A>C	90%+	−	CD43(−), CD20(+++), CD3(−), CD79a(+++), CD5(−), CD23(−), CD10(−), CD19(+++), CD22(++), CD21(−), CD30(−), ALK(ALK1)(−), Bcl6(10%+), CD138(−), MUM1(20%+), Bcl2(70%+), TdT(−), c-Myc(5%+), GFAP(−)
p173185	8	Non-GCB	PR (8.0)	L265P	NA	NA	NA	ERCC1(−), β-tubulin(+++), EGFR(+++), VEGF(+), ALK(−), CD56(−), CgA(−), Syn(−)
p651739	9	GCB	CR (23.0)	NA	NA	90%+	−	CD43(+), CD20(+++), CD3(+), CD79a(++), CD5(−), CD23(−), CD10(+++), CD21(−), CD30(−), ALK(ALK1)(−), Bcl6(60%+), CD138(−), MUM1(++), Bcl2(−), TdT(−), c-Myc(20%+), GFAP(−), Olig2(−)
p1013138	10	GCB	CR (12.5)	NA	NA	90%+	−	CD3(−), CD5(−), CD20(++), CD79a(++), CD30(−), ALK(ALK1)(−), SALL4(−), OCT3/4(−), AFP(−), GFAP(−), Olig2(−), MUM1(+), CD10(++), Bcl6(++), CD23(−), Bcl2(−), GCET-1(+), FOXP1(+), c-Myc(70%+), c-Met(−), P53(95%++), PD-L1(22C3)(TC <1%+, IC 70%+)
p2010722	11	Non-GCB	PR (16.6)	NA	NA	80%+	−	CK(−), CD20 and CD79a(+), CD3(−), CD5(−), Bcl-2(80%+), MUM-1(+), CD10(−), Bcl6(−)
p998505	12	Non-GCB	PR (22.2)	NA	NA	70%+	2%+	D3(+), CD5(++), CD20(+++), CD79a(+++), CD30(−), CD10(−), GFAP(−), Olig2(−), CK(−), CD43(++), CD23(−), CD21(−), ALK(ALK1)(−), Bcl6(20%+), CD138(−), MUM1(80%+), Bcl2(90%+++), TdT(−), GCET-1(−), FOXP1(+++), c-Myc(70%+), c-Met(−), P53(1%+), PD-L1(22C3)(70%+)
p1013897	13	GCB	CR (14.2)	NA	NA	85%+	−	CD20(+++), CD3(−), CD79a(+++), CD5(−), CD30(<1%+), ALK(ALK1)(−), CD23(−), CD10(+++), CD21(−), Bcl6(70%+), CD138(+), MUM1(40%+), Bcl2(5%+), TdT(−), Cyclin D1(−), c-Myc(40%+), c-Met(60%+), P53(70%+), PD-L1(22C3)(40%+)
p2020811	14	GCB	CR (10.8)	NA	NA	90%+	NA	CD3(+), CD5(+), CD79a(+), CD10(+), Bcl6(±), CD20(+++), Bcl6(80%+), MUM1(<5%+), CD10(+), Ki67(90%+), CD3(−), AE1/AE3(−), EMA(−), P40(−), CD3(−), GFAP(−)
P2003851	15	GCB	CR (13.1)	NA	NA	80%+	−	EMA(−), S100(−), GFAP(+), Syn(+), CgA(−), Olig2(+), NeuN(+), CD34(+), CD3(+), CD5(+), CD79a(+), CD20(+), CD43(10%+), CD30(−), ALK(ALK1)(−), Bcl6(>90%+), Bcl2(90%+), TdT(−), GCET-1(90%+), FOXP1(>90%+), c-Myc(40%+), c-Met(−), LMP-1(−), EBNA2(−), P53(60%+), PD(−), L1(22C3)(30%+)
p996213	16	GCB	CR (18.3)	NA	NA	NA	NA	NA
P1010986	17	GCB	CR (14.7)	NA	NA	95%+	−	CD43(+), CD20(+++), CD3(−), CD79a(++), CD5(−), CD23(−), CD10(60%+), CD21(−), CD30(−), ALK(ALK1)(−), Bcl6(60%+), CD138(−), MUM1(90%+), Bcl2(15%+), TdT(−), c-Myc(30%+)
P2052819	18	Non-GCB	PR (3.9)	NA	NA	90%+	−	GFAP(−), Olig2(−), CD20(+++), CD79a(++), CD3(−), CD5(−), CD21(−), CD23(−), CD10(−), Bcl6(60%++), MUM1(90%+++), CD138(−), Bcl2(90%+++), c-Myc(70%++), CD30(−), ALK(ALK1)(−)
P2045773	19	GCB	PR (5.2)	NA	NA	90%+	−	CD19(+++), CD20(+++), CD3(−), CD5(−), GFAP(−), Olig2(−), CD23(+), CD10(−), CD21(−), CD30(−), ALK(ALK1)(−), Bcl6(70%+), CD138(−), MUM1(70%+), Bcl-2(95%+), TdT(−), c-Myc(40%+), c-Met(−)

¹Still in remission.

PCNSL: Primary central nervous system lymphoma; ID: Identification number; COO: Cell of origin; NA: Not available; IHC: Immunohistochemistry; GCB: Germinal center B cell; CR: Complete response; SD: Stable disease; PR: Partial response: CD: Cluster of differentiation; Bcl6: B cell lymphoma 6; MUM-1: Multiple myeloma antigen 1; FOXP1: Forkhead box protein P1; Bcl2: B cell lymphoma 2; ALK: Anaplastic lymphoma kinase; PD-L1: Programmed death-ligand 1; GFAP: Glial fibrillary acidic protein; LCA: Leucocyte common antigen; TdT: Terminal deoxynucleotidyl transferase; GECT: Gene expression in developing tissues with micro computed tomography; CK: Cytokeratin; EMA: Epithelial membrane antigen; LMP-1: Epstein–Barr virus-encoded latent membrane protein 1; EBNA2: Epstein–Barr virus nuclear antigen 2; P53: Tumor protein 53; EGFR: Epidermal growth factor receptor; VEGF: Vascular endothelial growth factor; CgA: Chromogranin A; Syn: Syndecan; SALL4: Sal-like protein 4; AFP: Alpha fetoprotein; Olig2: Oligodendrocyte lineage transcription factor 2; TC: Tumor cells; IC: Immune cells; D3: Cyclin D3; NeuN: Neuronal nuclear antigen.

Table 3 Efficacy of high-dose methotrexate plus zanubrutinib for newly diagnosed primary central nervous system lymphoma

Parameter	N = 19
OS rate (%)	-
24-mo (95%CI)	94.1% (83.6%-100%)
Median PFS	-
24-mo (95%CI)	75.6% (53.4%-100%)
ORR (%)	84.2%
ASCT (consolidation therapy)	88.9%
Zanubrutinib (maintenance therapy)	80%
Median follow-up time (mo)	14.7
95%CI	3.9–30

OS: Overall survival; CI: Confidence interval; PFS: Progression-free survival; ORR: Objective response rate; ASCT: Autologous stem cell transplantation.

Table 4 Adverse events in patients treated with high-dose methotrexate plus zanubrutinib

Adverse event	Grade 1	Grade 2	Grade 3	Grade 4	Total (%)
Hematological toxicities
Leukopenia	3	7	1		11 (57.9)
Neutropenia	3	6	2		11 (57.9)
Lymphocytopenia	6	8	2		16 (84.2)
Thrombocytopenia	5			1	6 (31.6)
Anemia	8	10	1		19 (100)
Non-hematological toxicities
Transaminase increase	4				4 (21.1)
Creatinine increase	2	1			3 (15.8)
Hypoalbuminemia	16	2			18 (94.7)
Hypokalemia	10	4	1		15 (78.9)
Lung infection					NA

NA: Not applicable.