Baseline demographic and disease characteristics
| Characteristic . | R/R . | TN . | Overall . | |||
|---|---|---|---|---|---|---|
| Ibrutinib (n = 81) . | Zanubrutinib (n = 83) . | Ibrutinib (n = 18) . | Zanubrutinib (n = 19) . | Ibrutinib (n = 99) . | Zanubrutinib (n = 102) . | |
| Age, median (min, max), y | 69 (52, 90) | 69 (45, 87) | 72 (38, 89) | 74 (50, 81) | 70 (38, 90) | 70 (45, 87) |
| Age >75 y, n (%) | 16 (20) | 27 (33) | 6 (33) | 7 (37) | 22 (22) | 34 (33) |
| Males, n (%) | 53 (65) | 58 (70) | 12 (67) | 11 (58) | 65 (66) | 69 (68) |
| ECOG-PS | ||||||
| 0/1 | 76 (94) | 78 (94) | 16 (89) | 18 (95) | 92 (93) | 96 (94) |
| 2 | 5 (6) | 5 (6) | 2 (11) | 1 (5) | 7 (7) | 6 (6) |
| Prognostic category at study entry* | ||||||
| Low | 12 (15) | 16 (19) | 1 (6) | 1 (5) | 13 (13) | 17 (17) |
| Intermediate | 34 (42) | 30 (36) | 8 (44) | 8 (42) | 42 (42) | 38 (37) |
| High | 35 (43) | 37 (45) | 9 (50) | 10 (53) | 44 (44) | 47 (46) |
| Time from initial diagnosis, median (min, max), y | 5.9 (0.1, 25) | 5.3 (0.1, 23) | 1.7 (0.1, 17) | 0.5 (0.1, 9) | 4.9 (0.1, 25) | 4.4 (0.1, 23) |
| Prior lines of therapy, median (min, max), n | 1 (1, 6) | 1 (1, 8) | 0 (0, 0) | 0 (0, 0) | 1 (0, 6) | 1 (0, 8) |
| 0, n (%) | 0 | 0 | 18 (100) | 19 (100) | 18 (18) | 19 (19) |
| 1-3, n (%) | 74 (91) | 76 (92) | 0 | 0 | 74 (75) | 76 (75) |
| >3, n (%) | 7 (9) | 7 (8) | 0 | 0 | 7 (7) | 7 (7) |
| Prior stem cell transplant | 1 (1) | 3 (4) | 0 | 0 | 1 (1.0) | 3 (2.9) |
| IgM, median (min, max), g/L† | 33.4 (2.4, 108) | 30.4 (5.8, 73) | 36.8 (9.9, 100) | 35.7 (8.1, 87) | 34.2 (2.4, 108) | 31.8 (5.8, 87) |
| ≥40 | 30 (37) | 288 (34) | 8 (44) | 8 (42) | 38 (38) | 36 (35) |
| <40 | 50 (62) | 55 (66) | 10 (56) | 11 (58) | 60 (61) | 66 (65) |
| Missing data | 1 (1) | 0 | 0 | 0 | 1 (1.0) | 0 |
| β-2 Microglobulin, median, (min, max), mg/L | 4.2 (1.7, 13.6) | 4.1 (1.6, 21.7) | 4.1 (1.8, 10.3) | 4.7 (2.1, 12.1) | 4.2 (1.7, 13.6) | 4.3 (1.6, 21.7) |
| >3 mg/L, n (%) | 60 (74) | 62 (75) | 14 (78) | 13 (68) | 74 (75) | 75 (74) |
| MYD88‡/CXCR4 genotype | ||||||
| MYD88L265P/CXCR4WT | 73 (90) | 73 (88) | 17 (94) | 18 (95) | 90 (91) | 91 (89) |
| MYD88L265P/CXCR4WHIM | 8 (10) | 10 (12) | 0 (0) | 1 (5) | 8 (8) | 11 (11) |
| MYD88L265P/CXCR4UNK§ | 0 | 0 | 1 (6) | 0 | 1 (1.0) | 0 |
| Bone marrow involvement | 72 (89) | 77 (93) | 17 (94) | 19 (100) | 89 (90) | 96 (94) |
| Tumor cells, median (min, max), % | 60 (0, 90) | 60 (0, 90) | 70 (8, 90) | 70 (10, 90) | 60 (0, 90) | 60 (0, 90) |
| Extramedullary disease¶ | 58 (72) | 64 (77) | 15 (83) | 17 (90) | 73 (74) | 81 (79) |
| Lymphadenopathy | 53 (65) | 63 (76) | 14 (78) | 16 (84) | 67 (68) | 79 (78) |
| Splenomegaly | 10 (12) | 14 (17) | 3 (17) | 3 (16) | 13 (13) | 17 (17) |
| Other|| | 3 (4) | 0 | 0 | 1 (5) | 1 (1) | 4 (2) |
| Peripheral blood cytopenias | ||||||
| Hemoglobin ≤110 g/L | 43 (53) | 51 (61) | 10 (56) | 16 (84) | 53 (54) | 67 (66) |
| Platelet count ≤100 × 109/L | 12 (15) | 10 (12) | 0 | 2 (11) | 12 (12) | 12 (12) |
| Absolute neutrophil count ≤1.5 × 109/L | 7 (9) | 8 (10) | 0 | 3 (16) | 7 (7) | 11 (11) |
| Characteristic . | R/R . | TN . | Overall . | |||
|---|---|---|---|---|---|---|
| Ibrutinib (n = 81) . | Zanubrutinib (n = 83) . | Ibrutinib (n = 18) . | Zanubrutinib (n = 19) . | Ibrutinib (n = 99) . | Zanubrutinib (n = 102) . | |
| Age, median (min, max), y | 69 (52, 90) | 69 (45, 87) | 72 (38, 89) | 74 (50, 81) | 70 (38, 90) | 70 (45, 87) |
| Age >75 y, n (%) | 16 (20) | 27 (33) | 6 (33) | 7 (37) | 22 (22) | 34 (33) |
| Males, n (%) | 53 (65) | 58 (70) | 12 (67) | 11 (58) | 65 (66) | 69 (68) |
| ECOG-PS | ||||||
| 0/1 | 76 (94) | 78 (94) | 16 (89) | 18 (95) | 92 (93) | 96 (94) |
| 2 | 5 (6) | 5 (6) | 2 (11) | 1 (5) | 7 (7) | 6 (6) |
| Prognostic category at study entry* | ||||||
| Low | 12 (15) | 16 (19) | 1 (6) | 1 (5) | 13 (13) | 17 (17) |
| Intermediate | 34 (42) | 30 (36) | 8 (44) | 8 (42) | 42 (42) | 38 (37) |
| High | 35 (43) | 37 (45) | 9 (50) | 10 (53) | 44 (44) | 47 (46) |
| Time from initial diagnosis, median (min, max), y | 5.9 (0.1, 25) | 5.3 (0.1, 23) | 1.7 (0.1, 17) | 0.5 (0.1, 9) | 4.9 (0.1, 25) | 4.4 (0.1, 23) |
| Prior lines of therapy, median (min, max), n | 1 (1, 6) | 1 (1, 8) | 0 (0, 0) | 0 (0, 0) | 1 (0, 6) | 1 (0, 8) |
| 0, n (%) | 0 | 0 | 18 (100) | 19 (100) | 18 (18) | 19 (19) |
| 1-3, n (%) | 74 (91) | 76 (92) | 0 | 0 | 74 (75) | 76 (75) |
| >3, n (%) | 7 (9) | 7 (8) | 0 | 0 | 7 (7) | 7 (7) |
| Prior stem cell transplant | 1 (1) | 3 (4) | 0 | 0 | 1 (1.0) | 3 (2.9) |
| IgM, median (min, max), g/L† | 33.4 (2.4, 108) | 30.4 (5.8, 73) | 36.8 (9.9, 100) | 35.7 (8.1, 87) | 34.2 (2.4, 108) | 31.8 (5.8, 87) |
| ≥40 | 30 (37) | 288 (34) | 8 (44) | 8 (42) | 38 (38) | 36 (35) |
| <40 | 50 (62) | 55 (66) | 10 (56) | 11 (58) | 60 (61) | 66 (65) |
| Missing data | 1 (1) | 0 | 0 | 0 | 1 (1.0) | 0 |
| β-2 Microglobulin, median, (min, max), mg/L | 4.2 (1.7, 13.6) | 4.1 (1.6, 21.7) | 4.1 (1.8, 10.3) | 4.7 (2.1, 12.1) | 4.2 (1.7, 13.6) | 4.3 (1.6, 21.7) |
| >3 mg/L, n (%) | 60 (74) | 62 (75) | 14 (78) | 13 (68) | 74 (75) | 75 (74) |
| MYD88‡/CXCR4 genotype | ||||||
| MYD88L265P/CXCR4WT | 73 (90) | 73 (88) | 17 (94) | 18 (95) | 90 (91) | 91 (89) |
| MYD88L265P/CXCR4WHIM | 8 (10) | 10 (12) | 0 (0) | 1 (5) | 8 (8) | 11 (11) |
| MYD88L265P/CXCR4UNK§ | 0 | 0 | 1 (6) | 0 | 1 (1.0) | 0 |
| Bone marrow involvement | 72 (89) | 77 (93) | 17 (94) | 19 (100) | 89 (90) | 96 (94) |
| Tumor cells, median (min, max), % | 60 (0, 90) | 60 (0, 90) | 70 (8, 90) | 70 (10, 90) | 60 (0, 90) | 60 (0, 90) |
| Extramedullary disease¶ | 58 (72) | 64 (77) | 15 (83) | 17 (90) | 73 (74) | 81 (79) |
| Lymphadenopathy | 53 (65) | 63 (76) | 14 (78) | 16 (84) | 67 (68) | 79 (78) |
| Splenomegaly | 10 (12) | 14 (17) | 3 (17) | 3 (16) | 13 (13) | 17 (17) |
| Other|| | 3 (4) | 0 | 0 | 1 (5) | 1 (1) | 4 (2) |
| Peripheral blood cytopenias | ||||||
| Hemoglobin ≤110 g/L | 43 (53) | 51 (61) | 10 (56) | 16 (84) | 53 (54) | 67 (66) |
| Platelet count ≤100 × 109/L | 12 (15) | 10 (12) | 0 | 2 (11) | 12 (12) | 12 (12) |
| Absolute neutrophil count ≤1.5 × 109/L | 7 (9) | 8 (10) | 0 | 3 (16) | 7 (7) | 11 (11) |
Unless otherwise noted, data are n (%). Percentages may not add to 100% because of rounding.
ECOG-PS, Eastern Cooperative Oncology Group performance status; max, maximum; min, minimum; WHIM, warts, hypogammaglobulinemia, infections, myelokathexis; WT, wild-type.
Patients were assigned 1 point for each of the following baseline characteristics: age >65 years; hemoglobin ≤11.5 g/dL; platelet count ≤100 × 109/L; β-2 microglobulin level >3 mg/L; and M paraprotein levels >7.0 g/dL. Patients with a score of 0 or 1 (excepting age) were assigned to the low-risk category, those >65 years old or with a score of 2 were assigned to the intermediate-risk category. and those with a score ≥3 were assigned to the high-risk category.29 M-paraprotein levels were quantitated by serum protein electrophoresis.
Central laboratory nephelometric assessments.
Three patients (all zanubrutinib treated and all TN) had second missense mutations detected within the Toll/interleukin-1 receptor (TIR) binding domain of MYD88: M232T, V217F, and P182L. Additional mutations were identified in non-TIR binding domains in 4 patients: D165del (R/R zanubrutinib patient); W91ter, G93ter (R/R ibrutinib patient); L72M (RR zanubrutinib patient); and T107S, fs24ter (TN zanubrutinib patient). See supplemental Methods for the specific CXCR4WHIM mutations detected.
Mutation testing using a next-generation sequencing method performed in a local laboratory revealed the presence of MYD88L265P in baseline bone marrow aspirate.
Based on imaging studies, as assessed by independent review. Lymphadenopathy was defined as the presence of ≥1 lymph node with a long axis >1.5 cm or other extranodal lesions with a short axis >1.0 cm. Splenomegaly was defined as a spleen length (cranial to caudal) >13 cm.
Three patients had discrete extranodal splenic lesions; 1 patient had 2 breast lesions.