Patient characteristics and treatment
A total of 34 patients receiving R-M regimen were enrolled. The diagnosis was achieved by surgery (40.5%), or stereotactic biopsy (59.5%), and no patients were diagnosed based on CSF. All PCNSLs were confirmed to be DLBCL. The median age of patients was 62 years (range, 27 to 80 years; 23 patients were>60 years old, and 14 were ≤60 years old). Five patients (13.5%) had elevated LDH above the upper limit of normal. 77.1% (27/35) patients had non-germinal center B cell-like (non-GCB) DLBCL. Severn (20.6%) patients were consolidated with WBRT.
Fourteen patients receiving the R-MA regimen as induction chemotherapy were identified as the positive control group. The characteristics of the 51 patients are described in Table 1. These patients were treated according to their age, financial situation and willingness. The demographics and baseline clinical characteristics (sex, ECOG, LDH, deep structure involvement, biopsy type, Karnofsky performance status (KPS), CD10, C-Myc, Bcl-2, Bcl-6, MUM-1, pathological phenotype, and CSF protein) were not different between patients treated with the R-M and R-MA regimens, except for the age and number of lesions. Patients in the R-M group were older (p=0.006) than the R-MA group, and more patients in the R-M group had multiple lesions (p=0.024).
Table 1
Baseline patient characteristics and the distribution of lymphoma subtypes
Factors
|
|
Total(n=51)
|
R-M(n=37)
|
R-MA(n=14)
|
P-value
|
Age (year) (median, range)
|
60(27-80)
|
62(27-80)
|
56(41-64)
|
0.012
|
|
>60 y
|
25(49.0%)
|
23(62.2%)
|
2(14.3%)
|
|
|
≤60 y
|
26(51.0%)
|
14(37.8%)
|
12(85.7%)
|
0.002
|
Gender
|
Male
|
28(54.9%)
|
22(59.5%)
|
6(42.9%)
|
|
|
Female
|
23(45.1%)
|
15(40.5%)
|
8(57.1)
|
0.29
|
Multifocal lesions
|
Yes
|
24(47.1%)
|
21(56.8%)
|
3(21.4%)
|
|
No
|
27(52.9%)
|
16(43.2%)
|
11(78.6%)
|
0.024
|
Deep-brain involvement
|
Present
|
31(60.8%)
|
22(59.5%)
|
9(64.3%)
|
|
Absent
|
20(39.2%)
|
15(40.5%)
|
5(35.7%)
|
0.75
|
Biopsy type
|
Surgical
|
21(41.2%)
|
15(40.5%)
|
6(42.9%)
|
|
|
Stereotactic
|
30(58.8%)
|
22(59.5%)
|
8(57.1%)
|
0.88
|
ECOG score
|
1
|
0(0%)
|
0(0%)
|
0(0%)
|
|
|
2
|
26(51.0%)
|
17(45.9%)
|
9(64.3%)
|
|
|
3
|
15(29.4%)
|
12(32.4%)
|
3(21.4%)
|
|
|
4
|
10(19.6%)
|
8(21.6%)
|
2(14.3%)
|
0.51
|
KPS score
|
<70
|
32(62.7%)
|
24(64.9%)
|
8(57.1%)
|
|
|
≥70
|
19(37.3%)
|
13(35.1%)
|
6(42.9%)
|
0.61
|
LDH
|
Elevated
|
7(13.7%)
|
5(13.5%)
|
2(14.3%)
|
|
|
Normal
|
44(86.3%)
|
32(86.5%)
|
12(85.7%)
|
1.00
|
CSF protein
|
Elevated
|
22/34(64.7%)
|
16/25(64.0%)
|
6/9(66.7%)
|
|
|
Normal
|
12/34(35.3%)
|
9/25(36.0%)
|
3/9(33.3%)
|
1.00
|
C-Myc
|
Negative
|
24/45(53.3%)
|
17/32(53.1%)
|
7/13(53.8%)
|
|
|
Positive
|
21/45(46.7%)
|
15/32(46.9%)
|
6/13(46.2%)
|
0.96
|
Bcl-2
|
Negative
|
16/47(34.0%)
|
12/34(35.3%)
|
4/13(30.8%)
|
|
|
Positive
|
31/47(66.0%)
|
22/34(64.7%)
|
9/13(69.2%)
|
1.00
|
Bcl-6
|
Negative
|
10/49(20.4%)
|
8/36(22.2%)
|
2/13(15.4%)
|
|
|
Positive
|
39/49(79.4%)
|
28/36(77.8%)
|
11/13(84.6%)
|
0.71
|
CD10
|
Negative
|
38/49(77.6%)
|
29/36(80.6%)
|
9/13(69.2%)
|
|
|
Positive
|
11/49(22.4%)
|
7/36(19.4%)
|
4/13(30.8%)
|
0.40
|
MUM-1
|
Negative
|
7/48(14.6%)
|
7/35(20%)
|
0/13(0%)
|
|
|
Positive
|
41/48(85.4%)
|
28/35(80%)
|
13/13(100%)
|
0.17
|
Pathology phenotype
|
Non-GCB
|
35/48(72.9%)
|
27/35(77.1%)
|
8/13(61.5%)
|
|
GCB
|
13/48(27.1%)
|
8/35(22.9%)
|
5/13(38.5%)
|
0.28
|
Notes: CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B-cell-like; KPS, Karnofsky performance status; LDH, lactate dehydrogenase; R-M, combination regimen of high-dose methotrexate and rituximab; R-MA, combination regimen of rituximab, high-dose methotrexate and cytarabine. |
Response and survival
Thirty-seven patients received a total of 184 cycles of the R-M regimen with a median of 6 cycles per patient (range, 1-6). At the last follow-up, 20 achieved CR (54.1%), 8 achieved PR (21.6%), 0 had SD (0%), and 9 had PD (24.3%). Fourteen patients received a total of 39 cycles of the R-MA regimen, with a median of 3 cycles per patient (range, 1-6). At the last follow-up, 5 patients achieved CR (35.7%), 2 achieved PR (14.3%), 1 had SD (7.1%), and 6 had PD (42.9%). The R-M regimen produced a comparable CR rate (54.1% vs. 35.7%, p=0.24) and overall response rate (ORR) (75.6% vs. 50.0%, p=0.078), compared with the R-MA regimen (Figure 1A).
Follow-up data were available for all patients in both groups. The median follow-up duration was 30.0 months (range,1-76) in the R-M group, which was similar to 27.5 months (range, 1-51) in the R-MA group (p=0.44). The median OS was not reached in either cohort with estimated 3-year OS rates of 54.4% and 51.9% in the R-M and R-MA group, respectively. The median PFS of the R-M group was 19.0 months (95%CI, 16.0–22.0) and the median PFS of R-MA group was 9.0 months (95%CI, 0–27.3). The estimated 2-year PFS rates were36.6% and 42.9% in the R-M and R-MA groups, respectively. The PFS (Figure 1B).and OS (Figure 1C) for the R-M group were not inferior to the R-MA group (p=0.94, p=0.85, respectively.).
Toxicity and cost
Thirty-seven patients received a total of 184 cycles of the R-M regimen with a median of 6 cycles per patient (range, 1-6). Twenty-four of the 37 patients completed the entire protocol. Only 1 patient (2.7%) was withdrawn due to severe myelosuppression with infection and 9 patients (24.3%) were withdrawn due to disease progression. The remaining 3 patients were withdrawn due to personal reasons. Fourteen patients received a total of 39 cycles of the R-MA regimen, with a median of 3 cycles per patient (range, 1-6). Only three of the 14 patients completed the entire protocol. Indeed, five patients (35.7%) were withdrawn due to severe myelosuppression with infection, and six patients (42.9%) were withdrawn due to the disease progression. The total chemotherapy completion rate was higher in the R-M group than in the R-MA group (64.9% vs. 21.4%, p=0.006) (Figure 1D). The chemotherapy interruption rate due to toxicities was significantly lower in the R-M group than in the R-MA group (2.7% vs. 35.7%, p=0.004).
The most frequent toxicities were hematologic toxicities and infection, as summarized in Table 2. The R-M group experienced significantly fewer frequent grade 3-4 hematological toxicities (3.4% vs. 59.0%, p<0.001) and febrile neutropenia (2.7% vs. 41.0%, p<0.001) than the R-MA group. Patients in the R-M group experienced significantly less frequent grade 3 neutropenia (1.6% vs. 15.4%, p=0.001), grade 4 neutropenia (1.1% vs. 43.6%, p<0.001), grade 3 anemia (0.5% vs. 12.8%, p=0.001), grade 4 anemia (0% vs. 10.3%, p=0.001) and grade 4 thrombopenia (1.1% vs. 51.3%, p<0.001) than the R-MA group. Urinary tract infections (1.6% vs. 17.9%, p<0.001) and pneumonia (1.6% vs. 17.9%, p<0.001) were also observed much less frequently in the R-M group than in the R-MA group. Other nonhematological toxicities were generally mild to moderate and reversible and occurred at similar frequencies across both treatment groups. No treatment-related deaths were observed in either group. There were 2 cases of atrial fibrillation, one case of deep vein thrombosis, one case of acute heart failure, and one case of grade 4 skin rash in the R-MA group.
Table 2
Main adverse effects by treatment group
Toxicities
|
R-M (n=184 cycles)
|
R-MA (n=39 cycles) cecs)
|
P-value
|
Grade 3 neutropenia
|
3(1.6%)
|
6(15.4%)
|
0.001
|
Grade 4 neutropenia
|
2(1.1%)
|
17(43.6%)
|
<0.001
|
Grade 3 thrombopenia
|
4(2.2%)
|
3(7.7%)
|
0.10
|
Grade 4 thrombopenia
|
2(1.1%)
|
20(51.3%)
|
<0.001
|
Grade 3 anemia
|
1(0.5%)
|
5(12.8%)
|
0.001
|
Grade 4 anemia
|
0(0%)
|
4(10.3%)
|
0.001
|
Febrile neutropenia
|
5(2.7%)
|
16(41.0%)
|
<0.001
|
Urinary tract infection
|
3(1.6%)
|
7(17.9%)
|
<0.001
|
Pneumonia
|
3(1.6%)
|
7(17.9%)
|
<0.001
|
Oral candidiasis
|
3(1.6%)
|
0(0%)
|
1.00
|
Sepsis
|
1(0.5%)
|
1(2.6%)
|
0.32
|
Acute infectious enteritis
|
1(0.5%)
|
0(0%)
|
1.00
|
Herpes zoster
|
1(0.5%)
|
0(0%)
|
1.00
|
Grade 3 Hepatotoxicity
|
3(1.6%)
|
3(7.7%)
|
0.068
|
Grade 4 Hepatotoxicity
|
1(0.5%)
|
0(0%)
|
1.00
|
Creatinine elevated
|
2(1.1%)
|
0(0%)
|
1.00
|
Deep vein thrombosis
|
0(0%)
|
1(2.6%)
|
0.18
|
Atrial fibrillation
|
0(0%)
|
2(5.1%)
|
0.03
|
Acute heart failure
|
0(0%)
|
1(2.6%)
|
0.18
|
Grade 4 skin rash
|
0(0%)
|
1(2.6%)
|
0.18
|
The average LOS was 5.7 days (95%CI: 5.3-6.1) in the R-M group, which was shorter than 15.2 days (95%CI: 12.7-17.3) observed in the R-MA group (p<0.001) (Figure 1E). The mean total hospitalization cost per cycle of the R-M regimen per patient was $5,536 (95%CI: 4,830-6,454), with a mean total antibiotic cost per cycle per patient of $157 (95%CI: 37-291). The mean total hospitalization cost per cycle of the R-MA regimen per patient was $8,741 (95%CI: 6,904-10,352), with a mean total antibiotic cost per cycle per patient of $822 (95%CI: 417-1,185). The mean total hospitalization cost (Figure 1F). and mean total antibiotic cost per cycle per patient (Figure 1G) in the R-MA group were 1.58 times (P=0.0009) and 5.24 times (P=0.0026) that of the R-M group, respectively.
Univariate and multivariate analyses of prognostic indicators
The results of univariate and multivariate analyses of prognostic indicators are summarized in Table 3. The univariate analysis indicated that response of overall response after two cycles of chemotherapy (p=0.000), complete remission at the end of the induction therapy (p=0.002) and overall response at the end of the induction therapy (p=0.000) and GCB subtype (p=0.019) were associated with increased PFS (Figure 2A-D). While overall response after two cycles of chemotherapy (p=0.003), complete remission at the end of the induction therapy (p=0.01), overall response at the end of the induction therapy (p=0.004), age>58 (p=0.041) and ECOG>3 (p=0.007) were associated with increased OS (Figure 2E-H). Disappointingly, we did not observe any association of LDH or deep brain involvement with PFS or OS. We incorporated all those factors with p-values<0.1 in univariate analysis into the multivariate Cox analysis and revealed that overall response after two cycles of induction chemotherapy (p=0.073),complete remission at the end of induction chemotherapy (p=0.070) and ECOG >3 (p=0.007) were independent prognostic factors for OS. While overall response at the end of induction chemotherapy (p=0.049) and multifocal (p=0.067) were identified as dependent prognostic indicators for PFS.
Table 3
Univariate and multivariate analyses of overall and progression-free survival
|
PFS
|
OS
|
Variable
|
Univariate analysis
|
Multivariate analysis
|
Univariate analysis
|
Multivariate analysis
|
|
HR
|
95%CI
|
P-value
|
HR
|
95%CI
|
P-value
|
HR
|
95%CI
|
P-value
|
HR
|
95%CI
|
P-value
|
Age>58y
|
1.47
|
0.71-3.05
|
0.299
|
|
|
|
2.83
|
1.04-7.69
|
0.041
|
2.42
|
0.85-6.86
|
0.097
|
Deep-brain involvement
|
1.11
|
0.55-2.25
|
0.755
|
|
|
|
0.90
|
0.38-2.11
|
0.805
|
|
|
|
ECOG >3
|
1.94
|
0.89-4.20
|
0.095
|
1.80
|
0.73-4.42
|
0.202
|
2.83
|
1.15-7.00
|
0.024
|
4.85
|
1.54-15.25
|
0.007
|
Elevated LDH
|
1.12
|
0.53-2.38
|
0.764
|
|
|
|
1.73
|
0.58-5.12
|
0.323
|
|
|
|
Multiple focal
|
1.84
|
0.92-3.66
|
0.083
|
2.12
|
0.95-4.76
|
0.067
|
1.49
|
0.64-3.45
|
0.353
|
|
|
|
GCB subtype
|
0.24
|
0.07-0.79
|
0.019
|
0.35
|
0.10-1.22
|
0.100
|
0.28
|
0.07-1.21
|
0.089
|
0.38
|
0.083-1.70
|
0.204
|
CR after 2 cycles of treatment
|
0.53
|
0.23-1.24
|
0.144
|
|
|
|
0.71
|
0.26-1.92
|
0.495
|
|
|
|
OR after 2 cycles of treatment
|
0.18
|
0.08-0.39
|
0.000
|
0.67
|
0.16-2.83
|
0.584
|
0.25
|
0.10-0.62
|
0.003
|
0.20
|
0.04-1.16
|
0.073
|
CR at the end of treatment
|
0.32
|
0.15-0.66
|
0.002
|
0.63
|
0.24-1.67
|
0.349
|
0.28
|
0.11-0.74
|
0.010
|
0.30
|
0.08-1.10
|
0.070
|
OR at the end of treatment
|
0.16
|
0.07-.033
|
0.000
|
0.23
|
0.05-0.99
|
0.049
|
0.29
|
0.12-0.68
|
0.004
|
1.31
|
0.024-7.25
|
0.755
|