J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Original Article

Volume 11, Number 5, October 2022, pages 176-184

Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis

Figure 1. The median overall survival (OS) and progression-free survival (PFS) were 14.6 months (95% confidence interval (CI), 7.0 - 30.0 months) and 7.7 months (95% CI, 5.3 - 10.2 months), respectively. The mean follow-up time was 33.3 months. Overall, the 3-year OS in R-CHOP, R-mini-CHOP, R-CVOP, and R-COP is 47.0%, 50%, 50%, and 23%; 3-year PFS is 42%, 40%, 38%, and 15% (P = 0.453 and 0.292; 3-year OS and 3-year PFS).

Figure 2. We used multivariate analysis on overall survival. The stage, age-adjusted international prognostic index (aa-IPI), lactate dehydrogenase (LDH) × white blood cell (WBC) level and involved bone or bone marrow, lung or pleura, spleen, and kidney or adrenal glands strongly correlated with worse overall survival (OS) and progression-free survival (PFS). High body surface area (BSA) had positive effect on PFS. Higher Eastern Cooperative Oncology Group (ECOG), Charlson comorbidity index (CCI), and salvaged granulocyte colony-stimulating factor (G-CSF) use are also the independent factors for OS.

**Table 1.** Demographic and Clinical Characteristics of Total Patients
Characteristics	Total, N (%)	ACR, N (%)	Non-ACR, N (%)	P value
The cell of origin was measured with immunohistochemistry. aa-IPI: age-adjusted international prognostic index; ACR: anthracycline-containing; BSA: body surface area; CCI: Charlson comorbidity index; ECOG: Eastern Cooperative Oncology Group; GCB: germinal center B cell; G-CSF: granulocyte colony-stimulating factor; LDH: lactate dehydrogenase.
Total	84	29 (34.5)	55 (65.6)
Age (years)				0.012
< 85	65 (77.4)	27 (93.1)	38 (69.1)
≥ 85	19 (22.7)	2 (6.9)	17 (30.9)
CCI				0.005
Low (< 8)	63 (75.0)	27 (93.1)	36 (65.5)
High (≥ 8)	21 (25.0)	2 (6.9)	19 (34.5)
BSA (m²)				0.009
< 1.5	27 (32.1)	4 (13.8)	23 (41.8)
≥ 1.5	57 (67.9)	25 (86.2)	32 (58.2)
ECOG				0.012
0 - 2	65 (77.4)	27 (93.1)	38 (69.1)
3 - 4	19 (22.6)	2 (6.9)	17 (30.9)
Gender				0.406
Female	40 (47.6)	12 (41.4)	28 (50.9)
Male	44 (52.3)	17 (58.6)	27 (49.1)
Ann Arbor stage				0.854
Low	33 (39.3)	11 (37.9)	22 (40.0)
High	51 (60.7)	18 (62.1)	33 (60.0)
aa-IPI				0.136
0 - 1	37 (44.0)	16 (55.2)	21 (38.2)
2 - 3	47 (56.0)	13 (44.8)	34 (61.8)
Han’s criteria				0.255
GCB	16 (19.1)	6 (20.7)	10 (18.2)
Non-GCB	41 (48.8)	16 (55.2)	25 (45.4)
Not applicable	27 (32.1)	7 (24.1)	20 (36.4)
MYC expression				0.018
No	9 (10.7)	5 (17.2)	4 (7.3)
Yes	13 (15.5)	8 (27.6)	5 (9.1)
Not applicable	62 (73.8)	16 (55.2)	46 (83.6)
B symptoms				0.717
No	60 (71.4)	20 (69.0)	40 (72.7)
Yes	24 (28.6)	9 (31.0)	15 (27.3)
LDH				0.633
Normal	29 (34.5)	11 (37.9)	18 (32.7)
Abnormal	55 (65.5)	18 (62.1)	37 (67.3)
Extra-nodal sites				0.289
No	23 (27.4)	10 (34.5)	13 (23.6)
Yes	61 (72.6)	19 (65.5)	42 (76.4)
Bulky disease (≥ 7 cm)				0.388
No	68 (81.0)	22 (75.9)	46 (83.6)
Yes	16 (19.0)	7 (24.1)	9 (16.4)
G-CSF use				0.054
No	55 (65.5)	15 (51.7)	40 (72.7)
Yes	29 (34.5)	14 (48.3)	15 (27.3)
Line of chemotherapy				0.633
1	55 (65.5)	18 (62.1)	37 (67.3)
≥ 2	29 (34.5)	11 (37.9)	18 (32.7)

Table 1. Demographic and Clinical Characteristics of Total Patients

Characteristics

Total, N (%)

ACR, N (%)

Non-ACR, N (%)

P value

The cell of origin was measured with immunohistochemistry. aa-IPI: age-adjusted international prognostic index; ACR: anthracycline-containing; BSA: body surface area; CCI: Charlson comorbidity index; ECOG: Eastern Cooperative Oncology Group; GCB: germinal center B cell; G-CSF: granulocyte colony-stimulating factor; LDH: lactate dehydrogenase.

Total

29 (34.5)

55 (65.6)

Age (years)

0.012

< 85

65 (77.4)

27 (93.1)

38 (69.1)

≥ 85

19 (22.7)

2 (6.9)

17 (30.9)

CCI

0.005

Low (< 8)

63 (75.0)

27 (93.1)

36 (65.5)

High (≥ 8)

21 (25.0)

2 (6.9)

19 (34.5)

BSA (m²)

0.009

< 1.5

27 (32.1)

4 (13.8)

23 (41.8)

≥ 1.5

57 (67.9)

25 (86.2)

32 (58.2)

ECOG

0.012

0 - 2

65 (77.4)

27 (93.1)

38 (69.1)

3 - 4

19 (22.6)

2 (6.9)

17 (30.9)

Gender

0.406

Female

40 (47.6)

12 (41.4)

28 (50.9)

Male

44 (52.3)

17 (58.6)

27 (49.1)

Ann Arbor stage

0.854

Low

33 (39.3)

11 (37.9)

22 (40.0)

High

51 (60.7)

18 (62.1)

33 (60.0)

aa-IPI

0.136

0 - 1

37 (44.0)

16 (55.2)

21 (38.2)

2 - 3

47 (56.0)

13 (44.8)

34 (61.8)

Han’s criteria

0.255

GCB

16 (19.1)

6 (20.7)

10 (18.2)

Non-GCB

41 (48.8)

16 (55.2)

25 (45.4)

Not applicable

27 (32.1)

7 (24.1)

20 (36.4)

MYC expression

0.018

9 (10.7)

5 (17.2)

4 (7.3)

Yes

13 (15.5)

8 (27.6)

5 (9.1)

Not applicable

62 (73.8)

16 (55.2)

46 (83.6)

B symptoms

0.717

60 (71.4)

20 (69.0)

40 (72.7)

Yes

24 (28.6)

9 (31.0)

15 (27.3)

LDH

0.633

Normal

29 (34.5)

11 (37.9)

18 (32.7)

Abnormal

55 (65.5)

18 (62.1)

37 (67.3)

Extra-nodal sites

0.289

23 (27.4)

10 (34.5)

13 (23.6)

Yes

61 (72.6)

19 (65.5)

42 (76.4)

Bulky disease (≥ 7 cm)

0.388

68 (81.0)

22 (75.9)

46 (83.6)

Yes

16 (19.0)

7 (24.1)

9 (16.4)

G-CSF use

0.054

55 (65.5)

15 (51.7)

40 (72.7)

Yes

29 (34.5)

14 (48.3)

15 (27.3)

Line of chemotherapy

0.633

55 (65.5)

18 (62.1)

37 (67.3)

≥ 2

29 (34.5)

11 (37.9)

18 (32.7)

**Table 2.** Chemotherapy-Related AEs
	ACR	Non-ACR	P value
^aOne patient had event of OHCA, which occurred on day 16 after completion of the sixth cycle of R-CHOP, and suspected cardiovascular disease-related. Another two patients under R-COP treatment had event of acute myocardial infarction and proceeded to cardiac catheterization immediately. ^bEarly mortality (within 90 days from diagnosis): one SDH(R-CVOP), six rapid disease progression (three R-COP^IV, two R-COP^oral, and one R-CVOP), and three treatment complication (two R-CHOP and one R-COP^IV). ^cTwo patients in R-CVOP and R-CHOP group developed secondary myeloid neoplasm during follow-up. AE: adverse event; ACR: anthracycline-containing.
Total	29	55
All grade AE	15 (51.7)	33 (60.0)	0.155
Grade ≥ 3 AE	13 (44.8)	29 (52.7)	0.647
Febrile neutropenia	7 (24.1)	9 (16.4)	0.388
Grade ≥ 3 infection	7 (24.1)	15 (27.3)	0.756
Grade ≥ 3 hematological complication	8 (27.6)	14 (25.5)	0.833
Grade ≥ 3 polyneuropathy	2 (6.9)	1 (1.8)	0.274
Event of hospitalization	9 (31.0)	22 (40.0)	0.481
Treatment related mortality	3 (10.3)	7 (12.7)	1.000
Mortality cause^a			0.246
Survived	11 (37.9)	11 (20.0)
Progression^b	10 (34.5)	30 (54.5)
Side effect	3 (10.3)	5 (9.0)
Other^c	5 (17.2)	9 (16.4)
Cycle completed (≥ 6)			0.059
Yes	17 (58.6)	21 (38.2)
No, progression	1 (3.4)	13 (23.6)
No, complication	8 (27.6)	17 (30.9)
No, other reason	3 (10.3)	4 (7.3)

Table 2. Chemotherapy-Related AEs

ACR

Non-ACR

P value

^aOne patient had event of OHCA, which occurred on day 16 after completion of the sixth cycle of R-CHOP, and suspected cardiovascular disease-related. Another two patients under R-COP treatment had event of acute myocardial infarction and proceeded to cardiac catheterization immediately. ^bEarly mortality (within 90 days from diagnosis): one SDH(R-CVOP), six rapid disease progression (three R-COP^IV, two R-COP^oral, and one R-CVOP), and three treatment complication (two R-CHOP and one R-COP^IV). ^cTwo patients in R-CVOP and R-CHOP group developed secondary myeloid neoplasm during follow-up. AE: adverse event; ACR: anthracycline-containing.

Total

All grade AE

15 (51.7)

33 (60.0)

0.155

Grade ≥ 3 AE

13 (44.8)

29 (52.7)

0.647

Febrile neutropenia

7 (24.1)

9 (16.4)

0.388

Grade ≥ 3 infection

7 (24.1)

15 (27.3)

0.756

Grade ≥ 3 hematological complication

8 (27.6)

14 (25.5)

0.833

Grade ≥ 3 polyneuropathy

2 (6.9)

1 (1.8)

0.274

Event of hospitalization

9 (31.0)

22 (40.0)

0.481

Treatment related mortality

3 (10.3)

7 (12.7)

1.000

Mortality cause^a

0.246

Survived

11 (37.9)

11 (20.0)

Progression^b

10 (34.5)

30 (54.5)

Side effect

3 (10.3)

5 (9.0)

Other^c

5 (17.2)

9 (16.4)

Cycle completed (≥ 6)

0.059

Yes

17 (58.6)

21 (38.2)

No, progression

1 (3.4)

13 (23.6)

No, complication

8 (27.6)

17 (30.9)

No, other reason

3 (10.3)

4 (7.3)

**Table 3.** Distribution of Response and Adverse Events Between ACR and Non-ACR Groups
	ACR	Non-ACR	P value
ACR: anthracycline-containing; CR: complete remission; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate.
CR (n, %)	13 (44.8)	17 (30.9)	0.206
PR (n, %)	13 (44.8)	22 (40.0)	0.670
SD (n, %)	0	2 (3.6)	0.542
PD (n, %)	3 (10.3)	11 (20.0)	0.361
Unknown	0	3 (5.5)	0.548
ORR (n, %)	26 (89.6)	39 (70.9)	0.051

Table 3. Distribution of Response and Adverse Events Between ACR and Non-ACR Groups

ACR

Non-ACR

P value

ACR: anthracycline-containing; CR: complete remission; PR: partial response; SD: stable disease; PD: progressive disease; ORR: overall response rate.

CR (n, %)

13 (44.8)

17 (30.9)

0.206

PR (n, %)

13 (44.8)

22 (40.0)

0.670

SD (n, %)

2 (3.6)

0.542

PD (n, %)

3 (10.3)

11 (20.0)

0.361

Unknown

3 (5.5)

0.548

ORR (n, %)

26 (89.6)

39 (70.9)

0.051

**Table 4.** Regimen Combo and Percentile to Regular Reference Dose
Regimen/mean dose	C	O	A or V
^aIn R-CHOP group, R-mini-CHOP must fulfill both anthracycline ≤ 25 mg/m² and cyclophosphamide ≤ 400 mg/m². ^bWhen calculating the mean percentage of dose in each patient, we used cyclophosphamide 750 mg/m² per cycle as the baseline reference; the daily dose of cyclophosphamide would be summed up and divided by patient’s BSA; we used vincristine 1.4 mg/m² (maximum dose: 2 mg) and anthracycline 50 mg/m² as the baseline reference. A: anthracycline; C: cyclophosphamide; E: epirubicin; H: doxorubicin; O: vincristine; R: rituximab; V: etoposide; IV: by intravenously given; Oral: by orally given.
ACR^a (n = 29)	66.0% (range: 39-97%)	78.6% (range: 42-100%)	51.9% (range: 12-93%)	R-CHOP (n = 16): R 375 mg/m², C 750 mg/m², H 50 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days	R-CEOP (n = 3): R 375 mg/m², C 750 mg/m², E 75 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days	R-mini-CHOP (n = 10): R 375 mg/m², C ≤ 400 mg/m², H ≤ 25 mg/m², O 1.4 mg/m² (max: 1 mg), prednisone 40 mg/m² orally 5 days
Non-ACR R-CVOP^a (n = 8)	57.1% (range: 37-89%)	76.6% (range: 50-100%)	71.4% (range: 33-100%)	R-CVOP^oral (n = 5): R 375 mg/m², C 50 - 150 mg for 5 days orally, O 1.4 mg/m² (max: 2 mg), V 100 mg orally for 3 days, prednisone 40 mg/m² orally 5 days	R-CVOP^IV (n = 2): R 375 mg/m², C 750 mg/m², V 100 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days	R-CVP^oral (n = 1): R 375 mg/m², C 50 - 150 mg for 5 days orally, V 100 mg orally for 3 days, prednisone 40 mg/m² orally 5 days
Non-ACR R-COP (n = 47)	68.7% (range: 31-100%)	67.3% (range: 0-100%)	-	R-COP^IV (n = 26): R 375 mg/m², C 750 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days	^bR-COP^oral (n = 9): R 375 mg/m², C 50 - 150 mg for 5 days orally, O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days	^bR-CP^oral (n = 11): R 375 mg/m², C 50 - 150 mg for 5 days orally, prednisone 40 mg/m² orally 5 days

Table 4. Regimen Combo and Percentile to Regular Reference Dose

Regimen/mean dose

A or V

^aIn R-CHOP group, R-mini-CHOP must fulfill both anthracycline ≤ 25 mg/m² and cyclophosphamide ≤ 400 mg/m². ^bWhen calculating the mean percentage of dose in each patient, we used cyclophosphamide 750 mg/m² per cycle as the baseline reference; the daily dose of cyclophosphamide would be summed up and divided by patient’s BSA; we used vincristine 1.4 mg/m² (maximum dose: 2 mg) and anthracycline 50 mg/m² as the baseline reference. A: anthracycline; C: cyclophosphamide; E: epirubicin; H: doxorubicin; O: vincristine; R: rituximab; V: etoposide; IV: by intravenously given; Oral: by orally given.

ACR^a (n = 29)

66.0% (range: 39-97%)

78.6% (range: 42-100%)

51.9% (range: 12-93%)

R-CHOP (n = 16): R 375 mg/m², C 750 mg/m², H 50 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days

R-CEOP (n = 3): R 375 mg/m², C 750 mg/m², E 75 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days

R-mini-CHOP (n = 10): R 375 mg/m², C ≤ 400 mg/m², H ≤ 25 mg/m², O 1.4 mg/m² (max: 1 mg), prednisone 40 mg/m² orally 5 days

Non-ACR R-CVOP^a (n = 8)

57.1% (range: 37-89%)

76.6% (range: 50-100%)

71.4% (range: 33-100%)

R-CVOP^oral (n = 5): R 375 mg/m², C 50 - 150 mg for 5 days orally, O 1.4 mg/m² (max: 2 mg), V 100 mg orally for 3 days, prednisone 40 mg/m² orally 5 days

R-CVOP^IV (n = 2): R 375 mg/m², C 750 mg/m², V 100 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days

R-CVP^oral (n = 1): R 375 mg/m², C 50 - 150 mg for 5 days orally, V 100 mg orally for 3 days, prednisone 40 mg/m² orally 5 days

Non-ACR R-COP (n = 47)

68.7% (range: 31-100%)

67.3% (range: 0-100%)

R-COP^IV (n = 26): R 375 mg/m², C 750 mg/m², O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days

^bR-COP^oral (n = 9): R 375 mg/m², C 50 - 150 mg for 5 days orally, O 1.4 mg/m² (max: 2 mg), prednisone 40 mg/m² orally 5 days

^bR-CP^oral (n = 11): R 375 mg/m², C 50 - 150 mg for 5 days orally, prednisone 40 mg/m² orally 5 days