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 http://www.thejh.org

Original Article

Volume 7, Number 4, December 2018, pages 131-139

Efficacy of ESHAP Regimen in Transplant Ineligible Patients With Relapsed/Refractory T-Cell Lymphoma

Figure 1. (a) Kaplan-Meier plots of OS according to relapse or refractory disease after frontline chemotherapy. The median OS for patients with late, early relapses and refractory disease were 21, 17 and 3 months, respectively (P = 0.001). (b) Kaplan-Meier plots of second PFS according to relapse or refractory disease after frontline chemotherapy. The median PFS for patients with late, early relapses and refractory disease were 16, 8 and 2 months, respectively (P = 0.001).

Figure 2. (a) Kaplan-Meier plots of OS according to response after ESHAP. Median OS of patients achieving CR, PR and SD/PD were 39, 7 and 5 months, respectively (P < 0.0001). (b) Kaplan-Meier plots of second PFS according to response after ESHAP. Median second PFS of patients achieving CR, PR and SD/PD were 33, 2 and 2 months, respectively (P < 0.0001).

**Table 1.** Baseline Patient Characteristics at First Relapse According to Histological Subtypes
	PTCL-NOS (n = 18)	AITL (n = 5)	ALK+ ALCL (n = 1)	ALK- ALCL (n = 3)	ENKTL (n = 3)	HSTL (n = 2)	MEITL (n = 1)	All (n = 33)
ULN: upper limit of normal; ECOG: Eastern Cooperative Oncology Group; H-I: high-intermediate; IPI: International Prognostic Index; PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALK+ ALCL: anaplastic large cell lymphoma, ALK-positive; ALK- ALCL: anaplastic large cell lymphoma; ALK-negative; ENKTL: extranodal NK/T-cell lymphoma, nasal type; HSTL: hepatosplenic T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma; HBV: hepatitis B virus; HCV: hepatitis C virus; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisolone; CHOEP: CHOP + etoposide; EPOCH: etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin; ASCT: autologous stem cell transplantation; PS: performance status.
Male (%)	11 (61%)	3 (60%)	-	3 (100%)	1 (33%)	1 (50%)	1 (100%)	16 (49%)
Median age (range)	57 (33 - 79)	55 (51 - 63)	36	57 (48 - 68)	50 (33 - 67)	29 (27 - 32)	32	54 (27 - 79)
LDH > UNL (%)	11 (61%)	3 (60%)	1 (100%)	1 (33%)	3 (100%)	2 (100%)	1 (100%)	22 (67%)
ECOG 0 - 1 (%)	11 (61%)	5 (100%)	-	3 (100%)	2 (67%)	-	-	21 (64%)
Stage III - IV (%)	14 (78%)	5 (100%)	1 (100%)	3 (100%)	1 (33%)	2 (100%)	1 (100%)	27 (82%)
Extranodal involvement 0 - 1 site (%)	11 (61%)	4 (80%)	-	2 (67%)	3 (100%)	-	-	20 (61%)
H-I/high IPI (%)	8 (45%)	2 (40%)	1 (100%)	1 (33%)	1 (33%)	2 (100%)	1 (100%)	16 (49%)
B-symptoms (%)	7 (39%)	2 (40%)	1 (100%)	1 (33%)	-	2 (100%)	1 (100%)	14 (42%)
HBV infection (%)	1 (6%)	1 (20%)	-	1(50%)	-	-	-	3 (10%)
HCV infection (%)	2 (11%)	1 (20%)	-	-	-	-	-	3 (10%)
Frontline regimens (%)
CHOP	10 (55%)	3 (60%)	1 (100%)	3 (100%)	3 (100%)	2 (100%)	-	22 (67%)
CHOEP	7 (39%)	2 (40%)	-	-	-	-	1 (100%)	10 (30%)
EPOCH	1 (6%)	-	-	-	-	-	-	1 (3%)
Refractory (%)	7 (39%)	1 (20%)	1 (100%)	-	-	2 (100%)	1 (100%)	12 (36%)
Early relapse (%)	7 (39%)	2 (40%)	-	2 (67%)	-	-	-	11 (33%)
Late relapse (%)	4 (22%)	2 (40%)	-	1 (33%)	3 (100%)	-	-	10 (30%)
Reasons of ineligible for ASCT
Age	8 (44%)	2 (40%)	-	1 (33%)	1 (33%)	-	-	12 (36%)
Comorbidities	2 (11%)	1 (20%)	-	1 (33%)	-	-	-	4 (12%)
Active infection	2 (11%)	1 (20%)	-	-	-	-	-	3 (10%)
Poor PS	5 (27%)	-	1 (100%)	-	1 (33%)	2 (100%)	1 (100%)	10 (30%)
Socioeconomic problems	1 (6%)	1 (20%)	-	1 (33%)	1 (33%)	-	-	4 (12%)

Table 1. Baseline Patient Characteristics at First Relapse According to Histological Subtypes

PTCL-NOS (n = 18)

AITL (n = 5)

ALK+ ALCL (n = 1)

ALK- ALCL (n = 3)

ENKTL (n = 3)

HSTL (n = 2)

MEITL (n = 1)

All (n = 33)

ULN: upper limit of normal; ECOG: Eastern Cooperative Oncology Group; H-I: high-intermediate; IPI: International Prognostic Index; PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALK+ ALCL: anaplastic large cell lymphoma, ALK-positive; ALK- ALCL: anaplastic large cell lymphoma; ALK-negative; ENKTL: extranodal NK/T-cell lymphoma, nasal type; HSTL: hepatosplenic T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma; HBV: hepatitis B virus; HCV: hepatitis C virus; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisolone; CHOEP: CHOP + etoposide; EPOCH: etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin; ASCT: autologous stem cell transplantation; PS: performance status.

Male (%)

11 (61%)

3 (60%)

3 (100%)

1 (33%)

1 (50%)

1 (100%)

16 (49%)

Median age (range)

57 (33 - 79)

55 (51 - 63)

57 (48 - 68)

50 (33 - 67)

29 (27 - 32)

54 (27 - 79)

LDH > UNL (%)

11 (61%)

3 (60%)

1 (100%)

1 (33%)

3 (100%)

2 (100%)

1 (100%)

22 (67%)

ECOG 0 - 1 (%)

11 (61%)

5 (100%)

3 (100%)

2 (67%)

21 (64%)

Stage III - IV (%)

14 (78%)

5 (100%)

1 (100%)

3 (100%)

1 (33%)

2 (100%)

1 (100%)

27 (82%)

Extranodal involvement 0 - 1 site (%)

11 (61%)

4 (80%)

2 (67%)

3 (100%)

20 (61%)

H-I/high IPI (%)

8 (45%)

2 (40%)

1 (100%)

1 (33%)

2 (100%)

1 (100%)

16 (49%)

B-symptoms (%)

7 (39%)

2 (40%)

1 (100%)

1 (33%)

2 (100%)

1 (100%)

14 (42%)

HBV infection (%)

1 (6%)

1 (20%)

1(50%)

3 (10%)

HCV infection (%)

2 (11%)

1 (20%)

3 (10%)

Frontline regimens (%)

CHOP

10 (55%)

3 (60%)

1 (100%)

3 (100%)

2 (100%)

22 (67%)

CHOEP

7 (39%)

2 (40%)

1 (100%)

10 (30%)

EPOCH

1 (6%)

1 (3%)

Refractory (%)

7 (39%)

1 (20%)

1 (100%)

2 (100%)

1 (100%)

12 (36%)

Early relapse (%)

7 (39%)

2 (40%)

2 (67%)

11 (33%)

Late relapse (%)

4 (22%)

2 (40%)

1 (33%)

3 (100%)

10 (30%)

Reasons of ineligible for ASCT

Age

8 (44%)

2 (40%)

1 (33%)

12 (36%)

Comorbidities

2 (11%)

1 (20%)

1 (33%)

4 (12%)

Active infection

2 (11%)

1 (20%)

3 (10%)

Poor PS

5 (27%)

1 (100%)

1 (33%)

2 (100%)

1 (100%)

10 (30%)

Socioeconomic problems

1 (6%)

1 (20%)

1 (33%)

4 (12%)

**Table 2.** Response Rates and Median Survival According to Histological Subtypes
	PTCL-NOS (n = 18)	AITL (n = 5)	ALK+ ALCL (n = 1)	ALK- ALCL (n = 3)	ENKTL (n = 3)	HSTL (n = 2)	MEITL (n = 1)	All (n = 33)
CR: complete response; Cru: complete response, unconfirmed; PFS: progression-free survival; OS: overall survival; NR: not reached; PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALK+ ALCL: anaplastic large cell lymphoma, ALK-positive; ALK- ALCL: anaplastic large cell lymphoma, ALK-negative; ENKTL: extranodal NK/T-cell lymphoma, nasal type; HSTL: hepatosplenic T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma.
Overall response (%)	9 (50%)	2 (40%)	0	2 (67%)	2 (67%)	0	0	15 (46%)
CR/CRu (%)	8 (44%)	2 (40%)	0	1 (33%)	2 (67%)	0	0	13 (39%)
Median PFS (months)	8	3	2	9	33	1	1	8
Median OS (months)	11	18	5	21	NR	1	7	11

Table 2. Response Rates and Median Survival According to Histological Subtypes

PTCL-NOS (n = 18)

AITL (n = 5)

ALK+ ALCL (n = 1)

ALK- ALCL (n = 3)

ENKTL (n = 3)

HSTL (n = 2)

MEITL (n = 1)

All (n = 33)

CR: complete response; Cru: complete response, unconfirmed; PFS: progression-free survival; OS: overall survival; NR: not reached; PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALK+ ALCL: anaplastic large cell lymphoma, ALK-positive; ALK- ALCL: anaplastic large cell lymphoma, ALK-negative; ENKTL: extranodal NK/T-cell lymphoma, nasal type; HSTL: hepatosplenic T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma.

Overall response (%)

9 (50%)

2 (40%)

2 (67%)

15 (46%)

CR/CRu (%)

8 (44%)

2 (40%)

1 (33%)

2 (67%)

13 (39%)

Median PFS (months)

Median OS (months)

**Table 3.** Univariate Analysis ff Factor Affecting OS and Second PFS
	Median OS (months)	P-value	Median second PFS (months)	P-value
UNL: upper normal limit; ECOG: Eastern Cooperative Oncology Group; IPI: International Prognostic Index; PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALK+ ALCL: anaplastic large cell lymphoma, ALK-positive; ALK- ALCL: anaplastic large cell lymphoma, ALK-negative; ENKTL: extranodal NK/T-cell lymphoma, nasal type; HSTL: hepatosplenic T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma.
Age at relapse
< 60 years	7	0.70	3	0.35
> 60 years	11		8
Stage at relapse
Stage I - II	17	0.07	16	0.18
Stage III - IV	11		5
LDH at relapse
Normal	18	0.49	8	0.59
> UNL	7		3
Extranodal involvement at relapse
≤ 1	14	0.20	8	0.78
> 1	5		2
Performance status at relapse
ECOG 0 - 1	18	0.005	9	0.015
ECOG ≥ 2	5		2
Secondary IPI
Low	21	0.08	9	0.31
Low-intermediate	12		5
High-intermediate	10		5
High	5		2
Histologic subtypes
ENKTL	NR	0.02	33	0.03
ALK- ALCL	21		9
PTCL-NOS	11		8
AITL	18		4
ALK+ ALCL	5		2
HSTCL	1		1
MEITL	7		1
Disease status after frontline therapy
Late relapse disease (> 12 months)	21	0.001	16	0.001
Early relapse disease (< 12 months)	17		8
Refractory disease	3		2

Table 3. Univariate Analysis ff Factor Affecting OS and Second PFS

Median OS (months)

P-value

Median second PFS (months)

P-value

UNL: upper normal limit; ECOG: Eastern Cooperative Oncology Group; IPI: International Prognostic Index; PTCL-NOS: peripheral T-cell lymphoma-not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALK+ ALCL: anaplastic large cell lymphoma, ALK-positive; ALK- ALCL: anaplastic large cell lymphoma, ALK-negative; ENKTL: extranodal NK/T-cell lymphoma, nasal type; HSTL: hepatosplenic T-cell lymphoma; MEITL: monomorphic epitheliotropic intestinal T-cell lymphoma.

Age at relapse

< 60 years

0.70

0.35

> 60 years

Stage at relapse

Stage I - II

0.07

0.18

Stage III - IV

LDH at relapse

Normal

0.49

0.59

> UNL

Extranodal involvement at relapse

≤ 1

0.20

0.78

> 1

Performance status at relapse

ECOG 0 - 1

0.005

0.015

ECOG ≥ 2

Secondary IPI

Low

0.08

0.31

Low-intermediate

High-intermediate

High

Histologic subtypes

ENKTL

0.02

0.03

ALK- ALCL

PTCL-NOS

AITL

ALK+ ALCL

HSTCL

MEITL

Disease status after frontline therapy

Late relapse disease (> 12 months)

0.001

Early relapse disease (< 12 months)

Refractory disease

**Table 4.** Adverse Events During ESHAP Therapy
Adverse events	N (%)
Anemia
Grade 3	14 (42.4)
Grade 4	8 (24.2)
Neutropenia
Grade 3	3 (9.1)
Grade 4	12 (36.4)
Thrombocytopenia
Grade 3	3 (15.2)
Grade 4	6 (18.2)
Infection
Grade 3	8 (24.2)
Grade 4	3 (9.1)
Febrile neutropenia
Grade 3	5 (15.2)
Grade 4	4 (12.1)
Rising serum creatinine
Grade 1	7 (21.2)
Grade 2	5 (15.2)
Grade 3	0
Grade 4	1 (3.0)

Table 4. Adverse Events During ESHAP Therapy

Adverse events

N (%)

Anemia

Grade 3

14 (42.4)

Grade 4

8 (24.2)

Neutropenia

Grade 3

3 (9.1)

Grade 4

12 (36.4)

Thrombocytopenia

Grade 3

3 (15.2)

Grade 4

6 (18.2)

Infection

Grade 3

8 (24.2)

Grade 4

3 (9.1)

Febrile neutropenia

Grade 3

5 (15.2)

Grade 4

4 (12.1)

Rising serum creatinine

Grade 1

7 (21.2)

Grade 2

5 (15.2)

Grade 3

Grade 4

1 (3.0)

**Table 5.** The Results of Previously Reported Salvage Regimens for PTCLs [11-13, 21-26]
Regimens	Cohort	No. of patients	Median prior therapy (n)	Refractory disease (%)	Response rate	Median DOR (months)	Median PFS (months)	TRD (%)
ORR: overall response; CR: complete response; DOR: duration of response; PFS: progression free survival; TRD: treatment related death; GDP: gemcitabine, dexamethasone and cisplatin; mESHAP: etoposide, methylprednisolone, cytarabine and carboplatin; ICE: ifosfamide, carboplatin and etoposide; GEMOX: gemcitabine, oxaliplatin and dexamethasone; PTCLu: peripheral T-cell lymphoma, unspecified.
This study	Retrospective	33	1	36	46	39	18	8	3
GDP [21]	Prospective	25	1	36	64 (prior to ASCT)	32	NA	9.3 (including 4 transplanted cases)	0
mESHAP [23]	Retrospective	22	1	NA	32	18	NA	2.5 (including 3 transplanted cases)	0
ICE [24]	Retrospective	15	1	NA	20	7	NA	2 (including 3 transplanted cases)	0
Bendamustine [22]	Prospective	60	1	45	50	28	3.5	3.6	6.6
Gemcitabine [25]	Prospective	20 (PTCLu)	3	NA	55	30	34	NA	0
GEMOX [26]	Prospective	31	3	52	25	13	NA	10	0
Pralatrexate [11]	Prospective	111	3	NA	29	11	10.1	3.5	0.9
Romidepsin [12]	Prospective	131	2	NA	25	15	28	29	0
Belinostat [13]	Prospective	129	2	NA	25.8	10.8	13.6	1.6	0.7

Table 5. The Results of Previously Reported Salvage Regimens for PTCLs [11-13, 21-26]

Regimens

Cohort

No. of patients

Median prior therapy (n)

Refractory disease (%)

Response rate

Median DOR (months)

Median PFS (months)

TRD (%)

ORR (%)

CR rate (%)

ORR: overall response; CR: complete response; DOR: duration of response; PFS: progression free survival; TRD: treatment related death; GDP: gemcitabine, dexamethasone and cisplatin; mESHAP: etoposide, methylprednisolone, cytarabine and carboplatin; ICE: ifosfamide, carboplatin and etoposide; GEMOX: gemcitabine, oxaliplatin and dexamethasone; PTCLu: peripheral T-cell lymphoma, unspecified.

This study

Retrospective

GDP [21]

Prospective

64 (prior to ASCT)

9.3 (including 4 transplanted cases)

mESHAP [23]

Retrospective

2.5 (including 3 transplanted cases)

ICE [24]

Retrospective

2 (including 3 transplanted cases)

Bendamustine [22]

Prospective

3.5

3.6

6.6

Gemcitabine [25]

Prospective

20 (PTCLu)

GEMOX [26]

Prospective

Pralatrexate [11]

Prospective

111

10.1

3.5

0.9

Romidepsin [12]

Prospective

131

Belinostat [13]

Prospective

129

25.8

10.8

13.6

1.6

0.7