A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma

Yong-Pyo Lee; Ye Ji Jung; Junhun Cho; Young Hyeh Ko; Won Seog Kim; Seok Jin Kim; Sang Eun Yoon

doi:10.5045/br.2023.2023208

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Original Article

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Blood Res 2023; 58(4):

Published online December 31, 2023

https://doi.org/10.5045/br.2023.2023208

A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma

Yong-Pyo Lee^1#, Ye Ji Jung^2#, Junhun Cho³, Young Hyeh Ko³, Won Seog Kim^2,4, Seok Jin Kim^2,4, Sang Eun Yoon²

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¹Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Division of Hematology-Oncology, Departments of ²Medicine, ³Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, ⁴Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea

Correspondence to : Sang Eun Yoon, M.D., Ph.D.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
E-mail: starload0326@gmail.com

^#These authors contributed equally to this work.

*This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI22C0999). This study was also supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HR20C0025); a National Research Foundation of Korea grant funded by the Korean government (2022R1F1A1064058); and the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2023-00222838).

Received: October 26, 2023; Revised: November 27, 2023; Accepted: December 8, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
While treatment strategies for mantle cell lymphoma (MCL) have evolved, patients often experience disease progression and require additional treatment therapies. Ibrutinib presents a promising option for relapsed or refractory MCL (RR-MCL). This study investigated real-world treatment outcomes of ibrutinib in patients with RR-MCL.
Methods
A single-center retrospective analysis investigated clinical characteristics and survival outcomes of patients with RR-MCL, treated with ibrutinib.
Results
Forty-two patients were included, with 16 received rituximab and bendamustine, and 26 receiving anthracycline-based regimens as front-line treatment. During a median follow-up of 46.0 months, the response rate to ibrutinib was 69%, with 12 CRs and 8 partial responses. Disease progression (54.8%) and adverse events (11.9%) were the primary reasons for discontinuation. Median progression-free survival (PFS) and overall survival (OS) were approximately 16.4 and 50.1 months, respectively. Patients older than 70 years (P=0.044 and P=0.006), those with splenomegaly (P=0.022 and P=0.006), and those with a high-risk simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) (P＜0.001 and P＜0.001) exhibited siginificantly inferior PFS and OS. Notably, patients with a high-risk sMIPI relapsed earlier. Post-ibrutinib treatment yilded an OS of 12.2 months, while clinical trial participants demonstrated superior survival compared to those receiving chemotherapy alone.
Conclusion
This study underscores the importance of considering patient characteristics before administering ibrutinib as salvage therapy. Early relapse was associated with poor outcomes, highlighting the need for novel therapeutic strategies.

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Keywords: Ibrutinib, Mantle-cell, Lymphoma, Relapsed or refractory

Article

Original Article

Blood Res 2023; 58(4): 208-220

Published online December 31, 2023 https://doi.org/10.5045/br.2023.2023208

A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma

Yong-Pyo Lee^1#, Ye Ji Jung^2#, Junhun Cho³, Young Hyeh Ko³, Won Seog Kim^2,4, Seok Jin Kim^2,4, Sang Eun Yoon²

Correspondence to:Sang Eun Yoon, M.D., Ph.D.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
E-mail: starload0326@gmail.com

^#These authors contributed equally to this work.

*This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI22C0999). This study was also supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HR20C0025); a National Research Foundation of Korea grant funded by the Korean government (2022R1F1A1064058); and the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2023-00222838).

Received: October 26, 2023; Revised: November 27, 2023; Accepted: December 8, 2023

Abstract

Keywords: Ibrutinib, Mantle-cell, Lymphoma, Relapsed or refractory

Abstract

Fig 1.

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Figure 1.Kaplan-Meier curve of progression-free survival (PFS) (A) and overall survival (OS) for salvage ibrutinib therapy (B). Comparison of PFS and OS of ibrutinib treatment according to response (C, D), line of treatment (E, F), and progression of disease within 24 months of front-line treatment (G, H). Assessment of PFS according to age (I), presence of splenomegaly (J), and simplified mantle cell lymphoma international prognostic index (sMIPI) (K) and OS according to age (L), presence of splenomegaly (M), and sMIPI (N).

Blood Research 2023; 58: 208-220https://doi.org/10.5045/br.2023.2023208

Fig 2.

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Figure 2.Kaplan-Meier curves of overall survival according to early relapse (A) and type of response to salvage ibrutinib (B). Comparison of cumulative incidence of early relapse according to front-line treatment (C), simplified mantle cell lymphoma international prognostic index (D), age (E), presence of splenomegaly (F), and line of treat-ment of ibrutinib (G).

Blood Research 2023; 58: 208-220https://doi.org/10.5045/br.2023.2023208

Fig 3.

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Figure 3.Kaplan-Meier curves of overall survival for post-ibrutinib treatment (A). Comparison of overall survival according to participation in clinical trials (B). Swimmer plot of patients who received post-ibrutinib treatment (C).

Blood Research 2023; 58: 208-220https://doi.org/10.5045/br.2023.2023208

Table 1 . Baseline demographics and disease characteristics at diagnosis..

Characteristics		Total (N=42)	BR (N=16)	Anthracycline-based regimen (N=26)	P
Age (yr)	Median (range)	62 (38–78)	63 (50–78)	61 (39–70)
	<60	17 (40.5%)	2 (12.5%)	15 (57.7%)	0.004
	≥60	25 (59.5%)	14 (87.5%)	11 (42.3%)	0.004
Gender	Male	30 (71.4%)	11 (68.7%)	19 (73.0%)	0.763
Gender	Female	12 (28.6%)	5 (31.2%)	7 (27.0%)	0.763
ECOG-PS	0–1	39 (92.9%)	14 (87.5%)	25 (96.2%)	0.290
ECOG-PS	2–4	3 (7.1%)	2 (12.5%)	1 (3.8%)	0.290
B symptom	Absence	37 (88.1%)	13 (81.2%)	24 (92.3%)	0.283
B symptom	Present	5 (11.9%)	3 (18.7%)	2 (7.7%)	0.283
Leukocytosis	Absence	31 (73.8%)	8 (50.0%)	23 (88.5%)	0.006
Leukocytosis	Present	11 (26.2%)	8 (50.0%)	3 (11.5%)	0.006
Anemia	Absence	33 (78.6%)	9 (56.2%)	24 (92.3%)	0.006
Anemia	Present	9 (21.4%)	7 (43.7%)	2 (7.7%)	0.006
Thrombocytopenia	Absence	36 (85.7%)	11 (68.7%)	25 (96.2%)	0.014
Thrombocytopenia	Present	6 (14.3%)	5 (31.2%)	1 (3.8%)	0.014
Serum LDH	Absence	23 (54.8%)	7 (43.7%)	16 (61.5%)	0.261
Serum LDH	Elevated	19 (45.2%)	9 (56.2%)	10 (38.5%)	0.261
Serum β-2 microglobulin	Absence	23 (54.8%)	5 (31.2%)	18 (69.2%)	0.016
Serum β-2 microglobulin	Elevated	19 (45.2%)	11 (68.7%)	8 (30.8%)	0.016
Bone marrow involvement	Absence	13 (31.0%)	2 (12.5%)	11 (42.3%)	0.042
Bone marrow involvement	Present	29 (69.0%)	14 (87.5%)	15 (57.7%)	0.042
Number of extra-nodal involvement	Less than one	11 (26.2%)	2 (12.5%)	9 (34.6%)	0.113
Number of extra-nodal involvement	More than two	31 (73.8%)	14 (87.5%)	17 (65.4%)	0.113
Bulky (≥7 cm) mass	Absence	33 (78.6%)	10 (62.5%)	23 (88.5%)	0.046
Bulky (≥7 cm) mass	Present	9 (21.4%)	6 (37.5%)	3 (11.5%)	0.046
Pathology	Classic type	41 (97.6%)	16 (100.0%)	25 (96.2%)	0.427
Pathology	Pleomorphic/blastoid type	1 (2.4%)	0 (0.0%)	1 (3.8%)	0.427
Ki-67	<30%	33 (78.6%)	12 (75.0%)	21 (80.8%)	0.658
Ki-67	≥30%	9 (21.4%)	4 (25.0%)	5 (19.2%)	0.658
Ann Arbor stage	I/II	5 (11.9%)	1 (6.3%)	4 (15.4%)	0.375
Ann Arbor stage	III/IV	37 (88.1%)	15 (93.7%)	22 (84.6%)	0.375
sMIPI score	Low (0–3)	19 (45.2%)	3 (18.7%)	16 (61.5%)	0.002
	Intermediate (4–5)	18 (42.9%)	8 (50.0%)	10 (38.5%)
	High (6–11)	5 (11.9%)	5 (31.3%)	0 (0.0%)

Abbreviations: ASCT, autologous stem cell transplantation; BR, bendamustine plus rituximab; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase; sMIPI, simplified mantle cell lymphoma international prognostic index..

Table 2 . Univariate and multivariate analyses for progressiong-free survival and overall survival with salvage ibrutinib treatment..

Variables	Overall survival				Progression-free survival
	Univariate		Multivariate		Univariate		Multivariate
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Age (≥70 yr)	3.419 (1.340–8.726)	0.010	0.380 (0.106–1.358)	0.137	3.158 (1.395–7.146)	0.006	0.578 (0.201–1.661)	0.308
sMIPI score (high score)	5.325 (2.111–13.428)	<0.001	6.249 (2.067–18.892)	0.001	4.681 (2.086–10.501)	<0.001	2.874 (1.171–7.055)	0.021
Splenomegaly	3.303 (1.345–8.111)	0.009	1.983 (0.439–8.961)	0.374	2.338 (1.107–4.936)	0.026	1.373 (0.506–3.720)	0.534
Anthracycline-contai- ning front-line treatment	0.197 (0.075–0.516)	0.001	1.282 (0.354–4.647)	0.705	0.159 (0.063–0.402)	<0.001	0.273 (0.081–0.921)	0.036
POD 24 of front-line treatment	3.013 (1.190–7.625)	0.020	0.991 (0.242–4.070)	0.991	2.858 (1.336–6.117)	0.007	1.895 (0.737–4.876)	0.185
Previous number of treatments (≥2 lines )	0.730 (0.263–2.024)	0.546			1.230 (0.576–2.626)	0.593
Underwent ASCT before ibrutinib treatment	0.692 (0.230–2.086)	0.513			1.068 (0.468–2.439)	0.876
Duration of ibrutinib >12 months	0.023 (0.003–0.179)	<0.001	0.011 (0.001–0.110)	<0.001	0.041 (0.011–0.154)	<0.001	0.042 (0.010–0.180)	<0.001
Grade 3/4 adverse events	3.185 (1.203–8.433)	0.020	1.884 (0.612–5.798)	0.269	1.977 (0.789–4.953)	0.146

Abbreviations: ASCT, autologous stem cell transplantation; POD 24, disease progression within 24 months; sMIPI, simplified mantle cell lymphoma international prognostic index..

Table 3 . Comparison of patients with and without early disease relapse..

Characteristics		Early relapse (N=13)	Late relapse or no relapse (N=29)	P
Age (yr)	Median (yr), range	67 (51–77)	67 (45–81)
	<70	6 (46.2%)	21 (72.4%)	0.101
	≥70	7 (53.8%)	8 (27.6%)	0.101
Gender	Male	10 (76.9%)	20 (69.0%)	0.598
Gender	Female	3 (23.1%)	9 (31.0%)	0.598
ECOG-PS	0–1	12 (92.3%)	29 (100.0%)	0.131
ECOG-PS	2–4	1 (7.7%)	0 (0.0%)	0.131
sMIPI score	Low (0–3)	0 (0.0%)	7 (24.1%)	0.033
	Intermediate (4–5)	6 (46.2%)	14 (48.3%)
	High (6–11)	7 (53.8%)	8 (27.6%)
Splenomegaly (≥11 cm)	Absence	7 (53.8%)	11 (37.9%)	0.335
Splenomegaly (≥11 cm)	Present	6 (46.2%)	18 (62.1%)	0.335
Prior number of treatment	Prior 1 line	9 (69.2%)	20 (69.0%)	0.986
Prior number of treatment	Prior ≥2 lines	4 (30.8%)	9 (31.0%)	0.986
Front-line treatment	Anthracycline-based	6 (46.2%)	20 (69.0%)	0.159
Front-line treatment	Bendamustine-based	7 (53.8%)	9 (31.0%)	0.159
ASCT	Received	3 (23.1%)	7 (24.1%)	0.941
ASCT	Not received	10 (76.9%)	22 (75.9%)	0.941
Ibrutinib dose adjustment	Dose reduction	1 (7.7%)	5 (17.2%)	0.414
Ibrutinib dose adjustment	No dose reduction	12 (92.3%)	24 (82.8%)	0.414
Ibrutinib discontinuation	Discontinuation	13 (100.0%)	24 (82.8%)	0.111
Ibrutinib discontinuation	No discontinuation	0 (0.0%)	5 (17.2%)	0.111

Abbreviations: ASCT, autologous stem cell transplantation; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; sMIPI, simplified mantle cell lymphoma international prognostic index..

Table 4 . Summary of previous studies on ibrutinib therapy in relapsed or refractory mantle cell lymphoma..

Study	Pt. number	Front-line Tx.	Refractory to front-line Tx.	Upfront ASCT	Prior Tx.	ORR	PFS (median)	OS (median)	Ref
Phase 2	111	R-containing therapy (N=99, 89%)	50 (45%)	8 (13%)	3 (1–5)	67% (CR, 23%)	13 mo	22.5 mo	[5, 6]
Phase 3	280	R-containing therapy (N=280, 100%)	36 (26%)	N/A	2 (1–9)	72% (CR, 19%)	14.6 mo	Not reached	[7]
Retrospective	97	Intensive induction therapy (N=52, 54%) (R±hyper-CVAD, R-maxi CHOP)	7 (7%)	38 (39%)	2 (1–8)	65% (CR, 33%)	15 mo	22 mo	[8]
Phase 2	16	R-containing therapy (N=16, 100%)	1 (6.2%)	N/A	2.5 (1–4)	87.5% (CR, 12.5%)	N/A	N/A	[9]
Retrospective	33	R-CHOP (N=33)	N/A	6 (18.1%)	1 (33.3%). 2 (36.4%). ≥3 (30.3%).	64% (CR, 15%)	27.4 mo	35.1 mo	[10]
Retrospective	65	R-CHOP, R-bendamustine and R-hyper-CVAD (87%)	N/A	N/A	2 (1–6)	N/A	12.0 mo	18.5 mo	[11]
Retrospective	88	R±CHOP (N=63). R±hyper-CVAD (N=13). BR (N=6). VR-CAP (N=3). CVP/bendamustine (N=3).	N/A	5 (5.6%)	1 (1–6)	64.8% (CR, N/A)	20.8 mo	2-yr OS rate 79.5%	[12]
Retrospective	211	R-CHOP/mini-CHOP (N=70, 33%). Cytarabine-based regimen (N=60, 28%). R-bendamustine (N=45, 21%). VR-CAP (N=5, 2%). Others (N=31, 15%).	38 (18%)	53 (25%)	1	69% (CR, 27%)	17.8 mo	23.9 mo	[13]
Retrospective	77	CHOP/CHOP-like (N=42, 54%). Cytarabine-based regimen (N=25, 33%). Non-anthracycline regimen (N=10, 13%).	15 (20%)	19 (25%)	1 (29%). 2 (30%). ≥3 (41%).	66%. (CR, 31%).	10.3 mo	23.1 mo	[14]
Retrospective	42	R-CHOP (N=18, 43%). R-hyper-CVAD (N=8, 19%). R-bendamustine (N=16, 38%).	20 (47.6%)	6 (14.3%)	1 (1–5)	69% (CR, 50%)	19.2 mo	50.1 mo	Current study

Abbreviations: ASCT, autologous stem cell transplantation; BR, rituximab, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CVP, cyclophosphamide, vincristine, prednisone; Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin dexamethasone; LOT, line of therapy; N/A, non-available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Pt., patient; R, rituximab; Tx., treatment; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisolone..