Hematologic toxicity is rare in relapsed patients treated with belinostat: a systematic review of belinostat toxicity and safety in peripheral T-cell lymphomas

Figures & data

Figure 1 Systematic search of OVID returned 6 studies for efficacy and 46 for safety.

Notes: Three and 16 studies were included in the present review, respectively. Additionally, one of 32 abstracts reviewed was included in safety analysis only (not shown).

Table 1 Summary of contributing articles

Safety		Efficacy
Author/article, year	Patients (N)	Author/article, year	Patients (N)
O’Connor et al, 2015 (BELIEF)^Citation22	129	O’Connor et al, 2015 (BELIEF)^Citation22	120
Foss et al, 2015^Citation21	53	Foss et al, 2015^Citation21	24 PTCL
Steele et al, 2008^Citation19	6	Reimer et al, 2013^Citation23	1
Steele et al, 2011^Citation24	15
Gimsing et al, 2008^Citation20	16
MacKay et al, 2010^Citation25	32
Zain et al, 2010 (abstract)^Citation26	28
Giaccone et al, 2011^Citation27	41
Ramalingan et al, 2012^Citation28	13
Yeo et al, 2012^Citation29	60
Cashen et al, 2012^Citation30	21
Kirschbaum et al, 2014^Citation31	12
Puvvada et al, 2017^Citation32	5
Agarwal et al, 2016^Citation33	18
Puwada et al, 2012^Citation34	22
Reimer et al, 2013^Citation23	1
Total	512		145

Abbreviation: PTCL, peripheral T-cell lymphoma.

Table 2 Summary of safety analysis

Study	Study type	N	Dose	AEs, n (%) All grades occurring in >1 patients	Gr 3–4 AE, n (%)
Steele et al^Citation19	Phase I	46 advanced solid tumors	150–1,200 mg/m^2/d IV d 1–5 q21 days	Nausea, 33 (71.7) Vomiting, 33 (71.7) Lethargy, 15 (33) Fatigue, 13 (28.3) Constipation, 13 (28.3) Flushing, 11 (24) Diarrhea, 7 (15) Hyperglycemia, 4 (9)	Gr 3 fatigue, 4 (8.7) Gr 3 diarrhea, 2 (4.3) Gr 3 atrial fibrillation, 4 (8.7)
Steele et al^Citation24	Phase I	15 patients from Phase I trial	Oral belinostat	Nausea, 2 (13.3) Vomiting, 2 (13.3) Fatigue, 2 (13.3) Lymphopenia, 3 (20.0)	None
Gimsing et al^Citation20	Phase I	16 advanced hematological neoplasms (B-cell)	600–1,000 mg/m^2/d IV d 1–5 q21 days	Nausea, 8 (50) Vomiting, 5 (31) Fatigue, 5 (31) Flushing, 5 (31) Diarrhea, 3 (19) Neurologic, 3 (19) Xerostomy, 2 (12.5) Joint pain, 2 (12.5) Headache, 2 (12.5) Injection site rxn, 2 (12.5)	Gr 3 fatigue, 2 (12.5) Gr 3 status epilepticus, 1 (6.3) Gr 3 paresthesia, 1 (6.3) Gr 3 xerostomy, 1(6.3) Gr 3 vasculitis, 1 (6.3) Gr 4 tumor lysis, 2 (12.5)
MacKay et al^Citation25	Phase II	32 relapsed ovarian cancers	1,000 mg/m^2/d IV d 1–5 q21 days	Fatigue, 22 (69) Nausea, 19 (59) Vomiting, 11 (34) Diarrhea, 9 (28) Pneumonitis, 2 (6) Sinus bradycardia, 6 (19) Peripheral neuropathy, 5 (16) Headache, 5 (16) Hypersensitivity, 3 (9) Thrombosis, 3 (9) Leukopenia, 2 (6) Anemia, 4 (13) Elevated ALP, 2 (6)	Thrombosis, 3 (9) Hypersensitivity, 1 (3.1) Elevated ALP, 1 (3.1)
Zain et al (abstract)^Citation26	Phase I	28 Hodgkin and non-Hodgkin lymphomas	Oral belinostat 750–2,000 mg	Diarrhea, 25 (89.3) Anorexia, 24 (85.7) Fatigue, 23 (82.1) Nausea, 18 (64.3) Vomiting, 18 (64.3) Cough, 17 (60.7) Fever, 15 (53.6)	Gr 3 diarrhea, 9 (32), evenly distributed across cohorts Gr 3 diarrhea at 1,500 and 2,000 mg dose among four DLTs G2 3/4 thrombocytopenia, 5 (17.9)
Giaccone et al^Citation27	Phase II	41 advanced thymic tumors	1,000 mg/m^2/d IV d 1–5 q21 days	Injection site, 4 (9.8) Hypotension, 4 (9.8) Thrombocytopenia, 1 (2.4) Nausea, 3 (7.3) Anorexia, 3 (7.3) QTc prolongation, 1 (2.4) Leukopenia, 3 (7.3) Neutropenia, 2 (4.9) Lymphopenia, 9 (22.0) Anemia, 3 (7.3) Infection, 3 (7.3) Fever, 2 (4.9)	Gr 3 hypotension, 2 (4.9) Gr 3 QTc, 5 (12.3) Gr 3 lymphopenia, 4 (9.8) Gr 4 lymphopenia, 1 (2.4) Gr 3 infection, 1 (2.4)
Ramalingan et al^Citation28	Phase II	13 second-line mesotheliomas	1,000 mg/m^2/d IV d 1–5 q21 days	Anemia, 6 (46.2) Anorexia, 2 (15.4) Constipation, 2 (15.4) Dyspnea, 3 (23.1) Fatigue, 2 (15.4) Hyperglycemia, 6 46.2) Infection, 2 (15.4) Nausea, 2 (15.4) Hyponatremia, 3 (23.1)	Gr 3 AST, 1 (7.7) Gr 3 fatigue, 2 (15.4) Gr 3 hyponatremia, 3 (23.1) Gr 3 SVT, 1 (7.7) Gr 4 dyspnea, 1 (7.7) Gr 4 hypoxia, 1 (7.7)
Yeo et al^Citation29	Phase I/II	Phase I (18) Phase II (42) Hepatocellular cancer	600–1,400 mg/m^2/d	Fatigue, 20 (33.3) Injection site, 20 (33.3) Constipation, 14 (23.3) Nausea, 15 (25.0) Vomiting, 17 (28.3) Anorexia, 15 (25.0) Insomnia, 14 (23.3) Anemia, 3 (5) Abd pain, 16 (26.7)	Gr 3 increased ALT, 4 (1.7) Gr 3 diarrhea, 4 (1.7) Gr 3 Abd pain, 3 (5) Gr 3 anemia, 1 (1.7) Gr 4 anemia, 2 (3.3) Gr 4 Abd pain, 1 (1.7)
Cashen et al^Citation30	Phase II	21 MDS	1,000 mg/m^2/d IV d 1–5 q21 days	Fatigue, 6 (19) QTc prolongation, 2 (9.5) Constipation, 3 (14.3) Diarrhea, 2 (9.5) Cytokine-release syndrome, 2 (9.5) Dyspnea, 2 (9.5)	Fatigue, 2 (9.5) QTc prolongation, 1 (4.8) Febrile neutropenia, 1 (4.8) Headache, 1 (4.8)
Kirschbaum et al^Citation31	Phase II	12 AML	1,000 mg/m^2/d IV d 1–5 q21 days	LFT, 7 (58.3) Anorexia, 3 (25) Constipation, 2 (16.7) Fatigue, 6 (50) Nausea, 8 (66.7) Pain, 3 (25)	Gr4 hematoma, 1 (8) Gr 3 hyponatremia, 1 (8) Gr 3 QTc prolongation, 1 (8) Gr 3 mucositis,1 (8) Gr 3 febrile neutropenia, 1 (8) Gr 3 dehydration, 1 (8) Nausea, 1 (8)
O’Connor et al (BELIEF)^Citation22	Phase II	129 PTCL (safety)	1,000 mg/m^2, 87.6% at target	Nausea, 54 (41.8) Vomiting, 35 (27.1) Fatigue, 48 (37.2) Constipation, 30 (23.3) Pyrexia, 45 (34.9) Diarrhea, 30 (23.3) Thrombocytopenia, 21 (16.3) Neutropenia, 8 (3.5) Anemia, 41 (31.8) Infection, 13 (10.1) Dyspnea, 28 (21.7) Increased creatinine, 3 (2.3) Edema, 26 (20) Rash, 26 (20)	Pneumonia, 9 (7) Infection, 4 (3.1) Hematologic, 6 (4.6) Multiorgan failure, 3 (2.3)
Foss et al^Citation21	Phase II	24 PTCL 29 CTCL	1,000 mg/m^2/d IV d 1–5 q21 days	Nausea, 33 (66.7) Fatigue, 14 (33.3) Constipation, 14 (37.5) Vomiting, 14 (25) Pyrexia, 11 (25) Dizziness, 20.8 Diarrhea, 9 (20.8) Anorexia, 8 (20.8) Neurologic, 71 (3.2) Hypersensitivity, 9 (17.0) Dizziness, 11 (20.8) Edema, 8 (15.1) Rash, 81 (5.1) Hypokalemia, 14 (26.4) Dyspepsia, 7(13.2) Dyspnea, 7 (13.2)	Gr 3 paralytic ileus, 1 (5.6) Gr 3 pneumonitis, 1 (5.6) Gr 3 rash, 3 (16.8) Gr 3 cellulitis, 1 (5.6) Gr 3 edema, 1 (5.6) Gr 3 LFT, 2 (11.2) Gr 3 apraxia, 1 (5.6) Gr 4 thrombocytopenia, 1 (5.6)
Puvada et al, 2017^Citation32	Phase II	5 B-cell lymphoma	1,000 mg/m^2 IV d 1–5 q21 days for two cycles	Nausea, 4 (80) Thrombocytopenia, 3 (60) Pain, 3 (60) Edema, 2 (40) Elevated creatinine, 2 (40) Neuropathy, 2 (40)	Thrombocytopenia, 2 (40) Pain, 1 (20) Hypoglycemia, 1 (20)
Agarwal et al, 2016^Citation33	Phase I	18 patients with malignancies on warfarin	1,000 mg/m^2/d IV d 1–5 q21 days	Nausea, 12 (66.7) Vomiting, 7 (38.9) Diarrhea, 1 (5.6) Fatigue, 9 (50) Muscle spasms, 4 (22.2) Insomnia, 2 (11.1) Rash, 2 (11.1) Dyspepsia, 2 (11.1) Hiccups, 2 (11.1)	Nausea, 1 (5.6) Vomiting, 1 (5.6) Diarrhea, 1 (5.6)
Puwada et al, 2012^Citation34	Phase II	22 rel/ref aggressive B-cell lymphomas	1,000 mg/m^2/d IV d 1–5 q21 days	Fatigue, 8 (36.4) Nausea, 8 (36.4) Vomiting, 5 (22.7) Diarrhea, 4 (18.2) Constipation, 2 (9.1) Anorexia, 3 (13.6) Anemia, 8 (36.4) Thrombocytopenia, 5 (22.7) Lymphopenia, 2 (9.1) UTI, 2 (9.1)	Gr 3 anorexia, 1 (4.5) Gr 3 nausea, 1 (4.5) Gr 3 diarrhea, 1 (4.5) Gr 3 dehydration, 1 (4.5) Gr 3 neutropenia, 1 (4.5) Gr 3 lymphopenia, 1 (4.5) Gr4 lymphopenia, 1 (4.5) Gr 4 myelodysplasia, 1(4.5) Gr 4 muscle weakness, 1 (4.5)
Reimer et al^Citation23	Case report	1 PTCL	1,000 mg/m^2/d IV d 1–5 q21 days 28 cycles	Gr 1 hematologic	Gr 3 pulmonary alveolitis treated with steroids

Abbreviations: AE, adverse event; ALP, alkaline phosphatase; AML, acute myeloid leukemia; AST, aspartate aminotransferase; CTCL, cutaneous T-cell lymphoma; DLT, dose limiting toxicity; Gr, grade; IV, intravenous; LFT, liver function test; MDS, myelodysplastic syndrome; PTCL, peripheral T-cell lymphoma; UTI, urinary tract infection; d, day; q, every; rel/ref, relapsed refractory; SVT, supraventricular tachycardia.

Table 3 Summary of efficacy analysis

Study	Study type	PTCL (n)	ORR (n)	CR (n)	PR (n)	DOR	Dose	Discontinue for AE
O’Connor et al (BELIEF)^Citation22	Phase II	120	31	13	18	13.6 months	87.6% at target dose	16
Foss et al^Citation21	Phase II	24	6	2	4	109 days	Dose exposure: 7,450–83,415 mg over 3–182 days Median of ten doses	3
Reimer et al^Citation23	Case report	1a	1a	1a	–	39 months (ongoing)	28 cycles	Treated with maintenance, then discontinue in CR
Total		144	37	15	22
%			25.7	10.4	15.3

Note:

a Case report was not included in response calculations.

Abbreviations: AE, adverse event; CR, complete response; DOR, duration of response; ORR, overall response rate; PR, partial response; PTCL, peripheral T-cell lymphoma.

Table 4 Summary of patient characteristics from belinostat clinical trials in peripheral T-cell lymphoma

Study	Total N	Sex (%)	Race (%)	Age, years (range)	ECOG, n (%)	PTCL subtype, n (%)	Stage, n (%)
O’Connor et al, (BELIEF)^Citation22	120	M 51.7 F 48.3	W 105 (87.5) B 7 (5.8) A 3 (2.5) O 5 (4.2)	Median 64 (29–81)	0–1: 93 (77.5) 2: 26 (21.7) 3: 1 (0.8)	PTCL, nos 77 (64.2) AITL 22 (18.3) ALCL  ALK (−) 13 (10.8)  ALK (+) 2 (1.7) EATCL 2 (1.7) ENTCL 2 (1.7) HSTCL 2 (1.7)	1–2: 16 (13.3) 3: 42 (35) 4: 60 (50)
Foss et al^Citation21	24	M 70.8 F 29.2	W 16 (66.7) A7 (29.2) B 5 (17.2)	Median 64 (23–76)	N/A	PTCL, nos 13 (54.2) ALCL 3 (12.5) AITL 3 (12.5) ENKL 1 (4.2) ENKL, extravascular 1 (4.2) PTCL, skin 1 (4.2) SCPTCL 1 (4.2)	1–2: 5 (21) 3: 6 (25) 4: 12 (50)

Abbreviations: A, Asian; AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; B, black; EATCL, enteropathy-associated T-cell lymphoma; ENTCL, extranodal T-cell lymphoma; ENKL, extranodal NK/T-cell lymphoma; HSTCL, hepatosplenic T-cell lymphoma; O, other; PTCL, nos, peripheral T-cell lymphoma not otherwise specified; SCPTCL, subcutaneous panniculitis-like T-cell lymphoma; W, white; ECOG, Eastern Cooperative Oncology Group.

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