Targeting histone deacetylases in T-cell lymphoma

Figures & data

Table 1. HDAC Inhibitors with notable clinical data in T-cell lymphoma.[3]

Agent	Administration	Specificity	Structural class	FDA approvals in TCL^a
Romidepsin [12,38,111]	IV	Class I	Bicyclic peptide	R/R CTCL and PTCL
Vorinostat [12,39]	Oral	Pan	Hydroxamate	R/R CTCL
Belinostat [12,40]	IV	Pan	Hydroxamate	R/R PTCL
Chidamide [58]	Oral	Class I and IIb	Benzamide	–
Panobinostat [12,108]^b	Oral	Pan	Hydroxamate	–

^a No HDAC inhibitors are currently approved by the EMA. Romidepsin and vorinostat also have approvals in some other countries (e.g. Canada). Chidamide was recently approved in China (www.epidaza.com).

^b Panobinostat was recently approved by the FDA in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received ≥2 prior regimens, including bortezomib and an immunomodulatory agent [108].

CTCL: cutaneous TCL; EMA: European Medicines Agency; FDA: US Food and Drug Administration; HDAC: histone deacetylase; IV: intravenous; PTCL: peripheral TCL; R/R: relapsed/refractory; TCL: T-cell lymphoma.

Table 2. Overview of phase II studies of FDA-approved HDACi in CTCL.

	Romidepsin		Vorinostat
	Pivotal (N = 96) [41]	Supportive (n = 71) [36,49]	Pivotal [53]	Supportive [52]
Dosing	14 mg/m^2 as 4-hour IV infusion on days 1, 8, and 15 of 28-day cycles		400 mg oral daily	400 mg oral daily; 300 mg twice daily 3 days per week for 4 weeks, then 5 days every week; or 300 mg twice daily for 14 days (induction) with 7 days rest followed by 200 mg twice daily (maintenance)
Assessors	Investigators	Investigators	Investigators	Investigators
Response assessments	Composite primary assessment in skin (SWAT, erythroderma score), lymph nodes (RECIST), and blood (quantification by flow cytometry, occasionally morphology)	Composite primary assessment in skin (RECIST, presence/absence of erythroderma), lymph nodes (IWC 1999 [112]), blood (presence/absence by flow cytometry), BM involvement (present/absent)	Primary assessment in skin only (modified SWAT) Secondary/ad hoc assessments made in lymph nodes and blood	Physician’s Global Assessment (based on skin, lymph nodes, and all other disease manifestations)
Timing of response assessments	First day of each 28-day cycle	Not reported	Biweekly for first 2 months, every 4 weeks thereafter	Every 3 weeks
Patient-assessed pruritus assessments	100-mm VAS; CMRP defined as ≥30-mm decrease or score of 0 for 2 consecutive cycles	Not assessed	10-point VAS; relief defined as ≥3-point decrease or complete resolution for ≥4 consecutive weeks without increase in use of antipruritic medications	10-point VAS; relief defined as ≥3-point decrease or complete resolution for ≥4 consecutive weeks
Concomitant pruritus therapies	Not allowed	Stable doses of corticosteroids at study start allowed, with tapering to follow initiation of therapy	Stable doses of topical or systemic steroids for ≥3 months before study entry could continue on medication during study; supportive antihistamine treatment allowed	Stable doses of topical steroids or antihistamines for ≥2 weeks before study entry were maintained during study

CMRP: clinically meaningful reduction in pruritus; IV: intravenous; IWC: International Workshop Criteria; RECIST: Response Evaluation Criteria in Solid Tumors; SWAT: severity-weighted assessment tool; VAS: visual analog scale.

Table 3. Phase II data for FDA-approved HDACi in CTCL.

	Romidepsin		Vorinostat
	Pivotal (N = 96) [38,41,44]^a	Supportive (n = 84) [36,38]^b	Pivotal [39,53]^c	Supportive [39,52]^c^,^d
Key baseline characteristics
Age, median (range), years	57 (21–89)	57 (28–84)	60 (39–83)	65 (37–82)
Sex, male,	59 (61)	57 (68)	38 (51)	8 (62)
Stage ≥ IIB disease	68 (71)	74 (88)	61 (82)	11 (85)
ECOG
0	49 (51)	24 (29)	NR	NR
1	47 (49)	49 (58)	NR	NR
2	0	11 (13)	NR	NR
Duration of CTCL, median (range), years	3 (<1–26)	NR	2.6 (0.7–27.3)	3.7 (0.4–17.4)
Lymph involvement, n (%)	55 (57)	NR	34 (46)	8 (62)
Patients with blood involvement,  n (%)	37 (39)	NR	NR	8 (62)
Higher blood involvement, n (%)	13 (14)	NR	NR	NR
Sézary syndrome, n (%)	NR	NR	30 (41)	3 (23)
Pruritus scores on scale of 10	Mean 5.5 (SD 3.1)	NR	Median 6 (range, 0–10)	Median 10 (range, 3–10)
Prior systemic therapies, median (range)	3 (1–8)	2 (0–7) in initial 71 pts	3 (1–12)	5 (1–10)
Prior skin-directed therapies, median (range)	2 (1–5)	1 (0–3) in initial 71 pts	NR	NR
ORR/rate of CR, n (%)	33 (34)/6 (6)	28 (33)/5 (6)	22 (30)/1 (1)	4 (31)/0
Patients with stage IB–IIA disease	7 (25)/1 (4)	NR	4 (31)/0	0/0
Patients with stage ≥ IIB disease	26 (38)/5 (7)	NR	18 (30)/1 (2)	4 (36)
Time to response, median (range), months
All responders	2.0 (0.9–4.8)	1.9 (NR)	1.8 (0.9–5.6)	NR
Patients who achieved CR	4 (0.9–6.9)	NR	NR	NR
Duration of response, median (range), months	15.0 (< 0.1+–19.8+)	13.8 (1–127+)	NE (1.1+–14.5+)^e	NR
Most common all-grade AEs (≥20%), %	Nausea (56), asthenia/fatigue (53), infections (46), vomiting (34), anorexia (23), hypomagnesemia (22), diarrhea (20), pyrexia (20)	Nausea (86), asthenia/fatigue (77), anemia (72), thrombocytopenia (65), ECG ST-T wave changes (63), neutropenia (57), lymphopenia (57), infections (54), anorexia (54), vomiting (52), hypocalcemia (52), hyperglycemia (51), hypoalbuminemia (48), leukopenia (46), dysgeusia (40), constipation (39), hyperuricemia (33), pruritus (31), hypomagnesemia (28), AST increased (28), dermatitis (27), hypermagnesemia (27), hypophosphatemia (27), diarrhea (27), pyrexia (23), hypotension (23), ALT increased (22), hypokalemia (20), hyponatremia (20)	Fatigue (52), diarrhea (52), nausea (41), dysgeusia (28), thrombocytopenia (26), anorexia (24), weight decreased (21), muscle spasms (20)
Most common grade 3/4 AEs (≥3%), %	Infections (11), asthenia/fatigue (8), pyrexia (4), neutropenia (4), nausea (3), anemia (3), hypotension (3)	Lymphopenia (37), infections (33), neutropenia (27), leukopenia (22), anemia (16), thrombocytopenia (14), asthenia/fatigue (14), vomiting (10), hypophosphatemia (10), dermatitis (8), hyperuricemia (8), hypermagnesemia (8), hypocalcemia (6), nausea (6), pruritus (6), anorexia (4), hypotension (4), AST increased (4), ALT increased (4)	Thrombocytopenia (6), fatigue (4), nausea (4)
Serious AEs	Most commonly infection (all types pooled) and pyrexia	Most commonly infection (all types pooled), fatigue, arrhythmias, neutropenia, hypotension, hyperuricemia, edema	Most commonly pulmonary embolism, squamous cell carcinoma, and anemia
Discontinuations due to AEs	21%	11%	9% No AE led to discontinuation in >1 patient
	Most commonly infection, fatigue, dyspnea, QT prolongation, hypomagnesemia

^a Safety population includes 102 patients.

^b Note: the NCI 1312 study reported all abnormalities as AEs, regardless of clinical significance. Safety population includes 83 patients.

^c Safety data pooled for the 2 studies, including 86 patients.

^d Trial included 3 dosing regimens; only data for the approved dosing of 400 mg daily presented here.

^e Though median not reached, estimated to be ≥5 months.

AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CR: complete response; CTCL: cutaneous T-cell lymphoma; ECOG: Eastern Cooperative Oncology Group; NE: not estimable; NR: not reported; ORR: objective response rate.

Table 4. Overview of phase II studies of FDA-approved HDACi in PTCL.

	Romidepsin		Belinostat
	Pivotal (N = 131) [45,46]	Supportive (N = 47) [36,50]	Pivotal (N = 129) [56]
Dosing	14 mg/m^2 as 4-hour IV infusion on days 1, 8, and 15 of 28-day cycles		1000 mg/m^2 as 30-minute IV infusion on days 1–5 of 21-day cycles
Assessors	IRC^a	Investigators	IRC^a
Response assessments	1999 IWC [112]	1999 IWC [112] in patients with nodal disease; RECIST in patients with skin or visceral lesions	2007 IWC [113]
Timing of response assessments	Every 2 cycles	Every 2 cycles; every 3 cycles for patients in CR	Every 6 weeks for the first year and every 12 weeks for the second year

^a Investigator assessments were secondary.

CR: complete response; IRC: independent response committee; IV: intravenous; IWC: International Workshop Criteria; RECIST: Response Evaluation Criteria in Solid Tumors.

Table 5. Phase II data for FDA-approved HDACi in PTCL.

	Romidepsin		Belinostat
	Pivotal (N = 131) [38,45,46]^a	Supportive (N = 47) [36,38,50]^b^,^c	Pivotal (N = 129) [40,56,114]^d
Key baseline characteristics
Age, median (range), years	61 (20–83)	59 (27–84)	64 (29–81)
Male sex, n (%)	88 (68)	25 (53)	62 (52)
Time since diagnosis, median (range), years	1.3 (0.2–17.0)	NR	1.0 (0.2–22.2)
Stage III or IV disease, n (%)	91 (70)	45 (96)	102 (79)
ECOG, n (%)
0	46 (35)	20 (43)	41 (34)
1	66 (51)	23 (49)	52 (43)
2	17 (13)	4 (9)	26 (22)
3	0	0	1 (1)
PTCL subtype, n (%)
PTCL-NOS	69 (53)	27 (57)	77 (64)
AITL	27 (21)	7 (15)	22 (18)
ALK-negative ALCL	21 (16)	2 (4)	13 (11)
Other	13 (10)	11 (23)	8 (7)
Prior systemic therapies, median (range)	2 (1–8)	3 (1–6)	2 (1–8)
ORR/rate of CR^e, n (%)	33 (25)/19 (15)	17 (38)/8 (18)	31 (26)/13 (11)
Patients with PTCL-NOS	20 (29)/10 (14)	11 (41)/5 (19)	18 (23)/NR
Patients with AITL	8 (30)/5 (19)	1 (17)/0	10 (45)/4 (18)
Patients with ALK-negative ALCL	5 (24)/4 (19)	2 (100)/1 (50)	2 (15)/NR
Time to response, median (range), months
All responders	1.8 (1.4–5.3)	1.8 (NR–11)	1.3 (1.0–11.6)
Patients who achieved CR	3.7 (1.6–13.7)	NR	NR
Duration of response, median (range), months
All responders	28 (<1^f–48+)	9 (2–76+)	13.6 (95% CI, 4.5–29.4)
Patients who achieved CR	NE (<1^f–48+)	74 (3–76+)	NE (>29 months)
Most common all-grade AEs (≥20%), %	Nausea (59), asthenia/fatigue (55), thrombocytopenia (41), vomiting (39), diarrhea (36), pyrexia (35), constipation (30), neutropenia (30), anorexia (28), anemia (24), dysgeusia (21)	Asthenia/fatigue (77), nausea (75), thrombocytopenia (72), neutropenia (66), anemia (62), leukopenia (55), pyrexia (47), anorexia (45), vomiting (40), constipation (40), diarrhea (36), headache (34), dysgeusia (28), cough (21), dyspnea (21)	Nausea (42), fatigue (37), pyrexia (35), anemia (32), vomiting (29), constipation (23), diarrhea (23), dyspnea (22), rash (20), peripheral edema (20)
Most common grade 3/4 AEs (≥5%), %	Thrombocytopenia (24), neutropenia (20), anemia (11), asthenia/fatigue (8), leukopenia (6), pyrexia (6), vomiting (5)	Neutropenia (47), leukopenia (45), thrombocytopenia (36), anemia (28), asthenia/fatigue (19), pyrexia (17), vomiting (9), nausea (6)	Anemia (11), thrombocytopenia (7), dyspnea (6), fatigue (5)
Serious AEs	Most commonly infection (all types pooled), pyrexia, vomiting	Most commonly infection (all types pooled), pyrexia, AST increased, hypotension, anemia, thrombocytopenia, ALT increased, dehydration, and dyspnea	Most commonly pneumonia, pyrexia, infection (all types pooled), anemia, increased creatinine, thrombocytopenia, multiorgan failure
Discontinuations due to AEs	19%: most commonly thrombocytopenia and pneumonia	28%: most commonly thrombocytopenia, anemia, infection, and ALT increased	19%: most commonly anemia, febrile neutropenia, fatigue, multiorgan failure

^a Baseline and efficacy data provided for patients with histologically-confirmed PTCL (n = 130).

^b Efficacy data excludes 2 patients deemed ineligible for study (n = 45).

^c Note: the NCI 1312 study reported all abnormalities as AEs, regardless of clinical significance.

^d Baseline and efficacy data provided for evaluable patients (n = 120).

^e In GPI-06-0002, this includes both confirmed and unconfirmed CR.

^f Patient elected to undergo transplant following the first response assessment of CR.

AE: adverse event; AITL: angioimmunoblastic T-cell lymphoma; ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CR: complete response; ECOG: Eastern Cooperative Oncology Group; NE: not estimable; NOS: not otherwise specified; NR: not reported; ORR: objective response rates; PTCL: peripheral T-cell lymphoma.

Table 6. Key prescribing information for HDAC inhibitors approved in TCL [38–40].

	Romidepsin	Vorinostat	Belinostat
Warnings and precautions	• Thrombocytopenia, leukopenia,   and anemia  • Infections  • ECG changes  • Tumor lysis syndrome  • Embryo-fetal toxicity	• Pulmonary embolism and deep   vein thrombosis  • Thrombocytopenia and anemia  • Gastrointestinal toxicity  • Patients with mild and moderate   hepatic impairment should be   treated with caution  • Hyperglycemia  • Clinical chemistry abnormalities  • Severe thrombocytopenia and   gastrointestinal bleeding has   been reported with concomitant   use of vorinostat and other   HDAC inhibitors  • Embryo-fetal toxicity	• Thrombocytopenia, leukopenia,   and anemia  • Infection  • Hepatotoxicity  • Tumor lysis syndrome  • Embryo-fetal toxicity
Antiemetic use	Prophylactic antiemetics recommended for all patients	Nausea, vomiting, and diarrhea occur with vorinostat and may require the use of antiemetics, antidiarrheals, and fluid and electrolyte replacement to prevent dehydration	Nausea, vomiting, and diarrhea occur with belinostat and may require the use of antiemetic and antidiarrheal medications
Electrolyte replacement	Ensure that potassium and magnesium are within the normal range before administration of romidepsin	Measure and correct electrolytes at baseline. Monitor every 2 weeks during the first 2 months of therapy and at least monthly thereafter	Not mentioned
Contraindications	None	Severe hepatic impairment	None
Drug interactions	CYP3A4 inhibitors and inducers Warfarin or Coumadin derivatives P-gp inhibitors	Coumadin-derivatives Other HDAC inhibitors	UGT1A1 inhibitors Warfarin

ECG: electrocardiogram; HDAC: histone deacetylase.

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