Update on the treatment of cutaneous T-cell lymphoma (CTCL): Focus on vorinostat

Figures & data

Figure 1 HDACs and HATs regulate the balance of acetylation. HDAC inhibitors block removal of acetyl groups.

Table 1 Structure of HDAC-inhibitors

Short chain fatty acids	Butyrate, phenylbutyrate, valproic acid AN-9
Hydroxamic acids	Trichostatin A, vorinostat (SAHA)*, pyroxamide, LBH-589*, PXD-101*, LAQ-824
Cyclic	Romidepsin* (depsipeptide)
Benzamides	MS-275

* Activity in CTCL

Figure 2 Suberolyanilide hydroxamic acid.

Figure 3 Proposed mechanism of reaction.

Table 2 Vorinostat in CTCL: Patient demographicsa

Demographic	No. of patients	%
No. of patients	33
Sex
Male	18	55
Female	15	45
Median age, years	67
Performance status
Stage IA	1	3
Stage IB	2	6
Stage IIA	1	3
Stage ≥IIB	29	88
Prior therapy
Chemotherapy	29	88
Ontak	14	42
Bexarotene	22	67
Failed ECP+	15	45

a Phase 2A

Abbreviation: ECP, extracorporeal photopheresis.

Table 3 Phase II oral vorinostat: intent to treat response of 24% (8/33)

	400 mg qd (n = 13)	300 mg bid × 3–5 d/wk (n = 11)	300 mg bid × 2w 400 mg qd (n = 9)
Partial response	4 (31%)	1 (9%)	3 (33%)
Marked (patients)	2	1	3
Median PR duration (range/weeks)	15 (8–24)	16 (8–24)	13 (3–21)
Mean time to PR (weeks)	11	4	11
LN regression at 4 wks (patients)	7 of 9	3 of 8	5 of 9
>50%↓ pruritus (patients)	9 of 11	8 of 12	4 of 8

Abbreviations: LN, lymph node; PR, partial response.

Table 4 Oral vorinostat dosing and dose modification schedule

Treatment group	Dosing schedule	First dose reduction	Second dose reduction
1	400 mg every day*	350 mg every day	300 mg every day
2	300 mg twice daily × 3 d per wk × 4 wk, then 5 d every wk	250 mg × 3 d/wk	200 mg twice daily × 3 d/wk
3	Ind: 300 mg twice daily × 14 d with7 d rest; mtnc; 200 mg twice daily	200 mg twice daily	200 mg twice daily × 5 d/wk

Abbreviation: Ind, indicates induction; mtnc, maintenance.

* Initial 3 patients treated at 250 mg/m²/day

Figure 4 Vorinostat in CTCL: resolved large-cell tumor (*Phase 2A).

Table 5 Vorinostat in CTCL: Response ratesa

	400 mg qd (n = 13)	300 mg bid × 3–5 d/wk (n = 11)	300 mg bid 400 mg qd (n = 9)
Partial response	4 (31%)	1 (9%)	3 (33%)
marked (patients)	2	1	3
Median PR duration (range/weeks)	15 (8–24)	16 (8–24)	13 (3–21)
Mean time to PR (weeks)	11	4	11
LN regression at 4 wks (patients)	7 of 9	3 of 8	5 of 9
>50%↓ pruritus (patients)	9 of 11	8 of 12	4 of 8

a Phase 2A

Abbreviations: LN, lymph node; PR, partial response.

Table 6 Zolinza^™ (vorinostat) clinical or laboratory adverse events occurring in CTCL patients (incidence ≥ 10% of patients)

	Zolinza 400-mg once daily (n = 86)
Adverse events	All grades		Grades 3–5*
	n	%	n	%
Fatigue	45	52.3	3	3.5
Diarrhea	45	52.3	0	0.0
Nausea	35	40.7	3	3.5
Dysgeusia	24	27.9	0	0.0
Thrombocytopenia	22	25.6	5	5.8
Anorexia	21	24.4	2	2.3
Weight decreased	18	20.9	1	1.2
Muscle spasms	17	19.8	2	2.3
Alopecia	16	18.6	0	0.0
Dry mouth	14	16.3	0	0.0
Blood creatinine increased	14	16.3	0	0.0
Chills	14	16.3	1	1.2
Vomiting	13	15.1	1	1.2
Constipation	13	15.1	0	0.0
Dizziness	13	15.1	1	1.2
Anemia	12	14.0	2	2.3
Decreasd appetite	12	14.0	1	1.2
Peripheral edema	11	12.8	0	0.0
Headache	10	11.6	0	0.0
Pruritus	10	11.6	1	1.2
Cough	9	10.5	0	0.0
Upper respiratory infection	9	10.5	0	0.0
Pyrexia	9	10.5	1	1.2

* No grade 5 events were reported.

Table summarizes the frequency of specific adverse events, regardless of causality, in CTCL patients using the National Cancer Institute-Common Terminology Criteria for Adverse Events, version 3.0 (Olsen et al 2001; Foss et al 2005).

Table 7 Zolinza^™ (vorinostat) Study 1: Baseline patient characteristics (all patients as treated)

Characteristics CTCL stage, n (%)	Vorinostat (n = 74)
IB	(14.9%)
IIA	2 (2.7%)
IIB	19 (25.7%)
III	22 (29.7%)
IVA	16 (21.6%)
IVB	4 (5.4%)
Clinical Characteristics
Number of prior systemic treatments, median (range)	3.0 (1.0, 12.0)

Figure 5 Vorinostat in CTCL: stage IVA Sézary and keratoderma partial response (*Phase 2A).

Table 8 HDAC-Is in clinical trials for CTCL

HDAC-I in clinical trials for CTCL	Dosage	Favorability	Limitations
SAHA	400 mg PO daily	No IV access, no risk of sepsis, high tolerability	Fatigue, thrombocytopenia, pulmonary embolus, nausea
Depsipeptide	14 mg/m^2 IV day 1, 8, 15 of each month	Rapid decrease of Sezary cells and erythroderma	IV access with higher risk of sepsis, cardiac effects such as QT prolongation and arrhythmia
PXD-101	1000 mg/m^2 every 3 weeks	No hematological toxicity was identified	IV access with higher risk of sepsis, atrial fibrillation, diarrhea, fatigue
LBH 589	20 mg or 30 mg PO MWF in a 28 days cycle	No IV access, no risk of sepsis	Diarrhea, atrial fibrillation, fatigue, neutropenia, thrombocytopenia, anemia

Table 9 Proposed HDAC inhibitor combination strategies in CTCL

HDACi* + bexarotene: all stages

HDACi* + ECP + bexarotene: Sézary syndrome

HDACi* + methylation inhibitors

HDACi* + chemotherapy for induction and Tx of advanced disease

Topical HDACi* for early-stage disease

* Vorinostat and/or depsipeptide.

Table 10 Vorinostat in combination studies

Combination	Cell lines	Activity	Reference
Vorinostat + Radiation	Prostate (LNCaP)	Synergistic	Lakshmikanthan, 2006
Vorinostat + Epirubicin	Breast (MCF-7, SKBr3)	Synergistic	Marchion, 2004
Vorinostat + 5-Fluorouracil + irinotecan	Hepatoma(HepG2, Hep1B)	Additive	Ocker, 2005
Vorinostat + Flavopiridol	Leukemia (U937)	Synergistic	Almenara, 2002
Vorinostat + Imatinib	CML (LAMA-84)	Additive	Nimmanapalli, 2002
Vorinostat + ATRA	APL (NB4)	Additive/Synergistic	He, 2001

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