Overview of Cutaneous T-Cell Lymphoma and the Burden of Pruritus
Mechanisms of Pruritus in Patients with CTCL
Clinical Studies of Systemic Anti-lymphoma Agents, Including Assessments of Pruritus
Agent | Key trial details | Key efficacy data presented | Details of pruritus assessments provided | Use of anti-pruritic treatments on study |
---|---|---|---|---|
Romidepsin | ORR: 34% CR: 6% PR: 28% SD: 47% Median DOR: 15 mo | Patient-assessed 100-mm VAS; 0 mm = no itch to 100 mm = unbearable itching Moderate pruritus defined as VAS 30-69 mm; severe pruritus defined as 70–100 mm CMRP defined as a decrease in VAS of ≥30 mm for ≥2 consecutive cycles for patients with moderate to severe pruritus at baseline Complete resolution was described as VAS = 0 for 2 consecutive cycles | Concomitant anti-pruritic treatments not allowed | |
Bexarotene | Phase II/III study of patients (N = 94) with stage IIB-IVB CTCL refractory to ≥1 systemic anti-cancer therapy [62] | ORR: 45% (300-mg/m2/day dose) | Measured on a scale of 0–8 for up to 5 representative index lesions; 0 = none 2 = mild: less than average 4 = moderate: average 6 = severe: >25% worse than average 8 = very severe: near-worst severity Intermediate intervals of 1, 3, 5, 7 are to serve as midpoints between 0, 2, 4, 6, 8 Not stated whether the assessment was conducted with a VAS or verbally | Concomitant anti-pruritic treatments allowed |
Phase II/III study of patients (N = 58) with stage IA-IIA refractory CTCL or patients intolerant to or reaching a 6-mo plateau to prior treatment [63] | ORR: 54% (300-mg/m2/day dose) | |||
Open-label phase II trial of doxorubicin HCl followed by bexarotene in patients (N = 37) with stage IB-IIA CTCL poorly responsive to skin-directed therapies or stage IIB-IV CTCL [64] | ORR: 41% CR: 6% PR: 35% SD: 18% Median PFS: 5 mo Median OS: 18 mo | Patient assessed 100-mm VAS, where 0 = no pruritus and 100 = worst imaginable pruritus Pruritus relief was defined as an improvement in pruritus ≥30 mm from baseline or complete resolution of symptoms | Concomitant use of topical corticosteroids was permitted for patients with intense pruritus | |
Open-label pilot study in combination with rosiglitazone for patients (N = 4) with stage IA-IVA CTCL with SD with or PR to single-agent bexarotene [65] | ORR: 25% CR: 0% PR: 25% SD: 75% | Patient assessed 100-mm VAS | No details for use of concurrent anti-pruritic provided | |
Denileukin diftitox | Placebo controlled phase III study of patients (N = 144) with stage IA–III CTCL, ≤3 prior therapies, CD25 positive on ≥20% of T cells in biopsied skin lesions [67] | ORR: 44% CR: 10% PR: 34% SD: 35% Median PFS: 26 mo for 9-µg/kg/d dose, NR for 18-µg/kg/d dose Median DOR: 8 mo | Patient assessed 100-mm VAS Details on how “clinically significant improvement” was defined were not included | Premedication with an anti-histamine was required 30–60 min before study drug administration and allowed during and after the dosing period |
ORR: 30% CR: 10% PR: 20% SD: 32% Median DOR: 7 mo | Patient assessed 100-mm VAS scale; 0 = no itch, 100 mm = worst imaginable itch Clinically significant baseline pruritus defined as ≥20 mm Significant improvement defined as improvement of ≥20 mm | Premedication with an anti-histamine 30–60 min before study drug administration and use of 25 mg promethazine or 10 mg proclorperazine for nausea allowed; use of pruritus rescue medication was allowed and recorded | ||
Vorinostat | Phase II study in patients (N = 33) with stage IA-IVB CTCL refractory or intolerant to conventional therapy [71] | ORR: 24% CR: 0% PR: 24% Median DOR: 4 mo | Patient assessed score from 0 to 10; VAS or verbal not specified Pruritus relief was defined as a reduction of ≥3 points or compete resolution for ≥4 wk Complete resolution was a score of 0 for ≥4 wk | Anti-histamines and topical steroids allowed if stable dose for ≥2 wk (changes/increases not allowed on study) |
Phase IIb study in patients (N = 74) with stage ≥IB CTCL and ≥2 prior systemic therapies, 1 of which had to be bexarotene unless it was not tolerated [72] | ORR: 30% CR: 1% PR: 29% Median DOR: NR; estimated to be at least 5 mo | Patient assessed VAS from 0 to 10; 0 = no pruritus to 10 = worst imaginable Severe pruritus defined as a score of 7–10 points Pruritus relief defined as ≥3-point reduction in patients with a VAS score of ≥3 points, or a complete resolution of pruritus for ≥4 continuous weeks without the use of anti-pruritic medications | Supportive treatment with anti-histamines allowed; patients on topical (all) and systemic steroids (Sézary syndrome) for ≥3 mo were allowed to continue | |
Open-label, nonrandomized, escalating dose, phase I study, in combination with bexarotene, in patients (N = 23) with stage ≥ IB CTCL refractory to ≥1 prior systemic therapy (not including bexarotene) [73] | ORR: 17 CR: 0% PR: 17% SD: 65% | Patient assessed VAS of 0–10 Pruritus relief defined as reduction of ≥3 points from baseline or complete resolution | No details for use of concurrent anti-pruritic provided | |
Alemtuzumab | Phase II study in patients (N = 22) with CD52+ stage II–IV MF/SS with ≤5 systemic treatments and not responding adequately to PUVA, radiotherapy, chemotherapy, or interferon alpha [74] | ORR: 55% CR: 32% PR: 23% SD: 13% Median DOR: 12 mo | Patient assessed 100-mm point VAS, 0 indicates no itching; 100-mm indicates worse possible itching | Patients received anti-histamine 30 min before infusion until first dose reactions disappeared; use of corticosteroids during week 1 was optional |
Phase II study of patients (N = 8) with stage IIB–IV relapsed/refractory CTCL [75] | ORR: 38% CR: 0% PR: 38% SD: 25% | Self-assessment on a scale of 0–8; 0 = no itching to 8 = very severe itching Significant improvement defined as 50% improvement in self-assessment score | Promethazine and hydrocortisone allowed for infusion-related side effects | |
Extracorporeal photopheresis | Retrospective single center study of patients (N = 55) with stage III–IVB SS treated with ECP [76] | Good response: 62% PR: 18% | Method of pruritus assessment not detailed | No details for use of concurrent anti-pruritic provided |
Zanolimumab | Open-label phase II study of patients (N = 47) with refractory stage IB–IVB MF/SS [79] | ORR: 32% | Method of pruritus assessment not detailed | Topical steroids allowed as a rescue therapy for patients developing eczematous dermatitis not involving target lesions |
Belinostat | ORR: 14% CR: 10% PR: 3% SD: 35% Median DOR: 3 mo | Pruritus assessed using a 10-point scale; VAS or verbal not specified Severe pruritus defined as score 7–10 Pruritus relief defined as reduction of pruritus score of ≥3 points in patients with baseline score ≥3 | No details for use of concurrent anti-pruritic provided | |
Panobinostat | Open-label phase II study of patients with previous exposure to bexarotene (n = 79) or bexarotene naive (n = 60) with stage IB-IVA MF or SS who had ≥2 prior systemic therapies fail [81] | ORR: 17% CR: 1% PR: 16% SD: 21% Median PFS: 4.6 for bexarotene exposed; 3.7 mo for bexarotene naive Median DOR: 9.2 mo for bexarotene exposed; NR for bexarotene naive | Patients completed assessments via VAS throughout the study Pruritus relief not defined | No details for use of concurrent anti-pruritic provided |
Romidepsin
Bexarotene
Denileukin Diftitox
Vorinostat
Additional Agents
Summary and Recommendations
Method for quantification | Severity of pruritus should be quantified using a VAS (number on scale not defined) |
Definition of significant pruritus at baseline | Not defined, though recommendations assert the need to define |
Definition of clinically significant change or threshold | Not defined, though recommendations assert the need to define |
Comedications | Factors that could independently affect pruritus should be eliminated Any concomitant anti-pruritic agents should be at a stable dose or discontinued when making comparative pruritus measurements No claim of absence or resolution of pruritus should be made with concomitant use of anti-pruritic treatments |
Appropriate terminology | General terms that imply complete resolution (e.g., “relief”) should be avoided when referring to reduction or change in VAS |
Relationship to disease response | Changes in pruritus should be correlated to disease response to put results in perspective |