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Systematic Review

A systematic review on the management of pruritus in patients with cutaneous T-cell lymphoma

Farrah, Georgia BSc, MBBS (Hons) PGDipClinDerma,; Spruijt, Odette MBChC, DipObs, FRACP, FRAChPMa; McCormack, Chris MBBS, FACDa; Buelens, Odette MNa; Lazarakis, Smaro BEd (Sec)b; Prince, Miles MBBS (Hons) MD, FRACP, FRCPA, AFRCMA, MACD, FAHMSa

Author Information
doi: 10.1097/itx.0000000000000055
  • Open

Abstract

Introduction

Cutaneous T-cell lymphomas (CTCLs) represent a rare group of primary cutaneous lymphomas. Multiple subtypes of CTCL are recognized, of which mycosis fungoides (MF) and Sézary syndrome (SS) are the most common. In MF, neoplastic cells are derived from noncirculating skin resident effector memory T cells, whereas in SS, neoplastic T cells have a central memory T-cell phenotype. CTCL can range from an indolent to highly aggressive disease, and management should be tailored according to the disease stage1.

Early-stage disease is usually managed with skin-directed therapy, such as topical corticosteroids, topical chemotherapy, topical retinoids, phototherapy, and radiotherapy. Advanced-stage or transformed disease warrants systemic treatment, which may include systemic retinoids, interferon, histone deacetylase (HiDAC) inhibitors, systemic chemotherapy, and denileukin diftitox. Extracorporeal photophoresis and various investigational therapies also have a role in the treatment of advanced-stage disease1.

Patients with CTCL have a considerable burden of physical symptoms that affect their physical, social, and emotional wellbeing. Pruritus is the most commonly reported physical symptom in patients with CTCL, affecting up to 88% of patients2,3. Itch has a major negative impact on quality of life, interfering with daily activities, sleep, and mood4. The severity of CTCL-associated itch generally increases with disease progression. Pruritus is also more common in certain subtypes of CTCL, namely SS and folliculotropic MF4,5.

Pruritus is defined as an unpleasant sensation that provokes the desire to scratch. Pruritus is a multidimensional symptom, with effects on cognition and emotion. Pruritus is mediated by histamine-dependent and histamine-independent pathways6. Conventional antipruritic therapies such as antihistamines are largely ineffective in relieving CTCL-associated pruritus, suggesting unique pathophysiology2. Recent research has aimed to elucidate the mechanism of CTCL-associated pruritus. Possible mediators of pruritus in CTCL include interleukin (IL)-4, IL-31, and substance P5.

Treatments for relieving pruritus in CTCL have mainly focused on disease-directed therapies, aimed at controlling the underlying lymphoma. Improvement in pruritus has been included as a specific endpoint in recent clinical trials of disease-directed therapies for CTCL. As research on the pathophysiology of CTCL-associated pruritus is relatively recent, few studies on targeted itch-directed therapies are available5.

There are a lack of standardized methods used to measure and report itch in clinical studies. This makes it challenging to compare results from studies. A wide range of tools are used to measure the quality of life in patients with dermatological conditions, however, there is no agreed gold standard3.

We conducted a systematic review on interventions demonstrating efficacy in reducing pruritus in patients with CTCL. The primary aim of our study was to identify disease-directed and itch-directed therapies effective in reducing CTCL-associated pruritus. Our secondary aim was to outline the various tools used to quantify itch in clinical studies.

Materials and methods

A study protocol was finalized in April 2020 and submitted to the PROSPERO register of systematic reviews. (Prospero registration number CRD42020149210, published on April 28, 2020).

Eligibility criteria

We included all clinical studies published in a peer-reviewed journal that included itch as a specific study endpoint. Studies were included only if a tool was used to objectively quantify itch. We excluded nonhuman studies, conference abstracts, and studies published in a language other than English. Given the rarity of CTCL as a disease entity, we placed no restriction on study design.

Information sources and search strategy

A literature search was performed on the September 10, 2019 for the purpose of identifying relevant published articles. The search was run in Ovid Medline, Ovid Embase, and Ovid Emcare. The date of coverage was not restricted and results were limited to articles in English only.

In Medline, the search strategy consisted of subject headings (MESH) and various text words to identify the literature. Subject headings used in Ovid Medline included: “Lymphoma, T-Cell, Cutaneous,” “Pruritus,” and “Treatment outcome.”

Subject headings were combined with keywords (and their word variations) such as “mycosis fungoides,” “itch,” and “therapy” using the “OR” Boolean operator to cluster all similar indexed and free terms together. The “AND” Boolean operator was applied to link the different concepts.

Searches in Embase and Emcare followed a similar format to the Medline search with variations according to each database’s subject thesaurus.

Complete search strategies for each database are outlined in Appendix I.

Study selection

The clinical librarian (S.L.) performed the literature search, retrieved all abstracts, and deduplicated results. Titles and abstracts of identified studies were independently screened by the review team members (G.F., O.S.), according to the inclusion and exclusion criteria. Full-text articles were obtained for studies meeting the inclusion criteria, and their eligibility for inclusion was independently assessed by the review team (G.F., O.S.). The final agreement on study eligibility was resolved by consensus among the collaborators.

Data extraction

Data were independently extracted by the review team (G.F., O.S.) using a pilot-tested form. Data extracted included study design, number of study participants, subtype of CTCL in study patients, intervention, a tool used to quantify pruritus, improvement in itch due to treatment, and if other pruritus treatments were permitted.

Results

Study selection

A total of 1452 records were retrieved by the search strategy. After adjusting for duplicates, 1129 records remained. Of these, 1051 studies were discarded based on a review of titles and abstracts. The full texts of 78 articles were reviewed, of which 27 were eligible for inclusion in accordance with the selection criteria. A flow diagram detailing the inclusion and exclusion of studies from the systematic review is shown in Figure 1.

Figure 1
Figure 1:
Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram showing inclusion and exclusion of studies from the systematic review.

Study characteristics

Our review identified a total of 18 studies on disease-directed therapies, and 9 studies on itch-directed therapies. Studies were categorized into levels of evidence, according to the National Health and Medical Research Council’s framework7.

Bias assessment

All subtypes of CTCL were represented in studies, ranging from early-stage to advanced-stage disease. Most studies were unblinded and lacked a placebo control arm. A single randomized controlled trial (RCT) on the use of aprepitant was included, however, the study was small and underpowered. Almost all studies utilized descriptive statistics. The use of confounding anti-itch medications was permitted in 16 of the studies, and not permitted in 3 studies. It was unclear if other confounding treatments were used in 8 of the included studies.

Further assessments

Studies were heterogeneous in terms of methods used to quantify itch. As a result, a meta-analysis could not be performed.

Disease-directed therapies

Eighteen studies were identified on various disease-directed therapies. Most studies investigated the use of HiDAC inhibitors (7 studies).

HiDAC inhibitors

Six open-label interventional trials and 1 case series were identified on the use of HiDAC inhibitors, including the drugs romidepsin, vorinostat, quisinostat, and belinostat. The HiDAC studies included larger patient numbers than other studies and included patients with the advanced, treatment-refractory disease.

A significant reduction in pruritus was achieved with HiDAC inhibitors for patients with moderate and severe pruritus at baseline. A reduction in pruritus was found in both disease responders and nonresponders for the agents romidepsin8, vorinostat9,10, and quisinostat11.

Vorinostat was effective in reducing pruritus in patients with SS9,10. Although patients with SS were included in other HiDAC inhibitors trials, there was no specific comment on improvement in this subset of patients for other agents. Romidepsin demonstrated benefit in pruritus in patients with folliculotropic MF12, a variant typically associated with intractable pruritus.

Denileukin diftitox

One open-label interventional trial was found on the use of denileukin diftitox, an IL-2–diphtheria toxin fusion protein. The study included patients with the heavily pretreated disease. Denileukin diftitox only significantly reduced pruritus in patients with an objective disease response13.

Alemtuzumab

One open-label interventional trial was found on the use of alemtuzumab, a humanized monoclonal antibody against CD52. A small trial in patients with treatment-refractory, advanced-stage disease demonstrated a reduction in pruritus with alemtuzumab. Reduction in pruritus was achieved for both disease responders and nonresponders, however, the benefit in nonresponders was modest14.

Extracorporeal photopheresis (ECP)

One case report demonstrated a long-term reduction in pruritus with ECP in a patient with generalized syringotropic MF, a rare variant of folliculotropic MF15.

Total skin electron beam therapy (TSEBT)

One case series reported on the use of low-dose TSEBT in patients with MF, including 1 patient with folliculotropic MF. The patient with folliculotropic MF experienced a modest improvement in pruritus as a result of treatment16.

Thalidomide

One case report was identified on the use of thalidomide in a patient with early-stage, treatment-refractory MF. Pruritus relief was sustained long-term, even after cessation of thalidomide17.

Retinoids

One open-label interventional trial was found on the oral retinoid, bexarotene. The study included patients with advanced-stage, treatment-refractory disease. A modest reduction in pruritus was noted as a result of treatment with oral bexarotene18.

Two open-label interventional trials were identified on topical retinoids (tazarotene and bexarotene), including patients with early-stage disease. Topical retinoids demonstrated no benefit on pruritus in the studies identified19,20.

Combination therapy

Three open-label interventional trials were identified that used combination treatment. A trial on the use of vorinostat with bexarotene demonstrated improvement in pruritus in both disease responders and nonresponders21. Combination therapy with a HiDAC inhibitor and DNA methyltransferase inhibitor (valproate plus hydralazine) was investigated in one trial, with pruritus improving in all patients22. A trial investigating the use of combination therapy with bexarotene and rosiglitazone showed no significant reduction in pruritus23.

Itch-directed therapies

A total of 9 studies were identified on itch-directed therapies. Of these, 8 were on the use of the antiemetic aprepitant. One study was identified on the use of lignocaine administered via continuous subcutaneous infusion.

Aprepitant

Eight studies were identified on the use of aprepitant, including 1 RCT, 1 open-label interventional trial, 4 case series, and 2 case reports. Studies included patients with all stages of MF, including patients with SS. Aprepitant was effective in reducing pruritus, with a rapid time of onset (within hours to days). Reduction in pruritus could be sustained long term, for up to 13 months (until the patient passed away from disease) in 1 case report24.

One RCT concluded that aprepitant was not beneficial in patients with SS. However, the study included only 5 patients, was underpowered, and only followed patients for 21 days25.

Lignocaine via continuous subcutaneous infusion

A retrospective case series was identified on the use of lignocaine via continuous subcutaneous infusion. This study included patients with advanced CTCL, including patients hospitalized for end-of-life care. Lignocaine via continuous subcutaneous infusion was effective in reducing pruritus in patients with the advanced-stage disease6.

Tools used to quantify pruritus in studies

A variety of tools were used in clinical studies to quantify itch. All studies used some form of numerical scale. The most commonly used tools were the 10-point Visual Analogue Scale (VAS) (n=10), 100-mm VAS (n=5), and a Numerical Rating Scale (NRS) from 0 to 10 (scale from 0 to 10 [n=8], verbal scale from 0 to 10 [n=1]). Other measures included a scale of 0–8 using index lesions (n=2), and a scale of 0–5 (n=1).

A significant baseline level of pruritus was defined in only 7 studies. Significant baseline pruritus was defined as ≥30 mm on 100-mm VAS (n=1), ≥3 on 10-point VAS (n=2), ≥3 on a scale of 0–10 (n=1), >3 on 10-point VAS (n=1), >40 mm on a 100-mm VAS (n=1), and “persistent itching despite at least 1 previous antipruritic at full dose” (n=1).

Several studies included definitions of “moderate” and “severe” baseline pruritus. Definitions for moderate baseline pruritus included 30–69 mm on 100-mm VAS (n=2), 4–6 on 10-point VAS (n=1), 3–4 on scale of 0–5 (n=1), and 4–5 on scale of 0–8 (n=2). Definitions for severe baseline pruritus included 70–100 mm on 100-mm VAS (n=2), 7–10 on 10-point VAS (n=3), 7–10 on a scale of 0–10 (n=2), 5 on scale of 0–5 (n=1) and 6–8 on scale of 0–8 (n=2).

Definitions of a significant reduction in pruritus were extremely varied between studies, and are shown in Table 1. Some studies graded improvement in pruritus as “partial” or “complete,” again using varied definitions. Definitions of a partial response included a ≥3-point reduction in patients with baseline pruritus >3 on 10-point VAS (n=1), a 25%–50% reduction in 10-point VAS compared with baseline (n=1), and a VAS 3–6 on 10-point VAS on a treatment day (n=1). Definitions of a complete response included VAS of 0 on 100-mm VAS for at least 2 treatment cycles (n=1), the disappearance of pruritus for ≥4 continuous weeks without an increase in the use of antipruritic medications (n=1), and VAS 0–2 on 10-point VAS on a treatment day (n=1).

Table 1 - Summary of disease-directed and itch-directed studies identified by the systematic review.
Intervention Study Type Patients Level of Evidence7 CTCL Subtypes Measure of Pruritus Benefit? Definition of Significant Baseline Pruritus Definition of Significant Reduction in Pruritus Other Pruritus Treatments Permitted Results
Disease-directed
 HiDAC inhibitors
  Romidepsin Subanalysis of open-label, single-arm interventional trial12 30 IV Tumor-stage or folliculotropic MF 100-mm VAS Yes Baseline pruritus: No definition Grading of pruritus: Moderate-severe: VAS 30–100 mm Severe: VAS 70–100 mm Significant reduction in pruritus: No definition Grading of response: No definition No Tumor-stage MF: Moderate-severe pruritus at baseline: mean pruritus reduction −43 mm (±27) Severe at baseline: −45 mm (±29) Folliculotropic MF: Moderate-severe at baseline: mean pruritus reduction −53 mm (±35) Severe at baseline −60 mm (±42)
  Romidepsin Open-label, single-arm interventional trial8 96 IV Stage IB–IVA CTCL (most >stage IIB, heavily pretreated) Included patients with SS 100-mm VAS Yes Baseline pruritus: Significant pruritus: ≥30 on 100-mm VAS Grading of pruritus: Moderate: 30–69 on 100-mm VAS Severe: ≥70 on 100-mm VAS Significant reduction in pruritus: Decrease in VAS of ≥30 for ≥2 consecutive cycles in patients with pruritus ≥30 on 100-mm VAS at baseline Grading of response: Complete response: VAS of 0 on 100-mm VAS for at least 2 treatment cycles No Significant reduction of pruritus in 43% of patients, including 31% of patients with moderate pruritus at baseline, and 53% of patients with severe pruritus at baseline Complete response in 7/36 patients with severe pruritus at baseline Benefit in both disease responders and nonresponders
  Vorinostat Open-label, single-arm, interventional trial9 74 IV Stage IB–IV CTCL Included patients with SS 10-point VAS Yes Baseline pruritus: ≥3 on 10-point VAS Grading of pruritus: Severe: 7–10 on 10-point VAS Significant reduction in pruritus: ≥3-point improvement in VAS in patients with a baseline pruritus score of ≥3 on 10-point VAS, or complete resolution of pruritus for ≥4 continuous weeks, without an increase in the use of antipruritic medications Grading of response: No definition Permitted at stable doses 32% of patients had a significant reduction in pruritus (including both disease responders and nonresponders) In patients with severe pruritus, 43% had a significant reduction in pruritus Significant reduction in pruritus in patients with SS (5/16 patients with SS)
  Vorinostat Open-label, nonrandomized, non–placebo-controlled, dose-comparison interventional trial10 33 IV Treatment-refractory CTCL (most >stage IIB) Included patients with SS NRS (scale of 0–10) Yes Baseline pruritus: No definition Grading of pruritus: Severe: 7–10 on a scale of 0–10 Significant reduction in pruritus: ≥3-point improvement in scale of 0–10, or complete resolution of pruritus for at least 4 wk Grading of response: No definition Permitted at stable doses 45% of patients with baseline pruritus scores had a significant reduction in pruritus In patients with severe pruritus at baseline, 59% has a significant reduction in pruritus Reduction in pruritus also occurred in patients not achieving disease response, including patients with SS
  Vorinostat Prospective case series26 14 IV CTCL, any stage (progressive) Included patients with SS, folliculotropic MF NRS (scale of 0–10) Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Not specified 10/14 patients had improvement in pruritus (no elaboration on mean improvement), with the addition of vorinostat added to existing therapy
  Quisinostat Open-label, single-arm interventional trial11 26 IV Stage IB–IVA Included patients with SS 10-point VAS Yes Baseline pruritus: ≥3 on 10-point VAS Grading of pruritus: Severe: 7–10 on 10-point VAS Significant reduction in pruritus: ≥3-point decrease in patients with a baseline pruritus score ≥3 on 10-point VAS, or complete resolution of pruritus for ≥3 continuous weeks, without an increase in the use of antipruritus medications Grading of response: No definition Not specified 40% achieved a significant reduction in pruritus, including both disease responders (67%) and nonresponders (32%)
  Belinostat Open-label, single-arm interventional trial27 29 with CTCL (plus 24 with PTCL) IV CTCL, any stage (most stage IV, treatment-refractory) Included patients with SS NRS (scale of 0–10) Yes Baseline pruritus: ≥3 on a scale of 0–10 Grading of pruritus: Severe: 7–10 on a scale of 0–10 Significant reduction in pruritus: No definition Grading of response: No definition Not specified Reduction in pruritus in 7/15 patients who had baseline pruritus scores ≥3, including 3/6 patients with severe pruritus at baseline
 Denileukin diftitox Randomized, open-label, non–placebo-controlled, dose-comparison interventional trial13 71 IV Stage IB–IVA CTCL (heavily pretreated) 100-mm VAS FACT-G (Functional Assessment in Cancer Therapy-General questionnaire) 7-point global skin severity scale Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: Pruritus at baseline compared with end-of-treatment period using Wilcoxon signed-rank test, results considered statistically significant when P<0.05 Grading of response: No definition Yes (antihistamines, topical emollients, and bath additives only, systemic steroids not permitted) Median pruritus at baseline, the median decrease in pruritus severity at study endpoint: Disease responders: 5.3, 50% reduction at study endpoint (P<0.05) Nonresponders: 5.5, 6.3% reduction at study endpoint (not significant)
 Alemtuzumab Open-label, single-arm interventional trial14 22 IV Stage II–IV CTCL (treatment-refractory) Included patients with SS 10-point VAS Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Stable dose of <10mg prednisolone permitted All patients: median baseline VAS 8 (range: 1–10), end-of-treatment VAS 2 (range: 0–9) Disease responders (11/17): median baseline VAS 8 (range: 6–10), end-of-treatment VAS 1 (range: 0–6) Nonresponders (6/17): median baseline VAS 6 (range 1–9), end-of-treatment VAS 5 (0–10)
 ECP Case report15 1 NA Generalized syringotropic MF NRS (scale of 0–10) Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Topical corticosteroids permitted Baseline pruritus 10/10 After cycle 3, pruritus reduced to 7/10 After cycle 6, pruritus reduced to 1/10 Remained stable on monthly ECP for 15 mo (then pruritus progressed, added oral bexarotene)
 Low-dose TSEBT Retrospective case series16 8 IV MF (including folliculotropic) NRS (scale of 0–10) Dermatology Life Quality Index Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Not specified Mean scores for pruritus Before TSEBT: 3.43 After TSEBT: 1.88
 Thalidomide Case report17 1 NA Stage IB MF (treatment-refractory) NRS (scale of 0–10) Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Not specified Baseline pruritus score of 6, reduced to 2/10 at 8 wk of treatment Ceased treatment at week 18, with sustained relief of pruritus (no pruritus at 7 mo)
 Oral retinoids
  Bexarotene Open-label, nonrandomized, non–placebo-controlled, dose-comparison interventional trial18 94 IV Stage IIB–IVB CTCL (treatment-refractory) Included patients with SS Scale of 0–8 using index lesions Spitzer quality of life questionnaire Nonvalidated CTCL-specific questionnaire Yes Baseline pruritus: No definition Grading of pruritus: No definition Moderate: 4–5 on a scale of 0–8 Severe: 6–8 on a scale of 0–8 Significant reduction in pruritus: No definition Grading of response: No definition Yes Mean grade of pruritus decreased from 3.9/8 at baseline, to 3.2/8 at week 16 (does not separate disease responders and nonresponders) Improvement in nonvalidated CTCL-specific questionnaire, not Spitzer
 Topical retinoids
  Topical tazarotene gel Open-label, non–vehicle-controlled, single-arm interventional trial20 20 IV Early patch or plaque-stage MF <20% BSA Scale of 0–5 No Baseline pruritus: No definition Grading of pruritus: Moderate: 3–4 on a scale of 0–5 Severe: 5 on a scale of 0–5 Significant reduction in pruritus: Mean change in pruritus from baseline evaluated using the Wilcoxon signed-rank test (assuming P<0.05) Grading of response: No definition Yes Mean difference in pruritus from baseline −0.12 (P=0.55) No significant change in pruritus
  Topical bexarotene gel Open-label, non–vehicle-controlled, single-arm interventional trial19 50 IV Stage IA-IIA CTCL (treatment-refractory) Scale of 0–8 using index lesions Spitzer quality of life questionnaire Nonvalidated CTCL-specific questionnaire No Baseline pruritus: No definition Grading of pruritus: Moderate: 4–5 on a scale of 0–8 Severe: 6–8 on a scale of 0–8 Significant reduction in pruritus: No definition Grading of response: No definition Yes Mean grade of pruritus decreased from ∼2 at baseline, to ∼1 at week 16 (does not separate disease responders and nonresponders) Improvement in nonvalidated CTCL-specific questionnaire, not Spitzer
 Combination therapies
  Vorinostat+bexarotene Open-label, single-arm, dose-escalation interventional trial21 23 IV Stage IB–IVB Included patients with SS 10-point VAS Functional Assessment of Cancer Therapy-General Skindex-16 Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: ≥3-point reduction in pruritus score on 10-point VAS, or complete resolution Grading of response: No definition Not specified 7 patients experienced a significant reduction in pruritus Improvement in both disease responders and nonresponders
  Bexarotene+rosiglitazone Open-label, single-arm interventional trial23 4 IV Stage IA–IVA CTCL Included patients with SS 100-mm VAS Functional Assessment of Cancer Therapy-General No Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: Reduction in pruritus score on 100 mm VAS, with an improvement in quality of life measure (FACT-G) Grading of response: No definition Not specified 3 of 4 patients had improvements in pruritus scores, however, quality of life (as assessed by FACT-G) remained relatively unchanged for all 4 patients Concluded no meaningful improvement in itch
  Hydralazine+valproate Open-label, single-arm interventional trial22 14 IV MF, LyP 10-point VAS Yes Baseline pruritus: >3 on 10-point VAS Grading of pruritus: Moderate: 4–6 on 10-point VAS Severe: 7–10 on 10-point VAS Significant reduction in pruritus: ≥3-point reduction in patients with baseline pruritus >3 on 10-point VAS Grading of response: Partial response: ≥3-point reduction in patients with baseline pruritus >3 on 10-point VAS Complete response: no pruritus for ≥4 continuous weeks, without an increase in the use of antipruritic medications Permitted at stable doses All patients had moderate or severe pruritus at baseline All patients had improvement in pruritus, with complete response in 13 patients, and partial response in 1 patient
Itch-directed
 Aprepitant Randomized, double-blind, placebo-controlled cross-over trial25 5 Unable to grade SS 100-mm VAS Dermatology Life Quality Index No Baseline pruritus: >40 mm on 100-mm VAS Grading of pruritus: No definition Significant reduction in pruritus: Paired comparisons between time points were made using a Wilcoxon signed-rank test Hypotheses were tested at the level of α=0.05 Grading of response: No definition Yes, at stable doses Pruritus did not change over 7 d of treatment in the placebo arm, however, increased significantly during the aprepitant treatment However, study inadequately powered (according to full study protocol)
 Aprepitant Retrospective case series28 17 IV Stage IB–IV CTCL NRS (scale of 0–10) Qualitative Patient’s Global Assessment (PtGA) Yes Baseline pruritus: “Persistent itching despite at least 1 previous antipruritic at full dose” Grading of pruritus: No definition Significant reduction in pruritus: Compared mean pruritus at various time intervals, calculating confidence intervals and P-values (P<0.05) Grading of response: No definition Yes, at stable doses Mean baseline pruritus score 10/10, mean pruritus score after 1 mo 7/10 (95% CI: 5–8, P<0.001) Maximum benefit during first week of treatment, mean pruritus score 5/10 (95% CI: 3–7, P<0.001)
 Aprepitant Retrospective case series29 4 IV MF, LyP, cutaneous anaplastic lymphoma NRS (scale of 0–10) Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Yes Partial in all patients Beneficial for up to 12 mo
 Aprepitant Case series30 2 IV SS 10-point VAS Dermatology Life Quality Index Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Not specified Patient 1: Baseline VAS=8, at day 5 VAS=2 Patient 2: Baseline VAS=9, at day 5 VAS=3 Pruritus increased when aprepitant ceased
 Aprepitant Open-label, single-arm interventional trial31 5 IV Erythrodermic MF/SS Included patients with SS 10-point VAS Dermatology Life Quality Index Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: >50% reduction in 10-point VAS compared with baseline Grading of response: Partial response: 25%–50% reduction in 10-point VAS compared with baseline Yes, at stable doses Overall response rate 80% Baseline mean VAS 9.8 (±SD 0.4) Mean VAS after intervention 4.3 (±SD 3.4) (P=0.125) Reduction in VAS noted after 1 cycle of aprepitant, with further decreases at follow-up (24 wk)
 Aprepitant Case series32 3 IV SS 10-point VAS Dermatology Life Quality Index Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition No VAS at baseline to >day 2 to >day 7 Patient 1: 7 to >2 to >2 Patient 2: 8 to >3 to >3 Patient 3: 9 to >2 to >2
 Aprepitant Case report24 1 NA Tumor-stage MF NRS (verbal scale of 0–10) Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Yes Baseline VAS 10/10 At the 2-weekly evaluation, VAS 3/10 Continued benefit on quality of life due to reduction in pruritus for 13 mo (until the patient died from disease)
 Aprepitant Case report33 1 NA Stage IB MF 10-point VAS Dermatology Life Quality Index Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: No definition Grading of response: No definition Yes Baseline VAS 10/10 Week 1 of treatment VAS 2/10, week 2 VAS 2/10, remained steady for 5 mo (until time of publication) Benefit noted after the initial dose
 Lignocaine (via continuous subcut infusion) Retrospective case series6 19 IV Advanced CTCL Included patients with SS 10-point VAS (scratching behavior used if VAS not recorded) Yes Baseline pruritus: No definition Grading of pruritus: No definition Significant reduction in pruritus: VAS ≤6 on 10-point VAS on a treatment day Grading of response: Partial response: VAS 3–6 on 10-point VAS on a treatment day Complete response: VAS 0–2 on 10-point VAS on a treatment day Yes Complete response in a mean of 26.7% treatment days Partial response in a mean of 49.4% treatment days
CI indicates confidence interval; BSA, body surface area; CTCL, cutaneous T-cell lymphoma; ECP, extracorporeal photophoresis; HiDaC, histone deacetylase; LyP, lymphomatoid papulosis; MF, mycosis fungoides; NA, not available; NRS, Numerical Rating Scale; SS, Sézary syndrome; TSEBT, total skin electron beam therapy; subcut, subcutaneous; VAS, Visual Analogue Scale.

In addition to quantitative tools, several studies utilized qualitative tools to measure the quality of life. Qualitative tools included the Functional Assessment in Cancer Therapy-General questionnaire (n=3), patient-rated 7-point global skin severity scale (n=1), Dermatology Life Quality Index (n=6), Spitzer quality of life questionnaire (n=2), a nonvalidated CTCL-specific questionnaire (n=2), Skindex-16 (n=1) and Qualitative Patient’s Global Assessment (n=1)

Discussion

Pruritus is a common symptom of CTCL and has a major impact on the quality of life for both patients and their caregivers. A variety of disease-directed and itch-directed therapies demonstrated efficacy in relieving pruritus associated with CTCL. Pruritus relief can be achieved in patients with advanced-stage and treatment-refractory disease, including patients with folliculotropic MF and SS.

Our systematic review identified multiple disease-directed therapies effective in reducing CTCL-associated pruritus. Most evidence supported the use of HiDAC inhibitors. Other effective treatments include denileukin diftitox, alemtuzumab, ECP, TSEBT, thalidomide, bexarotene, combination therapy with vorinostat, and bexarotene, and combination therapy with valproate and hydralazine (HiDAC inhibitor and DNA methyltransferase inhibitor).

In some studies, pruritus was reduced in both patients achieving an objective disease response, and nonresponders. Pruritus relief was achieved for both disease responders and nonresponders with the agents romidepsin, vorinostat, quisinostat, alemtuzumab, and combination therapy with vorinostat and bexarotene. These results suggest that the clinical benefit of agents may extend beyond objective disease responses, and should be taken into consideration when assessing a patient’s response to treatment.

SS and folliculotropic MF are subtypes of CTCL associated with severe pruritus. Vorinostat was effective in reducing pruritus in patients with SS9,10. Folliculotropic MF involves deeper periadnexal structures and is generally considered resistant to skin-directed therapies. Our results demonstrate that the skin-directed therapies ECP and TSEBT are effective in reducing pruritus in patients with folliculotropic MF. The systemic therapy romidepsin also demonstrated efficacy in reducing pruritus in patients with folliculotropic MF.

A significant proportion of patients with CTCL develop the treatment-refractory disease, with severely debilitating pruritus. There is a need for targeted symptomatic approaches for those patients who do not respond to disease-directed therapies, or for when disease-directed therapies are not appropriate.

Our results support the use of the antiemetic aprepitant as a targeted treatment of CTCL-associated pruritus. Substance P is a neuropeptide released from sensory nerve endings in the skin. Substance P activates neurokinin-1 receptors present on keratinocytes, and on neurons in the dorsal root ganglia. High levels of substance P in keratinocytes are associated with pruritus. Aprepitant is a neurokinin-1 antagonist, inhibiting the effect of substance P2,5. Aprepitant demonstrated efficacy in reducing pruritus in patients with all stages of MF, including patients with SS. The effect is rapid in onset, and reduction in pruritus was sustained in some studies. These findings add to the body of evidence suggesting that substance P is an important mediator of pruritus in CTCL.

Lignocaine administered via continuous subcutaneous infusion is effective in reducing pruritus in patients with advanced-stage MF, including patients with SS. Lignocaine blocks sodium channels in neuronal cell membranes, and antagonizes kappa-opioid antagonist-induced scratching in mouse models34. Lignocaine administered by subcutaneous infusion should be considered in patients with intractable pruritus. This intervention also provides an important treatment option for symptom control in patients receiving end-of-life care.

Our systematic review highlights the variety of tools used to quantify itch in clinical studies and the subsequent difficulties in comparing results across studies. An ideal tool to quantify a symptom must be well-validated, appropriate for progressive conditions, simple to complete, and multidimensional3.

Our study identified the VAS as the most commonly used tool for measuring pruritus, using either a 100-mm VAS or 10-point VAS. The VAS was originally developed to assess the intensity of pain and has been adapted for use in the measurement of itch. The VAS is a 100-mm long line, on which patients indicate the severity of pruritus by crossing the line at the point that corresponds to their pruritus intensity. The VAS is a simple and reproducible tool and is one of the most commonly used methods of assessing pruritus severity. Studies have demonstrated that the VAS is a reliable method of pruritus assessment. The VAS is quick to perform and suitable for repeat assessments in clinical settings. The VAS demonstrates good test-retest reproducibility in patients with pruritic skin conditions. However, the VAS is a unidimensional tool, and only measures itch intensity. The tool is unsuitable for patients with motor deficits or cognitive issues, which may exclude the elderly or patients receiving end-of-life care35.

The next most frequently used measure of pruritus identified by our study was the NRS. The NRS is a similar method of pruritus measurement to the VAS. Patients rate pruritus intensity on a scale from 0 to 10 (no pruritus to worst imaginable pruritus)36. The NRS has been validated as a tool for assessing pain severity. In the study of itch, high concurrent validity in pruritus intensity assessment has been shown with both the VAS and NRS. However, discrimination of pruritus intensity using the VAS may be more sensitive than with the NRS37.

Studies included in our systematic review varied greatly in the definition of significant pruritus at baseline, and what constitutes a clinically meaningful reduction in pruritus. More recent trials on the use of HiDAC inhibitors defined a clinically meaningful reduction in pruritus as a ≥30 mm (or ≥3 points) improvement in VAS in patients with a baseline pruritus score of ≥30 mm (or ≥3 points), without an increase in the use of antipruritus medications, over a defined time period. This varied between 2 consecutive treatment cycles, 3 continuous weeks, and 4 continuous weeks8–11,22. In these studies, a ≥30 mm reduction in pruritus was prospectively selected as a clinically significant reduction in pruritus based on expert opinion, and previous use in other clinical trials8. A clinically significant reduction in pruritus should be defined more vigorously, ideally by incorporating the patient’s perception of pruritus relief.

The need for breakthrough medication can be considered a surrogate marker of a patient experiencing inadequate symptom relief. In the acute pain setting, the action of a patient not requesting breakthrough analgesia can be considered a marker that the patient perceives the therapy as effective. This marker has been used in previous studies to determine thresholds in pain scales that are considered clinically significant. This method places a stronger focus on the patient’s experience of pain, rather than arbitrarily assigning a numerical value as significant. This approach could be translated to research on pruritus. This information is simple to capture in the setting of a trial, and clinically appropriate. Although the choice of scales and analyses for the study of itch would differ, the same marker could be used to calculate a patient-determined clinically significant reduction in pruritus38–40.

To our knowledge, this is the first systematic review specifically addressing the management of itch in patients with CTCL. Patients with all stages of CTCL were represented across included studies, including patients with folliculotropic MF and SS, specific subtypes associated with severe and intractable pruritus. A wide range of treatment options were identified, including options appropriate for patients with end-stage disease.

Our systematic review has limitations. We limited results to articles published in English, excluded conference abstracts, and did not contact authors for further information regarding studies. Our systematic review retrieved no studies on certain treatments that are commonly used for the management of pruritus in clinical practice, including wet wraps, emollients, narrow-band UVB, topical and oral corticosteroids, naloxone, naltrexone, butorphanol, mirtazapine, and gabapentin5. We also found no studies on the disease-directed therapy mogamulizumab. This may be a reflection of our inclusion criteria.

The HiDAC inhibitors may be overrepresented in our results. As recent studies on the use of HiDAC inhibitors for CTCL included a reduction in pruritus as a study outcome, more of these studies met our inclusion criteria. This does not necessary imply that the HiDAC inhibitors are the most effective treatment for CTCL-associated pruritus.

We acknowledge that most included studies fall into low levels of evidence, particularly for itch-directed studies. Evidence supporting some agents was based only on case reports, and we acknowledge the risk of publication bias associated with case reports. However, given the rarity of CTCL as a disease entity, well-designed RCTs for this patient population are impracticable.

CTCL-associated pruritus is a debilitating symptom and requires a systematic treatment approach. We have identified multiple disease-directed and itch-directed therapies demonstrating efficacy in reducing pruritus in patients with CTCL.

Translating a subjective experience into an objective measure used for research and treatment evaluation is challenging. Our study identified the VAS and NRS as the most commonly used measures of pruritus in patients with CTCL. However, a unidimensional numerical scale alone does not adequately capture the patient’s experience of pruritus.

By drawing on the pain literature, various research techniques could be translated to the study of itch. The VAS or NRS should be validated to define a patient-determined clinically significant reduction in pruritus. For example, a patient not requiring breakthrough medication could be considered a surrogate marker of a patient experiencing adequate symptom relief. Validating the VAS or NRS for use in the study of itch would allow comparison of results between studies, as well as pooling of results across studies. This would assist in adding to the body of research on this rare and debilitating disease.

Assistance with the study

None.

Sources of funding

None.

Presentation

Preliminary data displayed as a poster presentation at the 10th World Congress on Itch 2019, Sydney, NSW, Australia.

Conflict of interest statement

The authors declare that they have no financial conflict of interest with regard to the content of this report.

Appendix

Appendix I - Search strategies for databases Ovid Medline, Ovid Embase, and Ovid Emcare.
Database: Ovid MEDLINE(R) ALL <1946 to September 06, 2019>
 Search Strategy:
  1 exp Lymphoma, T-Cell, Cutaneous/ (9438)
  2 (ctcl or cutaneous t-cell lymphoma* or mycosis fungoides or sezary or alibert-bazin or skin lymphoma*).mp. (10935)
  3 1 or 2 (12367)
  4 exp Pruritus/ (13306)
  5 (pruritus or itch*).mp. (31126)
  6 4 or 5 (32451)
  7 (treatment* or therap* or manag* or intervention* or control or alleviate or remed* or cure or phototherap* or antipruritic*).mp. (11202939)
  8 exp treatment outcome/ (995200)
  9 (“therapeutic use” or therapy).fs. (3585811)
  10 7 or 8 or 9 (11213178)
  11 3 and 6 and 10 (223)
  12 limit 11 to english language (193)
***************************
Database: Embase <1974 to 2019 September 06>
 Search Strategy:
  1 exp cutaneous T cell lymphoma/ (13724)
  2 (ctcl or cutaneous t-cell lymphoma* or mycosis fungoides or sezary or alibert-bazin or skin lymphoma*).mp. (19363)
  3 1 or 2 (19363)
  4 exp Pruritus/ (88103)
  5 (pruritus or itch*).mp. (97857)
  6 4 or 5 (101761)
  7 (treatment* or therap* or manag* or intervention* or control or alleviate or remed* or cure or phototherap* or antipruritic*).mp. (14818207)
  8 exp treatment outcome/ (1556096)
  9 (“therapeutic use” or therapy).fs. (1453047)
  10 7 or 8 or 9 (14982022)
  11 3 and 6 and 10 (1194)
  12 limit 11 to english language (1106)
***************************
Database: Ovid Emcare <1995 to 2019 week 36>
 Search Strategy:
  1 exp cutaneous T cell lymphoma/ (1313)
  2 (ctcl or cutaneous t-cell lymphoma* or mycosis fungoides or sezary or alibert-bazin or skin lymphoma*).mp. (1676)
  3 1 or 2 (1676)
  4 exp Pruritus/ (20606)
  5 (pruritus or itch*).mp. (21026)
  6 4 or 5 (21975)
  7 (treatment* or therap* or manag* or intervention* or control or alleviate or remed* or cure or phototherap* or antipruritic*).mp. (2743252)
  8 exp treatment outcome/ (473084)
  9 [(“therapeutic use” or therapy).fs.] (0)
  10 7 or 8 or 9 (2819668)
  11 3 and 6 and 10 (158)
  12 limit 11 to english language (153)
***************************

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      Keywords:

      Cutaneous T-cell lymphoma; Pruritus; Treatment

      Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Forum for the Study of Itch.