Patient-reported quality of life in patients with relapsed/refractory cutaneous T-cell lymphoma: Results from the randomised phase III ALCANZA study

: Background: Brentuximab vedotin was approved for adult patients with CD30-expressing cutaneous T-cell lymphoma treated with prior systemic therapy based on improved response rates and progression-free survival with brentuximab vedotin (1.8 mg/kg once every 3 weeks; ฀16 cycles) versus physician’s choice (methotrexate/bexarotene; ฀48 weeks) in the phase III ALCANZA study. Quality of life (QoL) in ALCANZA patients was also examined. Methods: QoL measures in ALCANZA were based on the Skindex-29, Functional Assessment of Cancer Therapy-General (FACT-G) and European QoL 5-dimension (EQ-5D) questionnaires. Results: Mean maximum reduction from the baseline Skindex-29 symptom domain score (key secondary end-point) was greater with brentuximab vedotin than physician’s choice (-27.96 versus -8.62); the difference, -18.9 (95% confidence interval -26.6, -11.2; adjusted p < 0.001), exceeded the study-defined minimally important difference (9.0-12.3). Mean changes from baseline to end-of-treatment visit total FACT-G scores were similar with brentuximab vedotin and physician’s choice (0.15 versus -2.29). EQ-5D changes were also comparable between arms. Among brentuximab vedotin-treated patients with peripheral neuropathy (PN), mean maximum reduction in Skindex-29 symptom domain was -35.54 versus -11.11 in patients without PN. PN had no meaningful effect on FACT-G and EQ-5D QoL scores. Conclusions: In summary, brentuximab vedotin produced superior reductions in symptom burden compared with physician’s choice, without adversely impacting QoL. QoL was unaffected by the presence of PN in brentuximab vedotin-treated patients. Clinical Abstract Background: Brentuximab vedotin was approved for adult patients with CD30-expressing cutaneous T-cell lymphoma treated with prior systemic therapy based on improved response rates and progression-free survival with brentuximab vedotin (1.8 mg/kg once every 3 weeks; (cid:2) 16 cycles) versus physician’s choice (methotrexate/bexarotene; (cid:2) 48 weeks) in the phase III ALCANZA study. Quality of life (QoL) in ALCANZA patients was also examined. Methods: QoL measures in ALCANZA were based on the Skindex-29, Functional Assessment of Cancer Therapy-General (FACT-G) and European QoL 5-dimension (EQ-5D) questionnaires. Results: Mean maximum reduction from the baseline Skindex-29 symptom domain score (key secondary end-point) was greater with brentuximab vedotin than physician’s choice ( e 27.96 versus e 8.62); the difference, e 18.9 (95% conﬁdence interval e 26.6, e 11.2; adjusted p < 0.001), exceeded the study-deﬁned minimally important difference (9.0 e 12.3). Mean changes from baseline to end-of-treatment visit total FACT-G scores were similar with brentuximab vedotin and physician’s choice (0.15 versus e 2.29). EQ-5D changes were also comparable between arms. Among brentuximab vedotin-treated patients with peripheral neuropathy (PN), mean maximum reduction in Skindex-29 symptom domain was e 35.54 versus e 11.11 in patients without PN. PN had no meaningful effect on FACT-G and EQ-5D QoL scores. Conclusions: In summary, brentuximab vedotin produced superior reductions in symptom burden compared with physician’s choice, without adversely impacting QoL. QoL was unaffected by the presence of PN in brentuximab vedotin-treated patients.


Introduction
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas characterised by clonal T-cell skin infiltrations [1,2]. Common CTCL variants include mycosis fungoides (MF; representing >50% of all CTCL cases), primary cutaneous anaplastic large-cell lymphoma (pcALCL) and Sézary's syndrome [3,4]. Because of the chronic recurrent nature of CTCL, complete responses (CRs) to treatment are rare, and patients frequently experience skin relapses or become treatment-refractory [5e7]. In addition, CTCL is often visibly disfiguring, causing pruritus and pain [8], with a symptom burden that can be highly detrimental to patients' well-being [9], making quality of life (QoL) maintenance a key patient-management goal [10].
Brentuximab vedotin, a CD30-targeting antibodye drug conjugate, is approved in Europe and the United States of America (USA) for treatment of CTCL patients, including pcALCL and CD30-expressing MF, who have received prior systemic therapy [11,12]. Approval was granted based on the phase III ALCANZA trial results (NCT01578499), demonstrating significantly improved objective response with brentuximab vedotin versus physician's choice (PC; methotrexate or bexarotene) in patients with previously treated CD30-expressing MF or pcALCL (56.3% versus 12.5%; p < 0.0001) [13], and an acceptable safety profile that was consistent with that in other malignancies.
Peripheral neuropathy (PN), one of the commonest toxicities associated with brentuximab vedotin, occurred in 67% of patients, versus 6% with PC.
To reflect the importance of QoL in CTCL, ALCANZA also evaluated patient-reported outcome (PRO) measures; results are reported here.

Study design and patient population
Study design and patient population have been described previously [13]. QoL questionnaires were administered before the first dose, on all even-numbered cycles thereafter, at the end-of-treatment and during post-treatment follow-up. The trial was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice, and appropriate regulatory requirements. Local ethics committees/institutional review boards approved the protocol, and patient safety was monitored via an Independent Data Monitoring Committee.
Functional Assessment of Cancer Therapy-General (FACT-G; version 4), a 27-item cancer-specific PRO measure, comprises four subscales (physical, social/ family, emotional and functional well-being) combined to obtain a total score (high score indicates better QoL) [17].
European QoL 5-dimension (EQ-5D), a five-item questionnaire, comprises a descriptive system and visual analogue scale (VAS) [18,19]. The three-level version recorded patients' perceptions of the impact of 'disability' (severe, moderate or none) on mobility, selfcare, usual activities, pain/discomfort and anxiety/ depression. The VAS recorded self-rated health on a 0e100 scale (worst-to best-imaginable health state). EQ-5D time trade-off indexed data were analysed using both United Kingdom (UK)-and USA-based value sets.

Minimal important differences
Minimal important difference (MID) is defined as the smallest change in score that is regarded as significant from a patient's or clinician's perspective to trigger changes in disease treatment or management. At the time of data cut-off, there was no validated Skindex-29specific MID for CTCL. Therefore, Skindex-29 symptom domain MIDs were estimated using three different distribution-based methods: half of a standard deviation (SD) approach, Cohen's moderate effect size and standard error of measurement (Supplementary Material, Methods) [20,21]. MIDs for the Skindex-29 symptom domain were estimated as 12.282, 11.238 and 9.045, respectively. FACT-G MID is reported as 2e3 points for physical and functional subscales, 2 points for the emotional subscale and 5e7 points for FACT-G total score [17]. The mean MID for EQ-5D time trade-off indexed data for both UK-and USA-based value sets was 0.074 (range e0.011 to 0.139) [18].

QoL objectives and assessment
Mean maximum reduction from baseline in Skindex-29 symptom domain was a key secondary end-point; other QoL secondary end-points included changes from baseline in Skindex-29 total, emotions and functioning domain scores, and FACT-G total and subscale scores. EQ-5D outcomes were an exploratory end-point.

Statistical analysis
p-Values were calculated using analysis of covariance, controlling for baseline symptom domain score, performance status score (0 and !1) and disease diagnosis (pcALCL and MF). p-Values adjusted for testing multiple key secondary end-points based on the weighted Holm's procedure were also provided.
Time to, and duration of, Skindex-29 symptom domain improvement were assessed using the three MIDs determined for symptom domain score. Time to Skindex-29 improvement was defined as the time from randomisation to the first reduction in symptom score of !MID, with patients censored at the date of their last Skindex-29 assessment before, or at end of treatment (EOT). Duration of Skindex-29 improvement was defined as the time from the first reduction in symptom score of !MID, before, or at EOT, to the date at which the reduction from baseline reverted to <MID. Time to, and duration of, Skindex-29 improvement were summarised descriptively using KaplaneMeier methodology.
Changes from baseline Skindex-29 total score and emotions/functioning domain scores, and changes from baseline FACT-G (total score and subscales) and EQ-5D scores over time were analysed to determine if response to, and side-effects of, therapy (specifically PN), were accompanied by measurable changes in PROs. QoL questionnaire scores were summarised with descriptive statistics.

Results
The population included 128 CD30-expressing CTCL patients randomised to receive brentuximab vedotin (n Z 64) or PC (n Z 64) [13]. Baseline characteristics and QoL scores were similar across study arms (Table  1). QoL questionnaire compliance was high in both arms (82.5e100% for brentuximab vedotin patients and 70.0e100% for PC patients) and was sustained throughout the study (Supplementary Table 1).

Skindex-29 symptom domain score
Mean Skindex-29 symptom domain scores over time are shown in Fig. 1 In the brentuximab vedotin arm, 63% (40/64) of patients achieved a reduction from baseline >MID of 12.3, versus 39% (25/64) of PC-treated patients. Using this MID, the median time to Skindex-29 symptom burden improvement was 2.1 versus 5.0 months, and the median duration of symptom burden improvement was 10.6 versus 3.5 months (Table 2) in brentuximab vedotin and PC arms, respectively. About 66% (42/64) and 44% (28/64) of patients achieved a reduction from baseline of >MID of 9.0 in brentuximab vedotin and PC arms, respectively. Using this MID, respective median times to Skindex-29 improvement were 2.1 versus 3.9 months, and median durations of improvement were not estimable versus 4.2 months in brentuximab vedotin and PC arms, respectively.
In a post-hoc analysis, most brentuximab vedotin-treated patients had reduced symptom burden regardless of response to treatment (Fig. 2).

FACT-G scores
FACT-G questionnaire results showed no significant treatment differences. Mean FACT-G total score changes from baseline to EOT were 0.15 (SD 16.388) with brentuximab vedotin and e2.29 (SD 17.171) with PC (Fig. 3); neither were >MID of 5e7 points [17]. However, brentuximab vedotin-treated patients had higher overall scores (better QoL) from cycles 2 to 12, and at EOT, versus PC-treated patients. Neither treatment group experienced meaningful differences in FACT-G scores for emotional, social/family, physical and functional subscales over time ( Supplementary Fig. 1).

EQ-5D scores
In both arms, no substantial changes from baseline EQ-5D score were observed over time (data not shown), although trends for overall higher scores were observed in the brentuximab vedotin arm. Mean changes from baseline to EOT in EQ-5D USA and UK time trade-offs were 0.02 and 0.03, respectively, in the brentuximab vedotin arm, and e0.02 and e0.04, respectively, in the PC arm. These results were not >MID for UK-and USA-indexed data of 0.074 (range e0.011 to 0.140).

Impact of PN on QoL in the brentuximab vedotin arm
Changes in QoL scores were also evaluated in brentuximab vedotin-treated patients according to occurrence/absence of treatment-emergent PN, and by PN grade (maximum grade 1 versus maximum grade 2/3). PN events were reported for 44 of 66 patients (67%) in the brentuximab vedotin arm [13], which were grade 1 (n Z 17), grade 2 (n Z 21) and grade 3 (n Z 6). Changes in Skindex-29 total score, FACT-G total score and EQ-5D VAS score over time in the brentuximab vedotin arm are shown by maximum grade of PN experienced (Fig. 4) and by PN presence or absence ( Supplementary Fig. 2). Mean maximum reduction in Skindex-29 symptom domain scores in patients with any PN were e35.54 (SD 23.991) versus e11.11 (SD 25.809) in patients without neuropathy (data not shown). Mean maximum reductions were similar in patients with grade 2/3 PN versus grade 1 PN (e36.72 versus e33. 33). No clinically meaningful differences in FACT-G total or EQ-5D VAS scores were seen between patients with or without PN (Supplementary Fig. 2).

Discussion
CTCL patients frequently report ongoing cutaneous symptoms, including rash, severe pruritus and hair loss, which can impact their QoL considerably (affecting social, emotional and functional aspects) and ability to undertake normal daily activities [8,22e24]. A 2005 survey of the US National Cutaneous Lymphoma Foundation reported that 41% of patients felt that CTCL had impacted work or school attendance, and 53% had experienced some degree of depression as a result of their disease [9]. Consequently, the ongoing evaluation of PROs for symptom burden and QoL is essential to ascertain if a treatment can improve and maintain patient well-being, and such measures should be routinely assessed in clinical trials for CTCL [25,26]. For relapsed/refractory CTCL patients, it is important that new therapeutics both improve clinical responses and reduce skin symptom burden without adversely impacting QoL.
ALCANZA demonstrated superior clinical efficacy with brentuximab vedotin versus PC in terms of response and progression-free survival [13]. To reflect the importance of QoL in CTCL, ALCANZA evaluated QoL PROs. The current analysis demonstrated that the key secondary end-point, Skindex-29 symptom burden, was significantly reduced with brentuximab vedotin versus PC. Despite the open-label study design, QoL questionnaire compliance was high (>70% in both arms), supporting the validity of these results.
Using Skindex-29, we observed a greater reduction from baseline symptom burden with brentuximab vedotin compared with PC. Treatment differences exceeded all three estimated MIDs, demonstrating a clinically meaningful improvement. These effects were sustained regardless of response status (post-hoc). A high proportion of patients individually achieved a clinically meaningful reduction in Skindex-29 symptom domain score with brentuximab vedotin, including some patients who did not achieve objective responses. During treatment, improvements were rapid (median time to improvement: 2.1 months) and durable (median duration >10 months) compared with patients receiving PC (3.9 and 3.5 months, respectively), highlighting the rapid and sustained benefits seen with brentuximab vedotin. There were no apparent treatment differences in Skindex-29 emotional and functioning domains over time; however, trends suggested a greater reduction in the impact of skin disease on QoL with brentuximab vedotin.Nosignificantorclinicallymeaningfultreatment differences were seen for the other PROs. Therefore, treatment with brentuximab vedotin improved cutaneous symptom burden (skin itching, burning, pain, irritation and bleeding) while maintaining other more general QoL aspects (e.g. emotions, functioning, social/ family, physical and overall health status) at a similar level to that achieved with previous standard-of-care treatment.
The evaluation of change from baseline in the context of MIDs for each PRO was used to aid interpretation of results; however, at the time of the ALCANZA study, there was no validated Skindex-29-specific MID for CTCL. Consequently, the study sponsor used distribution-based methods to calculate an appropriate MID range for the Skindex-29 data. An approach consistent with the European Medicines Agency guidance regarding the use of patient-reported outcomes in oncology studies [27]. Use of multiple independent distribution-based methods to generate a range of values produces a robust analysis [28]. However, each approach invariably results in different MID definitions, which will not define a single specific MID threshold, and these methods provide no information on the clinical relevance of the change [29]. Nevertheless, the difference in maximum mean reduction from baseline Skindex-29 symptom domain scores between brentuximab vedotin and PC arms exceeded all three study-derived MIDs.
PN, a known side-effect of brentuximab vedotin (median time to onset:~3 months) can often be dose-limiting [12,30,31]. Between 2010 and 2016, brentuximab vedotin-treated lymphoma patients reported that brentuximab vedotin-related PN affected their QoL (50%) and work (20%) [30]. The consensus among these patients was that brentuximab vedotin's benefits largely outweighed the risks [30]. However, 54% had Hodgkin lymphoma differentiating them from the ALCANZA population. Therefore, the importance of QoL and the magnitude of changes from baseline may differ for ALCANZA CTCL patients. In this analysis, QoL was neither affected adversely by brentuximab vedotin-related PN, nor did PN severity appear to affect skin symptom burden reductions. As the ALCANZA study was open-label, QoL scores may have been subject to bias because patients were aware that they were receiving brentuximab vedotin and may therefore have overestimated treatment benefit; however, the magnitude of this potential bias is difficult to quantify [32,33]. Furthermore, the number of patients with responses declined during treatment because of discontinuations in both arms, and no multiple imputation methodology was used to account for m i s s i n gd a t ao v e rt i m e ;n e v e r t heless, the trends observed during treatment were also observed at the EOT visit. As the study only looked at two specific variants of CTCL (MF and pcALCL), the QoL results should not be extrapolated across other CTCL disease subtypes, such as Sézary's syndrome. Finally, as none of the QoL questionnaires were disease-specific, it is unclear whether QoL changes related explicitly to CTCL have been captured. Despite these limitations, this analysis provides valuable information with an important patient perspective.
In conclusion, ALCANZA data indicate that brentuximab vedotin may improve the skin symptom burden of patients with previously treated CD30-expressing CTCL requiring systemic therapy compared with PC, as evidenced by superior reductions   in the Skindex-29 symptom domain. In addition, brentuximab vedotin did not adversely affect QoL compared with PC. QoL was also unaffected by the presence of PN in the brentuximab vedotin arm. In combination with the primary ALCANZA efficacy and safety data, the symptom burden and QoL findings provide compelling evidence supporting the use of brentuximab vedotin over methotrexate or bexarotene in previously treated CD30-expressing CTCL.

Funding sources
This research was co-funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Seattle Genetics, Inc., Bothell, WA, USA, and was also funded in part through the NIH/NCI Cancer Center Support Grant [grant number P30 CA008748]. Medical writing assistance was funded by Millennium Pharmaceuticals, Inc.

Conflict of interest statement
S.W., P.W., J.A.S. and L.G. declare no conflicts of interest. R.D. reports intermittent, project-focused consulting and/or advisory relationships with Novartis, MSD, Bristol-Myers Squibb, Roche, Amgen, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Pierre Fabre, Sun Pharma and Sanofi. H.M.P. reports consultancy, advisory roles or honoraria from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Celgene and Eisai, and research funding from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. S.M.H. reports consultancy or advisory roles from Affimed, Aileron Therapeutics, Merck Sharp and Dome, Kyowa Hakko Kirin Pharma, Corvus Pharmaceuticals, Inc., Celgene, Portola Pharmaceuticals, Takeda Millennium, Innate Pharma, Verastem, Miragen Therapeutics, Inc. and Seattle Genetics, and research funding from ADCT Therapeutics, Aileron, Forty-Seven, Infinity/ Verastem, Kyowa Hakko Kirin Pharma, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Seattle Genetics, Inc., Celgene and Trillium. M.D. reports research funding and consultancy from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Seattle Genetics, Inc. J.S. reports consultancy or advisory roles from Helsinn, Kyowa Hakko Kirin, Millennium Pharmaceuticals, Inc., Innate Pharma, 4SC and Mallinckrodt. P.Q. reports advisory roles from 4SC, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., and complied with the Good Publication Practice 3 ethical guidelines [34].