Challenges in R/R CLL and DLBCL: How to maintain good quality of life

On Sunday, November 8, 2020, the Lymphoma Hub will hold a virtual Satellite Symposium on the management and treatment of patients with relapsed/refractory (R/R) lymphoma. The symposium will take place at the European School of Haematology (ESH) conference, How to Diagnose and Treat Lymphoma, where a panel of international experts, Marie José Kersten, Kieron Dunleavy, Francesc Bosch, Astrid Pavlovsky, and the Lymphoma Hub Chair, Gilles Salles, will provide insight into their experiences managing patients with R/R disease. This article aims to compliment the materials that will be presented at the virtual symposium.

Figure 1. Overview of the challenges and treatment approaches when managing patients with R/R lymphoma

ADC, antibody-drug conjugate; BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; CAR, chimeric antigen receptor;  CLL, chronic lymphocytic leukemia; DH/TH, double hit/triple hit; DLBCL, diffuse large B-cell lymphoma; PI3K, phosphoinositide 3-kinase.
Schematic courtesy of Gilles Salles.  

Patients with R/R lymphoma experience a lower overall quality of life (QoL) as a result of disease symptoms and intensive treatments. The treatment landscape for lymphoma is ever evolving and targeted therapies have minimized off-target effects associated with conventional chemo- and radiotherapy. However, novel agents can still result in worsening of symptoms and thereby adversely affect patient QoL. To understand the impact of emerging therapies on patient QoL, it is essential to determine a form of baseline, taking into account the effects of both the disease itself and the current standard of care (SoC) regimens. Clinical trials and supplementary analyses now aim to establish the impact of emerging agents on patient wellbeing. For information on how patient QoL is optimized across clinical trials, watch the video below.

Here, we outline some of the leading therapies in R/R DLBCL/CLL which have been evaluated for their impact on patient QoL. Table 1 summarizes the most commonly implemented tools used to measure patient reported outcomes.

Table 1. Instruments used to measure patient reported outcomes in patients with DLBCL and CLL^1,2

DLBCL

In 2019, a systematic literature review identified studies that reported health-related QoL (HRQoL) in patients receiving SoC for the treatment of R/R DLBCL. Instruments used to determine patient reported outcomes included Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym), Short-form 36 (SF-36), and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Table 2 summarizes the key findings, which suggest that patients with R/R DLBCL receiving current SoC therapy experience a decline in HRQoL and health utility.³ This study was important in achieving a baseline HRQoL readout and sets a goal to strive towards when evaluating emerging therapies.

Table 2.  Patient reported outcomes for patients receiving SoC for R/R DLBCL³

CAR-T

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly emerging treatment in the R/R lymphoma setting, providing hope for patients with otherwise limited treatment options. There are a number of adverse events to evaluate when considering CAR T-cell therapy and, therefore, it becomes imperative to evaluate the impact of treatment on patient QoL. The interview below with Bregje Verhoeven summarizes the impact of CAR T-cell therapy on patient QoL.

A recent study by Richard T. Maziarz and colleagues sought to determine the impact of the CAR T-cell therapy, tisagenlecleucel, on HRQoL in patients with R/R DLBCL. The team conducted a 19.3-month follow-up analysis of the phase II JULIET trial to evaluate patient-reported HRQoL following a single dose of tisagenlecleucel using FACT-Lym and SF-36. The data showed that tisagenlecleucel demonstrated clinically meaningful and sustained improvements in HRQoL in those patients who responded to therapy.⁴

CLL

A systemic review, carried out by Catherine Waweru and coinvestigators, analyzed 12 primary studies to determine the impact of CLL on patient HRQoL. Across the eligible studies, patients with CLL reported impairment in fatigue, anxiety, physical functioning, social functioning, depression, sleep disturbance, and pain interference when compared with healthy controls. The study also identified female gender, increased disease severity, and ≥ 1 line of therapy as negative influencers of HRQoL.¹

Ibrutinib

The BTK inhibitor ibrutinib, is an effective treatment for R/R CLL, but there are a number of side effects associated with its use. For this reason, a clinical trial (NCT04016636) has been dedicated to specifically evaluate the impact of ibrutinib treatment on QoL in patients with CLL and is currently recruiting. The Lymphoma Hub previously investigated the effect that ibrutinib-associated hair and nail abnormalities had on patient QoL and it became clear that cutaneous, as well as systemic, side effects have a serious influence on patient happiness.   

Venetoclax

The oral BCL-2 antagonist venetoclax, has demonstrated encouraging response rates in patients with R/R CLL including those with TP53 disruptions and the del17p mutation. Not only has the agent shown clinical efficacy in these patients, but a number of studies have highlighted the positive impact of venetoclax on patient QoL.

Tara Cochrane and colleagues reported the preliminary data from the open-label, multicenter, phase III VENICE II study (NCT02980731) evaluating patient-reported HRQoL in patients who were ≥ 18 years old receiving venetoclax monotherapy for the treatment of R/R CLL. The study uncovered improvements from baseline in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue and disease effect subscales. These improvements were observed by week 12 and were sustained through week 48. The findings from this study suggest that venetoclax monotherapy is well tolerated in patients with R/R CLL, and the results improved QoL.⁵

A team led by William Wierda presented the data from a second interim analysis evaluating the impact of venetoclax monotherapy on patient QoL in a pivotal phase II trial (NCT01889186). The single-arm, multicenter study evaluated venetoclax monotherapy for patients aged ≥ 18 years old with R/R CLL del(17p). In this analysis, patients reported significant improvements from baseline which were sustained for up to 96 weeks, as shown in Figure 2.⁶

Figure 2. A Changes from baseline in EORTC-QLQ-C30, and B Changes from baseline in EORTC-QLQ-CLL-16 observed in patients receiving venetoclax monotherapy⁶

EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC-QLQ-CLL-16, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire chronic lymphocytic leukemia module 16.
(a) positive change represents improvement; (b) negative change represents improvement. 
Figure adapted from Wierda W et al., 2017.⁶

Conclusion

The impact of potential drug candidates on patient QoL should be addressed in the early stages of clinical development. This focus should mean that emerging treatments prove less of a burden to patients. It is important to understand the effect of both the underlying disease and current SoC regimens on patient wellbeing to determine the influence of novel agents on patient QoL. This article merely scratches the surface of the vast number of challenges faced in the R/R setting. Alas, extensive efforts are being made to address the factors that present obstacles. At the Lymphoma Hub Satellite Symposium, the panel will share their personal experiences of the challenges presented to them on a daily basis when treating patients with R/R lymphoma.