Why we should opt for continuous therapy in chronic lymphocytic leukaemia?

INTRODUCTION

The chronic lymphocytic leukaemia (CLL) treatment landscape has seen remarkable evolution since 2010. Traditional therapies like chemotherapy and monoclonal antibodies were once mainstays, but targeted therapies and immunotherapies have transformed management. Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib have demonstrated efficacy in inhibiting CLL progression by targeting B-cell receptor signalling pathways. Similarly, BCL-2 inhibitors, like venetoclax, disrupt anti-apoptotic mechanisms in CLL cells. Furthermore, CAR-T cell therapy and bispecific antibodies are promising avenues for engineering patients' T cells to target CLL cells. With personalised medicine approaches and ongoing clinical trials, the CLL treatment landscape continues to evolve, offering improved outcomes and quality of life for patients.¹

The debate between continuous therapy and fixed-duration (FD) therapy in CLL reflects the complexity of balancing treatment efficacy with toxicity and patient quality of life. Continuous therapy, often involving BTK inhibitors or BCL-2 inhibitors, aims to sustain disease control over the long term, potentially preventing relapse but necessitating ongoing drug exposure and monitoring. Conversely, FD therapy, typically utilising targeted therapy combinations of BCL2 inhibitor plus an anti-CD20 monoclonal antibody or a BTK inhibitor, aims for a finite treatment period, potentially allowing for treatment-free intervals but risking disease recurrence. Both approaches have demonstrated efficacy, and the choice depends on individual patient factors, including comorbidities, treatment tolerance, and preferences, emphasising the importance of shared decision-making in CLL management. Ongoing research aims to refine treatment strategies and optimise outcomes in this dynamic landscape.

When we talk about continuous therapy we usually refer to treatment with BTK inhibitors, while only few studies investigated the role of BCL2 inhibitor as a single agent in continuous therapy.^2-4

Ibrutinib, the first-in-class BTK inhibitor, revolutionising the treatment landscape of CLL and other B-cell malignancies, showed efficacy in both treatment-naive and relapsed/refractory CLL.^5,6 Its mechanism involves covalent irreversible inhibition of BTK, disrupting B-cell receptor signalling and promoting apoptosis in malignant B cells. Long-term results from the RESONATE trial demonstrated that ibrutinib significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to ofatumumab in relapsed/refractory CLL patients.⁵ Additionally, the RESONATE-2 trial showed superior PFS, OS, and overall response rate of ibrutinib compared to chlorambucil in treatment-naive CLL patients, particularly in those with high-risk genomic features.⁶ Notably, ibrutinib showed sustained efficacy across patient subgroups, regardless of del(17p) or TP53 mutation status, making it a cornerstone therapy for CLL management, offering durable responses and improved survival outcomes.

Acalabrutinib, a second-generation BTK inhibitor, offers a more selective inhibition profile, potentially reducing off-target effects and improving tolerability. Results from the ELEVATE-TN trial demonstrated that acalabrutinib significantly improved PFS compared to standard chemoimmunotherapy in treatment-naive CLL patients.⁷ Moreover, the ELEVATE-RR trial which compared acalabrutinib directly with ibrutinib in relapsed/refractory CLL patients, acalabrutinib demonstrated superiority in terms of PFS.⁸ This trial showcased acalabrutinib's efficacy and safety profile compared to ibrutinib. Notably, acalabrutinib exhibited lower rates of adverse events such as atrial fibrillation, hypertension and bleeding events. These findings position acalabrutinib as an effective and well-tolerated treatment option for CLL patients, particularly those with comorbidities or a need for long-term therapy.

Zanubrutinib, another second-generation BTK inhibitor, exhibits potent BTK inhibition with minimal off-target activity, contributing to its favourable safety profile. In both the ALPINE and SEQUOIA trials, zanubrutinib demonstrated significant efficacy in treating CLL and small lymphocytic lymphoma (SLL). Zanubrutinib notably improved PFS compared to standard ibrutinib in the ALPINE trial for relapsed/refractory cases,⁹ and surpassed bendamustine plus rituximab in PFS and overall response rates in the SEQUOIA trial for treatment-naive patients.¹⁰ Moreover, zanubrutinib exhibited a favourable safety profile, with low rates of adverse events such as atrial fibrillation and bleeding incidents, reinforcing its efficacy and tolerability as a frontline or salvage therapy option for CLL/SLL. While the better safety profile is likely related to the high selectivity of zanubrutinib for BTK, the improved outcome might be related to the better pharmacokinetic, while its plasma concentration always above the IC50, higher BTK occupancy within the lymph nodes, and less treatment discontinuation due adverse events.¹¹

The favourable safety profile of second-generation BTK inhibitors, coupled with their efficacy in CLL, position them as a compelling treatment option, potentially offering improved tolerability and quality of life for patients compared to ibrutinib.¹²

Although we would like to treat all patients with FD therapy, several points favour the use of continuous therapy with BTK inhibitors in CLL. We herein addressed the most pros and cons of continuous therapy with BTKi in patients with CLL.

PROS OF CONTINUOUS THERAPY

There are several favourable aspects for the use of continuous BTKi such as the efficacy in high-risk or bulky disease and the easier schedule. CLL displays a wide spectrum of clinical and biological diversity, ranging from those who will never require treatment to patients with short-term disease control and who relapse several times. The former an enriched in patients with a mutated IGHV gene and 13q deletion at FISH (fluorescence in situ hybridization), while the latter are featured by an unmutated IGHV gene, TP53 abnormalities (deletion and/or mutation) and complex karyotypes.^13-15

In Table 1 we summarised results of sub-analyses from clinical trials both in treatment-naive and relapse/refractory patients with TP53 abnormalities or complex karyotype who received fixed duration therapy with venetoclax-obinutuzumab¹⁶ or venetoclax-ibrutinib^17,18 or venetoclax-rituximab¹⁹ versus ibrutinib^5,6, acalabrutinib or zanubrutinib. Among treatment-naive patients the 3 years PFS is about 15-20% higher with a continuous BTK inhibitor therapy (range 75%-84%) than an FD (range 57%-73%), while differences are smaller among relapse-refractory patients.^19-21

Table 1. Comparisons of fixed-duration and continuous therapies in patients with TP53 abnormalities and complex karyotype.

	TP53 abnormalities (including del17p by FISH and/or TP53 mutation by sanger or NGS)
	Therapies	Trials	2-yy PFS	3-yy PFS	median PFS
TREATMENT NAIVE	VG	CLL14	~71%	~62%	~48m
	I+V	Captivate Glow Flair	~85% n.a. n.a.	~73% n.a. n.a.	n.r. n.a. n.a.
	Ibrutinib	Polled analysis	~87%	79%	78m
	Acalabrutinib	Polled analysis	~88%	78%	n.r.
	Zanubrutinib	Sequoia	~88%	~80%	n.r.
RELAPSED	VR	Murano	~80%	~51%	36m
	I+V	Vision Clarity	n.a. n.a.	n.a. n.a.	n.a. n.a.
	Ibrutinib	Resonate Alpine	~72% 55%	~52% ~40%	40.7m ~26m
	Acalabrutinib	Polled	~72%	~54%	~40m
	Zanubrutinib	Alpine	78%	~50%	38.6m
	Complex karyotype
TREATMENT NAIVE	VG	CLL13 no CK / iCK / hCK CLL14 NO CK / CK	~95% / ~95% / ~82% ~95% / ~80%	~85% / ~85% / ~57% ~80% / ~79%	n.r. / n.r. / ~43m n.r. / n.r.
	I+V	Captivate CK	~85%	~70%	n.r.
	Ibrutinib	Polled analysis no CK / CK	~84% / ~84%	~78% / ~75%	n.r.
	Acalabrutinib	Polled analysis CK	~91%	84%	n.r.
	Zanubrutinib	Sequoia no CK / CK	~95% / ~85%	~85% / ~80%	n.r. / n.r.
RELAPSED	VR	Murano no CG / CG	~92% / ~80%	~78% / ~50%	60 / 42m
	Ibrutinib	OSU study no CK / iCK / hCK	~82% / ~75% / ~55%	~80% / ~68% / ~52%	n.r. / 60m / ~36m
	Acalabrutinib	Pooled analaysis CK	~75%	~56%	~39m

VG = venetoclax-obinutuzumab, I+V = ibrutinib plus venetoclax, n.a.= not available, n.r. = not reached, PFS = progression free survival, CK = complex karyotype (≥ 3 chromosomal abnormalities), iCK = intermediate CK (3-4 chromosomal abnormalities), hCK = high CK (≥ 5 chromosomal abnormalities); CG = genome complexity (≥ 3 abnormalities); OSU study =. study by the Ohio state university.

In addition, both the CLL14 and the Murano trials, using venetoclax-obinutuzumab and venetoclax-rituximab in treatment-naive and relapse patients, respectively, showed that patients with bulky nodes (defined as patients whose lymph nodes were 5cm or larger) had almost 2-fold higher risk of relapse than patients with small lymph nodes.^16,19 Conversely, BTK inhibitors were highly active in the lymph nodes, regardless of their size, being able to cause their shrinkage already after a few days from the start of the drug.^5,6

One of the cornerstones of fixed duration therapy is the capability of combination therapies to reach undetectable measurable residual disease (uMRD, <10^-4) leading to long-term disease remissions. However, while the rates of uMRD are high for previously untreated patients,^16-19 these rates tend to decrease in heavily treated patients^20,21 (Table 2). Despite uMRD being very rare with BTK inhibitors, continuous treatment allows for long-term disease remission.^5-7,10

Table 2. Comparisons of measurable residual disease (MRD) rates according to the line of therapy.

	Flow-cytometry PB MRD EoT
	Therapies	Studies	uMRD4	uMRD2	dMRD2
TREATMENT NAIVE	VG	CLL13 CLL14 (AS-PCR)	86% 76%	9% 5%	0% 4%
	I+V	Captivate MRD Captivate FD Glow	75% 77% 61%	n.a.	n.a.
RELAPSED	VR	Murano (all) 2L 3L +3L	70% 69% 78% 55%	19% 24% 12% 9%	10% 7% 9% 36%
	I+V	Vision Clarity	30% ~57%	57% ~33%	13% ~10%

VG = venetoclax-obinutuzumab, I+V = ibrutinib plus venetoclax, VR = venetoclax-rituximab, uMRD4 = undetectable measurable residual disease <10^-4 events, uMRD2 undetectable measurable residual disease <10^-2 events, dMRD2 detectable measurable residual disease >10^-2 events, n.a.= not available.

Furthermore, another point forward the use of continuous treatment with BTK inhibitor is the easier schedules and formulations.^6,7,10 Since they are available as a capsule or tablet, they can be easily taken by the patients at home once a day for ibrutinib, twice a day for acalabrutinib and zanubrutinib. Conversely, access to the outpatient clinic for intravenous drugs, such as obinutuzumab or rituximab, or the management of the venetoclax ramp-up phase might be an issue for some elderly patients with comorbidities and/or for their caregivers.^16,18,19 In fact, recent retrospective studies confirmed the efficacy and feasibility of BTK inhibitors in octogenarian patients.^22,23

CONS OF CONTINUOUS THERAPY

There are also several aspects against the use of continuous BTKi such as adverse events, emergence of resistance or mutations and costs.

It is well known that a relevant number of patients develop adverse events, in particular cardiovascular events like atrial fibrillation, hypertension, bleeding and diarrhoea, and some of them discontinue therapy due to adverse events.^5-7,10,24-27 However, we learn that most adverse are common during the first years of treatment but their incidence decreases in the next years.^5,6 This is the case for diarrhoea, fatigue, bleeding and infections while the rate of hypertension onset increases during ibrutinib treatment in the Resonate-2 trial.⁶ In addition, some life-threatening ventricular arrhythmias events have been reported with ibrutinib and calabrutinib.²⁸ However, the rates of atrial fibrillation, hypertension and ventricular arrhythmias are much lower with acalabrutinib and Zanubrutinib.^10,28 Of note, a recent analysis demonstrated that patients who decrease ibrutinib dose after a cardiovascular adverse event experience a very low rate of adverse event recurrence and a trend for a longer PFS,²⁹ suggesting that lower doses of ibrutinib might be safer.

Interestingly, second-generation BTK inhibitors have been explored in patients who discontinued ibrutinib due to intolerance. A phase 2 study by Shadman M. et al showed that 68% of ibrutinib-intolerant and 73% of acalabrutinib-intolerant patients did not have recurrence of the same adverse events during zanubrutinib treatment. Of those adverse events that recurred during zanubrutinib treatment, none were at a higher grade, and 75% among ibrutinib-intolerant and 40% among acalabrutinib-intolerant patients were at a lower grade.³⁰

One of the major concerns regarding continuous treatment is the emergence of mutations of BTK or downstream signalling pathways gene such as PLCG2.^31-33 Although these mutations can arise both in patients failing BTK inhibitor, up to 65% of cases, and in responding patients, almost 10% of cases,³¹ Woyack J. et al showed that BTK mutations are more rare in patients taking ibrutinib as first-line therapy (3%) compared with relapsed patients (30%).³²

According to the literature, different kinds of BTK mutations exist. The most common mutation, i.e. C481x, involves the ATP binding site of BTK leading to the inability of ibrutinib, acalabrutinib, or zanubrutinib to covalently bind and inhibit the kinase.^31,32,34 Other, less common BTK mutations include L474x, also known as a gatekeeper, and L528W, also known as kinase-dead mutation.^32,34 Pirtobrutinib, a new non-covalent BTK inhibitor given as continuous therapy, showed activity in heavily pre-treated patients who previously relapsed after covalent BTK inhibitor in the phase 3 BRUIN trial.³⁵ In addition, pirtrobrutinib was able to clear C481x-mutated clones.³⁴ Other new drugs are being developed, such as the chimeric degradation activation compound, which can bind the E3 ligase complex and BTK, leading to its polyubiquitination and proteasomal degradation. These agents, such as BGB-16673, NX-5948 and NX-2127, might be active in patients harbouring L474x and/or L528W mutations.^36-38

Finally, the cost of FD therapy is lower than that of continuous therapy. However, if we consider retreatments, the whole cost of treatment for two FD regimes is not much lower than that of continuous therapy either in the frontline or relapse setting. This is shown in Figure 1.

Figure 1. Cost of treatments



We considered cost of BTKi and venetoclax as €3,000/months, obinutuzumab all 8 doses €30,000 and rituximab biosimilar all 6 cycles €12.000.

CONCLUSIONS

Although we would like to treat all patients with CLL with FD therapy, most of them will receive at least one continuous therapy in their lives. The debate between continuous therapy and FD therapy underscores the complexity of balancing treatment efficacy with toxicity and patient quality of life. Continuous therapy with BTK inhibitors has emerged as a cornerstone of CLL treatment, offering sustained disease control and durable responses across patient subgroups. The ease of administration and favourable safety profiles of second-generation BTK inhibitors such as acalabrutinib and zanubrutinib make them compelling treatment options, particularly for patients with comorbidities or long-term therapy needs. However, continuous therapy is not without its challenges. Adverse events, the emergence of resistance mutations, and higher costs are notable considerations. Yet, ongoing research is exploring strategies to mitigate these challenges, including dose adjustments, alternative therapies for intolerant patients, and novel agents targeting resistant mutations.

Ultimately, the choice between continuous therapy and FD therapy depends on individual patient factors, highlighting the importance of shared decision-making in CLL management. With continued advancements and refinement of treatment strategies, the outlook for CLL patients continues to improve, offering hope for better outcomes and quality of life. Accordingly, a recent pooled analysis of patients treated frontline with ibrutinib within three clinical trials, showed that initiating BTK inhibitor as first-line therapy improved overall survival to rates similar to an age-matched population.

Further insight will come from the CLL17 trial, a prospective randomised open-label multicenter phase 3 trial assessing ibrutinib versus venetoclax-obinutuzumab versus ibrutinib plus venetoclax for patients with previously untreated CLL.

BTK inhibitors have transformed CLL management, offering durable responses, prolonged progression-free survival, and improved quality of life for patients. Ongoing research aims to further elucidate their optimal sequencing, combination strategies, and long-term outcomes, highlighting the continuous evolution of CLL treatment. Up to me, contraindications to BTK inhibitors are a family history of sudden death, a history of ventricular tachycardia or fibrillation, uncontrolled or severe hypertension needing at least 3 drugs and the use of warfarin.

CONFLICT OF INTEREST

AV participated in advisory boards organised by Johnson&Johnson, AstraZeneca, Beigene, Abbvie, Takeda.

FUNDING

None

ACKNOWLEDGEMENTS

None

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Posted on 1 May, 20241 May, 2024