The evolving treatment paradigm of Chronic Lymphocytic Leukaemia

Novel targeted therapies are transforming patient outcomes, but further research is required to address unmet clinical needs

Paolo Ghia, Professor of Medical Oncology at the Università Vita-Salute San Raffaele in Milan, Italy, outlines the changing treatment landscape of chronic lymphocytic leukaemia (CLL). His work has supported many patients worldwide and he continues to teach, research and explicate the mechanisms underpinning this haematological condition.

Prof Paolo Ghia

With his background in immunology and focus on haematological disease, Prof Ghia is well-placed at the forefront of haematological research to define and target the molecular mechanisms at play in CLL. As he describes it, ‘the biology of the disease itself needs to be fundamentally understood’, only then can viable targets for therapeutic intervention be identified.

The evolution of the treatment landscape
Early in his career, Prof Ghia treated CLL solely with chemotherapeutics. Administered in progressive cycles with mounting toxicity, the patient experience was gruelling due to the constant risk of infection. As Prof Ghia explains, the clinical goal back then was to control the lymphocyte count, rather than modify the disease trajectory.

As more potent chemotherapies came on-stream, toxicity experienced by patients began to improve. While tolerability improved, the disease trajectory remained unchanged.

The step-change came with the advance of chemo-immunotherapeutics which changed the expectations of patient cohorts, and offered new hope in terms of progression free survival (PFS) and overall survival (OS) rates.1

Era of precision medicine
In addition to the identification of novel cellular targets, the advent of genetic profiling was a game-changer for treating CLL. Identifying genetic aberrations like TP53, 17p deletion, and IGHV mutational status shed superior prognostic data, indicating to clinicians the likelihood of response to certain therapeutics.2,3

As president of the European Research Initiative on CLL (ERIC), Prof Ghia observed the acceptance of precision diagnostics becoming widespread in recent years. Using biomarker analysis to direct clinical decision-making is now common practice.

“CLL is probably a rare example of a disease where precision medicine is already ubiquitously applied. Before initiating treatment, patients are stratified based on Ig status, TP53, then age, comorbidities and patient preferences are considered before treatment is selected.”

Novel targeted therapies, designed to induce BTK inhibition have proven to be transformative for patients living with CLL
Understanding the molecular pathways of downstream B-Lymphocyte signalling has been fruitful with the Bruton Tyrosine Kinase (BTK) pathway becoming a key clinical target.

“With chemo-immunotherapeutics, patients undergo six months of treatment before seeing a change, their risk of infection is prolonged and hospitalisations occur more frequently. BTK inhibitors have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment.”4

Results from both the CAPTIVATE study and GLOW study have shown that the combination of BTK inhibitors like ibrutinib plus BCL2 inhibitor venetoclax together have delivered deep and durable responses.5,6

“Managing the expectations of patients and ensuring they understand the transience of potential adverse events is an essential component of care. I have always tried to empower patients, explaining how the drugs work and what is happening. By outlining the possibility of adverse events in advance, we can better prepare our patients for what may come.”

Five year follow-up data from the fixed-duration cohort presented at the 2023 American Society of Haematology (ASH) Annual Meeting showed fixed-duration ibrutinib plus venetoclax continues to provide deep, durable remissions with clinically meaningful PFS, OS and time off treatment in the first-line setting, including in patients with high-risk disease features like 17p deletion and TP53.6

“This was a big step forward for patients, having a fixed oral means they can continue their life with good responses that last well. Approximately 80 per cent of those patients don’t require treatment for another four or five years – while it’s not curative, giving patients another five years off therapy is an excellent outcome.”6

Hope for the future
Looking to the future of CLL treatment, there is cause for optimism.

With greater tolerability, more oral treatments, and more predictable and manageable adverse events, out-patient care is likely to play a greater role for haematology patients, making a real difference in the lives of patients and hospital staff.

“Ten years ago, I went to my hospital’s CEO and expressed that I did not want more beds for my unit because I believed that the future of treatment for CLL would involve out-patient chair therapy instead of hospitalisation.”

However, lack of access to novel therapies continues to prevent many clinicians from delivering optimal care. “It is pitiful that due to limited access, even in Europe, doctors are unable to use better-tolerated and more effective treatments.”

Despite new therapies and improving outcomes for many patients, there are still some who do not respond well to existing treatments or experience relapse after initial remission. Double refractory CLL remains particularly challenging to treat and represents significant unmet clinical needs.

“The story of CLL is not yet over. By continuing to invest in research, we can gain a better understanding of the underlying mechanisms of CLL and develop more effective and targeted therapies to improve outcomes for all patients. This requires collaboration between researchers, clinicians, and patients to ensure that new discoveries are translated into meaningful improvements in patient care.”

References available upon request.

DOP: May 2024

This is an adertgorial feature on behalf of Janssen Ireland.

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