Frontline treatment of Chronic Lymphocytic Leukemia (CLL/SLL) in 2021

[CLLerinOz]

JCO Oncology Practice has recently published two important papers: a clinical review article by Elizabeth A Brem MD and Susan O'Brien MD and a commentary by Nitin Jain MD which outline the current frontline therapies for CLL.

Nitin Jain's excellent summary, titled 'Evolving Treatment Paradigm in Frontline CLL', reminds us that:

'The field of CLL has changed remarkably in the last few years with increasing utilization of targeted therapies and a substantial decrease in the use of chemoimmunotherapy. Until recently, chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab (FCR), bendamustine and rituximab, and chlorambucil and obinutuzumab were considered standard first-line therapy for patients with CLL. With the introduction of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib and B-cell lymphoma 2 inhibitor venetoclax, the treatment paradigm for CLL has changed dramatically.'

Regarding FCR, he says:

'The role of chemoimmunotherapy is restricted to young patients (typically age < 65 years) with CLL without significant comorbidities who have mutated immunoglobulin heavy chain and no del(17p)/TP53 mutation; this constitutes only about 10% of all patients with CLL requiring first-line therapy. For this patient population, the treatment with FCR regimen can lead to long-term disease-free survival in about 50%-55% of the patients.'

Regarding the start of treatment, he writes:

'It is important to emphasize that the treatment indications as per iwCLL 2018 criteria must be met before therapy is initiated for patients with CLL, even among patients with high-risk genomics such as those with del(17p) or TP53 mutation. When the patient meets treatment criteria, the treatment selection should be based on age, comorbidities, renal function, genomics of CLL, and patient preference.'

The summary article concludes:

'With the currently available therapeutic armamentarium and with the additional therapies in clinical trials such as novel noncovalent BTK inhibitors and cellular therapies, the therapy options will continue to evolve with time and hopefully, the majority of patients with CLL will be able to have a normal life expectancy in the future.'

The review article, 'Frontline Management of CLL in 2021', covers the following topics:

Incorporating Targeting Agents into Initial Therapy for CLL - BTKis, BCL2 Inhibition, Combining BTK and BCL2 Inhibitors

What Order Should These Drugs be Used In?

Special Considerations - CLL With TP53 Mutation or 17p Deletion, COVID-19

Summary:

'As detailed, we now have many effective, well-tolerated agents for the treatment of CLL. Questions still remain as to the optimal combination of agents, the sequencing of agents, and the duration of therapy. Using time-defined courses of therapy is possible, but whether the duration should be dictated by time or the achievement of MRD undetectability in either the peripheral blood or bone marrow remains an open question. It is possible that even if indefinite BTKi therapy is chosen, that MRD data will evolve and support at least a subset of patients stopping therapy at some point.

For most patients, a novel therapy is preferable in the frontline setting compared with chemoimmunotherapy. Given high response rates with ibrutinib, acalabrutinib, and venetoclax, there is no one clearly superior strategy or one-size-fits-all approach. The decision between BTKi- and venetoclax-based therapy will depend on the experience of the provider and the preferences and comorbidities of the patient. The next few years are anticipated to bring not only new drugs but also additional data on combinations and sequences of drugs as well as the potential for MRD testing to inform duration of therapy for individual patients.'

ascopubs.org/doi/full/10.12...

ascopubs.org/doi/abs/10.120...

(my emphasis)

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