“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.
The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.
The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.
Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.
However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
Frontline therapy
In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.
Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.
That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.
For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.
Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.
For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.
And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.