BTK inhibitors function as highly potent antiplatelet agents, an 'on-target' effect. Many surgeons are unaware, leading to significant post-operative bleeding if the drug isn't stopped. Patients must be educated to inform their surgical teams and advocate for themselves.
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The failure of an adjuvant trial for the TKI pazopanib was likely caused by a protocol change that reduced the dose to manage transaminitis. While well-intentioned to improve tolerability and adherence, the lower dose was sub-therapeutic. This serves as a critical lesson that managing side effects by compromising dose can nullify a drug's potential efficacy.
While pirtobrutinib works after covalent BTK inhibitors, no data shows covalent inhibitors work after pirtobrutinib failure. This uncertainty about future options makes clinicians cautious about using it as an initial therapy, especially for younger CLL patients who will need multiple treatments over their lifetime.
Non-covalent BTK inhibitors like pirtobrutinib are currently approved for use after covalent BTK inhibitors fail. Moving them to the frontline setting, as studied in BRUIN-313, disrupts the established treatment pathway and creates uncertainty for managing relapsed disease, as the standard 'next step' is removed.
BTK degraders work despite most kinase inhibitor resistance mutations. However, resistance to degraders themselves alters the BTK binding pocket so significantly that subsequent targeting with any BTK kinase inhibitor is unlikely to be effective, positioning them as a potential end-of-line therapy.
Although continuous BTK inhibitors have the most prospective data for high-risk CLL (17p/TP53 mutations), some highly motivated patients still opt for fixed-duration treatment. This requires a detailed conversation where clinicians must explain the trade-off: achieving a treatment-free period may come at the cost of needing second-line therapy sooner.
Pirtobrutinib is the first BTK inhibitor to show a rate of atrial fibrillation equivalent to a chemoimmunotherapy control arm in a randomized trial. This uniquely safe cardiovascular profile makes it a strong first-line candidate for older Chronic Lymphocytic Leukemia (CLL) patients or those with significant heart-related comorbidities.
While pirtobrutinib is effective after covalent BTK inhibitors, the reverse is unproven. Starting with pirtobrutinib frontline raises a critical unanswered question about whether patients will still respond to older covalent inhibitors, complicating sequencing decisions, especially for younger patients.
While atrial fibrillation is a well-known risk of BTK inhibitors, the more devastating and less-discussed risk is sudden death from ventricular arrhythmias. This is an 'on-target' class effect, making AFib just the 'tip of the iceberg' of cardiovascular toxicity.
Recent non-inferiority trials affirm that fixed-duration combination therapies are viable alternatives to continuous BTK inhibitors. However, clinicians must look beyond the headline conclusion, as numerical data can show slightly worse progression-free survival for high-risk subgroups within the acceptable non-inferiority margin, complicating treatment decisions.
Clinicians are hesitant to use newer, potentially safer non-covalent BTK inhibitors before established covalent inhibitors. While it's known that non-covalents work after covalents fail, the reverse is unproven, creating a one-way treatment path that reserves these newer agents for later lines of therapy.