Despite subsequent data not confirming an increased bleeding risk compared to other therapies, the initial studies on pacritinib showed a signal for increased bleeding. Consequently, it is still advised that the drug be stopped for several days prior to any major surgical procedure as a safety precaution.
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Due to fedratinib's significant GI side effect profile and the logistical difficulty of measuring thiamine levels, clinicians should proactively provide patients with thiamine supplements, anti-emetics, and anti-diarrheal therapies. Instructing patients to take the drug with food can also help mitigate GI toxicity.
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.
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.
Clinicians can reassure myelofibrosis patients that the drop in hemoglobin often seen when starting ruxolitinib does not carry the same negative prognostic weight as anemia caused by the disease itself. This distinction is crucial for managing patient expectations and continuing effective therapy despite initial side effects.
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.
To combat the significant myelosuppression from the standard 28-day venetoclax cycle in AML, many clinicians are adopting a strategy of performing a bone marrow biopsy around day 21 and pausing the drug if blast clearance is achieved to allow for hematologic recovery.
The development of new KIT inhibitors like bezuclastinib is largely fueled by the need for alternatives to high-dose avapritinib in advanced SM. Concerns about cognitive effects and rare intracranial hemorrhage with avapritinib create an opportunity for agents with less blood-brain barrier penetration.
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.
Recurrent non-melanoma skin cancers in patients on ruxolitinib may be attributable to its JAK1 inhibition. In such cases, a viable strategy is to switch the patient to a more JAK2-selective inhibitor, such as pacritinib or fedratinib, to potentially mitigate this specific side effect while maintaining disease control.
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.
