The US Food and Drug Administration issued a warning in June 2022 that the cancer drug duvelisib (Copiktra, Verastem Inc), a PI3 kinase inhibitor, may increase the risk of death and serious side effects. Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working. However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
Management of Bruton kinase inhibitors associated cardiac toxicity: Bruton’s TKIs have become a standard of care for patients with CLL, the most commonly diagnosed form of leukemia in the developed world. Despite the proven efficacy, these treatments carry an elevated risk of cardiovascular adverse events, such as atrial fibrillation, arrhythmias, and hypertension. Although newly developed and highly selective Bruton’s TKIs are believed to carry a lower risk for cardiac events, the overall impact remains understudied. Patients aged younger than 70 years and without risk factors for cardiac events should be recommended ibrutinib or a second-generation Bruton’s TKI. For patients with existing risk factors, agents such as acalabrutinib and zanubrutinib are preferred due to the lower risk of atrial fibrillation. These agents are also preferable for patients with confirmed cardiovascular disease. Patients with ongoing atrial fibrillation can still be candidates for Bruton’s, but second-generation agents are recommended. Patients with a history of atrial fibrillation and no other risk factors are considered candidates for standard-of-care treatment similar to patients without a history of atrial fibrillation. Patients with hypertension should be treated in accordance with current guidelines with consistent clinical monitoring of blood pressure. Treatment interruption and dose reductions are appropriate for patients who experience grade 3-4 toxicities. Bruton’s TKIs are avoided in patients with a history of congestive heart failure. Treatment with BCL-2 antagonists such as venetoclax may be better suited to these patients due to their fixed duration and lower adverse event risk. However, standard-of-care treatment may be considered in patients with well-controlled heart failure under the care of a multidisciplinary medical team. Because ibrutinib is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, Bruton’s TKIs should not be prescribed to patients with a history of myocardial infarction or ventricular arrhythmias. Multidisciplinary care teams should be employed to manage emerging cardiac events during treatment and maintain a continuity of care. Patients with limited risk factors may safely continue treatment after atrial fibrillation, while patients with recurrent events during ibrutinib treatment might be candidates for acalabrutinib. Home blood pressure monitoring is recommended for patients with emergent hypertension. Treatment discontinuation is recommended for patients with emergent heart failure along with the initiation of ACE inhibitors and beta blockers. Patients suitable for a referral to cardio-oncology include those “with a history of ventricular tachycardia or arrhythmia or difficult to manage congestive heart failure.
Zanubrutinib (Brukinsa) demonstrated superior efficacy and safety over ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to results of the randomized, phase 3 ALPINE study. Progression-free survival (PFS) was significantly higher for zanubrutinib versus ibrutinib Cardiac safety was also better with zanubrutinib, the second-generation Bruton's tyrosine kinase inhibitor, compared to ibrutinib Even in patients with high-risk CLL, there was a clear benefit of zanubrutinib over ibrutinib ascopost.com/issues/may-10-2022-supplement-hematologic-oncology-almanac/zanubrutinib-superior-to-ibrutinib-for-cllsll-in-phase-iii-alpine-trial/
Acalabrutinib should not be given concomitantly with proton pump inhibitors (PPIs). The solubility of acalabrutinib decreases with increasing gastric pH, leading to reduced plasma concentrations when this agent is administered with a gastric acid-reducing agent. Although other gastric acid-reducing agents, such as H2-receptor antagonists or antacids, can be given at least 2 hours after acalabrutinib, the long-lasting effect of PPIs on gastric pH dictates that these 2 therapies not be combined.[
Hi Doctor, I have a question. Does smudge cells always indicative of CLL? Someone I know is showing smudge cells in her hematology and shows 3.2K WBC. Isn’t high WBC count usually the main factor in determining leukemia? Can smudge cell be present and go away? Any response would be greatly appreciated. Thank you!
Smudge cells can be seen in some viral disease such as cytomegalovirus infection. In this case, when acute virus infection resolves, smudge cells disappear.
The US Food and Drug Administration issued a warning in June 2022 that the cancer drug duvelisib (Copiktra, Verastem Inc), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
Management of Bruton kinase inhibitors associated cardiac toxicity:
Bruton’s TKIs have become a standard of care for patients with CLL, the most commonly diagnosed form of leukemia in the developed world. Despite the proven efficacy, these treatments carry an elevated risk of cardiovascular adverse events, such as atrial fibrillation, arrhythmias, and hypertension.
Although newly developed and highly selective Bruton’s TKIs are believed to carry a lower risk for cardiac events, the overall impact remains understudied.
Patients aged younger than 70 years and without risk factors for cardiac events should be recommended ibrutinib or a second-generation Bruton’s TKI.
For patients with existing risk factors, agents such as acalabrutinib and zanubrutinib are preferred due to the lower risk of atrial fibrillation. These agents are also preferable for patients with confirmed cardiovascular disease.
Patients with ongoing atrial fibrillation can still be candidates for Bruton’s, but second-generation agents are recommended.
Patients with a history of atrial fibrillation and no other risk factors are considered candidates for standard-of-care treatment similar to patients without a history of atrial fibrillation.
Patients with hypertension should be treated in accordance with current guidelines with consistent clinical monitoring of blood pressure. Treatment interruption and dose reductions are appropriate for patients who experience grade 3-4 toxicities.
Bruton’s TKIs are avoided in patients with a history of congestive heart failure. Treatment with BCL-2 antagonists such as venetoclax may be better suited to these patients due to their fixed duration and lower adverse event risk. However, standard-of-care treatment may be considered in patients with well-controlled heart failure under the care of a multidisciplinary medical team.
Because ibrutinib is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, Bruton’s TKIs should not be prescribed to patients with a history of myocardial infarction or ventricular arrhythmias.
Multidisciplinary care teams should be employed to manage emerging cardiac events during treatment and maintain a continuity of care.
Patients with limited risk factors may safely continue treatment after atrial fibrillation, while patients with recurrent events during ibrutinib treatment might be candidates for acalabrutinib.
Home blood pressure monitoring is recommended for patients with emergent hypertension.
Treatment discontinuation is recommended for patients with emergent heart failure along with the initiation of ACE inhibitors and beta blockers.
Patients suitable for a referral to cardio-oncology include those “with a history of ventricular tachycardia or arrhythmia or difficult to manage congestive heart failure.
Idelalisib, a PI3K inhibitor was withdrawn from FDA. The final randomized study did not meet the goal.
Zanubrutinib (Brukinsa) demonstrated superior efficacy and safety over ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to results of the randomized, phase 3 ALPINE study.
Progression-free survival (PFS) was significantly higher for zanubrutinib versus ibrutinib
Cardiac safety was also better with zanubrutinib, the second-generation Bruton's tyrosine kinase inhibitor, compared to ibrutinib
Even in patients with high-risk CLL, there was a clear benefit of zanubrutinib over ibrutinib
ascopost.com/issues/may-10-2022-supplement-hematologic-oncology-almanac/zanubrutinib-superior-to-ibrutinib-for-cllsll-in-phase-iii-alpine-trial/
Acalabrutinib should not be given concomitantly with proton pump inhibitors (PPIs). The solubility of acalabrutinib decreases with increasing gastric pH, leading to reduced plasma concentrations when this agent is administered with a gastric acid-reducing agent. Although other gastric acid-reducing agents, such as H2-receptor antagonists or antacids, can be given at least 2 hours after acalabrutinib, the long-lasting effect of PPIs on gastric pH dictates that these 2 therapies not be combined.[
But ibrutinib has no significant interaction with PPIs.
Thank you for sharing this video and hope there will be more video about CLL in korean (or even in english)
Hi Doctor, I have a question. Does smudge cells always indicative of CLL? Someone I know is showing smudge cells in her hematology and shows 3.2K WBC. Isn’t high WBC count usually the main factor in determining leukemia? Can smudge cell be present and go away? Any response would be greatly appreciated. Thank you!
Smudge cells can be seen in some viral disease such as cytomegalovirus infection.
In this case, when acute virus infection resolves, smudge cells disappear.
좋은 정보 고마슴다 .
영어하는 사람도 알아듣기 어려운데
한국인을 위한 설명이 아쉽네요.
Thank you, I will try to make it in Korean