The use of Bruton\'s tyrosine kinase inhibitors (BTKi) is rapidly increasing for patients with mantle cell lymphoma (MCL). Side effects reported so far are usually manageable. However, here we present two cases of life-threatening aplastic anemia (AA) upon treatment with the BTKi acalabrutinib for MCL. The first patient died of neutropenic infection secondary to AA. The second patient was successfully treated with immunosuppressive treatment but the MCL relapsed shortly thereafter. AA is a potentially fatal complication that should be considered when patients present with pancytopenia during treatment with BTKi.

UNASSIGNED: Mantle cell lymphoma (MCL) is an uncommon non-Hodgkin lymphoma that is generally considered incurable. Covalent BTK inhibitors (cBTKi) are the cornerstone of treatment for relapsed or refractory (R/R) MCL, but treatment options are limited and prognosis is poor after cBTKi failure. Pirtobrutinib is a non-covalent BTK inhibitor that has demonstrated excellent efficacy and safety and represents an important new treatment in the evolving treatment landscape of R/R MCL.
UNASSIGNED: This review will provide an overview of the therapeutic landscape of R/R MCL, characteristics of pirtobrutinib, and efficacy and safety data of pirtobrutinib in R/R MCL from pivotal clinical trials. PubMed and major hematology conference proceedings were searched to identify relevant studies involving pirtobrutinib.
UNASSIGNED: For patients with R/R MCL that has progressed after treatment with cBTKi, pirtobrutinib is an important and efficacious treatment that confers favorable outcomes. In the post-cBTKi setting, when chimeric antigen receptor (CAR) T-cell therapy is not available or feasible, pirtobrutinib is the preferred treatment for R/R MCL. How to sequence or combine pirtobrutinib with CAR T-cell therapy and other available or emerging therapies requires further investigation. Future studies should also explore the role of pirtobrutinib in earlier lines of therapy for MCL.

Aim ASPEN is a randomized, open-label, Phase III study comparing zanubrutinib and ibrutinib in patients with Waldenström macroglobulinemia (WM). Materials & methods: Patient-reported outcomes were exploratory end points assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS scores. Results: Overall, 201 patients (102 zanubrutinib; 99 ibrutinib) were enrolled. Clinically meaningful differences were observed in diarrhea and nausea/vomiting in both the intent-to-treat population and in patients attaining very good partial response (VGPR) in earlier cycles of treatment, as well as in long-term physical functioning and fatigue in patients achieving VGPR. Conclusion: Treatment with zanubrutinib was associated with greater improvements in health-related quality of life compared with ibrutinib in patients with WM and MYD88 mutations.Clinical Trial Registration: NCT03053440 (ClinicalTrials.gov).
Patient quality of life is importantWhat is this article about? This article talks about a study called the ASPEN trial, which compares two medicines used for treating a rare blood cancer that doctors call Waldenström macroglobulinemia. The medicines are called zanubrutinib (ZAN) and ibrutinib (IBR). They work in the same way, by blocking a protein called Bruton tyrosine kinase. When patients take medicines for an illness, it is important to learn about their physical, social, emotional and mental well-being (quality of life). In this study, we asked patients to fill out questionnaires about their well-being before starting the study treatment for their blood cancer, and again a few times while taking the medication, to see if there were any changes.What were the results of the study? There were two groups of patients. One group took ZAN and the other took IBR. The patients could not choose which medicine they were going to take. Results from both groups of patients were compared. Patients taking ZAN did not feel worse or better about their diarrhea and sickness, but those taking IBR said these symptoms had become worse. Both medicines improved how patients were feeling. However, improvement in tiredness and physical ability was larger in patients taking ZAN than those on IBR, especially for the patients whose cancer was getting better.What do the results mean? For patients with a rare blood cancer in this study, those taking ZAN had a better quality of life than those taking IBR.

We conducted this first systematic review and meta-analysis to assess the competitive advantage of 2nd-generation Bruton tyrosine kinase inhibitors (BTKi) compared to 1st-generation BTKi in chronic lymphocytic leukemia (CLL). The literature search was conducted from PubMed, Web of Science, Embase databases, and hematology annual conferences. Data of over response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted to a pool meta-analysis of efficacy; adverse events (AEs) were also extracted to a pool meta-analysis of safety. Bias risk assessment and meta-analysis were performed by Review Manager 5.3 and STATA 14 software. A total of 3649 patients from 29 cohorts were included. The results showed that the benefits of ORR and 24-month PFS in 2nd-generation BTKi compared to 1st-generation BTKi were not significant in the whole population but only in the relapsed or refractory (R/R) CLL patient subgroup (ORR: 86.4% vs. 76.2%, p = 0.013; 24-month PFS: 76.9% vs. 67.9%, p = 0.004). Any-grade AEs were comparable between 1st- and 2nd-generation BTKi, but grade 3 or higher AEs were significantly less frequent with 2nd-generation BTKi versus 1st-generation BTKi (grade 3 or higher: 53.1% vs. 72.5%; p = 0.002). Headache was more frequent with 2nd-generation BTKi, while diarrhea and atrial fibrillation were more frequent with 1st-generation BTKi. Only for patients with relapsed or refractory CLL did 2nd-generation BTKi have a competitive advantage, while adverse effects still need to be considered. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, Identifier 42022342488.

This real-world retrospective cohort study using Australian Pharmaceutical Benefits Scheme (PBS) 10% investigated changes in chronic lymphocytic leukemia (CLL) treatment by line of therapy, time-to-next-treatment, treatment duration, and overall survival (OS). Overall, 803 patients received their first PBS-reimbursed CLL medication between 1 January 2011 to 31 July 2021 (median age: 70 years; 64.6% male), 289 post-1 August 2020. In 2011, most first-line (1 L) prescribing was fludarabine, cyclophosphamide, and rituximab (FCR). By 2021, common 1L were chlorambucil ± CD20 (26.1%), Bruton Tyrosine Kinase inhibitor (BTKi) (26.1%), and CD20 monotherapy (23.9%). In 2011, relapsed/refractory (R/R) CLL treatment was CD20 monotherapy or FCR. By 2021, BTKi (57.7%) and venetoclax ± CD20 (26.1%) were most common. Compared to FCR, 1 L treatment duration (Hazard Ratio) was shorter for CD20 monotherapy (1.7) or chlorambucil ± CD20 (2.5). In R/R CLL, median duration was 24 (ibrutinib) and 19 months (venetoclax). Median OS was 127 months. CLLtreatment pattern shave greatly changed in Australia since the introduction of novel therapies.

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

BACKGROUND: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment.
METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs).
RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy.
CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

The advent of Bruton tyrosine kinase inhibitor (BTKi) therapy with ibrutinib introduced a highly effective targeted therapy in the management of chronic lymphocytic leukemia (CLL). However, due to the adverse effect profile some patients cannot tolerate this novel therapy. Newer, more potent and targeted BTK inhibitors such as acalabrutinib have been developed. Acalabrutinib is an irreversible and second generation BTKi that covalently inhibits BTK with greater selectivity than ibrutinib. As novel BTKis are developed, a greater understanding of their efficacy and adverse effect rates can assist clinicians and patients in the shared clinical decision-making process. A search was conducted using the PICOS model and PRISMA guidelines. PubMeb, Embase, and Cochrane Library databases were searched using the keywords: Acalabrutinib, Acalabrutinib Monotherapy, Tyrosine Kinase Inhibitor, and Relapsed/Refractory (R/R) CLL. After initial literature review 12 studies were chosen for evaluation in this meta-analysis. Meta-analysis and follow up meta-regression models were completed. The results were as follows: ORR 82% (95% CI 74%-90%, I2 = 84.14%, p < 0.01), CR 4% (95% CI 2%-6%, I2 = 0.00%, p = 0.99), mortality rate 12% (95% CI 6%-19%, I2 = 87.23%, p < 0.01), mortality rate due to adverse effect 7% (95% CI 3%-10%, I2 = 67.67%, p = 0.01), mortality due to pneumonia 2% (95% CI 1%-3%, I2 = 0.00%, p = 0.43), mortality due to CLL progression 4% (95% CI 2%-6%, I2 = 61.03%, p = 0.04), neutropenia (≥ grade 3) 18% (95% CI 15%-20%, I2 = 0.00%, p = 0.70), thrombocytopenia (≥ grade 3) 7% (95% CI 4%-11%, I2 = 54%, p = 0.09), anemia (≥ grade 3) 9% (95% CI 6%-12%, I2 = 36.93%, p = 0.18), pneumonia (≥ grade 3) 10% (95% CI 6%-14%, I2 = 66.37%, p = 0.02) and atrial fibrillation 7% (95% CI 3%-11%, I2 = 80.13%, p = 0.00). The results demonstrate that acalabrutinib shows efficacy in the treatment of R/R CLL with tolerable adverse reaction rates.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was the overall response rate at Week 12 according to the Castleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be considered with caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD.
OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin.
METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed.
RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient\'s positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%).
CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.