Approved and emerging Bruton's tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: The Bruton's tyrosine kinase (BTK) pathway has proven to be an effective and transformative therapeutic target in the treatment of chronic lymphocytic leukemia (CLL), fueling the growth of BTK inhibitors (BTKis) and landmark approval of first-generation BTKi, ibrutinib. However, ibrutinib's side effect profile left an unmet need for BTKis with improved tolerability, thus spurring the subsequent development of second-generation acalabrutinib and zanubrutinib. The treatment landscape continues to evolve with studies using BTKi combination therapies, notably with venetoclax, with and without an anti-CD20 monoclonal antibody as well as third-generation BTKis aimed to overcome BTKi resistance. AREAS COVERED: This article details the current literature highlighting the efficacy, toxicities, and potential therapeutic combinations of approved and preclinical BTKis. EXPERT OPINION: BTKis have signaled the start of a new treatment paradigm in CLL and improved clinical outcomes, especially for patients with high-risk disease. However, drug resistance, low CR rates, and indefinite treatment necessitate the development of novel BTKis and fixed duration combination therapy. The results from recently completed and ongoing clinical trials are eagerly awaited with the potential promise of reduced treatment durations and financial burden while achieving durable remissions.

An Evaluation of Clinical Efficacy of Immune Checkpoint Inhibitors for Patients with Anaplastic Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid malignancy that is associated with poor prognosis. Current treatment options include surgery, radiation, cytotoxic chemotherapy, and multikinase inhibitor therapy. The role of immunotherapy in ATC is an area of active interest and recent evidence suggests that it may be a potentially effective treatment option. Methods: We report a case series of 13 patients with locally advanced or metastatic unresectable ATC who received immune checkpoint inhibitor therapy (pembrolizumab or nivolumab) at a single institution. Results: The patients' median age was 70 years, 54% (7/13) were male, and 85% (11/13) had stage IVC disease with lungs and lymph nodes being the most common sites of metastases. Ten patients had tumor tissue available for programmed death-ligand 1 (PD-L1) expression testing, all of which were positive for PD-L1, and seven of these patients also had a BRAFV600E mutation. The median progression-free survival was 1.9 months and median overall survival (OS) was 4.4 months. The objective response rate was 16% (2/13). Two patients had partial response (PR), and three patients had durable stable disease. Among patients with a clinical benefit, after a median follow-up of 13.5 months, median OS had not been reached (range 4+ to 29+ months). Responses were ongoing in four subjects. The one-year survival rate was 38% (5/13). Six patients (46%) experienced an immune-related adverse event, and 15% (2/13) experienced a grade 3 or higher adverse event, including one patient with grade 5 immune checkpoint-related thyroiditis. Conclusions: Immune checkpoint blockade was well tolerated with a toxicity profile consistent with published literature on PD-1/PD-L1-targeting therapies. For ATC patients, immune checkpoint inhibition may represent an effective treatment option with robust sustained responses seen in a subset of patients.

First-line gemcitabine plus nab-paclitaxel versus FOLFIRINOX for metastatic pancreatic cancer in a real-world population.

Aim: To compare the overall survival (OS) among patients who received first-line modified gemcitabine plus nab-paclitaxel (G/nab-P) or 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) for metastatic pancreatic cancer. Methods: A single-center, retrospective, real-world study was conducted. Results: The median OS was 9.4 months versus 7.5 months in the mFOLFIRINOX and modified G/Nab-P groups, respectively (p = 0.16). An exploratory subgroup analysis excluding patients who received one infusion and had an Eastern Cooperative Oncology Group performance score of 2 demonstrated similar OS of 11.3 months and 8.9 months, respectively. Median progression-free survival and time-to-treatment failure were not significantly different. Higher rates of adverse events were noted with mFOLFIRINOX. Conclusion: mFOLFIRINOX did not significantly prolong OS compared with modified G/nab-P and was associated with increased toxicities.

Pancreatic cancer that has spread to other parts of the body cannot be cured and patients usually have a limited time to live after diagnosis. It is therefore important to choose an effective treatment while minimizing the side effects of chemotherapy and maintaining patients' quality of life. Initial chemotherapy regimens include a combination of gemcitabine plus nab-paclitaxel (G/nab-P) or 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). While some studies have found that patients treated with FOLFIRINOX may live longer, they also experience more side effects. This single-center study showed that patients treated with modified G/nab-P and FOLFIRINOX regimens had similar survival outcomes but FOLFIRINOX was associated with increased toxicities.