Blood Neoplasia最新文献

Abstract

The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)–driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and overall survival rates for both treatment-naïve patients and those with relapsed/refractory CLL. Notably, a substantial proportion of patients achieved undetectable MRD. Clinical trial updates following the initial published results have shown consistency and durability of responses over time. In this review, the initial investigator-initiated trial results for ibrutinib and venetoclax are discussed, several multicenter clinical trial designs and outcomes are examined, variables such as chromosome 17p deletion that influence treatment responses are addressed, and the safety of the regimen is discussed. In addition, we reviewed the usage of this combination in other B-cell malignancies and discussed how current knowledge can be used for shaping the future CLL treatment regimens.

Abstract

The enhanced utilization of native L-asparaginase (L-Asp) aims to improve treatment outcomes for adult patients with non-Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL). In this measurable residual disease 2014 (MRD2014) study, we modified our protocol to include an augmented dose of native L-Asp. Compared with former MRD2008, the total dose of L-Asp was raised from 36 000 U/m² to 232 000 U/m² in patients aged 16 to 35 and from 36 000 U/m² to 132 000 U/m² in patients aged 36 to 65 years. Adult patients with ALL were enrolled between January 2014 and December 2019 based on the following eligibility criteria: non-L3 ALL, age 16 to 65 years, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate liver and kidney functions (serum bilirubin ≤ 2.0 mg/dL; serum creatinine ≤ 2.0 mg/dL). The median follow-up time was 1128 days (range, 35-2400). A total of 81 patients with non-Ph ALL (40 males and 41 females; median age, 39 years [range, 16-64]) in whom MRD status was assessed were included. Complete remission was achieved in 72 patients (89%). The probability of 3-year event-free survival (EFS) and overall survival (OS) in these patients were 55% and 72%, respectively. The outcomes for patients aged 16 to 35 years demonstrated remarkable improvement. The 3-year EFS of MRD2008 at 45% significantly increased to 71% for MRD2014. Our study unequivocally demonstrated the beneficial effects of augmented use of L-Asp in this adolescent and young adult population. This trial was registered at UMIN Clinical Trials Registry as #UMIN000012382.

Abstract

Abstract

Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, is a standard-of-care first-line (1L) treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Dosing flexibility (adjustment to daily dose of <420 mg/d) with ibrutinib can help prevent recurrence or worsening of adverse events while maintaining long-term efficacy. This study compared time to next treatment among patients with CLL/SLL in the United States initiating 1L single-agent ibrutinib at 420 mg/d (index date) and staying on this dose vs patients with dose adjustment (DA) within 3 to 12 months. Two databases were used: Komodo claims (a majority from community practices) and Acentrus electronic medical records (from academic and nonteaching hospital systems). To account for immortal time bias (patients with DA survived on 1L therapy until DA) and overlap between follow-up time and definition of treatment strategies, a target trial emulation approach was used, in which patients were cloned at index date and contributed follow-up to both treatment strategy arms until deviation from the strategy. Among 3343 patients in Komodo (mean age: 67.5 years; 37.6% female) and 1171 patients in Acentrus (mean age: 70.4 years; 34.6% female) who initiated 1L single-agent ibrutinib 420 mg/d, 18.0% and 19.6%, respectively, had a DA. DA was not associated with an increased risk of having a next treatment in both databases (adjusted hazard ratio [95% confidence interval]: Komodo: 0.95 [0.80-1.14], Acentrus: 1.14 [0.80-1.62]). These findings suggest that a flexible dosing approach with ibrutinib may be effective in allowing patients to achieve optimal outcomes while remaining on long-term continuous 1L treatment.