In the CLL14 study, patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions were randomized to 12 cycles of venetoclax-obinutuzumab (Ven-Obi, n = 216) or chlorambucil-obinutuzumab (Clb-Obi, n = 216). Progression-free survival (PFS) was the primary end point. Key secondary end points included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS), and rates of adverse events. Patient reported outcomes of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared with Clb-Obi (median, 76.2 vs 36.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.52; P < .0001). Likewise, TTNT was longer after Ven-Obi (6-year TTNT, 65.2% vs 37.1%; HR, 0.44; 95% CI, 0.33-0.58; P < .0001). In the Ven-Obi arm, presence of del(17p), unmutated immunoglobulin heavy-chain variable region, and lymph node size of ≥5 cm were independent prognostic factors for shorter PFS. The 6-year OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR, 0.69; 95% CI, 0.48-1.01; P = .052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi than in the Clb-Obi arm (median, 82.1 vs 65.1 months; HR, 0.70; 95% CI, 0.51-0.97). Follow-up-adjusted second primary malignancies incidence rates were 2.3 and 1.4 per 1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL. This trial was registered at www.ClinicalTrials.gov as #NCT02242942.

Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, whereas the remaining patients displayed monoallelic mutations. TP53-multihit alterations were predictive of an increased risk of leukemic transformation. The impact of monoallelic alterations was dependent on the variant allele frequency (VAF); patients with TP53-monoallelic mutations and VAF <20% exhibited behavior similar to TP53 wild type, and those with TP53-monoallelic mutations and VAF ≥20% presented outcomes equivalent to TP53-multihit patients. This study underscores the importance of considering TP53 allelic state and VAF in the risk stratification and treatment decision-making process for patients with MDS-del(5q).

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that is clinically characterized by its heterogeneous behavior, with courses ranging from indolent to highly aggressive cases with limited prognosis. Targeted treatment alternatives in first-line and relapse settings are more and more shaping the therapeutic landscape of MCL. The development and implementation of new targeted and immunotherapeutic approaches have already improved outcomes for patients with MCL with refractory or relapsed disease. However, long-term prognosis is still limited, and patients with relapsed/refractory (R/R) disease, especially those failing Bruton tyrosine kinase (BTK) inhibitor treatment, usually have a dismal outcome. This review summarizes the current and emerging treatment options for R/R MCL, focusing on the implementation of combined targeted treatment strategies such as BTK inhibitors and BCL2 inhibitors, as well as immune-therapeutic approaches including chimeric antigen receptor T cells and bispecific antibodies.