Search

•The CLL-IPI retains prognostic value for PFS, but its impact appears diminished in predicting survival with targeted drugs.•Improved survival with targeted therapies vs chemoimmunotherapy underscores the need to reevaluate prognostic tools amid treatment shifts.

Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine.

The coronavirus infectious disease (COVID-19) shows a remarkable symptomatic heterogeneity. Several risk factors including advanced age, previous illnesses, and a compromised immune system contribute to an unfavorable outcome. In patients with hematologic malignancy, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly reduced explaining why the mortality rate of hematologic patients hospitalized for a SARS-CoV-2 infection is about 34%. Active immunization is an essential pillar to prevent SARS-CoV-2 infections in patients with hematologic malignancy. However, the immune response to SARS-CoV-2 vaccines may be significantly impaired, as only half of patients with hematologic malignancy develop a measurable antiviral antibody response. The subtype of hematologic malignancy and B cell–depleting treatment predict a poor immune response to vaccination. Recently, antiviral drugs and monoclonal antibodies for pre-exposure or postexposure prophylaxis and for early treatment of COVID-19 have become available. These therapies should be offered to patients at high risk for severe COVID-19 and vaccine nonresponders. Importantly, as the virus evolves, some therapies may lose their clinical efficacy against new variants. Therefore, the ongoing pandemic will remain a major challenge for patients with hematologic malignancy and their caregivers who need to constantly monitor the scientific progress in this area.

Observation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. At a median follow-up of 31 months, the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs 47.8 months; hazard ratio = 0.25; 95% confidence interval = 0.14-0.43, P < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs were atrial fibrillation, pneumonia, and rash in the ibrutinib group, and basal cell carcinoma, pneumonia, and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug–drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of “watch and wait.” This trial was registered at www.clinicaltrials.gov as #NCT02863718.

Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<10−4 by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141.

Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<10−4by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.govas #NCT02345863, #NCT02401503, and #NCT02689141.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

•Time-limited acalabrutinib, venetoclax, and obinutuzumab induced deep and ongoing remission in patients with relapsed/refractory CLL.•The addition of ctDNA-based analyses to conventional FCM appears to improve early detection of molecular and clinical relapses.

The coronavirus infectious disease (COVID-19) shows a remarkable symptomatic heterogeneity. Several risk factors including advanced age, previous illnesses and a compromised immune system contribute to an unfavorable outcome. In patients with hematologic malignancy, the immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is significantly reduced explaining why the mortality rate of hematologic patients hospitalized for a SARS-CoV-2 infection is about 34%.

Introduction:Targeted agents, in particular BCL2-inhibitors (BCL2i) and BTK-inhibitors (BTKi), have profoundly improved the outcome of patients (pts) with chronic lymphocytic leukemia (CLL) and are considered standard treatment. However, the transition from treatments evaluated within clinical trials into routine clinical practice can be complex. We here present real-world data from the German CLL Study Group (GCLLSG) registry and report outcomes and treatment sequences of pts treated with either BCL2i (venetoclax) or BTKi (acalabrutinib, ibrutinib, spebrutinib, tirabrutinib, or zanubrutinib) as first administered targeted agent.

INTRODUCTION:IGLV3-21 R110is a point mutation that can confer the ability for autonomous signaling to B cell receptors (BCR) using light chains encoded by the allele IGLV3-21 ∗ 01or IGLV3-21 ∗ 04. Chronic lymphocytic leukemia (CLL) patients with IGLV3-21 R110have a shorter time to first treatment and shorter overall survival, independent of their IGHV mutational status. However, outcomes of CLL patients using IGLV3-21 R110have not been evaluated in clinical trials of BTK inhibitors.

Background and Significance:PRT2527 is an investigational, potent, and highly selective cyclin-dependent kinase 9 inhibitor that is being developed for select relapsed or refractory (R/R) hematologic malignancies. CDK9, a key regulator of transcription elongation, has been studied as a potential target for therapy in transcriptionally addicted cancers that are dependent on oncogenic drivers with short half-lives. Although most of these drivers do not respond to direct inhibition, studies suggest that a subset of drivers, eg MYC, MYB, and MCL-1, may be targeted indirectly via CDK9 inhibition. Several nonselective CDK9 inhibitors have shown clinical activity in multiple tumor types, however, tolerability was poor (Mandal, et al. Cancers (Basel). 2021). PRT2527 has demonstrated high specificity and promising antitumor activity in preclinical studies, and a favorable tolerability profile in preliminary data from a Phase 1 study (NCT05159518) in adults with advanced solid tumors. These support further development of PRT2527 in hematologic malignancies as monotherapy and in combination with targeted agents. Combination of CDK9 inhibition and Bruton tyrosine kinase (BTK) inhibition may drive a durable response by enhancing apoptotic priming and shifting dependency toward CDK9 targets MCL1 and BFL1. Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible BTK inhibitor that upregulates the proapoptotic signaling molecule BCL2 modifying factor, an endogenous inhibitor of BCL2, BCLXL, and BCLW (Kong, et al. ChemMedChem. 2018). PRT2527 as monotherapy or in combination with zanubrutinib may be an effective treatment option for select R/R hematologic malignancies.

Background