Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up. METHODS: GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18-64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib-venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil-obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2-6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77). FINDINGS: Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib-venetoclax (n=106) or chlorambucil-obinutuzumab (n=105). At a median of 46 months (IQR 43-47) of follow-up, progression-free survival remained superior for the ibrutinib-venetoclax group (hazard ratio 0·214 [95% CI 0·138-0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0-82·0) for ibrutinib-venetoclax and 24·8% (16·5-34·1) for chlorambucil-obinutuzumab. Following the primary analysis, one patient in the chlorambucil-obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib-venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil-obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib-venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil-obinutuzumab group (of which 10 were due to post-treatment infections). INTERPRETATION: After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option. FUNDING: Janssen Research & Development and Pharmacyclics.

Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study.

PURPOSE: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS: Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS: Ibrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION: Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.

Treatment Outcomes and Roles of Transplantation and Maintenance Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma: Results From Large Real-World Cohorts.

PURPOSE: Commonly used first-line (1L) treatments for mantle cell lymphoma include high-dose cytarabine-based induction followed by autologous stem-cell transplant (ASCT) for younger patients and several chemoimmunotherapy regimens for older patients. Continuous debates exist on the role of ASCT in younger patients and maintenance rituximab (MR) after bendamustine plus rituximab (BR). METHODS: Retrospective data from 4,216 patients with mantle cell lymphoma in the Flatiron Health electronic record-derived deidentified database diagnosed between 2011 and 2021, mostly in US community oncology settings, were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and MR were validated in an independent cohort of 1,168 patients from 12 academic centers. RESULTS: Among 3,614 patients with documented 1L treatment, BR was the most used. Among 1,265 patients age < 65 years, 30.5% received cytarabine-based induction and 23.5% received ASCT. There was no significant association between ASCT and real-world time to next treatment (hazard ratio [HR], 0.84; 95% CI, 0.68 to 1.03; P = .10) or overall survival (HR, 0.86; 95% CI, 0.63 to 1.18; P = .4) among ASCT-eligible patients. Among MR-eligible patients, MR after BR versus BR alone was associated with a longer real-world time to next treatment (HR, 1.96; 95% CI, 1.61 to 2.38; P < .001) and overall survival (HR, 1.51; 95% CI, 1.19 to 1.92; P < .001). The efficacy findings were consistent in the validation cohort. CONCLUSION: In this large cohort of patients treated primarily in the US community setting, only one in four young patients received cytarabine or ASCT consolidation, suggesting the need to develop treatments that can be delivered effectively in routine clinical practice. Together with the validation cohort, data support future clinical trials exploring regimens without ASCT consolidation in young patients, whereas MR should be considered for patients after 1L BR and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Systematic Literature Review of Economic Evaluations, Costs/Resource Use, and Quality of Life in Patients with Mantle Cell Lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma. While treatment of patients with MCL and their outcomes are previously published, the availability of heath economics evidence is unclear. OBJECTIVE: The aim of this paper was to conduct a comprehensive review of studies relating to economic evaluations, costs and resource use, and health-related quality of life (HRQoL) in patients with MCL. METHODS: Search strategies were designed to capture studies reporting economic or HRQoL outcomes published in the previous 11 years (2007-2018). The following electronic databases were searched: MEDLINE, Embase, NHS Economic Evaluation Database (NHS EED), and EconLit. In addition, we reviewed congress abstracts presented over the previous 2 years (2015 and 2016; where 2017 proceedings had occurred, these were searched instead of 2015). Publications were screened in duplicate by two reviewers and supplementary searches were carried out on health technology assessment websites. Searches were first conducted in October 2017 and updated in March 2018. FINDINGS: The systematic literature review identified 11 economic evaluations (in 16 publications), seven studies reporting data relating to costs or resource use, and five relating to HRQoL. Four economic evaluations presented results for patients with MCL modelled in the first-line setting, while seven modelled patients in the relapsed/refractory setting. The majority of economic evaluations were conducted using a Markov model with three to five health states. Seven studies assessed resource use and reported adverse events as key drivers of increased costs and resource use. Across the five studies reporting HRQoL, disparate measures were used. Two studies reported improvement in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) total scores following treatment and found that clinical response to treatment was associated with improvement in overall HRQoL. CONCLUSIONS AND RELEVANCE: The published economic and HRQoL evidence in MCL, although scarce, reveals that the economic and HRQoL burden associated with MCL is substantial. In highlighting this evidence, this analysis underlines a critical unmet need for more effective treatments with improved outcomes in MCL.

The 5-year follow-up of a real-world observational study of patients in the United Kingdom and Ireland receiving ibrutinib for relapsed/refractory mantle cell lymphoma.

This is a 5-year real-world study of 65 patients treated with ibrutinib for relapsed/refractory mantle cell lymphoma across the UK and Ireland. Ibrutinib was well tolerated with no fatal adverse events. The median progression-free survival and overall survival (OS) was 12 and 18·5 months, respectively. Overall, 80% of patients discontinued treatment, predominantly for progressive disease. On discontinuation, 20% received alternative immunochemotherapy with a median OS of 24 months. Ibrutinib was used as a bridge to transplant in 8% (median OS not reached). These observations are comparable with trial outcomes with encouraging responses to immunochemotherapy at relapse.

Clinical efficacy and safety of first-line treatments in patients with mantle cell lymphoma: A systematic literature review.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin's lymphoma (NHL) with a median overall survival (OS) of approximately 3-5 years. Systematic literature reviews (SLRs) identified efficacy and safety data for first-line therapies, reported in randomised controlled trials (RCTs) and non-randomised interventional studies (NRISs). Nine and 20 independent studies were included in the RCT and NRISs SLRs, respectively. Differences in the regimens and patient outcomes varied according to patient age and suitability for autologous stem cell transplantation (ASCT). In elderly patients ineligible for transplant, OS ranged from 40 months to 69.6 months. In young transplant-eligible patients, OS ranged from 53 months to 152.4 months. Despite the paucity of directly comparable evidence on the efficacy and safety of MCL therapies, these SLRs highlight that MCL remains a difficult NHL subtype to treat, with short survival highlighting the unmet need for newer treatments that improve patient outcomes.

Real-world analysis of treatment patterns and clinical outcomes in patients with newly diagnosed chronic lymphocytic leukemia from seven Latin American countries.

OBJECTIVE: To describe chronic lymphocytic leukemia (CLL) treatment patterns and patient outcomes in Latin America. METHODS: This chart review study (NCT02559583; 2008-2015)evaluated time to progression (TTP) and overall survival (OS) outcomes among patients with CLL who initiate done (n = 261) to two (n = 96) lines of therapy (LOT) since diagnosis. Differences in TTP and OS were assessed by Kaplan-Meier analysis, with a log-rank test for statistical significance. Association between therapeutic regimen and risk for disease progression or death was estimated using Cox proportional hazard regression. RESULTS: The most commonly prescribed therapies in both LOTs were chlorambucil-, followed by fludarabine- and cyclophosphamide (C)/CHOP-based therapies. Chlorambucil- and C/CHOP-based therapies were largely prescribed to elderly patients (≥65 years) while fludarabine-based therapy was predominantly used by younger patients (≤65 years). In LOT1, relative to chlorambucil-administered patients, those prescribed fludarabine-based therapies had lower risk of disease progression (hazard ratio [HR] and 95% confidence interval [CI] 0.32 [0.19-0.54]), whereas C/CHOP-prescribed patients had higher risk (HR 95%CI 1.88 [1.17-3.04]). Similar results were observed in LOT2. There was no difference in OS between treatments in both LOTs. DISCUSSION: Novel therapies such as kinase inhibitors were rarely prescribed in LOT1 or LOT2in Latin America. The greater TTP observed forfludarabine-based therapies could be attributed to the fact that fludarabine-based therapies are predominantly administered to young and healthy patients. CONCLUSION: Chlorambucil-based therapy, which has limited benefits, is frequently prescribed in Latin America. Prescribing novel agents for fludarabine-based therapy-ineligible patients with CLL is the need of the hour. Trial registration: ClinicalTrials.gov identifier: NCT02559583.

Systematic literature review of the global burden of illness of mantle cell lymphoma.

Background: Mantle cell lymphoma (MCL), a rare and aggressive disease, accounts for approximately 5% of all B-cell non-Hodgkin's lymphomas. Evidence on the burden of this disease, for patients and healthcare providers, is scarce.Methods: Four systematic literature reviews were developed to identify epidemiological, real-world clinical, economic and humanistic burden data on patients with MCL. Electronic databases searched included MEDLINE and Embase, NHS EED and Econlit.Results: Eight epidemiological studies, 19 clinical burden, 2 economic impact and 0 quality of life studies were identified. The range of standardized MCL incidence rates was 0.1-1.27/100,000. Overall survival rates of patients at 3 years differed by age at diagnosis (≤65 years: 76-81%, >65 years: 46-64%) and disease stage (stage I: 73-80%, stage IV: 48-53%). Outcomes were poorer in previously treated patients, and those with later stage or blastoid disease, and improved with more recent diagnosis/treatment. Hospitalization is a major contributor to healthcare cost and differs by therapy toxicity.Conclusions: We identified significant data gaps for many G20 countries for epidemiology, real-world clinical, economic and humanistic burden. These literature reviews demonstrate the ongoing unmet need for MCL patients globally. Future research to further understand the real-world impact of MCL is needed along with new therapeutic options to improve patient outcomes.

Burden of illness of follicular lymphoma and marginal zone lymphoma.

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

Disparities in HIV knowledge and attitudes toward biomedical interventions among the non-medical HIV workforce in the United States.

Non-medical, community-based workers play a critical role in supporting people living with (or at risk of acquiring) HIV along the care continuum. The biomedical nature of promising advances in HIV prevention, such as pre-exposure prophylaxis and treatment-as-prevention, requires frontline workers to be knowledgeable about HIV science and treatment. This study was developed to: measure knowledge of HIV science and treatment within the HIV non-medical workforce, evaluate workers' familiarity with and attitudes toward recent biomedical interventions, and identify factors that may affect HIV knowledge and attitudes. A 62-question, web-based survey was completed in English or Spanish between 2012 and 2014 by 3663 US-based employees, contractors, and volunteers working in AIDS service organizations, state/local health departments, and other community-based organizations in a non-medical capacity. Survey items captured the following: respondent demographics, HIV science and treatment knowledge, and familiarity with and attitudes toward biomedical interventions. An average of 61% of HIV knowledge questions were answered correctly. Higher knowledge scores were associated with higher education levels, work at organizations that serve people living with HIV/AIDS or who are at a high risk of acquiring HIV, and longer tenure in the field. Lower knowledge scores were associated with non-Hispanic Black or Black race/ethnicity and taking the survey in Spanish. Similarly, subgroup analyses showed that respondents who were non-Hispanic Black or Hispanic (versus non-Hispanic white), as well as those located in the South (versus other regions) scored significantly lower. These subpopulations were also less familiar with and had less positive attitudes toward newer biomedical prevention interventions. Respondents who took the survey in Spanish (versus English) had lower knowledge scores and higher familiarity with, but generally less positive attitudes toward, biomedical interventions. In summary, low knowledge scores suggest the need for additional capacity-building efforts and training for non-medical HIV workers, particularly those who provide services in the communities most affected by HIV.