Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL.

ABSTRACT: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Family Caregiver Comfort with Telehealth Technologies: Differences by Race and Ethnicity in a Cross-Sectional Survey.

Background: Telehealth has seen widespread use since the onset of the COVID-19 pandemic, and 82% patients required assistance in accessing their telehealth appointments. This assistance commonly comes from a family caregiver who may or may not be comfortable using the technologies associated with telehealth. The objective of our study was to analyze a demographically representative survey of U.S. family caregivers to understand the level of comfort using telehealth technologies among family caregivers. Methods: A secondary analysis of survey data collected during the COVID-19 pandemic in 2020. Level of caregiver comfort using computers, smartphones, and tablets was determined through three Likert-style questions. Proportional odds logistic regression was used to understand the associations between demographic variables and level of caregiver comfort using each technology, when adjusting for covariates. Results: A total of 340 caregivers were included in the analysis. Compared with non-Hispanic white caregivers, Asian caregivers had higher odds (odds ratio [OR] 3.14; 95% confidence interval [CI] 1.36, 8.02; p = 0.01) of expressing comfort using computers; black caregivers (OR 0.46; 95% CI 0.21, 0.98; p = 0.04) and Hispanic caregivers (OR 0.36; 95% CI 0.17, 0.79; p = 0.01) expressed lower odds of comfort using smartphones; and Asian caregivers had higher odds (OR 4.64; 95% CI 2.05, 11.69; p = 0.001) of expressing comfort using tablets. Conclusion and Implications: There are identified disparities in the level of technological comfort using computers, smartphones, and tablets by different racial and ethnic groups. Health systems should consider early stakeholder involvement in the design of telehealth technologies, culturally responsive training materials on telehealth technology use to reduce disparities in comfort using telehealth technologies.

Communicating visit information to family caregivers: How does method matter? A national survey.

OBJECTIVES: The clinic visit is a critical point of contact for family caregivers. However, only 37% of family caregivers are able to accompany patients to visits. When they cannot attend, caregivers receive visit information to assist with their caregiving. However, little is known about how method of receiving information from clinic visits is associated with important caregiver outcomes. This study sought to determine whether mode of receiving clinic visit information (speaking with the patient, attending the visit, or using an after-visit summary [AVS]) was associated with changes in caregiver burden, caregiver preparedness, and the positive aspects of caregiving. METHODS: Cross-sectional web-based survey of a national sample of adult family caregivers. Multiple linear regression models determined associations between communication modes and caregivers' burden, preparedness, and positive aspects of caregiving, adjusting for sociodemographic covariates. RESULTS: Respondents (N = 340) were mostly male (58%), White (59%), ranged from 18 to 85 years old, and supported patients with conditions including diabetes, dementia, and cancer. Speaking with patients was associated with increases in positive aspects of caregiving (95% CI = 2.01, 5.42) and an AVS was associated with increases in positive aspects of caregiving (95% CI = 0.4, 3.56) and preparedness for caregiving (95% CI = 0.61, 3.15). Using any method of receiving information from visits was associated with the greatest increase in preparedness, compared to not receiving visit information. We did not observe an association between method of communication and caregiver burden. SIGNIFICANCE OF RESULTS: Method of communicating visit information is associated with improvements in caregiver preparedness and the positive aspects of caregiving, though caregiver burden may be unaffected by information exchange. Given the limitations of current communication methods, future work should explore directionality of the associations we found and identify visit communication strategies with caregivers that optimize caregiver and patient outcomes.

Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10-1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.

Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy.

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase Î´ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.

Outcomes of limited stage primary bone diffuse large B-cell lymphoma in the rituximab era: a multicenter, retrospective study.

Primary bone diffuse large B cell lymphoma (DLBCL) is a rare variant of extranodal non-Hodgkin lymphoma (NHL) historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited-stage disease. We conducted a multicenter retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field. A total of 112 patients were included: 78 received CIT and radiation (RT group), and 34 received CIT alone (no RT group). The OS at 10 years was 77.9% in the RT group and 89.0% in the no RT group (p = 0.42). The RFS at 10 years was 73.5% in the RT group and 80.3% in the no RT group (p = 0.88). Neither improved OS nor RFS was associated with the addition of consolidative RT. Subgroup analysis of patients only achieving a partial response after CIT suggests that these patients may benefit from consolidative RT.

Many People With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022. WHAT WERE THE RESULTS?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years. WHAT DO THE RESULTS OF THE STUDY MEAN?: In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 (ClinicalTrials.gov) Clinical Trial Registration: NCT01724346 (ClinicalTrials.gov).

Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.

BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL.

BACKGROUND: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen). CONCLUSIONS: Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).

How I treat early-relapsing follicular lymphoma.

Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma, with generally favorable outcomes but a variable clinical course. Recent studies have elucidated the consistent and reproducible frequency of early disease progression in FL, occurring in ∼20% of patients. Relapse of FL within 24 months of chemoimmunotherapy (POD24) is now established as a robust marker of poor survival, leading to increased risk of death. Currently, there is no established method of identifying patients at risk for early disease progression at the time of their FL diagnosis. However, numerous studies worldwide are investigating clinical, pathologic, and radiographic biomarkers to help predict POD24, thereby improving subsequent outcomes and adapting therapy based on individual risk. There is also a paucity of standardized treatments for patients with POD24, but investigations are ongoing testing novel targeted therapies and autologous stem cell transplantation strategies. This review provides an overview of early-relapsing FL and our approach to patient management based on recent available data.

Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.

Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.

Precision Assessment of COVID-19 Phenotypes Using Large-Scale Clinic Visit Audio Recordings: Harnessing the Power of Patient Voice.

COVID-19 cases are exponentially increasing worldwide; however, its clinical phenotype remains unclear. Natural language processing (NLP) and machine learning approaches may yield key methods to rapidly identify individuals at a high risk of COVID-19 and to understand key symptoms upon clinical manifestation and presentation. Data on such symptoms may not be accurately synthesized into patient records owing to the pressing need to treat patients in overburdened health care settings. In this scenario, clinicians may focus on documenting widely reported symptoms that indicate a confirmed diagnosis of COVID-19, albeit at the expense of infrequently reported symptoms. While NLP solutions can play a key role in generating clinical phenotypes of COVID-19, they are limited by the resulting limitations in data from electronic health records (EHRs). A comprehensive record of clinic visits is required-audio recordings may be the answer. A recording of clinic visits represents a more comprehensive record of patient-reported symptoms. If done at scale, a combination of data from the EHR and recordings of clinic visits can be used to power NLP and machine learning models, thus rapidly generating a clinical phenotype of COVID-19. We propose the generation of a pipeline extending from audio or video recordings of clinic visits to establish a model that factors in clinical symptoms and predict COVID-19 incidence. With vast amounts of available data, we believe that a prediction model can be rapidly developed to promote the accurate screening of individuals at a high risk of COVID-19 and to identify patient characteristics that predict a greater risk of a more severe infection. If clinical encounters are recorded and our NLP model is adequately refined, benchtop virologic findings would be better informed. While clinic visit recordings are not the panacea for this pandemic, they are a low-cost option with many potential benefits, which have recently begun to be explored.

Integrating Option Grid Patient Decision Aids in the Epic Electronic Health Record: Case Study at 5 Health Systems.

BACKGROUND: Some researchers argue that the successful implementation of patient decision aids (PDAs) into clinical workflows depends on their integration into electronic health records (EHRs). Anecdotally, we know that EHR integration is a complex and time-consuming task; yet, the process has not been examined in detail. As part of an implementation project, we examined the work involved in integrating an encounter PDA for symptomatic uterine fibroids into Epic EHR systems. OBJECTIVE: This study aims to identify the steps and time required to integrate a PDA into the Epic EHR system and examine facilitators and barriers to the integration effort. METHODS: We conducted a case study at 5 academic medical centers in the United States. A clinical champion at each institution liaised with their Epic EHR team to initiate the integration of the uterine fibroid Option Grid PDAs into clinician-facing menus. We scheduled regular meetings with the Epic software analysts and an expert Epic technologist to discuss how best to integrate the tools into Epic for use by clinicians with patients. The meetings were then recorded and transcribed. Two researchers independently coded the transcripts and field notes before categorizing the codes and conducting a thematic analysis to identify the facilitators and barriers to EHR integration. The steps were reviewed and edited by an Epic technologist to ensure their accuracy. RESULTS: Integrating the uterine fibroid Option Grid PDA into clinician-facing menus required an 18-month timeline and a 6-step process, as follows: task priority negotiation with Epic software teams, security risk assessment, technical review, Epic configuration; troubleshooting, and launch. The key facilitators of the process were the clinical champions who advocated for integration at the institutional level and the presence of an experienced technologist who guided Epic software analysts during the build. Another facilitator was the use of an emerging industry standard app platform (Health Level 7 Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources) as a means of integrating the Option Grid into existing systems. This standard platform enabled clinicians to access the tools by using single sign-on credentials and prevented protected health information from leaving the EHR. Key barriers were the lack of control over the Option Grid product developed by EBSCO (Elton B Stephens Company) Health; the periodic Epic upgrades that can result in a pause on new software configurations; and the unforeseen software problems with Option Grid (ie, inability to print the PDA), which delayed the launch of the PDA. CONCLUSIONS: The integration of PDAs into the Epic EHR system requires a 6-step process and an 18-month timeline. The process required support and prioritization from a clinical champion, guidance from an experienced technologist, and a willing EHR software developer team.

An Audio Personal Health Library of Clinic Visit Recordings for Patients and Their Caregivers (HealthPAL): User-Centered Design Approach.

BACKGROUND: Providing digital recordings of clinic visits to patients has emerged as a strategy to promote patient and family engagement in care. With advances in natural language processing, an opportunity exists to maximize the value of visit recordings for patients by automatically tagging key visit information (eg, medications, tests, and imaging) and linkages to trustworthy web-based resources curated in an audio-based personal health library. OBJECTIVE: This study aims to report on the user-centered development of HealthPAL, an audio personal health library. METHODS: Our user-centered design and usability evaluation approach incorporated iterative rounds of video-recorded sessions from 2016 to 2019. We recruited participants from a range of community settings to represent older patient and caregiver perspectives. In the first round, we used paper prototypes and focused on feature envisionment. We moved to low-fidelity and high-fidelity versions of the HealthPAL in later rounds, which focused on functionality and use; all sessions included a debriefing interview. Participants listened to a deidentified, standardized primary care visit recording before completing a series of tasks (eg, finding where a medication was discussed in the recording). In the final round, we recorded the patients' primary care clinic visits for use in the session. Findings from each round informed the agile software development process. Task completion and critical incidents were recorded in each round, and the System Usability Scale was completed by participants using the digital prototype in later rounds. RESULTS: We completed 5 rounds of usability sessions with 40 participants, of whom 25 (63%) were women with a median age of 68 years (range 23-89). Feedback from sessions resulted in color-coding and highlighting of information tags, a more prominent play button, clearer structure to move between one's own recordings and others' recordings, the ability to filter recording content by the topic discussed and descriptions, 10-second forward and rewind controls, and a help link and search bar. Perceived usability increased over the rounds, with a median System Usability Scale of 78.2 (range 20-100) in the final round. Participants were overwhelmingly positive about the concept of accessing a curated audio recording of a clinic visit. Some participants reported concerns about privacy and the computer-based skills necessary to access recordings. CONCLUSIONS: To our knowledge, HealthPAL is the first patient-centered app designed to allow patients and their caregivers to access easy-to-navigate recordings of clinic visits, with key concepts tagged and hyperlinks to further information provided. The HealthPAL user interface has been rigorously co-designed with older adult patients and their caregivers and is now ready for further field testing. The successful development and use of HealthPAL may help improve the ability of patients to manage their own care, especially older adult patients who have to navigate complex treatment plans.

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma.

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.