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Summary Background We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. Methods This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2–8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8–24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [ clinicaltrials.gov ( NCT03824483 ). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. Findings Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52–70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0–27·3), 33 (89%) of 37 patients (95% CI 75–97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8–12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0–18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. Interpretation BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. Funding Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Context Tafasitamab+LEN, a chemotherapy-free, novel treatment for R/R DLBCL, demonstrated efficacy in ASCT-ineligible patients in the single-arm Phase II L-MIND study (NCT02399085). Objective To compare outcomes in patients treated with tafasitamab+LEN in the L-MIND study with matched patient populations treated with commonly administered NCCN-/ESMO-recommended therapies for non-transplant-eligible patients with R/R DLBCL in routine clinical practice. Design RE-MIND2 (NCT04150328) is an observational, retrospective cohort study. The L-MIND tafasitamab+LEN cohort was matched with RE-MIND2 patients using estimated propensity score-based 1:1 nearest neighbor matching balanced for nine patient and disease baseline characteristics: age ( 9 /L), anemia (cut-off upper limit of normal). Setting Academic, public, and private hospitals in Europe, North America, and Asia-Pacific. Patients Age: ≥18 years old with histologically confirmed DLBCL. Prior systemic therapy for DLBCL: ≥1, including ≥1 anti-CD20 therapy. Interventions Data are presented for tafasitamab+LEN vs all (pooled) systemic therapies, tafasitamab+LEN vs bendamustine+rituximab (BR), and tafasitamab+LEN vs rituximab+gemcitabine+oxaliplatin (R-GemOx). Main Outcome Measures The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate, complete response rate, progression-free survival, event-free survival, duration of response, and time to next treatment. Results In RE-MIND2, 3,454 patients were enrolled from 200 centers. For the comparative analysis, 76 patients from the L-MIND tafasitamab+LEN study were included in the full analysis set. Strictly matched pairs of patients (standardized mean difference ≤0.2) included: tafasitamab+LEN vs pooled therapies, n=76 pairs; tafasitamab+LEN vs BR, n=75 pairs; and tafasitamab+LEN vs R-GemOx, n=74 pairs. Tafasitamab+LEN was associated with longer OS compared with pooled therapies (HR: 0.55; p=0.0076), BR (HR: 0.42; p Conclusions Results of this analysis suggest that tafasitamab+LEN has improved OS vs commonly used regimens. Funding This study was funded by MorphoSys AG.

Purpose/Objective(s) Indolent non-Hodgkin lymphomas (iNHL), such as follicular lymphoma (FL) and marginal zone lymphoma (MZL) are highly radiosensitive. Previously untreated patients with localized disease are potentially curable (PC) with RT. While standard of care remains 24Gy, de-escalation to very low dose radiotherapy (VLDRT) of 4Gy reduces toxicities and treatment duration. Use of VLDRT outside of palliation remains controversial, however, we hypothesize it may be sufficient for most lesions. Materials/Methods We present the largest single institution VLDRT experience of adults with FL/MZL treated between 2005-2018 with modern principles including PET staging and involved site radiotherapy (ISRT). Outcomes include best clinical/radiographic response using Lugano criteria between 1.5-6 months post-VLDRT, and cumulative incidence of local progression (LP), distant progression and overall progression, all using death as competing risk. Outcomes were stratified by VLDRT intent; lesions considered PC were localized sites without prior treatment. All other sites were considered non-curable. Competing risk regression was used to identify potential histologic/clinical predictors of LP. Results In total, 250 patients were treated to 299 lesions including 52 potentially curative (PC) sites (Table 1). Post-VLDRT, overall response rate was 90% for all treated sites with 68% achieving complete response (CR). With median follow-up of 2.4y, the 2y cumulative incidence of LP was 25% for the entire cohort. PC patients had considerably lower 2y-LP of 9% (95% CI 3-19%) compared to 29% (95% CI 23-34%) for the non-curable. Lesion size > 6cm was associated with lower odds of CR and greater risk of LP relative to lesions 0-2cm. There was no suggestion of inferior outcomes for PC patients relative to non-curable. The probability of receiving additional RT to the same site 2y post VLDRT is 15% (95% CI 11-19%), and subsequent response after additional RT was 68% CR (n = 30/45), 18% partial response (n = 8), and 14% non-response (n = 6). Conclusion We demonstrate that modern VLDRT approaches utilizing PET staging and ISRT result in excellent ORR with nearly 70% CR. Importantly, the cumulative incidence of LP at 2 years post VLDRT is low at 25%, highlighting the possibility of durable remissions. Given clinical versatility and apparent efficacy for PC patients, we support an adaptive ISRT stepwise strategy where patients will be treated initially with VLDRT, reserving full dose treatment for those with suboptimal response. A prospective, multicenter study by ILROG has been developed to compare PC patients randomized to standard 24 Gy versus this proposed response-adapted approach.

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1,088 patients with grade 1-3A FL of whom 238 patients with stage II-IV disease were initially treated with R-CHOP and 346 patients treated with R-chemotherapy. Patients (N=484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (PET, vs. CT) and early POD status using event defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Findings: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had 5-year OS of 57·6% for CT-staged patients compared with 70·6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53·9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients compared with PET-staged patients (16·7% vs. 6·3%), which was associated with a 9.7 fold higher risk for death. Interpretation: In FL, pre-treatment PET-staging reduced the prognostic impact of early POD compared with CT-staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy. Funding: NCI Cancer Center Support Grant (P30 CA008748). Declaration of Interest: 1) Connie L. Batlevi: Research Support: Janssen, Novartis, Epizyme, Xynomics; Honorarium: Dava Oncology. 2) Fushen Sha: None 3) Anna Alperovich: None. 4) Andy Ni: None. 5) Katy Smith: None 6) Zhitao Ying: None. 7) John F. Gerecitano: Currently employed by Janssen. Honoraria: Bayer, Epizyme, Roche, Genentech, Abbvie. 8) Paul A. Hamlin: consultancy at Portola Pharmaceutics, Celgene, Karyopharm, Juno Therapeutics; research funding from Portola, Molecular Templates, Incyte, JJ research funding from ADCT therapeutics, Aileron,Celgene, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin, Millenium/Takeda, Seattle Genetics, Trillium. 10) Anita Kumar: Research Support: Abbvie, Adaptive Biotechnologies, Celgene, Pharmacyclics, Seattle Genetics; Scientific Advisory Board: Celgene. 11) Matthew J. Matasar: Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics, GlaxoSmithKline. Consulting: Genentech, Bayer, Merck, Juno, Roche, Teva, Rocket Medical, Seattle Genetics. Research: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics. Travel: Genentech, Roche, Seattle Genetics, Bayer. 12) Alison J. Moskowitz: consultancy at Kyowa Hakko Kirin Pharma, Miragen Therapeutics, Takeda Pharmaceuticals, ADC therapeutics, Seattle Genetics, Cell Medica, Bristol-Myers Squibb, Erytech Pharma; research funding from Incyte, Seattle Genetics, BMS, and Merck. 13) Craig H. Moskowitz: Consulting: Astra Zeneca, BMS, Karyopharm Therapeutics, Merck, Seatle Genetics, Takeda, Vaniam Group; Scientific Advisory Board: Astra-Zeneca, Karyopharm Therapeutics, Merck, Seattle Genetics, Takeda, Vaniam Group; Research support: BMS, Merck, Seattle Genetics. 14) Ariela Noy: Research funding from Pharmacyclics, NIH, Raphael Pharma; consulting for: Janssen, Pharmacyclics, Medscape, Targeted Oncology. 15) Maria Lia M. Palomba: Honoraria from Merck, Celgene, Juno and Pharmacyclics. 16) Carol Portlock: None 17) David Straus: Advisory Board and research support: Seattle Genetics. 18) Andrew D. Zelenetz: consultancy at Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotechnology; research funding MEI Pharma, MorphoSys, Sandoz, Celgene, Roche, Gilead; Board of Directors (DMC Chair) Beigene. 19) Venkatraman E Seshan: None. 20) Stefano Luminari: Consulting/Advisory boards: Roche, Celgene, Sandoz, Gilead 21) Luigi Marcheselli: None. 22) Massimo Federico: Research support: Mundipharma s.r.l., Chephalon/Teva, Celgene, Millennium/Takeda, and Roche. Consulting/Advisory boards: Takeda, Roche, Celgene, Sandoz, and Spectrum. 23) Anas Younes: Research Support: Janssen, Curis, Merck, BMS, Syndax, and Roche; Honorarium: Janssen, AbbVie, Merck, Curis, Epizyme, Roche, Takeda; Consulting: Biopath, Xynomics, Epizyme, Roche. Ethical Approval: This is a retrospective study of adult patients (≥18 years old) diagnosed between the years of 1998 to 2009 with FL managed at Memorial Sloan Kettering Cancer Center (MSKCC). The institutional review board approved this study.

Recurrent hospitalizations with hyponatremia are commonly encountered in older adults admitted to Internal Medicine wards. However, the incidence and the prognostic implication of this phenomenon have never been studied.Medical charts of all older adults (≥75 years) admitted to Internal Medicine wards at a tertiary medical center during 2009-2010 with symptomatic moderate to severe hyponatremia (blood sodium ≤130 meq/l) upon admission were reviewed. The study group included patients with one or more hospitalizations with hyponatremia in the year following the first hospitalization with hyponatremia. The control group included patients with a single hospitalization with hyponatremia. Mortality rates were studied one year following the second hospitalization with hyponatremia in the study group and one year following the single hospitalization with hyponatremia in the control group. Regression analysis was used to study the association between recurrent hospitalizations with hyponatremia and 1-year mortality while controlling for demographics, chronic co-morbidities, albumin serum levels, and the number of hospitalizations.The cohort included 431 older adults: 301 (69.8%) women; mean age of 84.6±5.6 years. Overall, 120 (27.8%) patients had recurrent hospitalizations with hyponatremia and 125 (29.0%) patients died within a year. 1-Year mortality rates were higher in patients with recurrent hospitalizations with hyponatremia than in patients with a single hospitalization with hyponatremia (42.5% vs. 23.8%; p0.0001). Regression analysis showed that recurrent hospitalizations with hyponatremia were independently associated with 1-year mortality (odds ratio 1.9; 95% confidence interval 1.1-3.2; p=0.018).Recurrent hospitalizations with hyponatremia in older adults are common and associated with 1-year mortality.

Automated morphological assessment of peripheral blood slides has become an important modality facilitating characterization and quantification of cells in a uniform, fast and robust manner. In this study, we evaluated the morphological diversity in peripheral blood films of 94 chronic lymphocytic leukemia (CLL) patients using the DM1200 CellaVision automated microscopy system. Aberrant lymphocytes and smudge cells were enumerated and correlated with CLL immunophenotype, chromosomal aberrations and prognostic parameters. Herein, we show that the percentages of aberrant and smudge cells was highly variable between patients and did not correlate with each other. Increased aberrant lymphocytes and fewer smudge cells were associated with an atypical immunophenotype including low expression of CD23, higher levels of FMC7 and bright surface levels of CD20. High fraction of aberrant lymphocytes also was associated with trisomy 12. These cells were predominantly of small/medium size, sometimes with cleft nuclei. No correlation was noted between aberrant or smudge cells and clinical stage, CD38, ZA70 or time to first treatment. Taken together, automated morphological analysis of peripheral blood leukocytes emerged as a powerful and robust tool for the quantitative morphological stratification of CLL. Integration of the automated morphological features discriminates between different CLL phenotypes and distinct chromosomal aberrations.

Patients with acute decompensated heart failure (ADHF) are frequently treated with unnecessary antibiotics since they are confused with pneumonia patients.To study the efficacy of measuring C-reactive protein (CRP) levels on admission and CRP velocity in differentiating ADHF from pneumonia.A retrospective observational study of ADHF and pneumonia patients admitted to a tertiary hospital during 2 years. Patients who were already treated with antibiotics on admission were excluded. Efficacy of CRP as a diagnostic marker was evaluated by using receiver operator curves (ROC).Overall, 72 ADHF and 50 pneumonia patients were included in the study. The mean CRP levels on admission were 13.5+/-13.5 mg/L for the ADHF patients and 127+/-84 mg/L for the pneumonia patients (p0.001). CRP increases ofor =0.56 mg/L/h were diagnostic of pneumonia. CRP levels on admission together with CRP increases had a sensitivity of 0.96 and a specificity of 0.972 (p0.001) as markers to distinguish pneumonia from ADHF.This study emphasizes the dynamic nature of biomarkers. Demonstrating the efficiency of repeated CRP measurements in an acute setting will provide clinicians with a valuable tool for establishing the correct diagnosis and refraining from unnecessary use of antibiotics.

Article-at-a-Glance Background After-hours telephone communications are common in patient management. Patterns of communication of key information during after-hours phone calls were evaluated, and the utility of problem-specific Situation, Background, Assessment, Recommendation (SBAR) forms in improving this communication was assessed. Methods In a randomized trial using a simulated on-call setting, 20 nurses called physicians regarding six cases adapted from inpatient records and based on the six most common reasons for after-hours nurse-physician communication. Three of the cases were handled without the SBAR forms (control cases), and three cases were handled with the forms (SBAR cases). Two cue types of communication were evaluated: situation cues, which conveyed the patient's situation (for example, a patient is confused), and background cues, which conveyed problem-specific data indicated on the SBAR forms (for example, the patient has a low sodium level). Results Ninety-two phone calls were analyzed (43 SBAR/49 controls). Most of the nurses reported the situation cues (SBAR 88%, control 84%, p = .60) but not the background cues. There was a trend toward fewer background cues communicated in the SBAR cases (14% versus 31%, p = .08). In 14% of the cases, on average, nurses omitted information or reported wrong information regarding the background cue. Physicians asked questions that resulted in the communication of the cues in a minority of the cases when the background cues were not originally provided by the nurses (SBAR 6%, control 16%, p = .39). Conclusions In after-hours phone communication between physicians and nurses, significant information was often not communicated and physicians did not elicit the necessary information. Simply providing an SBAR–based form did not ensure complete communication of key information.