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In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination.The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes.Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection.Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population.Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

Neutrophil to Lymphocyte Ratio (NLR) combines a marker of inflammation and reduced cell turnover to reflect age related alterations in the immune system. Whether NLR can serve as a biomarker of frailty and predict survival among older adults with Multiple Myeloma (MM) is unknown.We used an electronic health record-derived database to identify older adults (age ≥ 60y) with incident MM diagnosed between 1/2011 and 2/2020, with known pre-treatment absolute neutrophil and lymphocyte count up to 90 days before the start of therapy. The calculated NLR values were stratified into quartiles (Q1-Q4). We constructed a previously validated, simplified frailty index combining age, comorbidity and ECOG performance status. We measured the association between NLR quartiles and this frailty index using a logistic regression, adjusted for age, sex and race/ethnicity. We used Kaplan Meier methods and multivariable Cox regression to assess the impact of NLR on overall survival adjusting for potential confounders.We identified 1729 older adults with newly diagnosed MM, at a median age of 73y (IQR: 67-78y). The median NLR was 2.13 (IQR: 1.44 to 3.31). Of the 1135 evaluable patients, 55% met criteria for frailty. Multivariable analysis revealed a 2.1-fold higher odds of frailty (95%CI = 1.42-3.10, p 0.001) for patients in the NLR Q4 group vs. NLR Q1 group. In a multivariable analysis, adjusting for age, sex, race/ethnicity, M-protein type, stage, high risk cytogenetics, baseline creatinine, LDH and type of first line therapy, patients in NLR Q4 group had a 1.51 times increased hazards of death (95%CI = 1.15-1.98, p 0.002) when compared to those in NLR Q1 group.NLR, a readily available laboratory biomarker, is associated with frailty measured using a simplified frailty index as well as inferior overall survival among older adults with MM. Future studies should explore its value as a screening tool to identify frail older adults with MM.

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non–B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non–recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19.Significance:Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies.This article is highlighted in the In This Issue feature, p. 171

Supplementary Figure from Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials.Significance:Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access.This article is highlighted in the In This Issue feature, p. 1426

Supplemental tables, figures, and list of participants

PURPOSE: To examine the impact of global risk, a measure comprising age, comorbidities, function, and cognitive statuses, on treatment selection and outcomes among older home care recipients with diffuse large B-cell lymphoma. METHODS: From SEER-Medicare, we selected home care recipients diagnosed with diffuse large B-cell lymphoma in 2011-2015, who had pretreatment Outcome and Assessment Information Set (OASIS) evaluations. We created a global risk indicator categorizing patients as low-, moderate-, or high-risk on the basis of OASIS assessments. We examined the association of global risk with receipt of therapy and among chemotherapy recipients, with mortality, emergency department visits, hospitalization, and intensive care unit admission within 30 days from first treatment in logistic models, reporting adjusted odds ratios (OR) with 95% CI. We compared overall survival across risk groups estimating adjusted hazard ratios. RESULTS: Of the 1,232 patients (median age, 80 years), 65% received chemotherapy. High-risk patients ( v moderate-risk) were less likely to receive any chemotherapy (OR, 0.50; 95% CI, 0.39 to 0.64) and curative regimens (OR, 0.59; 95% CI, 0.40 to 0.86) if treated, although even in the moderate-risk group, only 61% received curative regimens. High-risk patients were more likely to experience acute mortality (OR, 2.24; 95% CI, 1.43 to 3.52), emergency department visits (OR, 1.35; 95% CI, 1.00 to 1.83), hospitalization (OR, 1.60; 95% CI, 1.19 to 2.17), or intensive care unit admission (OR, 1.52; 95% CI, 1.04 to 2.22) and had inferior overall survival (hazard ratio, 1.41; 95% CI, 1.11 to 1.78). CONCLUSION: Global risk on the basis of OASIS is easily available, suggesting a potential way to improve patient selection for curative treatment and institution of preventive measures.

Key Points The NGS-MRD assay detected clonotypic DNA in 100% of CSF samples from patients who had lymphoma with parenchymal CNS involvement.Clonotypic DNA in CSF was present in 36% of newly diagnosed aggressive lymphomas and was associated with a 29% risk of CNS recurrence., Visual Abstract, The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)–based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis.

While the bone marrow (BM) microenvironment is significantly remodelled in acute myeloid leukaemia (AML), molecular insight into AML-specific alterations in the microenvironment has been historically limited by the analysis of liquid marrow aspirates rather than core biopsies that contain solid-phase BM stroma. We assessed the effect of anthracycline- and cytarabine-based induction chemotherapy on both haematopoietic and non-haematopoietic cells directly in core BM biopsies using RNA-seq and histological analysis. We compared matched human core BM biopsies at diagnosis and 2 weeks after cytarabine- and anthracycline-based induction therapy in responders (5% blasts present after treatment) and non-responders (≥5% blasts present after treatment). Our data indicated enrichment in vimentin (VIM), platelet-derived growth factor receptor beta (PDGFRB) and Snail family transcriptional repressor 2 (SNAI2) transcripts in responders, consistent with the reactivation of the mesenchymal population in the BM stroma. Enrichment of osteoblast maturation-related transcripts of biglycan (BGN), osteopontin (SPP1) and osteonectin (SPARC) was observed in non-responders. To the best of our knowledge, this is the first report demonstrating distinct osteogenic and mesenchymal transcriptome profiles specific to AML response to induction chemotherapy assessed directly in core BM biopsies. Detailing treatment response-specific alterations in the BM stroma may inform optimised therapeutic strategies for AML.

In HER2-positive breast cancer (HER2+ BC), neoadjuvant chemotherapy (NACT) with dual HER2-targeted therapy achieves high pathologic complete response (pCR) rates. Anthracycline-free NACT regimens avoid toxicities associated with anthracyclines, but every 3-week TCHP also has substantial side effects. We hypothesized that a weekly regimen might have equivalent efficacy with less toxicity; we also investigated whether poorly responding patients would benefit from switching to AC. Patients with clinical stage II–III HER2+ BC received weekly paclitaxel 80 mg/m2 and carboplatin AUC2 with every 3-week trastuzumab and pertuzumab (wPCbTP), with the option of splitting the pertuzumab loading dose. After 12 weeks, responding patients continued wPCbTP for another 6 weeks, while non-responders switched to AC. Dose modifications and post-op therapy were at investigator discretion. In 30 evaluable patients, the pCR rate was 77% (95% CI 58–90%); 12/14 (86%) in ER-negative and 11/16 (69%) in ER-positive. Only two patients transitioned to AC for non-response, of which one achieved pCR. There were no episodes of febrile neutropenia or grade ≥ 3 peripheral neuropathy, though several patients who continued wPCbTP stopped before week 18. Split-dose pertuzumab was associated with less grade ≥ 2 diarrhea (40%) than the standard loading dose (60%). pCR rates with our regimen were as high as reported with TCHP with fewer grade ≥ 3 toxicities, though diarrhea remains a concern. Too few patients had a suboptimal response to adequately test switching to AC. The wPCbTP regimen should be considered an alternative to TCHP as neoadjuvant therapy for HER2+ BC. ClinicalTrials.gov identifier: NCT02789657.

PURPOSE Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Ollila et al address a challenging problem: can the risk for central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma be predicted better on a molecular basis? They report that most tumors with CNS recurrence have recognizable molecular features that fall into two categories: those that resemble primary CNS lymphoma and those that resemble high-grade lymphoma. These data suggest that it is time to revisit identification of patients who may benefit from CNS prophylaxis, while highlighting how challenging that is.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P

Background Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. Methods We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. Results The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. Conclusion Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Introduction Burkitt lymphoma (BL) is an ultra-aggressive B-cell lymphoma which represents ~1% of adult and ~30% of pediatric lymphomas.1 Apart from the sporadic variant predominant in the United States (US), BL may occur as immunodeficiency-associated or endemic variants. BL is curable in most patients with short-course, dose-intense immunochemotherapy. Molecular underpinning of BL has been well understood, but not yet translated into targeted therapy. About 90% show MYC rearrangement with an immunoglobulin gene (the classical IGH-MYC t(8;14), IGK, or IGL) but otherwise BL has fewer karyotypic abnormalities than other high-grade lymphomas. Commonly mutated genes include the centroblastic transcription factor TCF3 (25%, activating mutations) or its inhibitor ID3 (60%, inactivating mutations), cell cycle regulators CCND3 (30%) and CDKN2A/B (10%), as well as TP53 (35%).2 Of note, tonic PI3K-AKT-mTOR signaling contributes to BL sustained cell survival. The prognostic impact of specific molecular features remains undefined.

Background: Patients with hematologic malignancies (HM) often receive aggressive care at the end of life (EOL). Early palliative care (PC) has been shown to improve EOL care outcomes, but its benefits are less established in HM than in solid tumors. Objectives: We sought to describe the use of billed PC services among Medicare beneficiaries with HM. We hypothesized that receipt of early PC services (rendered >30 days before death) may be associated with less aggressive EOL care. Design: Retrospective cohort analysis Setting/Subjects: Using the Surveillance, Epidemiology, and End Results-Medicare registry, we studied patients with leukemia, lymphoma, myeloma, myelodysplastic syndrome, or myeloproliferative neoplasm who died between 2001 and 2015. Measurements: We described trends in the use of PC services and evaluated the association between early PC services and metrics of EOL care aggressiveness. Results: Among 139,191 decedents, the proportion receiving PC services increased from 0.4% in 2001 to 13.3% in 2015. Median time from first encounter to death was 10 days and 84.3% of encounters occurred during hospitalizations. In patients who survived >30 days from diagnosis (N = 120,741), the use of early PC services was more frequent in acute leukemia, women, and black patients, among other characteristics. Early PC services were associated with increased hospice use and decreased health care utilization at the EOL. Conclusion: Among patients with HM, there was an upward trend in PC services, and early PC services were associated with less aggressive EOL care. Our results support the need for prospective trials of early PC in HM.

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving >80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of >1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH >3xULN, Hgb 3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH >3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS >90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Background The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. Methods We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. Results Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33–1.95) and fungal (OR, 2.20; 95% CI, 1.28–3.76) coinfections. Conclusions Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.

The "triplet" regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide-dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib-dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first-line regimens using real-world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event-free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72-0.95) and EFS (HR = 0.68; 95% CI, 0.61-0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68-0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83-0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide-dexamethasone may be the preferred line doublet considering its advantage over VD.

In a large observational study in patients with COVID-19 and cancer, survival was not significantly influenced by receipt of COVID-19 treatments, except hydroxychloroquine plus any other treatment, which was associated with reduced survival., Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. Significance: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access. This article is highlighted in the In This Issue feature, p. 1426

Objectives Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma. Patients and methods Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival. Results Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea. Conclusions Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX.