Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Seroconversion and outcomes after initial and booster COVID-19 vaccination in adults with hematologic malignancies.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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.

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study.

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<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR], 1.53, 95% confidence interval [CI], 1.14-2.06, P=0.004) and overall survival (aHR, 1.62, 95%CI, 1.18-2.22, P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95%CI, 4-8%). It was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-HR, 4.38, 95%CI, 2.16-8.87, P<0.001). Baseline CNS involvement in BL is relatively common and portends inferior prognosis independent of first-line regimen selection. In real-world practice, regimens with highly CNS-penetrant intravenous systemic agents were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in DA-EPOCH-R.

High-grade B-cell lymphoma, not otherwise specified: CNS involvement and outcomes in a multi-institutional series.

ABSTRACT: Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal = 6, parenchymal = 4, and both = 1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR = 3.5) and testicular (in men) or female pelvic (in women) involvement (OR = 8.1). There was no significant difference in survival outcomes between patients with HGBL NOS with (median PFS = 4 years) or without (median PFS = 2.4 years) baseline CNS involvement (P = 0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% vs 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-germinal center B-cell subtype, and "dual-expresser lymphoma" phenotype, however, high CNS IPI was not. The prognosis of relapsed HGBL NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and chimeric antigen receptor T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × 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. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs 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.

CD5 expression in marginal zone lymphoma predicts differential response to rituximab or bendamustine/rituximab.

We examined outcomes of 244 patients with marginal zone lymphoma (MZL) diagnosed in 2010-2020, of which 25 (10%) expressed CD5. CD5 expression was present in 22% of splenic, 8% of nodal, and 5% of extranodal MZL, and showed frequent blood/bone marrow involvement, elevated lactate dehydrogenase, and TP53 deletions. CD5 expression was not associated with progression-free or overall survival, but it conferred a significantly higher risk of histologic transformation (22% versus 4% at 5 years, p = 0.002). Among patients receiving first-line rituximab monotherapy, CD5 expression was associated with lower response rate (30% versus 77%, p = 0.006), PFS (25% versus 45% at 3 years, p = 0.003) and OS (44% versus 77%, p = 0.010), whereas CD5 status did not significantly affect outcomes of patients receiving bendamustine with rituximab (P for interaction = 0.012 for progression-free survival). CD5-positive MZL may have a propensity to leukemic dissemination, histologic transformation, and may derive benefit from first-line bendamustine/rituximab rather than rituximab alone.

Thrombosis in COVID-19: A Narrative Review of Current Literature and Inpatient Management.

COVID-19 infection has been associated with an increased incidence of thrombotic events leading to poor patient outcomes. Given the rapid rise of the COVID-19 pandemic, the ability to conduct prospective trials has been limited and data regarding the use of standard-dose versus intermediate-dose thromboprophylaxis, use of empiric therapeutic anticoagulation, and use of extended-duration thromboprophylaxis after discharge has been largely based upon observational data without any high-quality prospective data guiding their use. In this article, we will review the incidence and frequency of arterial and venous thrombotic events along with the current literature surrounding the use of intermediate-dose thromboprophylaxis, empiric therapeutic anticoagulation, and use of extended-duration thromboprophylaxis for patients hospitalized with COVID-19.

Burkitt Lymphoma International Prognostic Index.

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.

Burkitt lymphoma: bridging the gap between advances in molecular biology and therapy.

Genomic studies have revealed molecular mechanisms involved in the pathogenesis of Burkitt's lymphoma, including the ID3/TCF3-dependent centroblast gene expression program, tonic PI3K-AKT-mTOR signaling, and deregulation of cell cycle and apoptosis through mutations in cyclin D3, CDKN2A, or TP53. Unfortunately, these advances have not been translated into treatment, which relies on dose-intense cytotoxic chemotherapy. While most patients achieve long-term survival, options for relapsed/refractory disease are lacking, as Burkitt lymphoma is often excluded from clinical trials of novel approaches. The lower-intensity, dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) regimen constitutes a major advance allowing for treatment of older and HIV-positive patients but needs augmentation to better address the central nervous system involvement. Furthermore, DA-EPOCH-R provides a platform for the study of targeted or immunotherapeutic approaches while de-escalating cytotoxic agents and their associated adverse effects. In this review we discuss the epidemiology and molecular genetics of BL, first-line treatment considerations, and potential novel treatment strategies.

Treatment for metastatic adenocarcinoma of the stomach and gastroesophageal junction: 2020.

Gastric and gastroesophageal junction (GEJ) cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and is generally less than a year. Standard front-line chemotherapy includes two- or three-drug regimens with the addition of trastuzumab in HER2-positive disease. With an increased understanding of the biology of cancer over the past few decades, targeted therapies have made their way into the treatment paradigm of many cancers. They been examined in the first- and second-line settings in the treatment of gastroesophageal cancer though has yielded few viable treatment options. One success is ramucirumab either as monotherapy or in combination with paclitaxel is the preferred choice in second-line therapy. While immunotherapy has been considered a breakthrough in oncology over the past decade, the response rates in gastric and gastroesophageal cancers have been relatively low compared to other cancers, resulting in its limited approval and mostly reserved for second-line therapy or beyond. In this article, we will review the standard first- and second-line treatment regimens. Furthermore, this article will review the use of targeted therapies and immunotherapy in treatment of gastric and gastroesophageal cancers. Lastly, we will touch upon future treatment strategies that are currently under investigation.

Intensity of anticoagulation and survival in patients hospitalized with COVID-19 pneumonia.

BACKGROUND: SARS-CoV-2 infection has noted derangements in coagulation markers along with significant thrombotic complications. Post-mortem examinations show severe endothelial injury and widespread thrombotic microangiopathy in the pulmonary vasculature. Early reports describing the use of prophylactic anticoagulation demonstrated improved survival, leading to the adoption of prophylactic and therapeutic anticoagulation guided by D-dimer levels. The clinical usefulness of D-dimer values, trends, and more intensive anticoagulation remains an area of clinical interest. OBJECTIVES: Assess the outcomes and laboratory trends in COVID-19 patients stratified by intensity of anticoagulation at time of admission. PATIENTS AND METHODS: Retrospectively review the differences in clinical outcomes and laboratory trends in patients hospitalized with COVID-19 in the Lifespan Health System. RESULTS: Between 27 February and 24 April 2020, 468 patients were hospitalized. Initial use of high-intensity thromboprophylaxis was associated with improved 30-day mortality (adjusted RR 0.26; 95% confidence interval [CI], 0.07-0.97; p = 0.045) without a significant increased rate of bleeding (p = 0.11). In severe COVID-19, D-dimer significantly increased during hospitalization with standard thromboprophylaxis (p < 0.001) but remained stable or decreased with high-intensity prophylaxis or therapeutic anticoagulation. CONCLUSION: Patients who received high-intensity prophylactic anticoagulation had a downtrend in D-dimer levels and improved 30-day mortality. This suggests a role in anticoagulation in mitigating adverse outcomes associated with COVID-19; however, further randomized, prospective studies are needed.

Enforcing the "4T": An In-Line Calculator for HIT Antibody Ordering in the Electronic Medical Record.

Heparin-induced thrombocytopenia (HIT) remains a difficult clinical diagnosis, even with the under-utilized standardized scoring systems, like the '4T' score, to aid in clinical decision-making. Our quality improvement study sought to assess the use of '4T' score, improve the use of HIT antibody (HITA) testing and improvement management of possible HIT by implementing an in-line calculator with guidance within our electronic medical record (EMR) at our institution. We retrospectively reviewed patient charts between October 2017 and October 2018, assessing practices before and after implementation of the '4T' in-line calculator in April 2018. HITA were ordered inappropriately (for 4T <4) in 141 (67%) of 210 instances (75 before and 66 after). We found no statistically significant difference in positive predictive value (PPV) or 4T documentation in provider notes after its implementation. We were able to identify problematic areas in HIT management, such as the ordering of non-heparin anticoagulants, and implement additional changes addressing these problems.

Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End-Stage Renal Disease Requiring Chronic Hemodialysis.

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single-dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62-year-old 156-kg African-American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patient's death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.