Hypertension treatment for patients receiving ibrutinib: a multicenter retrospective study.

ABSTRACT: Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took ß blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% confidence interval [CI], 10.0 to -0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI, 10.9 to -0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

Case Report: Serum methotrexate monitoring by immunoassay: confusion by by-product, confusion by antidote.

Methotrexate is a commonly used agent in the treatment of many malignancies and rheumatologic/inflammatory diseases. Working by inhibiting dihydrofolate reductase and thereby preventing eventual formation of tetrahydrofolate, methotrexate inhibits synthesis of purines and thymidylate, therefore disabling a malignant cell's ability to replicate. While it is able to effectively do this, methotrexate also holds potential for significant toxicity. Therefore, serum methotrexate monitoring is of utmost importance when administering the drug, particularly when high doses are used. Although there are several different measurement systems, the immunoassay is a commonly used monitoring system that may be prone to interference when using agents with similar carbon backbone as methotrexate, including folinic acid (leucovorin) at high doses, as well as in the setting of glucarpidase use and consequent methotrexate breakdown. However, adjusting leucovorin dosing policy and being aware of the potential of the immunoassay to be "confused" by similar molecules have allowed for the efficient and effective use of the immunoassay while preventing prolonged hospital stays at our institution.

Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Nurse-Driven Interprofessional Rounds: Improving Care Coordination and Length of Stay.

BACKGROUND: Inpatient oncology units care for patients with some of the most complex medical conditions outside of the intensive care unit. These patients benefit from structured care coordination. Reduced ability to admit patients to oncology beds contributes to delays in specialty care. OBJECTIVES: This quality improvement initiative established nurse-driven interprofessional rounds (IPRs) to reduce length of stay (LOS), improve discharge time of day, and enhance care coordination, patient flow, and access to care in the community. METHODS: Care coordination during enhanced IPRs (eIPRs) included estimation of discharge dates, comparison of LOS to a standard geometric mean LOS, and discussion of clinical milestones and barriers to progression and discharge. Data analysis evaluated the effect of eIPRs on key outcomes. FINDINGS: Although LOS variance was reduced by 15.8% and 44.1% in all-unit and hematology-oncology discharges, respectively, the results were not significant. Discharges by 2 pm improved significantly for all-unit and hematology-oncology populations, respectively. Patient flow measured by accepted patient transfers requesting hematology-oncology services improved significantly.

A Survey of Cancer Risk Behaviors, Beliefs, and Social Drivers of Health in New Hampshire and Vermont.

Compared with urban areas, rural areas have higher cancer mortality and have experienced substantially smaller declines in cancer incidence in recent years. In a New Hampshire (NH) and Vermont (VT) survey, we explored the roles of rurality and educational attainment on cancer risk behaviors, beliefs, and other social drivers of health. In February-March 2022, two survey panels in NH and VT were sent an online questionnaire. Responses were analyzed by rurality and educational attainment. Respondents (N = 1,717, 22%) mostly lived in rural areas (55%); 45% of rural and 25% of urban residents had high school education or less and this difference was statistically significant. After adjustment for rurality, lower educational attainment was associated with smoking, difficulty paying for basic necessities, greater financial difficulty during the COVID-19 pandemic, struggling to pay for gas (P < 0.01), fatalistic attitudes toward cancer prevention, and susceptibility to information overload about cancer prevention. Among the 33% of respondents who delayed getting medical care in the past year, this was more often due to lack of transportation in those with lower educational attainment (21% vs. 3%, P = 0.02 adjusted for rurality) and more often due to concerns about catching COVID-19 among urban than rural residents (52% vs. 21%; P < 0.001 adjusted for education). In conclusion, in NH/VT, smoking, financial hardship, and beliefs about cancer prevention are independently associated with lower educational attainment but not rural residence. These findings have implications for the design of interventions to address cancer risk in rural areas. Significance: In NH and VT, the finding that some associations between cancer risk factors and rural residence are more closely tied to educational attainment than rurality suggest that the design of interventions to address cancer risk should take educational attainment into account.

Adnexotropic and granulomatous mycosis fungoides following TNF-α inhibitor treatment.

Recent publications have documented an increased prevalence of cutaneous T-cell lymphoma (CTCL) in patients undergoing tumor necrosis factor alpha (TNF-α) inhibitor therapy. Herein, we present an uncommon manifestation of mycosis fungoides (MF) with unique pathological findings after the initiation of adalimumab therapy for the treatment of psoriasis. One year after starting treatment, the patient noticed a slowly growing, eroded plaque on the left cheek, the biopsy of which demonstrated mixed granulomatous and adnexotropic lymphocytic infiltrate with features characteristics of MF. In the following months, the patient developed pink- and violet-colored scaly plaques on the right posterior upper arm and right medial upper arm. Biopsy of these plaques also revealed findings compatible with MF. T-cell receptor (TCR) clonality studies by PCR revealed identical T-cell clones in the samples obtained from the cheek, right posterior upper arm, and right medial upper arm. TCR clonality studies of a long-standing psoriatic plaque on the right thigh failed to reveal similar T-cell clones. Blurring of histopathologic presentation by TNF-α inhibitors could greatly complicate the identification of MF subtypes. Providers treating patients with TNF-α inhibitors must be aware of the risk of cutaneous lymphoma development and the potential deviations from their expected presentations. In patients without an initial biopsy, the possibility of pre-existing CTCL with psoriasiform presentation should be considered.

Brentuximab vedotin plus doxorubicin and dacarbazine in nonbulky limited-stage classical Hodgkin lymphoma.

ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).

Race and Ethnicity-Conscious Clinical Research Best Practices.

This Viewpoint describes the concept of race-conscious medicine in oncology.

Primary cutaneous gamma-delta T-cell lymphoma masquerading as leukemia cutis in a patient recently diagnosed with small lymphocytic lymphoma: Clues to the diagnosis.

A 54-year-old man recently diagnosed with small lymphocytic lymphoma (SLL) had waxing and waning, indurated, erythematous plaques on his legs, with leukopenia and anemia disproportionate to the SLL burden in his marrow and pelvic lymph nodes. Punch biopsy of a plaque performed to evaluate for leukemia cutis revealed a lymphocytic lobular-panniculitis-like infiltrate resembling lupus panniculitis, but a preponderance of CD8+/Ki-67+ T-cells surrounding adipocytes raised concern for subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Additional immunohistochemistry (IHC) studies showed that the adipotropic T-cells expressed TCR-gamma, supporting the rare, unexpected diagnosis of Primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL). The patient subsequently met diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH). PCGDTCL is an aggressive, HLH-associated lymphoma requiring different management than SPTCL and SLL. This case illustrates how PCGDTCL can co-exist with B-cell lymphoma and resemble panniculitis on biopsies. PCGDTCL and SPTCL should enter the differential diagnosis whenever patients present with the constellation of lobular panniculitis and unexplained cytopenias. In the present case, close clinicopathologic correlation and judicious use of IHC on a small sample allowed for a prompt diagnosis.

Utilization of an Outpatient Integrated Infusion Suite to Decrease Length of Stay, Increase Revenue, and Improve Patient Experience for Elective Chemotherapy Admissions.

PURPOSE: Reduction of chemotherapy start times (CST) and length of stay (LOS) for elective chemotherapy admissions is a priority. The aim of this project was to improve efficiency of patient care while simultaneously increasing revenue by reducing LOS and transitioning high-cost chemotherapy to the outpatient setting. METHODS: A multidisciplinary quality improvement team proposed building a new outpatient infusion suite in close proximity to the inpatient unit. This suite was then integrated into the flow of elective inpatient chemotherapy admissions and discharges for etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R). Quality measures such as CST, LOS, and revenue were used to evaluate the new infusion suite. RESULTS: In the pilot phase of the study, the average CST improved by approximately 1 hour 45 minutes (P = .0218). The mean LOS was reduced from 4.3 to 4.1 midnights (P = .0214). In terms of hours, LOS was reduced from 105.8 to 95.5 hours (P < .0001). A mean quarterly revenue of $309,410 US dollars was noted during the pilot that had not been previously billed. These improvements were sustained throughout the control phase. CONCLUSION: Delays in CST and prolonged LOS lead to patient dissatisfaction and increased cost to the health care system. Focus groups and patient feedback are important when designing and implementing new workflows. The creation of an outpatient integrated infusion suite allows medical centers to meet patients' expectations of reducing number of visits while also reducing LOS and capturing new revenue. Adherence to scheduling guidelines further reduces the CST for elective chemotherapy administration.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma.

Metabolic dysfunctions enabling increased nucleotide biosynthesis are necessary for supporting malignant proliferation. Our investigations indicate that upregulation of fatty acid synthase (FASN) and de novo lipogenesis, commonly observed in many cancers, are associated with nucleotide metabolic dysfunction in lymphoma. The results from our experiments showed that ribonucleotide and deoxyribonucleotide pool depletion, suppression of global RNA/DNA synthesis, and cell cycle inhibition occurred in the presence of FASN inhibition. Subsequently, we observed that FASN inhibition caused metabolic blockade in the rate-limiting step of the oxidative branch of the pentose phosphate pathway (oxPPP) catalyzed by phosphogluconate dehydrogenase (PGDH). Furthermore, we determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. Through cell-free enzyme assays consisting of FASN and PGDH, we delineated that the PGDH-catalyzed ribulose-5-phosphate synthesis is enhanced in the presence of FASN and is suppressed by increasing concentrations of NADPH. Additionally, we observed that FASN and PGDH were colocalized in the cytosol. The results from these experiments led us to conclude that NADP-NADPH turnover and the reciprocal stimulation of FASN and PGDH catalysis are involved in promoting oxPPP and nucleotide biosynthesis in lymphoma. Finally, a transcriptomic analysis of non-Hodgkin's lymphoma (n = 624) revealed the increased expression of genes associated with metabolic functions interlinked with oxPPP, while the expression of genes participating in oxPPP remained unaltered. Together we conclude that FASN-PGDH enzymatic interactions are involved in enabling oxPPP and nucleotide metabolic dysfunction in lymphoma tumors.

A case report of blastic plasmacytoid dendritic cell neoplasm in a hispanic child.

Plasmacytoid dendritic cell neoplasms are aggressive and rare hematologic malignancies characterized by clonal expansion of plasmacytoid dendritic cells with frequent cutaneous involvement. The pathogenesis is not well established, and it shows enhanced expression of CD56, CD4 and CD123 detected by flow cytometry and immunohistochemistry. We report a case report of this rare disease in a hispanic child with complete remission after using a protocol for high-risk acute lymphoblastic leukemia.

Acute myeloid leukemia with hepatic infiltration presenting as obstructive jaundice.

We present the case of a 55-year-old woman who presented with laboratory studies concerning for acute myeloid leukemia (AML) as well as obstructive cholestasis. In similar previously reported cases, concerns of chemotherapy toxicity exacerbated by liver dysfunction or concerns of untreated, concurrent cholecystitis in a neutropenic patient often delay initiation of chemotherapy for full medical workup. At admission, our patient was started on the cytoreductive agent hydroxyurea. By day 10 of her medical workup, her liver function had improved with total bilirubin levels normalizing. At that time, full-dose 7 + 3 induction with cytarabine and daunorubicin was then initiated.

Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial.

BACKGROUND: Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. METHODS: We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. FINDINGS: 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. INTERPRETATION: The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. FUNDING: TG Therapeutics.

Small lymphocytic lymphoma mimicking primary cutaneous marginal zone lymphoma with colonization of germinal center follicles.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is primarily a disease of older adults and is occasionally an incidental finding on skin biopsies accompanying epithelial neoplasms and insect bite reactions. In rare instances, however, it produces leukemic infiltrates showing clinical and histopathologic overlap with primary cutaneous B-cell lymphomas including primary cutaneous marginal zone lymphoma (PCMZL). Even less frequently, such findings serve as the initial disease manifestation. We present an exceptional case of a 61-year-old man with no past medical history whose clinical and histopathologic findings raised consideration for PCMZL with abnormal B-cells colonizing germinal center follicles; however, faint CD5 and CD23 co-expression raised the differential diagnosis of CLL/SLL. In light of an ambiguous clinical presentation with widely distributed papules and plaques, peripheral blood flow cytometry was also performed, revealing high count of CLL-type monoclonal B lymphocytosis. Subsequent workup revealed bone marrow involvement and mesenteric lymphadenopathy, supporting the diagnosis of SLL. Follicular colonization by SLL has not been previously reported. Our case underscores the importance of subtle immunophenotypic clues and correlations with clinical and radiologic findings in the workup of B-cell lymphomas presenting in the skin.

Unraveling subcutaneous panniculitis-like T-cell lymphoma: An association between subcutaneous panniculitis-like T-cell lymphoma, autoimmune lymphoproliferative syndrome, and familial hemophagocytic lymphohistiocytosis.

Germline HAVCR2 mutations, recently identified in a large subset of patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL), are associated with an increased risk of hemophagocytic lymphohistiocytosis (HLH). Discovery of this heritable HLH/SPTCL diathesis has expanded our understanding of a rare and molecularly heterogeneous lymphoma. Furthermore, patients with SPTCL have excellent survival unless they develop HLH. Therefore, through compiling data on SPTCL-related conditions that predispose patients to HLH, we are better able to predict which patients with SPTCL have the greatest risk of mortality. We present the first case of SPTCL with concomitant HLH and autoimmune lymphoproliferative syndrome (ALPS) in a patient who was subsequently diagnosed with familial HLH (F-HLH) attributable to a germline STXBP2 splice-site mutation. She had wild-type HAVCR2. Reports including ours show how SPTCL can evolve in the setting of an exaggerated host inflammatory response attributable to a variety of unusual underlying etiologies.