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Effective mentorship is a pivotal factor in shaping the career trajectory of trainees interested in classical hematology (CH), which is of critical importance due to the anticipated decline in the CH workforce. However, there is a lack of mentorship opportunities within CH compared with medical oncology. To address this need, a year-long external mentorship program was implemented through the American Society of Hematology (ASH) Medical Educators Institute (MEI). Thirty-five hematology/oncology (H/O) fellows interested in CH and 34 academically productive faculty mentors from different institutions across North America were paired in a meticulous process that considered individual interests, experiences, and background. Pairs were expected to meet virtually once a month. Participation in a scholarly project was optional. A mixed-methods sequential explanatory design was used to evaluate the program using mentee and mentor surveys, a mentee interview, and a mentee focus group. Thirty-three (94.2%) mentee-mentor pairs completed the program. Sixty-three percent of mentee respondents worked on a scholarly project with their mentor; several mentees earned publications, grants, and awards. Mentee perception that their assigned mentor was a good match was associated with a perceived positive impact on confidence (p=0.0423), career development (p=0.0423), and professional identity (p=0.0302). Furthermore, twenty-three (66%) mentees accepted CH faculty positions after fellowship. All mentor respondents believed that this program would increase retention in CH. This mentorship program demonstrates a productive, beneficial way of connecting mentees and mentors from different institutions to improve the careers of CH trainees, with the ultimate goal of increasing retention in CH.
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Several health policy institutes recommend reducing the number of indicators monitored by hospitals to better focus on indicators most relevant to local contexts. To determine which indicators are the most appropriate to eliminate, one must understand how indicator selection processes are undertaken. This study classifies hospital indicator selection processes and analyzes how they align with practices outlined in the 5-P Indicator Selection Process Framework. This qualitative, multiple case study examined indicator selection processes used by four large acute care hospitals in Ontario, Canada. Data were collected through 13 semistructured interviews and document analysis. A thematic analysis compared processes to the 5-P Indicator Selection Process Framework. Two types of hospital indicator selection processes were identified. Hospitals deployed most elements found within the 5-P Indicator Selection Process Framework including setting clear aims, having governance structures, considering indicators required by health agencies, and categorizing indicators into strategic themes. Framework elements largely absent included: adopting evidence-based selection criteria; incorporating finance and human resources indicators; considering if indicators measure structures, processes, or outcomes; and engaging a broader set of end users in the selection process. Hospitals have difficulty in balancing how to monitor government-mandated indicators with indicators more relevant to local operations. Hospitals often do not involve frontline managers in indicator selection processes. Not engaging frontline managers in selecting indicators may risk hospitals only choosing government-mandated indicators that are not reflective of frontline operations or valued by those managers accountable for improving unit-level performance.
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Gobierno , Política de Salud , Humanos , Hospitales , Ontario , Investigación CualitativaRESUMEN
Although there are more than 100 clinically distinct lymphoid neoplasms with varied prognoses and treatment approaches, they generally share high sensitivity to glucocorticoids, cytotoxic chemotherapy, and radiation. The disease control rates for lymphoid malignancies are higher than many solid tumors, and many are curable even when presenting with extensive involvement. Novel targeted therapies have improved disease control and cure rates for nearly all subtypes of lymphoid neoplasms. Surgical oncologists will primarily be involved in obtaining biopsies of sufficient quality to allow accurate diagnosis. However, there are scenarios in which surgical intervention may be necessary to address an oncologic emergency.
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Linfoma no Hodgkin , Linfoma , Mieloma Múltiple , Cirujanos , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , Linfoma/terapia , PronósticoRESUMEN
Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.
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Linfoma Folicular , Linfoma de Células B Grandes Difuso , Linfoma de Células del Manto , Humanos , Adulto , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Inmunoterapia Adoptiva , Linfocitos TRESUMEN
BACKGROUND: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. METHODS: We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per µL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. FINDINGS: Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. INTERPRETATION: Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. FUNDING: National Institutes of Health and National Cancer Institute.
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Infecciones por VIH , Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/patología , Brentuximab Vedotina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Doxorrubicina/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológicoRESUMEN
Writing proficiency facilitates higher achievement in educational and professional endeavors, yet most students fail to meet national writing benchmarks by the end of high school. Attentional control and overall reading skill are documented to result in better writing quality; however, most research on these relationships has focused on early elementary students (K-3rd grade. This project evaluated the relationship between attentional control, hyperactivity-impulsivity, word reading, and reading comprehension to overall writing performance on a high-stakes writing test. Participants included 266 fourth-grade struggling readers who completed the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN; Swanson et al., 2001, 2012) for attentional control and hyperactivity-impulsivity, the Woodcock-Johnson III (WJ-III; Woodcock et al., 2001) Letter-Word Identification test for word reading, the WJ-III Passage Comprehension test for reading comprehension, and the State of Texas Assessments of Academic Readiness (STAAR) writing test for overall writing. Hyperactivity-impulsivity was not related to word reading (ß = 0.02, p > .05), reading comprehension (ß = 0.06, p > .05), or writing (ß = 0.14, p > .05), whereas attentional control (ß = 0.51, p < .01) and reading comprehension (ß = 0.55, p < .001) contributed to overall writing. Reading comprehension (ß = 0.55, p < .01) had a greater impact on writing than word reading (ß = 0.13, p > .05), which suggests that as academic rigor increases in the upper elementary school grades (4th grade and higher), basic skills are less predictive of success on complex tasks such as writing. Implications for increasing writing proficiency through research and practice are discussed.
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Comprensión , Lectura , Humanos , Niño , Atención , Escritura , EscolaridadRESUMEN
Autologous hematopoietic cell transplantation (auto-HCT) has long been the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR-T therapy in the second-line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking; therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with a few key statements as follows: (1) in the first-line setting, there is no role for auto-HCT consolidation for patients achieving complete remission (CR) following R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) or similar therapy in non-double-hit/triple-hit cases (DHL/THL) and in DHL/THL cases receiving intensive induction therapies, but auto-HCT may be considered in eligible patients receiving R-CHOP or similar therapies in DHL/THL cases; (2) auto-HCT consolidation with thiotepa-based conditioning is standard of care for eligible patients with primary central nervous system lymphoma achieving CR with first-line therapy; and (3) in the primary refractory and early relapse setting, the preferred option is CAR-T therapy, whereas in late relapse (>12 months), consolidation with auto-HCT is recommended for patients achieving chemosensitivity to salvage therapy (complete or partial response), and CAR-T therapy is recommended for those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/terapia , Rituximab/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Vincristina/uso terapéutico , Prednisona/uso terapéutico , Doxorrubicina/uso terapéutico , RecurrenciaRESUMEN
Graduate medical education training in hematology in North America is accredited by the Accreditation Council for Graduate Medical Education (ACGME). Trainees routinely review peripheral blood smears (PBS) in providing clinical care. Competency in PBS review at graduation is required by the ACGME. However, there are no consensus guidelines on best practices surrounding PBS review, education, or competency. We describe the generation of proposed theory and the consensus recommendations developed through a multi-institutional focus group, developed using constructivist grounded theory and a modified nominal group technique. Eight academic hematologists, spanning classical and malignant hematology, enrolled and participated in 2 one-hour focus groups. All routinely worked with fellows and half had formally instructed trainees on PBS interpretation. Focus group data were analyzed using mixed-methods techniques. Tenets of emerging theory were identified through inductive coding. Consensus recommendations (CR) were generated. Participants reviewed CR in an iterative fashion until consensus was reached. Strong consensus was reached on multiple aspects of PBS education. All agreed that trainees should learn PBS review through a systematic approach. Group discussion focused on disorders of red and white blood cells. The diagnoses of acute leukemia and thrombotic microangiopathies were most commonly discussed, with specific emphasis on disorders in which prompt recognition was required to avert significant patient morbidity. These CR offer external validity to future research and curricular development for both PBS review and other visuospatial tasks in medical education.
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Competencia Clínica , Hematología , Humanos , Educación de Postgrado en Medicina , Acreditación , América del NorteRESUMEN
PURPOSE: Kaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS. EXPERIMENTAL DESIGN: The primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS. Secondary objectives included correlating response with natural killer (NK) and T-cell subsets, plasma cytokines, viral copy number, and KSHV gene expression in biopsies. Four dose levels of oral lenalidomide taken 21 consecutive days of 28-day cycles were evaluated in adults with HIV-KS on antiretroviral therapy with controlled viremia. RESULTS: Fifteen and 23 participants enrolled in phases I and II, respectively, 76% of whom had received prior KS therapy. The MTD was not reached, declaring 25 mg as the recommended phase II dose (RP2D). The most frequent adverse events were neutropenia, fatigue, leukopenia, and diarrhea. Of the 25 evaluable participants receiving RP2D, 60% responded. Correlative studies performed in a subset of participants demonstrated a significant increase in proportions of blood T cells with T-regulatory phenotype, and plasma cytokines trended toward a less inflammatory pattern. Clinical response was associated with loss of KSHV transcription. CONCLUSIONS: Lenalidomide is active in HIV-KS. The most common adverse events were manageable. With 60% of participants receiving RP2D obtaining a partial response and <10% discontinuing due to adverse events, the response and tolerability to lenalidomide support its use in HIV-KS. See related commentary by Henry and Maki, p. 2485.
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Infecciones por VIH , Herpesvirus Humano 8 , Sarcoma de Kaposi , Citocinas/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Lenalidomida/efectos adversos , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/patologíaRESUMEN
INTRODUCTION: Chimeric antigen receptor T (CAR-T) cells targeting CD19 result in durable responses in approximately 40% of DLBCL patients. Loncastuximab tesirine, an antibody drug conjugate targeting CD19 with a pyrrolobenzodiazepine payload, has activity against DLBCL. PATIENTS AND METHODS: We evaluated the outcomes of 13 DLBCL patients relapsed after CAR-T cells treated with loncastuximab in the LOTIS-2 trial. RESULTS: Six patients (46%) had responses to loncastuximab (CR, n = 2). Median OS, PFS and duration of response after loncastuximab were 8.2, 1.4 and 8 months, respectively. CONCLUSION: Loncastuximab can achieve responses in patients progressing after CAR-T cells. Sequencing CD19-targeting therapies is possible in cases without CD19 loss.
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Antineoplásicos , Inmunoconjugados , Receptores Quiméricos de Antígenos , Antígenos CD19 , Antineoplásicos/uso terapéutico , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Inmunoterapia AdoptivaRESUMEN
In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.
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Inmunoconjugados , Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Adulto , Antígenos CD19 , Humanos , Inmunoconjugados/uso terapéutico , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológicoRESUMEN
This single-center, retrospective cohort study evaluates whether insurance coverage and Ryan White HIV/AIDS Program assistance are associated with differences in treatment and survival outcomes in Kaposi sarcoma and aggressive non-Hodgkin lymphoma among people with HIV (PWH). Participants were classified as having private, Medicare, Medicaid, or no insurance. Hazard ratios (HRs) for progression and death were estimated using Cox proportional hazards regression models. Propensity score weighting was used to adjust for imbalances in age, ethnicity, and performance status. Among 191 participants, 18% had private insurance, 14% had Medicare, 46% had Medicaid, and 23% were uninsured. Forty-four percent received Ryan White assistance. Participants with Medicare and those without Ryan White assistance were older. Those without Ryan White assistance also had worse performance status. No differences in CD4+ T cell counts, HIV viral loads, highly active antiretroviral therapy adherence, time to treatment, and regimen selection were detected. After adjustment with propensity score weighting, participants without Ryan White assistance had a greater risk of death [adjusted HR 4.06, 95% confidence interval (CI) 1.45-11.41, p = .008] and progression (adjusted HR 3.39, 95% CI 1.43-8.05, p = .006) than those with Ryan White assistance. We conclude that among people with AIDS-defining cancers, those with Medicare and those without Ryan White assistance had higher mortality, possibly due to age and other medical comorbidities. Notably, underinsured PWH who received Ryan White assistance experienced similar outcomes as those with private insurance.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Cobertura del Seguro , Neoplasias , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Medicare , Neoplasias/complicaciones , Neoplasias/terapia , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Benzodiazepinas/uso terapéutico , Inmunotoxinas/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Benzodiazepinas/efectos adversos , Neutropenia Febril/inducido químicamente , Femenino , Humanos , Inmunotoxinas/efectos adversos , Masculino , Persona de Mediana Edad , Recurrencia , Trombocitopenia/inducido químicamente , Adulto JovenRESUMEN
EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Genes myc , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recuento de Linfocito CD4 , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , ADN Viral/sangre , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/virología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/aislamiento & purificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Estimación de Kaplan-Meier , Linfoma Relacionado con SIDA/complicaciones , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/virología , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/virología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Prednisona/administración & dosificación , Prednisona/efectos adversos , Supervivencia sin Progresión , Estudios Prospectivos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversos , Carga Viral/efectos de los fármacos , Vorinostat/administración & dosificación , Vorinostat/efectos adversosRESUMEN
PURPOSE: AIDS-related Kaposi sarcoma is often incompletely controlled, requiring serial therapies. Kaposi sarcoma herpesvirus (KSHV) induces transformation of endothelial cells, where it resides in a predominately latent state. We hypothesized proteasome inhibition would have direct antitumor activity, induce lytic activation of KSHV, and inhibit HIV infectivity, improving control of both Kaposi sarcoma and HIV. The primary objective was determining the MTD of bortezomib in AIDS-Kaposi sarcoma. Secondary objectives included estimating the impact of bortezomib on Kaposi sarcoma response, KSHV plasma DNA copy number (PDCN), and HIV viral loads (VL). PATIENTS AND METHODS: A 3+3 dose escalation design was employed evaluating four dose levels of bortezomib (0.75, 1, 1.2, or 1.6 mg/m2) administered intravenously on days 1, 8, and 15 of 28-day cycles in patients with relapsed/refractory (r/r) AIDS-Kaposi sarcoma taking antiretroviral therapy. RESULTS: Seventeen patients enrolled. No dose-limiting toxicities occurred and the MTD was not reached. The most common adverse events included diarrhea, fatigue and nausea. Among 15 evaluable patients, partial response (PR) occurred in nine (60%), with a PR rate of 83% in the 1.6 mg/m2 cohort; the remainder had stable disease (SD). Median time to response was 2.1 months. Median change in KSHV PDCN was significantly different between those with PR versus SD. During cycle 1, seven of 11 evaluable patients had decreases in HIV VL. CONCLUSIONS: Bortezomib is well-tolerated and active in AIDS-Kaposi sarcoma. The 60% PR rate is notable given the dose-finding nature of the study in a r/r population. Changes in KSHV PDCN and HIV VL trended as hypothesized.
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Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Bortezomib/uso terapéutico , Células Endoteliales/patología , Herpesvirus Humano 8/aislamiento & purificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Sarcoma de Kaposi/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/patología , Adulto , Antineoplásicos/uso terapéutico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Seguridad del Paciente , Proyectos Piloto , Sarcoma de Kaposi/patología , Resultado del TratamientoRESUMEN
PURPOSE: ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate comprising a CD19-targeting antibody and pyrrolobenzodiazepine dimers. A first-in-human study evaluated the safety and preliminary clinical activity of loncastuximab tesirine in patients with B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: A multicenter, phase I, dose-escalation and dose-expansion study enrolled patients ages ≥18 years with relapsed/refractory (R/R) B-cell NHL. Patients received loncastuximab tesirine every 3 weeks at doses assigned by a 3+3 dose-escalation design. Dose escalation was used to assess the safety and tolerability of loncastuximab tesirine to determine the dose for expansion. Secondary objectives evaluated clinical activity, characterized the pharmacokinetic profile, and evaluated antidrug antibodies. RESULTS: During dose escalation, 88 patients with R/R B-cell NHL were treated with loncastuximab tesirine at doses 15 to 200 µg/kg. Treatment-emergent adverse events (TEAEs) were experienced by 87/88 (98.9%) patients. Most common TEAEs (≥20% of patients) were hematologic abnormalities, fatigue, edema, liver test abnormalities, nausea, rash, and dyspnea. Grade ≥3 TEAEs (≥5% of patients) included hematologic abnormalities, liver test abnormalities, fatigue, and dyspnea. Overall response rate at doses ≥120 µg/kg was 59.4% (41 of 69 patients; 40.6% complete response; 18.8% partial response). Median duration of response, progression-free survival, and overall survival (all doses) were 4.8, 5.5, and 11.6 months, respectively. Drug exposure increased with increasing dose, showing moderate accumulation with multiple doses ≥150 µg/kg. There was no evidence of immunogenicity. CONCLUSIONS: Loncastuximab tesirine had promising activity with acceptable safety in this dose-escalation study. A phase II study with initial dosing at 150 µg/kg has been initiated based on these results.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD19/química , Antineoplásicos/uso terapéutico , Benzodiazepinas/química , Inmunoconjugados/uso terapéutico , Linfoma de Células B/terapia , Recurrencia Local de Neoplasia/terapia , Pirroles/química , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD19/inmunología , Benzodiazepinas/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Pronóstico , Terapia Recuperativa , Tasa de Supervivencia , Adulto JovenRESUMEN
Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.
Asunto(s)
Linfoma Folicular/terapia , Linfoma de Células B Grandes Difuso/terapia , Oncología Médica/normas , Recurrencia Local de Neoplasia/terapia , Adulto , Cuidados Posteriores/normas , Antineoplásicos Inmunológicos/normas , Antineoplásicos Inmunológicos/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/normas , Linfoma Folicular/inmunología , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Oncología Médica/métodos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Inhibidores de las Quinasa Fosfoinosítidos-3/normas , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Estados UnidosRESUMEN
Inadequate responders demonstrate significant risk for learning disabilities. Previous investigations of the cognitive profiles of inadequate and adequate responders have not included measures of executive functions (EF), which have well-documented associations to reading comprehension. We evaluated EF performance on a common factor comprised of shared variance across tasks as well as five separable EF factors in the context of an intensive reading intervention for struggling fourth graders. To determine if EF performance at pretest is associated with subsequent responder status, we compared EF performance of three subgroups of students: inadequate and adequate responders and typical students not at-risk for reading disabilities. Results of discriminant function analyses and linear regression models comparing groups were largely null; EF performance at pretest demonstrated only small associations with responder status. These results suggest that the assessment of EF may have limited value in predicting which individual students will respond to intensive reading interventions.
Asunto(s)
Brentuximab Vedotina/farmacología , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma de Efusión Primaria/tratamiento farmacológico , Antineoplásicos Inmunológicos/farmacología , Brentuximab Vedotina/uso terapéutico , Humanos , Antígeno Ki-1/metabolismo , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin's lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.