Quality of life assessment in diffuse large B-cell lymphoma (DLBCL) in REFLECT: a prospective, non-interventional, multicenter, German study, assessing Sandoz rituximab in combination with CHOP.

Health-related quality of life (HRQoL) data are important indicators of health status in patients with lymphoma. The objective of this analysis was to assess the impact of treatment with Sandoz rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on HRQoL in treatment-naïve adult patients with diffuse large B-cell lymphoma (DLBCL) included in the prospective, real-world REFLECT study. REFLECT is the first prospective study to assess HRQoL in patients with DLBCL treated with a rituximab biosimilar. HRQoL was assessed via the patient-reported European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire at baseline, mid-treatment (month 3), end of treatment (month 6), and follow-up (months 9 and 12). Subgroup analyses were performed to evaluate the influence of baseline characteristics on HRQoL, and associations between baseline HRQoL and treatment response. HRQoL was assessed in 169 patients. Mean global health status score remained stable from baseline (54.8) to mid-treatment (month 3; 54.7), before steadily improving through to end of treatment (month 6; 61.4), and follow-up month 9 (64.9) and month 12 (68.8). Similar trends were observed across most functional and symptom subscales. Higher cognitive, physical, or role functioning, and less appetite loss, diarrhea, fatigue, or pain at baseline, were all associated with an improved likelihood of reaching a complete versus partial response at the end of treatment. Overall, these findings confirm the HRQoL benefits of R-CHOP therapy in treatment-naïve adult patients with DLBCL, and suggest that baseline HRQoL may be predictive of treatment response.

Time-dependent cost comparison and health economic impact analysis of second-line interventions for transplant-ineligible patients with relapsed or refractory diffuse large B cell lymphoma.

OBJECTIVES: Novel interventions (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tafasitamab-lenalidomide [Tafa-L], polatuzumab-rituximab-bendamustine [pola-BR]) improve clinical outcomes in second-line (2 L) treatment of transplant-ineligible patients with early relapse or refractory (R/R) diffuse large B cell lymphoma (DLBCL). The costs vary depending on the respective treatment regimen and the treatment duration, difficult comparability in reimbursement decisions. The objective was to analyze the health economic impacts of novel 2 L interventions and conventional immunochemotherapies (bendamustine-rituximab [BR], rituximab-gemcitabine-oxaliplatin [R-GemOx]) from a German healthcare payer's perspective as a function of treatment duration. METHODS: An economic model was developed to compare treatment costs of 2 L interventions depending on the treatment duration. Treatment duration was measured by progression-free survival (PFS), identified based on a systematic review. Total and average costs were calculated over 5 years to evaluate incremental costs at median PFS for each intervention. RESULTS: Average costs per month at median PFS ranged from €2846 (95% CI: 5067-1641) to €40 535 (95% CI: 91180-N/A) for BR and liso-cel, respectively. Incremental costs at the lowest median PFS (R-GemOx: 5.3 months) revealed -€664, €5560, €11 817, €53 145, and €67 745 for BR, Tafa-L, pola-BR, axi-cel, and liso-cel as compared to R-GemOx, respectively. CONCLUSIONS: Analyses uncovered a variation of incremental costs of 2 L transplant-ineligible DLBCL interventions as a function of time leading to amortization of high-priced interventions.

Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Real-world total cost of care by line of therapy in relapsed/refractory diffuse large B-cell lymphoma.

AIMS: There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy. METHODS: Treatment costs and resources in the R/R setting were assessed by LoT. A sensitivity analysis identified any potential confounding of the results caused by the impact of the COVID-19 pandemic on healthcare utilization and costs. Overall, 310 patients receiving a second- or later-line treatment were included; baseline characteristics were similar across LoTs. Inpatient costs represented the highest percentage of total costs, followed by outpatient and pharmacy costs. RESULTS: Mean TCC per-patient-per-month generally increased by LoT ($40,604, $48,630, and $59,499 for second-, third- and fourth-line treatments, respectively). Costs were highest for fourth-line treatment for all healthcare resource utilization categories. Sensitivity analysis findings were consistent with the overall analysis, indicating results were not confounded by the COVID-19 pandemic. LIMITATIONS: There was potential misclassification of LoT; claims data were processed through an algorithm, possibly introducing errors. A low number of patients met the inclusion criteria. Patients who switched insurance plans, had insurance terminated, or whose enrollment period met the end of data availability may have had truncated follow-up, potentially resulting in underestimated costs. CONCLUSION: Total healthcare costs increased with each additional LoT in the R/R DLBCL setting. Further improvements of first-line treatments that reduce the need for subsequent LoTs would potentially lessen the economic burden of DLBCL.

Cost-effectiveness analysis 3L of axicabtagene ciloleucel vs tisagenlecleucel and lisocabtagene maraleucel in Japan.

Aim: Cost-effectiveness analysis (CEA) was performed to compare axicabtagene ciloleucel (axi-cel) with tisagenlecleucel (tisa-cel) and lisocabtagene (liso-cel) for treatment of relapsed or refractory large B-cell lymphoma in adult patients after ≥2 lines of therapy in Japan. Materials & methods: Cost-effectiveness analysis was conducted using the partition survival mixture cure model based on the ZUMA-1 trial and adjusted to the JULIET and TRANSCEND trials using matching-adjusted indirect comparisons. Results & conclusion: Axi-cel was associated with greater incremental life years (3.13 and 2.85) and incremental quality-adjusted life-years (2.65 and 2.24), thus generated lower incremental direct medical costs (-$976.29 [-¥137,657] and -$242.00 [-¥34,122]), compared with tisa-cel and liso-cel. Axi-cel was cost-effective option compared with tisa-cel and liso-cel from a Japanese payer's perspective.

[Box: see text].

Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

BACKGROUND: Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab. METHODS: Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing. RESULTS: Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here. CONCLUSIONS: This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.

Real-World Survival, Healthcare Resource Utilization, and Costs Among U.S. Elderly Patients With Diffuse Large B-Cell Lymphoma (DLBCL) Treated With R-GemOx in the Relapsed/Refractory Setting.

BACKGROUND: Little recent real-world evidence exists on overall survival, healthcare resource utilization (HCRU), and costs among R/R DLBCL patients treated with the combination of rituximab, gemcitabine, and oxaliplatin (R-GemOx), a widely-used regimen for patients ineligible for stem cell transplant due to age or comorbidities. PATIENTS AND METHODS: This retrospective analysis used 2014 to 2019 U.S. Medicare claims. Individuals aged ≥66 years with a new DLBCL diagnosis between October 1, 2015 and December 31, 2018 and continuous fee-for-service Medicare Part A, B, and D coverage in the 12 months pre- and postindex were followed to identify the sample of patients with evidence of R-GemOx treatment in the second-line (2L) or third-line (3L) setting. Outcomes included overall survival, all-cause and DLBCL-related HCRU, and costs after R-GemOx initiation. RESULTS: The final sample included 157 patients who received treatment with R-GemOx in the R/R settings (mean (SD) age 77.5 (6.0) years, 39.5% age>80 years; 66.9% male; 91.1% White). Of these, 126 received R-GemOx in the 2L setting and 31 received R-GemOx in the 3L setting. Median overall survival from R-GemOx initiation was 6.9 months and 6.8 months in the 2L and 3L setting, respectively. Rates of all-cause hospitalization (68.1% [2L] and >90% [3L]) and hospice use (42.9% [2L] and 51.7% [3L]) were high in the 12 months after R-GemOx initiation. All-cause total costs were substantial ($144,653 [2L] and $142,812 [3L]) and approximately 80% of costs were DLBCL-related within 12 months of R-GemOx initiation. CONCLUSION: Elderly U.S. Medicare beneficiaries diagnosed with DLBCL who initiated R-GemOx treatment in the R/R setting have poor overall survival, high rates of HCRU, and substantial costs.

Noninvasive minimal residual disease assessment in relapsed/refractory large B-cell lymphoma using digital droplet PCR.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes.

The impact of marginalization on diffuse large B-cell lymphoma overall survival: a retrospective cohort study.

The aim of this study was to describe the impact of marginalization on DLBCL overall survival (OS) within the Canadian setting. We conducted a population-based retrospective cohort study of adult patients with newly diagnosed DLBCL in Ontario between 1 January 2005 and 31 December 2017 receiving a rituximab-containing chemotherapy regimen with curative intent followed until 1 March 2020. Our primary exposure of interest was the Ontario Marginalization Index (ON-Marg). The primary outcome was 2-year OS, accounting for patient age, sex, cancer characteristics, comorbidity burden, and rural dwelling status. While two-year overall survival was inferior for individuals in the most deprived marginalization quintile (70.4% Q5 vs. 76.0% Q1), after adjustment for relevant covariates neither the composite ON-Marg nor any of its dimensions had a significant effect. Within the Canadian context, among patients who receive chemotherapy, marginalization may not have a significant association with overall survival when accounting for key patient covariates, lending support for preserved outcomes.

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

BACKGROUND/AIM: This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. PATIENTS AND METHODS: To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. RESULTS: Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. CONCLUSION: ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

Ibrutinib Plus RCHOP versus RCHOP Only in Young Patients with Activated B-Cell-like Diffuse Large B-Cell Lymphoma (ABC-DLBCL): A Cost-Effectiveness Analysis.

The standard treatment for Diffuse Large B-Cell Lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). However, many patients require subsequent treatment after relapsed disease. The ABC subtype of DLBCL (ABC-DLBCL) has a worse prognosis, and the PHOENIX trial explored adding ibrutinib to RCHOP for this patient population. The trial showed favorable outcomes for younger patients, and our study aimed to inform clinical decision-making via a cost-effectiveness model to compare RCHOP with and without ibrutinib (I-RCHOP). A Markov decision analysis model was designed to compare the treatments for patients younger than 60 years with ABC-DLBCL. The model considered treatment pathways, adverse events, relapses, and death, incorporating data on salvage treatments and novel therapies. The results indicated that I-RCHOP was more cost-effective, with greater quality-adjusted life years (QALY, 15.48 years vs. 14.25 years) and an incremental cost-effectiveness ratio (ICER) of CAD 34,111.45/QALY compared to RCHOP only. Sensitivity analyses confirmed the model's robustness. Considering the high market price for ibrutinib, I-RCHOP may be more costly. However, it is suggested as the preferred cost-effective strategy for younger patients due to its benefits in adverse events, overall survival, and quality of life. The decision analytic model provided relevant and robust results to inform clinical decision-making.

Resultados de 15 años de tratamiento del Linfoma Difuso a Grandes Células B con Rituximab en primera línea en el Uruguay / Results of 15 years of treatment of Diffuse Large Cell B-Cell Lymphoma with Rituximab in first line in Uruguay

INTRODUCCIÓN: El rituximab es un anticuerpo monoclonal quimérico, (murino-humano), producido por ingeniería genética, dirigido contra el antígeno CD20. Dicho antígeno es una proteína transmembrana de superficie que participa en funciones de activación, diferenciación y proliferación, así como en la transducción de señales. Constituye un marcador del linfocito B que se expresa en los linfocitos pre- B y linfocitos B maduros normales como también en el 95% de loslinfomas no Hodgkin (LNH) de origen B, por lo que loconstituye en un blanco de tratamiento de estos linfomas. El rituximab se une al antígeno CD20 en las células B que lo expresan, sean normales o malignas, y determina su depleción mediante acción anti-proliferativa y apoptótica directas y por acciónindirecta a través del complemento con activación de la citotoxicidad celular. Presenta acción sinérgica con algunos agentes quimioterápicos, lo que ha llevado a su usocombinado en algunos planes de quimioinmunoterapia en la práctica clínica. OBJETIVOS: El objetivo primario evaluar la sobrevida global de los pacientes con LDGCB tratados con quimioinmunoterapia en primera línea, bajo cobertura del FNR. METODOLOGÍA: Diseño de estudio: Estudio analítico de una cohorte histórica de pacientes con LDGCB que iniciaron tratamiento con quimio inmunoterapia en primera línea de tratamiento entre el 1º enero de 2005 y el 31 de diciembre de 2019. Criterios de inclusión: Pacientes con diagnóstico de LDGCB en primera línea de quimio inmunoterapia incluyendo aquellos con diagnóstico de linfoma folicular evolucionado, leucemias transformadas, pacientes con compromiso de SNC, linfomas símil Burkitt linfoma de la zona gris; de origen centro germinal o no. En quienes se estableció diagnóstico únicamente por biopsia con anatomía patológica e IHQ en cualquier estadio de la enfermedad. Bajo protocolo de tratamiento quimioterápico validado para su uso asociado al rituximab, en inducción, de tipo CHOP like con intención curativa. Documentando que se les haya autorizado al menos la 1 dosis de rituximab. Criterios de exclusión: Imposibilidad de recibir el tratamiento con intención curativa por comorbilidades asociadas. Se admitieron pacientes que asociaron tratamiento radiante y pacientes con diagnóstico de VIH, VHB y VHC. RESULTADOS: En el período considerado se recibieron 3203 solicitudes de tratamiento de inducción de la remisión con rituximab para 2644 pacientes con Linfoma No Hodgkin. El diagnóstico por anatomía patológica de LDGCB estaba en 1699 solicitudes (53,04%) y el resto fueron linfomas del manto 154 (4,81%), 987 (30,54 %) linfoma folicular grado I y II, 345 (10,77%) a linfoma folicular grado III y 27 (0,84%) pacientes no tenían dato de diagnóstico. De las 1699 solicitudes para pacientes con LDGCB el tratamiento se autorizó en 1597 (94,0%) de los casos y no se autorizó en 102 (6%). Respecto a la situación al momento de la solicitud del tratamiento, entre los 1597 LDGCB con tratamientos autorizados, 1585 tenían cargado el dato de situación clínica, de los cuales 1413 (89,21%) se trataba del debut de la enfermedad, 112 de recaída (7,07%), 13 de progresión lesional bajo tratamiento (0,82%), 10 pacientes en remisión parcial (0,63%), 4 por resistencia a tratamiento previo (0,25%), otra situación 29 (1,83%) y sin dato 3 solicitudes (0,19%). Analizaremos las características de la población de 1413 pacientes con diagnóstico de LDGCB con solicitud autorizada al debut de la enfermedad. CONCLUSIONES: La normativa para rituximab se basa en evidencia científica de trabajos fase III con impacto en calidad de vida y supervivencia global. Brinda la posibilidad del uso universal y equitativo del rituximab, mejorando la calidad de asistencia de los LDGCB y esto se refleja en la obtención de resultados comparables con estándares internacionales. Encontramos una proporción de pacientes menor a la esperada del interior del país y de la asistencia pública. La misma se ha corregido parcialmente para la población del interior y se ha acentuado en la asistencia pública. A través de la normativa de financiación, rituximab está disponible para toda la población en forma equitativa, por lo que sería importante conocer con más precisión los factores que llevan a dicha asimetría para poder generar acciones que favorezcan a que todos accedan por igual a la medicación. Los resultados de supervivencia encontrados en el presente estudio son los esperados de acuerdo con los trabajos de referencia utilizados en el diseño de la normativa de cobertura de rituximab lo que refleja un trabajo de buena calidad en diagnóstico, evaluación, tratamiento y seguimiento a nivel nacional.

Brentuximab Vedotina en linfomas / Brentuximab Vedotin in Lymphomas

INTRODUCCIÓN: Los linfomas son un grupo heterogéneo de enfermedades linfoproliferativas malignas. Se dividen en linfoma Hodgkin y linfomas no-Hodgkin. La mayoría de los linfomas tienen una buena respuesta a las primeras líneas de tratamiento que generalmente incluyen quimioterapia y, en ocasiones, trasplante de células madres. Sin embargo, los pacientes refractarios o que recaen luego del tratamiento de primera o segunda línea tienen mal pronóstico y escasas opciones terapéuticas. Se postula el uso de Brentuximab Vedotina (BV) para el tratamiento de linfomas que expresan la proteína de membrana CD30, como son el linfoma Hodgkin clásico (LHC), el linfoma anaplásico de células grandes (LACG), el linfoma difuso de células B grandes (LDCBG) y la micosis fungoide y síndrome de Sézary (MF/SS). TECNOLOGÍA: El brentuximab vedotina (BV) es un anticuerpo monoclonal anti-CD30. La dosis es 1,8 mg/kg de peso por vía endovenosa cada 21 días y se recomiendan 8 a 16 ciclos. Los eventos adversos graves más frecuentes son la neuropatía periférica y la neutropenia. OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de Brentuximab Vedotina para linfoma Hodgkin clásico en distintos escenarios, linfoma anaplásico de células grandes refractario o recaído, linfoma difuso de células B grandes refractario o recaído y micosis fungoide y síndrome de Sézary refractario o recaído. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas (incluyendo Medline, Cochrane y CRD), en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias y económicas, guías de práctica clínica y políticas de cobertura de otros sistemas de salud cuando estaban disponibles. RESULTADOS: Se incluyeron un meta-análisis, un ECA, diez series de casos, tres documentos de ETS, diez guías de práctica clínica y nueve políticas de cobertura. En el LHC refractario o recaído a la segunda línea de tratamiento (comúnmente un trasplante autólogo de células madres [auto-TCM]), no se encontraron estudios comparativos. Un meta-análisis indirecto comparó una serie de casos tratados con BV (n=102) con un grupo control heterogéneo de series de casos y estudios retrospectivos con tratamientos estándar (n=2518). Se evidenció una diferencia en la mediana de sobrevida global de 40,5 meses (IC95%: 30,8-no estimable) con BV comparado con 26,4 meses (IC95%: 23,5-28,5, p<0,0001) del tratamiento estándar, aunque la interpretación de estos resultados tiene serias limitaciones. La tasa de respuesta objetiva (TRO, definida como las remisiones completas más las remisiones parciales) del BV fue 72%, con 33% de remisiones completas (RC). Los eventos adversos (EA) más frecuentes fueron la neuropatía periférica (42%), náuseas (35%), fatiga (34%) y la neutropenia (19%). En pacientes con LHC con alto riesgo de recaída luego de un auto-TCM, un ECA (n=327) evaluó el BV vs. placebo como tratamiento de consolidación. Al momento del análisis no se demostró una diferencia en la sobrevida global; la sobrevida libre de progresión fue 42,9 meses con BV y de 24,1 meses en el grupo placebo (HR: 0,57; IC 95%: 0,4­0,81; p<0,01). Los estudios analizados sobre el uso de BV en LHC como primera línea de tratamiento (1 serie de casos) o como puente a un TCM de rescate (1 serie de casos y 2 estudios retrospectivos) no mostraron beneficios claros del BV. En una serie de casos (n=58) con LACG sistémico refractario o recaído el BV mostró en una TRO de 86% (RC 57%), lo cual es considerado superior a las escasas alternativas terapéuticas disponibles. En el uso de BV para el LDCBG y la MF/SS refractarios o recaídos se analizaron una serie de casos para la primera indicación (n=49) y dos series de casos para la segunda (n=32 y 28). No se encontraron ventajas claras con respecto a otras terapias establecidas. Las guías de práctica clínica, las evaluaciones de tecnologías sanitarias y las políticas de cobertura limitan el uso del BV al tratamiento del LHC refractario o recaído y del LACG refractario o recaído. Su uso es controvertido en otras indicaciones. CONCLUSIONES: La evidencia encontrada es de baja calidad. El uso de brentuximab vedotina en el linfoma Hodgkin clásico refractario o recaído y en el linfoma anaplásico de células grandes sistémico refractario o recaído ha demostrado una alta tasa de respuestas, aunque faltan estudios comparativos y su impacto en la sobrevida a largo plazo es incierto. Ante las limitadas opciones terapéuticas y el mal pronóstico de estos pacientes la mayoría de las sociedades internacionales y financiadores de salud lo consideran una alternativa válida. La evidencia es de baja calidad sobre el uso de brentuximab vedotina en el linfoma Hodgkin clásico como consolidación luego del trasplante autólogo de células madres, como puente al trasplante alogénico de células madres o como primera línea de tratamiento, así como también en el linfoma difuso de células B grandes y en la micosis fungoide y síndrome de Sézary. La falta de mejoría en la sobrevida y la posibilidad de alternativas terapéuticas hacen que no se la considere como estándar de tratamiento y no sea financiado para estas indicaciones.(AU)

INTRODUCTION: Lymphomas comprise a heterogeneous group of malignant lymphoproliferative diseases. They divide into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Most lymphomas have good response to first-line therapies, which generally include chemotherapy and, occasionally, stem cell transplantation. However, patients who are refractory or who relapse after first or second-line therapy have poor prognosis and few therapeutic options. The use of brentuximab vedotin (BV) is proposed for the treatment of lymphomas expressing CD30 membrane protein, such as classical Hodgkin's lymphoma (CHL), anaplastic large-cell lymphoma (ALCL), diffuse large-B-cell lymphoma (DLBCL) and mycosis fungoides and Sézary syndrome (MF/SS). TECHNOLOGY: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody. The dose is 1.8 mg/kg; it is administered intravenously every 21 days and 8 to 16 cycles are recommended. The most common serious adverse events are peripheral neuropathy and neutropenia. PURPOSE: To assess the available evidence on the efficacy, safety and coverage policy related aspects on the use of brentuximab vedotin for classical Hodgkin's lymphoma in different settings, refractory or relapsed anaplastic large-cell lymphoma, refractory or relapsed diffuse large-B-cell lymphoma and refractory or relapsed mycosis fungoides and Sézary syndrome. METHODS: A bibliographic search was carried out on the main databases (such as MEDLINE, Cochrane and CRD), in general Internet engines, in health technology assessment agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments (HTA) and economic evaluations; clinical practice guidelines and coverage policies of other health systems, when available. RESULTS: One meta-analysis, one RCT, ten case series, three HTA documents, ten clinical practice guidelines and nine coverage policies were included. In relapsed CHL or refractory to second line therapy (commonly an autologous stem-cell transplantation [ASCT]), no comparative studies were found. One indirect meta-analysis compared a case series treated with BV (n=102) with a heterogeneous control group of case series and retrospective studies with standard treatments (n=2518). A difference in the median overall survival of 40.5 months was observed (95%CI: 30.8-cannot be estimated) with BV compared with 26.4 months (95%CI: 23.5-28.5, p<0.0001) of standard treatment, although the interpretation of these results has serious limitations. The objective response rate (ORR, defined as complete remissions plus partial remissions) with BV was 72%; 33% were complete remissions (CR). The most common adverse events (AE) were peripheral neuropathy (42%), nausea (35%), fatigue (34%) and neutropenia (19%). In patients with CHL at high risk of relapse after ASCT, one RCT (n=327) evaluated BV vs. placebo as consolidation therapy. At the time of analysis, no difference was demonstrated in overall survival; progression-free survival was 42.9 months with BV and 24.1 months in the placebo group (HR: 0.57; 95% CI: 0.4­0.81; p<0.01). The studies analyzing the use of BV in CHL as first line therapy (one case series) or as a bridge to a salvage treatment with ASCT (one case series and two retrospective studies) did not show clear benefits for BV. In one case series (n=58) with refractory or relapsed systemic ALCL treated with BV showed an ORR of 86% (CR 57%), which is considered better than the scarce therapeutic options. When using BV for cases of refractory or relapsed DLBCL and MF/SS, a case series in the first indication (n=49) and two case series in the second indication (n=32 and 28) were analyzed. No clear advantages were found compared with the other established therapies. The clinical practice guidelines, the health technology assessments and the coverage policies limit the use of BV for the treatment of refractory or relapsed CLH and refractory or relapsed ALCL. Its use is controversial for other indications. CONCLUSIONS: The evidence found is of poor quality. The use of brentuximab vedotin for refractory or relapsed classical Hodgkin ́s lymphoma and refractory or relapsed systemic anaplastic large-cell lymphoma has demonstrated a high response rate, although comparative studies are missing and its impact on long-term survival is uncertain. In view of the limited therapeutic options and the poor prognosis these patient have most international societies and health sponsors consider it a valid option. The evidence on the use of brentuximab vedotin is of low quality for classical Hodgkin ́s lymphoma as consolidation therapy after autologous stem cell transplant, as bridge to allogenic stem cell transplant or as first-line therapy, as well as for refractory or relapsed diffuse large B cell lymphoma and in mycosis fungoides and Sézary syndrome. The lack of improved survival and the availability of other therapeutic alternatives are the reason not to consider it as a standard treatment and it is therefore not covered for this indications.(AU)

Rituximabe no tratamento do linfoma não Hodgkin difuso de grandes células B / Rituximab in the treatment of diffuse large B-cell non-Hodgkin's lymphoma

INTRODUÇÃO: Os linfomas não Hodgkin (LNH) são um grupo heterogêneo de tumores malignos, caracterizados por crescimento anormal das células do sistema linfático. Aproximadamente 85% dos LNH derivam de células B e 25%, de células T. De acordo com o REAL (Revised European-American Lymphoma), os LNH são classifi cados como indolentes, com curso clínico lento e progressivo por vários anos ou agressivos, de evolução rápida, os quais, se não tratados, podem ser fatais em alguns meses. O subtipo mais comum de LNH agressivo é o linfoma difuso de grandes células B (LDGCB), que representa 60 a 70% dos LNH agressivos e mais de 30% de todos os LNH. De acordo com o Instituto Nacional do Câncer (INCA)5 , o número de casos de LNH praticamente duplicou nos últimos 25 anos, particularmente entre pessoas acima de 60 anos. Dados disponíveis no DATASUS revelam que no período de janeiro de 2008 a agosto de 2009, o LNH apresentou uma taxa de mortalidade de 10,49%, sendo responsável por 1.667 óbitos. TECNOLOGÍA: Tecnologia O rituximabe é um anticorpo monoclonal quimérico camundongo/humano que se liga especificamente ao CD20, antígeno transmembrana presente nos linfócitos pré-B e nos linfócitos B maduros. O CD20 é expresso em pelo menos 90% das células B dos linfomas não Hodgkin. Após a ligação ao antígeno CD20, o rituximabe provoca a lise do linfócito B. CONCLUSÃO: As evidências de eficácia do esquema R-CHOP comparado ao esquema CHOP foram obtidas das revisões sistemáticas (RS) realizadas por Knight et al. (2004), Cheung et al. (2007) e Murdoch & Sager (2008). Os resultados dos estudos primários para o desfecho sobrevida livre de eventos são consistentes e o uso do rituximabe esteve associado signifi cativamente em todos os estudos ao aumento da probabilidade de sobrevida livre de eventos e de sobrevida global; houve maior percentual de sobrevida nos pacientes que usaram rituximabe, com resultados estatisticamente signifi cativos em três estudos avaliados pelas RS. Não foram encontrados estudos sobre a segurança do RCHOP em longo prazo, o que justifi ca o acompanhamento do uso dessa tecnologia. Quanto à abordagem econômica, o esquema R-CHOP mostrou-se custo-efetivo em relação ao esquema CHOP em todos os estudos de custo-efetividade apresentados e realizados em outros países. Não há estudo de custoefetividade brasileiro. Contudo, realizou-se um exercício de custo-efetividade do esquema R-CHOP para o Brasil, o qual apontou que o referido esquema não seria custoefetivo, sendo que o preço de aquisição do medicamento foi a variável crucial neste resultado. A realização de um estudo de custo-efetividade bem desenhado, baseado em dados nacionais, seria muito útil para gerar o conhecimento necessário para auxiliar a tomada de decisão pelos gestores de saúde, quanto à adição do rituximabe ao esquema CHOP para a quimioterapia de 1ª linha dos pacientes com LDGCB.