Assessment of Retinal Microvasculature and Choroidal Vascularity After Intra-arterial Chemotherapy for Retinoblastoma.

PURPOSE: To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC). DESIGN: Retrospective clinical cohort study. METHODS: This study included 12 unilateral RB eyes treated with IAC (RB tumor), 12 contralateral normal eyes (RB fellow), and 12 healthy controls. The macular retinal thickness and retinal microvascular structure, including the foveal avascular zone (FAZ) area, macular and peripapillary superficial vessel density (SVD), and deep vessel density (DVD), were measured by optical coherence tomography angiography (OCTA). The choroidal thickness (ChT) and choroidal vascularity, including total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI), were measured by spectral-domain optical coherence tomography (SD-OCT). A comparison among the 3 groups was conducted, and the correlations among the parameters were analyzed. RESULTS: Among the 3 cohorts, the foveal retinal thickness, SVD, DVD, ChT, TCA, LA, SA, and CVI were significantly lower in RB tumor compared to RB fellow and the control eyes (all P < .01). There were no significant differences in the parameters between the contralateral and control eyes. The correlation analyses indicated a significant negative correlation between the total melphalan dose and foveal and parafoveal DVD, ChT, and LA. CONCLUSIONS: The retinal microvascular density and choroidal vascularity were lower in unilateral RB treated with IAC, and seemed to be related to the total melphalan dose. There were no measurable changes in the contralateral eyes.

Kinetic Ensemble of Tau Protein through the Markov State Model and Deep Learning Analysis.

The ordered assembly of Tau protein into filaments characterizes Alzheimer's and other neurodegenerative diseases, and thus, stabilization of Tau protein is a promising avenue for tauopathies therapy. To dissect the underlying aggregation mechanisms on Tau, we employ a set of molecular simulations and the Markov state model to determine the kinetics of ensemble of K18. K18 is the microtubule-binding domain of Tau protein and plays a vital role in the microtubule assembly, recycling processes, and amyloid fibril formation. Here, we efficiently explore the conformation of K18 with about 150 µs lifetimes in silico. Our results observe that all four repeat regions (R1-R4) are very dynamic, featuring frequent conformational conversion and lacking stable conformations, and the R2 region is more flexible than the R1, R3, and R4 regions. Additionally, it is worth noting that residues 300-310 in R2-R3 and residues 319-336 in R3 tend to form sheet structures, indicating that K18 has a broader functional role than individual repeat monomers. Finally, the simulations combined with Markov state models and deep learning reveal 5 key conformational states along the transition pathway and provide the information on the microsecond time scale interstate transition rates. Overall, this study offers significant insights into the molecular mechanism of Tau pathological aggregation and develops novel strategies for both securing tauopathies and advancing drug discovery.

Eficacia y seguridad de melfalan intra vitreo en pacientes pediátricos con retinoblastoma / Efficacy and safety of intravitreal melphalan in pediatric patients with retinoblastoma

INTRODUCCION: El retinoblastoma es el cáncer ocular más comúnmente diagnosticado en edad pediátrica. Representa alrededor del 2.5-4% de todos los tumores malignos pediátricos. En los países desarrollados, la tasa de incidencia alcanza hasta 4.4 casos por millón, cifra relativamente superior que la de países de ingresos bajos. 1 El retinoblastoma puede tener una tasa de supervivencia global menor del 30%.2 Es clásicamente diagnosticado en pacientes menores de 36 meses con leucocoria. 3-4-5-6 La edad media de diagnostica es alrededor de los 18-20 meses, y el 95% de niños son diagnosticados dentro de los primeros 5 años.7-8 Anualmente, aproximadamente cincuenta pacientes nuevos son diagnostican de retinoblastoma en el INEN. 9 La siembra vítrea es considerada un factor de riesgo mayor para la conservación ocular. Corresponde a focos tumorales avasculares, por lo que es difícil conseguir una dosis "tumoricida" con quimioterapia endovenosa a este nivel. Por ello se ideó una técnica segura de inyección intravítrea (IV). La aplicación de quimioterapia intravítrea se realiza a través de la inserción de una aguja 30 G a nivel de la pars plana libre del tumor, a 2.5- 3.5 mm del limbo esclerocorneal en el meridiano deseado libre del tumor. Se inyecta el agente quimioterápico y antes de retirar la aguja, se aplica crioterapia. El objetivo de la quimioterapia IV es el control de la siembra vítrea.10 De no alcanzarse control de la siembra vítrea, el ojo comprometido por esta será enucleado. ESTRATEGIA DE BÚSQUEDA DE INFORMACIÓN: ¿En los pacientes con diagnóstico de retinoblastoma con clasificación C y D, cuál es la eficacia y seguridad del Melfalan intravítreo? La estrategia de búsqueda sistemática de información científica para el desarrollo del presente informe se realizó siguiendo las recomendaciones de la Pirámide jerárquica de la evidencia propuesta por Haynes y se consideró los siguientes estudios: Sumarios y guías de práctica clínica. Revisiones sistemáticas y/o meta-análisis. Ensayos Controlados Aleatorizados (ECA). Estudios Observacionales (cohortes, caso y control, descriptivos). No hubo limitaciones acerca de la fecha de publicación o el idioma para ningún estudio. De acceso libre: MEDLINE (a través de Pubmed) Fecha de búsqueda: La búsqueda sistemática incluyó a todos los estudios publicados sin límite de antigüedad. CONCLUSIONES: Retinoblastoma es el cáncer ocular más frecuente diagnosticado en edad pediátrica y la siembra vítrea es considerada un factor de riesgo mayor para la conservación ocular. La quimioterapia intravítrea es un método a través del cual se inyecta Melfalan a través de la pars plana, alcanzándose niveles suficientes de quimioterapia a nivel local, con el objetivo de destruir la siembre vítrea. Un sumario recomienda quimioterapia intravítrea como una opción de tratamiento de la siembra intravítrea de retinoblastoma. La "Guía técnica: Procedimiento Médico Quirúrgico Oncológico del Retinoblastoma", publicada por el Departamento de Oftalmología del INEN durante el 2023, recomienda el uso intravítreo con Melfalan 50 ug para retinoblastoma del grupo C y D. Una revisión sistemática determinó que las complicaciones oculares significativas secundarias a la quimioterapia intravítrea son poco comunes (AMSTAR II ­ Nivel muy bajo de confianza). Un estudio prospectivo determinó que la quimioterapia es segura y puede alcanzar tasas de salvataje ocular de hasta el 30.3%, y que existe una aparente superioridad del Melfalan intravítreo por encima del Carboplatino (Calidad de evidencia Moderada, según GRADE). Dos estudios retrospectivos determinaron que Melfalan alcanza una regresión del 100% en siembra vítrea focal y 65% en siembre difusa. La tasa de salvataje ocular obtenida es del 73.68% y durante el seguimiento no presentaron metástasis a distancia (Calidad de evidencia Muy Baja, según GRADE). Melfalan ha sido utilizado de forma intravítrea en el INEN, demostrando ser seguro.

The cost of multiple myeloma and its complications: A single-center study from Oran, Algeria.

BACKGROUND: The expenses of multiple myeloma (MM) represent a real economic and societal burden for patients and health authorities. However, very little is known about the situation in Algeria. Therefore, the aim of this study is to evaluate the costs generated by the management of MM and its complications in Algerian patients. MATERIALS AND METHODS: An observational retrospective study conducted on patients diagnosed with MM, from January 1st, 2019 to April 31st, 2023, at the Establishment Hospitalier Universitaire November 1st, Oran. A bottom-up costing methodology was used to assess the phase-specific cost and the complication burden. RESULTS: In total, 249 qualified for the study. For autologous stem cell transplantation (ASCT) eligible patients, the mean per patient cost of treating myeloma was estimated at: induction regimen ($4072); ASCT ($2899); consolidation ($1538); and maintenance ($355.76). The mean drug cost for ASCT-ineligible patients was $1421. The use of generic bortezomib and generic melphalan has led to a reduction in expenses of $1,075,181 ($5,024 per patient; 55.35%) and $10,864 ($487 per patient; 15.07%), respectively. Another cost-saving adaptation was ASCT using non-cryopreserved (NC) stem cells. The cost of managing MM complications was $177,782 per year. CONCLUSION: A number of adjustments have been implemented to the management of MM over time to improve clinical efficacy and reduce costs in Algeria. However, this may have come with a startlingly high cost of complications.

Assessment of Stem Cell Transplant Eligibility in Recipients with Oral Foci of Infection: Appropriate Conditioning Regimens.

OBJECTIVES: It is unclear whether patients with oral foci of infection should be approved for hematopoietic stem cell transplant with or without posttransplant cyclophosphamide. We compared the presence of oral foci of infection status on the effects of various conditioning regimens for such patients. MATERIALS AND METHODS: Three groups were classified as autologous (carmustine-etoposide-cytarabinemelphalan, mitoxantrone-melphalan, and melphalan 200 mg/m² groups; n = 502 patients), and 6 groups were classified as allogeneic (busulfan-fludarabinerabbit anti-T-lymphocyte globulin, busulfanfludarabine-posttransplant cyclophosphamide, fludarabine-cyclophosphamide-anti-T-lymphocyte globulin, busulfan-fludarabine-anti-T-lymphocyte globulin-posttransplant cyclophosphamide, total body irradiation-posttransplant cyclophosphamide, and other; n = 428 patients). Data were collected from a database that met international accreditation requirements. We evaluated dental radiological findings and calculated interobserver reliability. RESULTS: Oral foci of infections increased febrile neutropenia and bacterial infection frequencies in both groups but only increased mucositis frequency in patients with allogeneic treatment. The frequencies of oral foci of infection-related complications were similar in both the autologous and allogeneic groups. Rate of graft-versus-host disease was not affected by oral foci of infection status. Periodontitis/cysts and periapical lesions increased the risk of infections at day 100 in the mitoxantrone-melphalan group versus the melphalan 200 mg/m² group. We observed no differences among the autologous transplant groups in terms of early mortality. Similarly, no differences in early mortality were observed among the allogeneic groups. CONCLUSIONS: Transplant is a valid option in patients with oral foci of infections undergoing various autologous and allogeneic transplant protocols when time is of the essence, even at myeloablative dose intensities.

Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies.

INTRODUCTION: Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN. METHODS: These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022). RESULTS: In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports. CONCLUSION: These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).

Effectiveness, Safety, and Cost Implications of Outpatient Autologous Hematopoietic Stem Cell Transplant for Multiple Myeloma.

BACKGROUND AND OBJECTIVE: Autologous hematopoietic stem cell transplant (aHCT) has become standard care for patients with multiple myeloma (MM). Outpatient aHCT with high-dose melphalan conditioning has reduced costs and length of hospital stay. This study aimed to highlight the effectiveness, safety, and cost implications of outpatient vs inpatient aHCT at a tertiary academic medical center, as well as the utility of growth factor use in these patients. PATIENTS AND METHODS: Using an institutional HCT database, a total of 100 patients undergoing aHCT for MM were identified; 50 patients who underwent aHCT in the outpatient setting (chemotherapy and stem cell infusion followed by inpatient admission if needed) were compared with 50 patients in the inpatient setting (chemotherapy and stem cell infusion followed by discharge to outpatient setting). Patients were excluded if the melphalan dose was less than 200 mg/m2. Outcomes assessed through retrospective chart review included time to engraftment, incidence of infection, febrile neutropenia, growth factor use, and total length of inpatient stay through day +100. RESULTS: Time to neutrophil and platelet engraftment was shorter in the outpatient group than in the inpatient group (14 vs 16 days and 19 vs 21 days, respectively; P < 0.001). Median length of hospital stay was also shorter in the outpatient group (8.5 vs 15.5 days, respectively; P < 0.001). Ninety percent of the outpatient group required admission for neutropenic fever, and 60% of these patients received growth factor support starting at a median of 9 days after stem cell infusion, for a median duration of 4 days. Compared to 16 patients who did not receive growth factor support, these patients had a significantly shorter time to neutrophil recovery (13 days with vs 15 days without growth factor, P = 0.02) and no difference in the total length of hospital stay (8 days with vs 10 days without growth factor, P = 0.43). CONCLUSION: For adult patients with MM undergoing aHCT, the outpatient setting is safe and reduces the total length of hospital stay and thus overall transplant costs. Growth factor support for patients with febrile neutropenia may not reduce length of stay for subsequent hospitalizations.

Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial.

BACKGROUND: Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies. METHODS: EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667. FINDINGS: Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]). INTERPRETATION: Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma. FUNDING: The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Carfilzomibe no tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia / Carfilzomib in the treatment of patients with relapsed or refractory multiple myeloma who have received prior therapy

INTRODUÇÃO: O mieloma múltiplo (MM) é uma neoplasia hematológica maligna caracterizada pela proliferação descontrolada de plasmócitos alterados na medula óssea, resultando na produção aumentada de imunoglobulinas não funcional (proteína monoclonal). O acúmulo destas imunoglobulinas e a interação dos plasmócitos com outras células da medula óssea resultam em anemia, lesões ósseas, infecções, hipercalcemia, injúria renal, fadiga e dor. A incidência mundial informada pelo Globocan é de 2,2 novos casos por 100.000 habitantes em homens e 1,5/100.000 em mulheres, com ocorrência, a nível mundial, de 176 mil novos casos e 117 mil mortes em 2020. Carfilzomibe é um agente antineoplásico, inibidor de proteassoma que se liga seletiva e irreversivelmente nos sítios ativos. Tem atividade antiproliferativa e pró-apoptóticas. PERGUNTA DE PESQUISA: Kyprolis® (carfilzomibe) em combinação com dexametasona é eficaz e seguro no tratamento de pacientes com mieloma múltiplo recidivado ou refratário que receberam uma terapia prévia quando em comparação a bortezomibe, ciclofosfamida, dexametasona, cisplatina, doxorrubicina, doxorrubicina lipossomal, etoposídeo, melfalana, vincristina ou talidomida? EVIDÊNCIAS CLÍNICAS: O demandante realizou as buscas na literatura utilizando as seguintes bases de dados: The Cochrane Library, Medline via PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Centre for Reviews and Dissemination (CRD), o que resultou na inclusão de 14 publicações. Na análise conduzida pela Secretaria Executiva foram consideradas 12 publicações referentes a um ensaio clínico randomizado e uma publicação de revisão sistemática. O estudo ENDEAVOR foi um ensaio clínico de fase III, multicêntrico, aberto, que incluiu 929 participantes randomizados para receber carfilzomibe+dexametasona ou bortezomibe+dexametasona. A mediana de SLP foi 18,7 meses (IC 95%, 15,6 a não estimável) no grupo que recebeu carfilzomibe comparado a 9,4 meses (IC 95%, 8,4 a 10,4) no grupo que recebeu bortezomibe, resultando em uma magnitude de benefício absoluto de 9,3 meses (HR 0,53 [IC95% 0,44 a 0,65]; p< 0,0001). A duração mediana de resposta foi 21,3 meses (IC95% 21,3 a não estimável) no grupo carfilzomibe e 10,4 meses (IC95% 9,3 a 13,8) no grupo bortezomibe. Em ambos os grupos, 98% dos participantes apresentaram eventos adversos (qualquer grau), sendo a anemia (43% versus 28%), diarreia (36,7% versus 40,6%) e febre (32,6% versus 15,4%) os eventos mais frequentes nos grupos carfilzomibe e bortezomibe, respectivamente. Os eventos adversos mais comuns grau 3 ou maior foram reportados em 81,9% dos participantes do grupo carfilzomibe (n=379) e 71,1% no grupo bortezomibe (n=324), sendo a anemia (17,3% no grupo carfilzomibe e 10,1% no grupo bortezomibe), hipertensão (14,9% versus 3,3%), trombocitopenia (12,5% versus 14,7%),os três eventos mais frequentes. Insuficiência cardíaca grau 3 ou superior, foi mais frequente no grupo carfilzomibe (6%) que no grupo bortezomibe (2%.). AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade. Na análise do cenário base, em um horizonte temporal de 30 anos, carfilzomibe acrescentou ganhos incrementais de 1,19 QALY, resultando em uma razão de custo utilidade incremental (RCEI) de R$ 195.310,00 por QALY. No cenário proposto pela Secretária-Executiva (horizonte temporal de 10 anos e valor de utilidade derivada do estudo ENDEAVOR), carfilzomibe gerou benefício de 0,63 QALY, com RCEI de R$ 365.830,00 por QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Com o desconto apresentado pelo demandante, a incorporação de carfilzomibe ao SUS implica em custos adicionais ao sistema de saúde no montante de aproximadamente R$ 365 milhões em cinco anos. A principal limitação da análise foi a estimativa da população. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 10 tecnologias potenciais para compor o esquema terapêutico de pacientes adultos com mieloma múltiplo recidivado ou refratário: Belantamabe mafodotin, Ciltacabtageno autoleucel, Elranatamab, Iberdomida, Idecabtagene vicleucel, Isatuximabe, nivolumabe, selinexor, teclistamab, venetoclax. Tais medicamentos são anticorpo monoclonal ligado a um antineoplásico, anticorpo biespecífico, anticorpo monoclonal, imumodulador, terapias baseadas em células T autólogas geneticamente modificadas (CAR-T), inibidor SINE, ou inibidor de Bcl-2. A maioria não possui registro na FDA, EMA ou Anvisa. CONSIDERAÇÕES FINAIS: Os resultados sugerem eficácia e segurança do carfilzomibe na população elegível, porém, no horizonte temporal de 10 anos, com QALY < 1, RCEI de R$ 365.830,00 por QALY e impacto orçamentário de aproximadamente R$ 17 milhões no primeiro ano de incorporação e R$ 131 milhões no 5º ano da incorporação, totalizando R$ 365 milhões em cinco anos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 109ª Reunião Ordinária da Conitec, realizada no dia 08 de junho de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação de carfilzomibe para o tratamento de mieloma múltiplo recidivado ou refratário no SUS. Os membros consideraram a evidência científica boa e favorável ao carfilzomibe, porém, a RCEI e o impacto orçamentário foram considerados muito altos para o tratamento de uma doença que já tem outras opções terapêuticas disponíveis no SUS. CONSULTA PÚBLICA: Entre os dias 08/07/2022 e 27/07/2022 foram recebidas 421 contribuições, sendo 152 pelo formulário para contribuições técnico-científicas e 269 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. A maioria foi a favor da incorporação de carfilzomibe no SUS (97% via formulário técnico-científico e 100%). O principal benefício apontado nas contribuições técnico-científicas foi sobre a eficácia, aumento da sobrevida e qualidade de vida, além da disponibilidade de mais uma opção terapêutica e promoção da igualdade no tratamento nos sistemas público e privado de saúde. A empresa detentora do registro do medicamento atualizou o preço do medicamento, e consequentemente os valores do impacto orçamentário e avaliação econômica. No impacto orçamentário o valor ficou em R$ 95,3 milhões em cinco anos. Nas contribuições de experiência e opinião, a totalidade dos respondentes discordou da recomendação preliminar da Conitec. No âmbito das opiniões e experiências positivas, foi mencionada a necessidade de garantir o acesso ao carfilzomibe, especialmente por representar uma alternativa para pacientes recidivados e refratários. Também foi citada a eficácia da tecnologia. Como dificuldades, destacou-se a falta de acesso pelo SUS. Em relação a outros medicamentos, foram mencionados benefícios, mas, também, a eficácia limitada no caso de pacientes recidivados. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec, em sua 112ª Reunião Ordinária, realizada no dia 31 de agosto de 2022, deliberaram por maioria simples, recomendar a não incorporação no SUS de carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia, no SUS. Não houve apresentação de dados clínicos adicionais. Com o preço do medicamento atualizado, ainda assim não se mostrou custo-efetivo. Foi assinado o Registro de Deliberação nº 765/2022. DECISÃO: Não incorporar, no âmbito do Sistema Único de Saúde - SUS, o carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, conforme a Portaria nº 107, publicada no Diário Oficial da União nº 184, seção 1, página 75, em 27 de setembro de 2022.

Juvenile exposure and adult risk assessment with single versus repeated exposure of melphalan in the germ cells of male SD rat: Deciphering the molecular mechanisms.

Melphalan significantly contributes to the increase in childhood cancer survival rate. It acts as a gonadotoxic agent and leads to testes damage, dysbalance in gonadal hormones, and impairment in the germ cell proliferation. Therefore, it might be a potent threat to male fertility in individuals who have undergone melphalan treatment during childhood cancer. However, the molecular mechanisms of melphalan-induced gonadal damage are not yet fully explored and they need to be investigated to determine the benefit-risk profile. In the present study, juvenile male SD rats were subjected to single and intermittent cycles of melphalan exposure in a dose-dependent (0.375, 0.75 and 1.5 mg/kg) manner. Methods of end-points evaluations were quantification of micronuclei formation in peripheral blood, sperm count, sperm motility and head morphology, sperm and testicular DNA damage, histological studies in testes, oxidative/nitrosative stress parameters. A single cycle of exposure at high dose (1.5 mg/kg) produced significant effect on micronuclei formation only after the first week of exposure, whereas failed to produce significant effect at the end of the sixth week. Intermittent cycles of exposure at the dose of 1.5 mg/kg produced significant alterations in all the parameters (micronuclei in peripheral blood, testes and epididymides weight and length, MDA, GSH and nitrite levels, sperm count and motility, sperm head morphology, testicular and sperm DNA damage, protein expression in testes and histological parameters). So, time of exposure as well as the amount of exposure (total dosage administered) is critical in determining the magnitude of the damage in germ cell risk assessment.

Eficacia y seguridad de daratumumab en combinación con bortezomib, melfalán y prednisona en pacientes adultos con mieloma múltiple de nuevo diagnóstico no candidatos a trasplante de células progenitoras hematopoyéticas / Efficacy and safety of daratumumab in combination with bortezomib, melphalan and prednisone in adult patients with newly diagnosed multiple myeloma who are not candidates for hematopoietic stem cell transplantation

INTRODUCCIÓN: se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de daratumumab junto a bortezomib, melfalán y prednisona en comparación con bortezomib, melfalán y prednisona en el tratamiento de pacientes adultos con mieloma múltiple de nuevo diagnóstico no candidato a trasplante de células progenitoras hematopoyéticas. El mieloma múltiple (MM) es una neoplasia hematológica rara, maligna e incurable que se caracteriza por la proliferación de un clon de células plasmáticas derivadas de células B (Kyle et al., 2003). Esta neoplasia suele afectar a mayores de 60 años con edad promedio de aparición entre los 70 y 75 años (Turesson et al., 2010). Su incidencia es mayor en hombres que en mujeres en hasta 1.5 veces (Blimark et al., 2018). La clasificación del riesgo en MM se basa en los resultados de hibridación in situ con fluorescencia (FISH) para translocaciones específicas y otros exámenes para determinar niveles de lactato deshidrogenasa y células plasmáticas en sangre (Palumbo et al., 2015). Así se clasifican en: 1) MM de alto riesgo; y 2) MM de riesgo estándar. Los pacientes con MM de nuevo diagnóstico (MMND) requieren un trasplante de células madre autólogas (TCMA) o trasplante de células progenitoras hematopoyéticas (TCPH) como parte de su tratamiento (Chari et al., 2018; Mahajan et al., 2018). Sin embargo, no todo paciente con MMND es elegible para un TCPH porque se debe tener en consideración el riesgo de progresión, el estado general, la edad y la presencia de comorbilidades para su indicación (Mahajan et al., 2018). EsSalud cuenta con medicamentos que podrían ofrecerse para el tratamiento de MMND no elegibles a TCPH como bortezomib, lenalidomida y dexametasona; los cuales están recomendados por las GPC. Sin embargo, los especialistas de la institución sugieren que el uso de daratumumab en combinación con bortezomib, melfalán y prednisona podría ser una alternativa que brinden mejoras en desenlaces clínicos relevantes con un adecuado perfil de seguridad. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de daratumumab más bortezomib, melfalán y prednisona en pacientes con MMND no candidatos a TCPH. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), Instituto de Calidad y Eficiencia en la Atención de la Salud (IQWiG, por sus siglas en alemán), Agency for Healthcare Research and Quality (AHRQ), Guidelines International Network (GIN), National Health and Medical Research Council (NHMRC), Haute Autorité de Santé (HAS), International HTA Database, la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la OMS, el Ministerio de Salud de Chile, el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en oncología, tales como: European Society for Medical Oncology (ESMO), el Grupo Español de Mieloma, National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), Cancer Care Ontario (CCO), la British Society for Hematology (BSH). Finalmente, se realizó una búsqueda en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: Luego de la búsqueda bibliográfica (hasta julio de 2021), se incluyeron cuatro GPC desarrolladas por la Sociedad Europea de Oncología Médica (ESMO) en colaboración con la Asociación Europea de Hematología (EHA), la American Society of Clinical Oncology (ASCO) en colaboración con Cancer Care Ontario (CCO), la British Society for Hematology (BSH) y la National Comprehensive Cancer Network (NCCN); así como 2 ETS realizadas por Ludwing Boltzmann Institute (LBI) y Haute Autorité de Santé (HAS), y un ensayo clínico aleatorizado (ECA) de fase III de etiqueta abierta denominado ALCYONE (NCT02195479). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso de daratumumab en combinación con bortezomib, melfalán y prednisona en pacientes con nuevo diagnóstico de mieloma múltiple no candidatos a trasplante de células progenitoras hematopoyéticas.

Seguridad y eficacia del Melfalan Intravítreo (IV) en pacientes con Retinoblastoma Grado C y D / Safety and efficacy of Intravitreal (IV) Melphalan in patients with Grade C and D Retinoblastoma

INTRODUCCIÓN: Retinoblastoma es la neoplasia maligna primaria intraocular más frecuente en pediatría. Durante el periodo 2005-2009, la incidencia anual en pacientes < 15 años fue 4.1 por cada 1,000,000 en los Estados Unidos y la edad media de diagnóstico fue 18-20 meses. En nuestra institución, se diagnostican 50 pacientes nuevos de retinoblastoma al año. Los pacientes con retinoblastoma clasificación C y D se caracterizan por presentar siembra vítrea y es considerado un factor de riesgo mayor para la conservación ocular, ya que son focos tumorales avasculares, por lo que es difícil conseguir una dosis "tumoricida" adecuada a este nivel con quimioterapia endovenosa. Por este motivo se desarrollaron opciones de terapia que puedan tener efecto intravítreo como la aplicación de quimioterapia intravítrea, reconocida en sumarios internacionales como upTodate. METODOLOGÍA: La búsqueda en pubmed reportó una revisión sistemática publicada en el 2014, con el objetivo de evaluar la seguridad de la aplicación de quimioterapia IV. El melfalan fue la quimioterapia más utilizada (88.5%) en esta revisión sistemática y demostró ser un tratamiento muy seguro. Solo 17 pacientes presentaron eventos adversos significativos y 21 eventos oculares menores. La proporción de pacientes con eventos adversos potencialmente significativos por melfalan fue 0.031 (n=8/261; IC 95%, 0.013-0.060). RESULTADOS: No se encontraron ensayos prospectivos en nuestra búsqueda sistemática, sin embargo, se encontraron series retrospectivas de casos. Suzuki S publicó un estudio retrospectivo donde incluyeron 264 ojos de 250 pacientes que recibieron 1067 inyecciones IV. En este caso melfalan IV alcanzó 68% de remisión completa de la siembra vítrea en los ojos tratados. Xue K también publicó un reporte retrospectivo de casos, incluyendo 9 pacientes con siembra vítrea refractaria. Todos los pacientes recibieron melfalan IV y todos obtuvieron (100%) control de la siembra vítrea. 5. El departamento de oftalmología del INEN reporto que aproximadamente 09 pacientes con retinoblastoma se beneficiarían anualmente de quimioterapia intravítrea. La cantidad de aplicaciones por pacientes son 06 en promedio. El costo necesario para el tratamiento completo con melfalan es de S/. 9,180. CONCLUSIÓN: El panel de ETS y los representantes del departamento de Oftalmología discutió la aplicación de la presente tecnología, concluyéndose que, a pesar de existir escasa evidencia, la aplicación de melfalan intravítreo es una opción segura y eficaz en una población de pacientes con alto riesgo de progresión de enfermedad y enucleación.

Exploration on the drug solubility enhancement in aqueous medium with the help of endo-functionalized molecular tubes: a computational approach.

One major problem in the pharmaceutical industry is the aqueous solubility of newly developed orally administered drug candidates. More than 50% of newly developed drug molecules suffer from low aqueous solubility. The therapeutic effects of drug molecules are majorly dependent on the bioavailability and, in essence, on the solubility of the used drug molecules. Thus, enhancement of drug solubility of sparingly soluble drug molecules is a need of modern times. Considering the high importance of drug solubility, we have computationally shown the enhancement of drug solubility for seven class II (poorly water-soluble) drug molecules in a water medium. The uses of supramolecular macrocycles have immense importance in the same field. Thus, we have used two synthetic supramolecular receptors named host-1a and host-1b to enhance the water solubility of fluorouracil, albendazole, camptothecin, clopidogrel, indomethacin, melphalan, and tolfenamic acid drug molecules. Biomedical engagements of a supramolecular receptor commence with the formation of stable host-drug complexes. These complexations enhance the water solubility of drug molecules and sustain the release rate and bioavailability of drug molecules. Thus, in this work, we focus on the formation of stable host-drug complexes in water medium. Molecular dynamics simulation is applied to analyze the structural features and the energetics involved in the host-drug complexation process. The information obtained at the atomistic level helps us gain better insights into the key interactions that operate to produce such highly stable complexes. Thus, we can propose that these two supramolecular receptors may be used as drug solubilizing agents, and patients will benefit from this theragnostic application shortly.

BeEAM conditioning regimen is a safe, efficacious and economical alternative to BEAM chemotherapy.

In many stem cell transplant centres, BCNU, etoposide, cytarabine and melphalan (BEAM) high-dose chemotherapy (HDCT) has been replaced by the more economic and available bendamustine, etoposide, cytarabine, melphalan (BeEAM) regimen. However, there is a paucity of information on the efficacy and safety of BeEAM HDCT. We describe our experience with BeEAM HDCT in terms of safety, efficacy and cost-savings. We compare overall and progression-free survival to a cohort of patients previously transplanted at our institution with the older BEAM regimen. We performed a retrospective chart review of 41 lymphoma patients undergoing BeEAM HDCT at the Royal University Hospital in Saskatoon, Saskatchewan between 2015 and 2019 to elicit regimen safety in the first 100 days post-transplant. Furthermore, we calculated overall and progression-free survival and constructed corresponding Kaplan-Meier curves, comparing the results to a historical cohort of BEAM patients (n = 86). Finally, we conducted an economic analysis using the financials available at our centre's pharmacy. With regards to BeEAM HDCT, we report a 100-day transplant-related mortality of 2.4%. Additionally, we report acceptable rates of typhlitis (27%), grade III-IV mucositis (4.9%) and grade III-IV nephrotoxicity (2.4%). In terms of overall and progression-free survival, we found no statistical difference between BeEAM and BEAM (p = 0.296; 0.762, respectively). Finally, our economic analysis revealed a net savings of $21,200 CAD per transplant when BeEAM is used in replacement of BEAM. The acceptable safety profile of BeEAM and its comparable efficacy to BEAM are encouraging for the perseverance of this cost-effective HDCT regimen.

Toxicity assessment of concurrent gabapentin/pregabalin administration with high-dose melphalan in autologous hematopoietic cell transplant recipients.

A theoretical pharmacokinetic interaction mediated through L-amino acid transporter 1 and 2 exists between gabapentin (GP) and pregabalin (PG) with melphalan. Peripheral neuropathy is a common toxicity of various multiple myeloma regimens commonly utilized prior to autologous hematopoietic cell transplant (auto-HCT) with high-dose melphalan (HD-Mel). Therefore, it is likely concurrent administration of either GP or PG will occur in patients receiving HD-Mel conditioning for auto-HCT, which could potentially increase cellular uptake and worsen the mucosal injury. A retrospective chart review of adult patients from January 2012 to July 2016 who received HD-Mel (140-200 mg/m2) at West Virginia University Medicine was performed to assess toxicity and outcomes in these patients. A total of 80 patients were included in the study, with 30 patients receiving GP or PG and 50 control patients. There were no significant differences in grade 2 or higher mucositis, admissions for nausea/vomiting/diarrhea, intravenous opioid requirements, oral topical therapies, antidiarrheal medication use, rescue anti-emetics, days of nausea or vomiting, pain scores, neutrophil or platelet engraftment, treatment-related mortality, progression-free survival, or overall survival. Our data suggest that it is safe to continue GP/PG therapy throughout HD-Mel therapy, with no negative transplant outcomes. Prospective studies or evaluations of larger databases are necessary to better characterize the clinical effect of concomitant therapy.

Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial.

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10-4-10-5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

Single response assessment of transplant-ineligible multiple myeloma: a supplementary analysis of JCOG1105 (JCOG1105S1).

BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

Cost-Effectiveness Analysis of Adding Daratumumab to a Regimen of Bortezomib, Melphalan, and Prednisone in Newly Diagnosed Multiple Myeloma.

INTRODUCTION: The ALCYONE trial found that daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) can significantly improve progression-free survival (PFS) and overall survival (OS) for patients with transplant-ineligible, newly diagnosed multiple myeloma (MM) in China. In the present study, we evaluated the cost-effectiveness of D-VMP versus VMP for patients with newly diagnosed MM in China. METHODS: A Markov model was used to estimate the cost-effectiveness of frontline D-VMP versus VMP for MM. The life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. A series of sensitivity analyses was performed to assess the robustness of the model and address uncertainties in variable estimates. Subgroup analysis was also performed. RESULTS: D-VMP provided an additional 2.99 LYs and 1.67 QALYs compared with VMP, with incremental $64,920 per LY and $116,015 per QALY gained. The results of the univariable sensitivity analysis showed that the parameter that had the greatest impact on the ICER was the cost of subsequent treatment and daratumumab. When the cost of daratumumab was 100%, 70%, 50%, and 30% of the current price, the probability of D-VMP being cost-effective was 2.49%, 16.11%, 39.09%, and 70.73% at the willingness-to-pay (WTP) threshold of $30,950/QALY, respectively. The results demonstrated that the ICER in all subgroups remained > $30,950/QALY. CONCLUSION: D-VMP versus VMP is likely to exceed the commonly accepted values of cost-effectiveness in patients with transplant-ineligible, newly diagnosed MM in China.

Early relapse after high-dose melphalan autologous stem cell transplant predicts inferior survival and is associated with high disease burden and genetically high-risk disease in multiple myeloma.

Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients.

Pig-a gene mutation assay study design: critical assessment of 3- versus 28-day repeat-dose treatment schedules.

The in vivo Pig-a assay is being used in safety studies to evaluate the potential of chemicals to induce somatic cell gene mutations. Ongoing work is aimed at developing an Organisation for Economic Cooperation and Development (OECD) test guideline to support routine use for regulatory purposes (OECD project number 4.93). Among the details that will need to be articulated in an eventual guideline are recommended treatment and harvest schedules. With this in mind, experiments reported herein were performed with Wistar Han rats exposed to aristolochic acid I (AA), 1,3-propane sultone, chlorambucil, thiotepa or melphalan using each of two commonly used treatment schedules: 3 or 28 consecutive days. In the case of the 3-day studies, blood was collected for Pig-a analysis on days 15 or 16 and 29 or 30. For the 28-day studies blood was collected on day 29 or 30. The effect of treatment on mutant reticulocytes and mutant erythrocytes was evaluated with parametric pair-wise tests. While each of the five mutagens increased mutant phenotype cell frequencies irrespective of study design, statistical significance was consistently achieved at lower dose levels when the 28-day format was used (e.g. 2.75 vs 20 mg/kg/bw for AA). To more thoroughly investigate the dose-response relationships, benchmark dose (BMD) analyses were performed with PROAST software. These results corroborate the pair-wise testing results in that lower BMD values were obtained with the 28-day design. Finally, mutagenic potency, as measured by BMD analyses, most consistently correlated with the mutagens' tumorigenic dose 50 values when the lengthier treatment schedule was used. Collectively, these results suggest that both 3- and 28-day treatment schedules have merit in hazard identification-type studies. That being said, for the purpose of regulatory safety assessments, there are clear advantages to study designs that utilise protracted exposures.