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Abstract Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P

Background: Impact of Merkel cell polyomavirus (MCPyV) associated Merkel cell carcinoma (MCC) has not been assessed in the Icelandic population, nor in a whole population elsewhere. Objectives: The primary objective was to assess trends in the incidence of MCC in Iceland and the association with MCPyV. Secondary objectives aimed to analyze MCC outcomes. Methods: In this retrospective cohort study, patients diagnosed with MCC between 1981 and 2021 were identified from the Icelandic Cancer Registry. Patients were separated into 2 groups based on MCPyV immunochemistry staining. Age-standardized incidence was calculated and Joinpoint analysis was used to assess incidence trends. A Cox proportional hazards model was used to assess survival differences between the 2 groups. Results: Overall incidence of MCC increased from 0.015 to 0.26 per 100,000 persons, though the incidence of MCPyV positive cases recently decreased while negative cases increased. MCPyV negative tumors were associated with sun exposure (P

Abstract Background Despite decades of research, an effective schistosomiasis vaccine remains elusive. The radiation-attenuated (RA) cercarial vaccine remains the best model for eliciting high levels of protection. We have recently explored this model in mice to identify potentially protective pathways by examining gene expression patterns in peripheral blood mononuclear cells (PBMC). Methods Herein, we reanalyzed the transcriptomic data from PBMC obtained from vaccinated and infected C57BL/6 mice in three timepoints (Days 7 and 17 after infection or vaccination and Day 7 post-challenge). In addition, we generated new data on PBMC collected 35 days after infection. Deconvolution analysis was performed to estimate immune cell composition by CIBERSORTx. Gene co-expression networks and over-representation analysis (ORA) were performed using the CEMiTool package. Protein-protein interaction networks were constructed using STRING, and the hub proteins for each module were identified using Cytoscape. Results Co-expression network analysis identified a module (M2) associated with the infection process, grouping genes related to a Th2 immune response, and a second module (M6) associated with the vaccination process, displaying pathways related to a Th1 response, CD8 + T cells and NK cells. Within each module, five hub proteins were identified based on protein-protein interaction networks. The M2 infection module revealed Chil3, Il4, Cx3cr1, Emr1 and Ccl2 as hubs, while module M6, associated with vaccination, disclosed Prf1, Klrc1, IFN-γ, Ncr1 and Tbx21 as hub proteins. Conclusions Our data point to the potentiald role of NK cells that may contribute to the RA vaccine response through the production of IFN-γ orchestrated by the T-bet transcription factor (Tbx21). Graphical Abstract

Abstract Objective We developed an in-house bioinformatics pipeline to improve the detection of respiratory pathogens in metagenomic sequencing data. This pipeline addresses the need for short-time analysis, high accuracy, scalability, and reproducibility in a high-performance computing environment. Results We evaluated our pipeline using ninety synthetic metagenomes designed to simulate nasopharyngeal swab samples. The pipeline successfully identified 177 out of 204 respiratory pathogens present in the compositions, with an average processing time of approximately 4 min per sample (processing 1 million paired-end reads of 150 base pairs). For the estimation of all the 470 taxa included in the compositions, the pipeline demonstrated high accuracy, identifying 420 and achieving a correlation of 0.9 between their actual and predicted relative abundances. Among the identified taxa, 27 were significantly underestimated or overestimated, including only three clinically relevant pathogens. We also validated the pipeline by applying it to a clinical dataset from a study on metagenomic pathogen characterization in patients with acute respiratory infections and successfully identified all pathogens responsible for the diagnosed infections. These findings underscore the pipeline’s effectiveness in pathogen detection and highlight its potential utility in respiratory pathogen surveillance.

Abstract Background The expansion of sequencing technologies as a result of the response to the COVID-19 pandemic enabled pathogen (meta)genomics to be deployed as a routine component of surveillance in many countries. Scaling genomic surveillance, however, comes with associated costs in both equipment and sequencing reagents, which should be optimized. Here, we evaluate the cost efficiency and performance of different read lengths in identifying pathogens in metagenomic samples. We carefully evaluated performance metrics, costs, and time requirements relative to choices of 75, 150 and 300 base pairs (bp) read lengths in pathogen identification. Results Our findings revealed that moving from 75 bp to 150 bp read length approximately doubles both the cost and sequencing time. Opting for 300 bp reads leads to approximately two- and three-fold increases, respectively, in cost and sequencing time compared to 75 bp reads. For viral pathogen detection, the sensitivity median ranged from 99% with 75 bp reads to 100% with 150–300 bp reads. However, bacterial pathogens detection was less effective with shorter reads: 87% with 75 bp, 95% with 150 bp, and 97% with 300 bp reads. These findings were consistent across different levels of taxa abundance. The precision of pathogen detection using shorter reads was comparable to that of longer reads across most viral and bacterial taxa. Conclusions During disease outbreak situations, when swift responses are required for pathogen identification, we suggest prioritizing 75 bp read lengths, especially if detection of viral pathogens is aimed. This practical approach allows better use of resources, enabling the sequencing of more samples using streamlined workflows, while maintaining a reliable response capability.

Periacetabular osteotomy is the gold standard treatment for acetabular dysplasia. The great variability of acetabular dysplasia requires a personalized preoperative planning improved by 3D reconstruction and computer-assisted surgery. To plan the displacement of the acetabular fragment by a pelvic osteotomy, it is necessary to define a reference plane and a method to characterize 3D acetabular orientation. A scoping review was performed on PubMed to search for articles with a method to characterize the acetabulum of native hips in a 3D reference frame. Ninety-eight articles out of 3815 reports were included. Three reproducible reference planes were identified: the anterior pelvic plane, the Standardization and Terminology Committee plane used in gait analysis, and the sacral base plane. The different methods for 3D analysis of the acetabulum were divided in four groups: global orientation, triplanar measurements, segmentation, and surface coverage of the femoral head. Two methods were found appropriate for reorientation osteotomies: the global orientation by a vector method and the triplanar method. The global orientation method relies on the creation of a vector from the acetabular rim, from the acetabular surface or from successive planes. Normalization of the global acetabular vector would correct acetabular dysplasia by a single alignment maneuver on an ideal vector. The triplanar method, based on angle measurements at the center of the femoral head, would involve correction of anomalies by considering axial, frontal, and sagittal planes. Although not directly fit for reorientation, the two others would help to candidate patients and verify both planning and postoperative result.

Abstract Background Pericoronitis, an inflammation near wisdom teeth, often occurs when they are partially emerged, especially in the lower jaw. Commonly, the gingiva partially envelops the tooth. Treatments vary from gingival surgery to extraction. This study assessed the efficacy of a mouthwash with Chlorhexidine, Benzydamine, Nanosilver, Amoxicillin, and Metronidazole for pain reduction and enhancement of maximum mouth opening in acute pericoronitis cases. Materials and methods In this randomized controlled clinical trial conducted at the Gorgan Dental Faculty, 48 pericoronitis patients were randomized into two groups. The control group used a 0.12% chlorhexidine mouthwash, while the case group used a mouthwash containing Chlorhexidine, Benzydamine, Nanosilver, Amoxicillin, and Metronidazole. The study recorded Visual Analog Scale (VAS) scores for 7 days, and Maximum mouth opening (MMO) was measured at the start and after 7 days. The analysis was performed using SPSS v20. Results In this study, we compared the effects of a combined mouthwash with those of a chlorhexidine mouthwash on pericoronitis in 48 patients, with an average age of 21.56 years. No significant difference in pain reduction was observed between the groups; however, both groups exhibited decreased pain and improved MMO post-treatment. The gender distribution was balanced across both groups. Conclusion The results indicate that both chlorhexidine mouthwash and combined mouthwash significantly improved maximum mouth opening. Nonetheless, there were no notable differences in efficacy between the two groups. These findings suggest that these mouthwashes may be beneficial for oral hygiene, warranting further in-depth research. Trial registration Registered on 12/03/2023, registration number IRCT20230104057046N1.

AbstractObservational studies that have reported an association between aspirin use in chronic obstructive pulmonary disease (COPD) with reductions in mortality and COPD exacerbations were shown to be affected by time-related biases. We assessed this association using a prevalent new-user study design that avoids these biases. We used the United Kingdom’s Clinical Practice Research Datalink (CPRD) to form a cohort of patients with COPD. Aspirin initiators were matched on time and propensity score with nonusers during 2002–2018. The outcomes were all-cause mortality and COPD exacerbation within a one-year follow-up. Hazard ratios (HR) and 95% confidence interval (CI) of each outcome associated with aspirin use compared to nonuse were estimated using an as-treated approach. The study cohort included 10,287 initiators of aspirin and 10,287 matched nonusers. The cumulative incidence of all-cause mortality at one year was 11.5% for aspirin users and 9.2% for nonusers. The HR of all-cause mortality associated with aspirin initiation was 1.22 (95% CI: 1.08–1.37), while for severe exacerbation it was 1.21 (95% CI 1.08–1.37), compared with nonuse. The HR of a first moderate or severe exacerbation with aspirin use was 0.90 (95% CI 0.85–0.95). These estimates did not vary by platelet count. This large population-based study, designed to emulate a trial, found aspirin use in patients with COPD associated with a higher risk of all-cause mortality and severe exacerbation, but a lower risk of moderate or severe exacerbation. Further research is warranted to assess this reduction in moderate or severe exacerbations, particularly in patients with cardiovascular risk factors.

Disproportionality analyses are the most-commonly used study design used in the post-marketing phase to detect suspected adverse drug reactions in individual case safety reports. Recent years have witnessed an exponential increase in published articles on disproportionality analyses, thanks to publicly accessible databases. Unfortunately, this trend was accompanied by concerns on lack of transparency and misinterpretation of results, both generating unjustified alarm and diluting true signals into overwhelming noise. The READUS-PV guideline for reporting disproportionality analysis was developed to tackle this emerging issue. In this perspective article, we describe the rationale behind the development of the READUS-PV guideline, the first collaborative initiative to harmonize the reporting of disproportionality analyses. The adoption of the checklists will assist researchers, regulators, and reviewers in the reporting, assessment, and publication of disproportionality analyses. Acknowledging the challenges ahead of effective implementation, we advocate for a global endorsement by Pharmacology Journals. A wide dissemination of the READUS-PV guideline is crucial to foster transparency and reproducibility of pharmacovigilance research, supporting an effective exploitation of disproportionality analysis among other irreplaceable post-marketing research tools to ensure drug safety.

Introdução: A nitrofurantoína é frequentemente utilizada para profilaxia de infecções urinárias. Nesses casos, o uso contínuo e prolongado da droga expõe o paciente a variados efeitos adversos. Entre os mais comuns, destacam-se náuseas, êmeses, cefaleia e diarreia. Contudo, manifestações mais raras, tais quais fibrose pulmonar e lesão hepática induzida por drogas (DILI - do inglês, drug induced liver injury), são descritas na literatura. Há poucos relatos na literatura da associação concomitante de fibrose pulmonar e hepatite autoimune devido ao uso de nitrofurantoína. Objetivo: Relatar caso de fibrose pulmonar concomitante a DILI autoimune-like induzidas por uso de nitrofurantoína. Método: Relato de caso. Resultados: C.P.C., 62 anos, feminina, portadora de asma, hipotireoidismo e infecção urinária de repetição, em uso de nitrofurantoína profilática há 4 anos. Procurou atendimento devido a dispneia com piora progressiva nos últimos 30 dias, associada a astenia, fadiga e tosse não produtiva. Tomografia de tórax evidenciou alterações fibroatelectásicas e bronquiectasias difusas bilateralmente, com predomínio perihilar, associadas a extensas opacidades consolidativas em vidro fosco. Apresentava dao hepático com elevação de transaminase oxalacética 878 (VR 40) e transaminase pirúvica 2006 (VR 35). Realizadas sorologias, excluídas causas infecciosas. Solicitadas provas reumatológicas, com fator antinuclear (FAN) reagente, título 1/160, padrão nuclear pontilhado quasi-homogêneo (fenótipo autoimune-like). Evoluiu com melhora clínica e laboratorial após suspensão da Macrodantina e uso de corticoterapia sistêmica com metilprednisolona. Posteriormente, confirmada hipótese de doença intersticial pulmonar fibrosante por nitrofurantoína através do anatomopatológico. Conclusão: O presente trabalho relata um caso raro de ocorrência concomitante de dois efeitos adversos raros associados à nitrofurantoína, antimicrobiano amplamente utilizado na prática médica. O reconhecimento precoce de tais eventos é essencial para um correto manejo e, consequentemente, melhor prognóstico.

Introdução: A dengue é uma doença viral transmitida por artrópodes, cuja gravidade depende de inúmeros fatores, entre eles fatores relacionados ao hospedeiro. Infecções bacterianas durante o curso da dengue podem ocorrer, mas ainda não tem seu mecanismo totalmente elucidado. Bacteremias durante quadro de dengue são raras e associadas a mau prognóstico. Até o momento não há na literatura bacteremia por S aureus e N gonorrhoeae de paciente infectado por dengue. Objetivo: Relatar caso de vasculite séptica por S aureus e N gonorrhoeae em paciente infectado por dengue. Método: Relato de caso e revisão da literatura. Resultados: Paciente masculino 28 anos, previamente hígido, com múltiplas parceiras sexuais, com febre alta de início súbito, artralgia, cefaleia e mialgia, associado a lesões necróticas por todo corpo há 2 dias. Procurou atendimento no 3° dia de sintomas, com NS1 reagente. Como manteve febre e aumento das lesões por todo corpo após 15 dias, retorna para atendimento necessitando de internação. No exame físico apresentava lesões púrpuras e algumas necróticas, algumas com aspecto hemorrágico por todo corpo. Apresentava leucocitose 15 mil, PCR 7,20 mg/dL e VHS 102 mm, creatinina 1,30 mg/dL, ureia 30 mg/dL. Iniciado empiricamente ceftriaxone e teicoplanina. Realizou ecocardiograma transtorácico e transesofágico, tomografia de tórax e abdome normais. Dengue IgM reagente e sorologia para HIV não reagente. Hemoculturas com crescimento de Neisseria gonorrhoeae e S aureus (em 2 amostras) confirmado por método automatizado, provas manuais e MALDI-TOF. Anatomopatológico da pele com achados tardios de vasculite séptica em resolução. Paciente com resolução do quadro com uso de ceftriaxone por 14 dias e normalização das provas inflamatórias, e segue em investigação ambulatorial para imunodeficiências primárias. Conclusão: Relatamos caso de doença estafilocócica e gonocócica disseminada em paciente com dengue. Há relatos na literatura de doença gonocócica disseminada, principalmente associadas a deficiência de complemento, mas até o momento não há relatos de caso de bacteremia por S aureus e N gonorrhoeae simultaneamente em paciente com dengue. Ainda não está claro como a dengue pode predispor à superinfecção e à bacteremia. Diferentes mecanismos hipotéticos são a imunidade enfraquecida induzida, a grave neutropenia e a translocação bacteriana observada durante a doença no curso da doença.

Introdução: Endoftalmite é uma infecção grave dos tecidos e/ou fluidos intraoculares. Majoritariamente, associa-se a mecanismos exógenos, como traumas, cirurgias ou inoculação direta. Vias endógenas são infrequentes. A Escherichia coli, um bacilo gram-negativo, raramente pode causar endoftalmite através de disseminação hematogênica. Objetivo: Relatar caso de paciente com endoftalmite por E coli. Método: Relato de caso. Resultados: J.C.L., feminino, 67 anos, portadora de diabetes mellitus e retinopatia diabética, sem cirurgias oculares prévias. Procurou atendimento por astenia, náuseas, calafrios e piora da acuidade visual. Na admissão apresentava hemograma com 19 mil leucócitos, PCR 41 mg/dL, creatinina 5,18 mg/dL, ureia 194 mg/dL, além do parcial de urina com 750.000 leucócitos e líquor normal. Iniciado ceftriaxone empírico por diagnóstico de pielonefrite. Paciente evoluiu pior com dor retro orbitária, cefaleia e anopsia 24 horas, necessitando de evisceração por endoftalmite no 7o dia de internação. Hemoculturas, urocultura e cultura de tecido positivas para E. coli multissensível. Apresentou piora da função renal com necessidade de diálise, além de quadro de trombose venosa profunda em membro inferior esquerdo. Complicou com pneumonia e necessidade de ampliar antibiótico para meropenem, completando 28 dias de esquema no total, com negativação das hemoculturas e resolução do quadro de insuficiência renal dialítica. Recebeu alta para acompanhamento ambulatorial e anticoagulação via oral. Conclusão: O presente caso destaca a importância da identificação precoce dos sinais e sintomas dessa infecção ocular para que o diagnóstico e tratamento possam ser prontamente iniciados. Existem poucos dados na literatura da prevalência de endoftalmite por E coli, e são escassos os relatos de casos evidenciando esse tipo de infecção. O diagnóstico requer um índice de suspeição elevado quando observado envolvimento ocular em um paciente com bacteremia, sendo que a intervenção precoce, possivelmente, produz melhores resultados.

Introdução: A varicela é uma doença viral contagiosa causada pelo vírus varicela zoster (VVZ), pertencente à família Herpesviridae e comumente se apresenta como uma manifestação cutânea autolimitada. Embora na maioria dos casos a doença segue um curso leve sem complicações, alguns pacientes podem desenvolver complicações extremamente raras, como o tromboembolismo pulmonar (TEP). Há poucos relatos na literatura de varicela associadas a fenômenos trombóticos, como o TEP. Os fatores causais ainda são pouco compreendidos. Objetivo: Relatar caso embolia pulmonar aguda após infecção por varicela. Método: Relato de caso. Resultados: M.F., 38 anos, masculino, tabagista, previamente hígido. Procurou atendimento devido à erupção cutânea papulovesicular pruriginosa, com polimorfismo regional, disseminada em todo corpo com 3 dias de evolução. Apresentava contato recente e prolongado com familiar internada por Herpes-Zóster. Paciente não soube informar varicela na infância e negava vacinação prévia. Procurou atendimento novamente após 11 dias com dor torácica ventilatório dependente e dispneia. Angiotomografia positiva para TEP. Sorologias para HIV, sífilis e hepatites B e C não reagentes. IgM e IgG para varicela reagentes. Realizados aciclovir e anticoagulação plena, evoluiu com resolução dos quadros. Conclusão: Relatos de complicações trombóticas devido ao VVZ não são comuns na literatura médica. Eles incluem principalmente casos de trombose no sistema nervoso central e sua minoria de embolia pulmonar. Apresentamos um interessante caso de infecção por VVZ complicada em paciente adulto imunocompetente, associada à embolia pulmonar após contato com familiar com Herpes-Zóster para chamar atenção que infecções auto limitadas podem levar a fenômenos trombóticos graves.

Introdução e objetivos: Diante da heterogeneidade clínica da COVID-19, os parâmetros hematológicos têm sido utilizados para definição de prognóstico e monitoramento da doença. Dentre eles, podemos citar a contagem de leucócitos totais, neutrófilos, linfócitos, plaquetas, bem com a relação neutrófilo linfócito (RNL). Baseado no exposto, o objetivo do estudo foi avaliar os marcadores hematológicos em indivíduos hospitalizados com COVID-19 e associá-los aos desfechos de convalescência ou óbito, no município de Irecê- Bahia. Material e métodos: A pesquisa foi realizada com abordagem retrospectiva de caráter descritivo documental, com consulta nas bases de dados SRAG e SG do DATASUS, bem como aos prontuários médicos, considerando pacientes hospitalizados no período de 2020 a 2021 no Hospital Municipal de Irecê-BA. Resultados: Foram incluídos no estudo 174 pacientes, com idade de 18 a 98 anos, sendo maioria do sexto masculino (59,2%). A maior parte deles evoluiu para cura (46%), de modo que 20,7% foram a óbito e 33,3% tiveram o desfecho declarado como regulados (transferidos para unidades de saúde com infraestrutura mais avançada). Dentre os parâmetros hematológicos, a contagem de eritrócitos e linfócitos, os níveis de hemoglobina e hematócrito estiveram mais baixos nos pacientes que foram a óbito (p = 0,03; p = 0,02; p = 0,01 e p = 0,04, respectivamente). Por outro lado, a contagem de leucócitos totais, neutrófilos e RNL foram mais elevadas nesse mesmo grupo, (p = 0,002; p = 0,001; e p = 0,0001, respectivamente). Discussão: Estudos demonstram aumento na contagem de leucócitos e neutrófilos e diminuição na contagem de plaquetas, linfócitos e eosinófilos em pacientes com COVID-19 grave (Zhang et al., 2021). Alagbe e colaboradores (2024) concluíram que os pacientes que não sobreviveram tiveram linfocitopenia e anemia, bem como neutrofilia e aumento da RNL. Este último parâmetro é um preditor de SRAG por SARS-CoV-2. No presente estudo, pacientes com menos de 50 anos e RNL inferior a 3,13 tiveram baixa probabilidade de desenvolver doença grave, enquanto aqueles que apresentaram relação igual ou superior a 3,13 necessitaram de maior assistência e monitoramento. Já os pacientes na faixa de 50 anos ou mais e RNL inferior a 3,13 apresentam risco moderado de desenvolver a doença crítica, ao passo que aqueles com RNL igual ou superior a 3,13 tiveram alto risco, sendo a maioria transferidos para UTI. No estudo apresentado por Kumari (2023), os pacientes podem ser classificados em não grave quando o RNL for menor que 5,86, em graves quando a razão foi de 5,86 até 8,99 e por fim, os críticos com valores maiores que 8,99. Contribuindo com os estudos, Chen (2020), em sua análise apresentou mediana de 13,4 para os indivíduos que não sobreviveram, 3,71 para os convalescentes e 8,96 para os casos graves. Ao comparar esses dados da literatura com os obtidos neste estudo, a mediana da RNL para os pacientes que foram a óbito foi de 12,7, dos convalescentes foi de 6 e dos regulados foi de 9,7. Conclusão: Pacientes com COVID-19 em estado crítico e com piores desfechos apresentaram maior relação neutrófilo-linfócito (RNL), hemoglobina reduzida, leucocitose, neutrofilia e linfocitopenia. Esses achados reforçam a importância da monitorização desses parâmetros como parte da avaliação clínica, etapa crucial para o desenvolvimento de estratégias terapêuticas mais eficazes e direcionadas para esses pacientes.

Abstract Introduction: The lack of specialized professionals potentially contributes to the inability to meet the demand for kidney transplantations. Moreover, there is no universal proposal for the training process of transplantation surgeons. We aimed to explore the characteristics of the training program and professional activities of kidney transplantation teams in the state of Minas Gerais, Brazil. Methods: We invited the surgeons of all 19 active kidney transplantation centers in Minas Gerais to participate in this cross-sectional study. Demographic and professional training data were compared using linear and logistic regression models. Results: The response rate among the centers was high (89%); half of the surgeons answered the survey (39/78). Most of the centers were public teaching institutions, under a production-based payment contract, with a mean of 6 ± 2.4 surgeons/team; 94.2% of the centers had urologists. The surgeons were 95% male (age of 46.3 ± 9.7 years) and 59% were urologists. Most were involved in organ procurement and transplantation; only one surgeon worked exclusively with transplantation. The mean period since training was 13 ± 9.4 years, with a mean of 10 ± 9.7 years as part of the transplantation team. Only 25.6% had specialized or formal training in transplantation, with only one completing a formal medical residency for kidney transplantation. The lack of training programs was the most frequently cited reason. Conclusion: Kidney transplantation surgeons are not exclusive and most have not completed a formal fellowship program in transplantation because they are not available. These data indicate the need to improve training programs and facilitate the formation of new kidney transplantation teams.

BackgroundHistorically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting.MethodsMini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses.ResultsAmong 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT.ConclusionLow-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.