Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

Assessing dairy goat welfare in intensive or semi-intensive farming conditions in Mexico.

We aimed to verify whether a low number of relevant animal-based indicators was able to discriminate 33 semi-intensive (grazing during the day and confinement during the night with access to an outdoor paddock; S-INT) and 8 intensive farms (permanent confinement with access to an outdoor paddock; INT) located in the Mexican semi-desert. In addition, we implemented the resource-based assessment scheme Animal Needs Index (ANI) with the identified animal-based indicators to compare the overall level of welfare in INT and S-INT. In particular, we used a protocol made up of 2 parts. The first comprised 4 evaluation sheets (locomotion, flooring, environment, management) and resource-based indicators derived from ANI, and the second one comprised a set of validated animal-based measures focusing on physical conditions and clinical signs of disease derived from the Animal Welfare Indicators scheme and reported in 2 additional sheets. The scoring system was also derived from ANI, with partial scores for each sheet to be summed to obtain the total score. A total of 1,116 dairy goats were assessed. All the observations and recordings were performed by an expert veterinarian evaluator assisted by an auxiliary, and longevity was retrieved from the farm records. The prevalence of animals displaying dirtiness, ocular discharge, abscesses, and claw overgrowth were higher in INT than in S-INT. Disbudding was routinely performed in INT only. Therefore, scurs, indicating improper disbudding, were recorded only in INT. In addition, the longevity of goats raised in S-INT was higher than in INT. Conversely, the prevalence of goats affected by anemia (i.e., FAMACHA scores >2) or lean (i.e., body condition score <2) tended to be higher in S-INT than in INT. No significant differences between the 2 groups of farms were detected for wounds, nasal discharge, integument alterations, fecal soiling, uterine prolapse, and subclinical mastitis. The results obtained using only animal-based measures were confirmed when resource-based variables were also included in the assessment, as 3 out of 6 sheets of the evaluation scheme (i.e., flooring, environment, and health-physical conditions) were scored higher in the S-INT than in the INT. As a consequence, the total score was also higher for S-INT than for INT. We conclude that the selected set of validated animal-based measures was able to discriminate between farms from different production systems. In particular, higher welfare levels were observed in S-INT farms, where the animals were allowed to spend most of the day on natural pasture, compared with INT farms, where the animals were constantly confined. Nevertheless, a certain degree of improvement should also be promoted in terms of anemia and body condition in S-INT farms.

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients.

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.

Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR-MCL). We report the long-term outcome and safety profile of a single-centre, single arm, open-label, phase 2 study of RR-MCL treated with IR. Overall, the median follow-up time was 47 months (range 1-52 months), median duration on treatment was 16 months (range 1-53 months) and median number of treatment cycles was 17 (range 1-56). Twenty-nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty-eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1-2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression-free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL-related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR-MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR-MCL is under exploration.

Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib.

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

Phase II Study of Bortezomib in Combination with Cyclophosphamide and Rituximab for Relapsed or Refractory Mantle Cell Lymphoma.

BACKGROUND: Relapsed or refractory mantle cell lymphoma (MCL) has a poor prognosis. The best outcome is achieved in patients who have a partial or complete response to salvage treatment and proceed to allogeneic stem cell transplant. PATIENTS AND METHODS: Twenty-one patients were given a combination regimen of bortezomib, cyclophosphamide, and rituximab at MD Anderson Cancer Center as part of a single-arm, prospective, open-label phase II clinical trial. The median age was 66 years, with a median number of prior treatments of three. Sixty-seven percent had failed intensive chemoimmunotherapy and 43% were intermediate/high risk according to the MCL international prognostic index score, with a median Ki-67 proliferation index of 45% in those who were tested. RESULTS: The rates of overall and complete response achieved were 74% and 42%, respectively, with median progression-free and overall survivals of 9 months and 36.4 months, respectively. The regimen's toxicity profile was acceptable; only 25% of the cycles resulted in grade 3 or 4 neutropenia or thrombocytopenia, and only 3% of cycles produced grade 3-4 fatigue. There were no episodes of grade 3-4 neuropathy. CONCLUSION: The combination of bortezomib with cyclophosphamide and rituximab is an effective and well-tolerated regimen in patients with relapsed/refractory MCL. Because of its low toxicity, future combinations of this regimen with other promising drugs that have different mechanisms of action offer a realistic possibility that may improve outcomes for patients who have MCL. The Oncologist 2017;22:549-553 IMPLICATIONS FOR PRACTICE: The combination of bortezomib with cyclophosphamide and rituximab represents an additional effective novel salvage regimen for mantle cell lymphoma. This combination adds to the growing list of treatment options available for patients with mantle cell lymphoma.

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial.

BACKGROUND: Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity. METHODS: Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients. FINDINGS: Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment. INTERPRETATION: Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data. FUNDING: Pharmacyclics LLC, an AbbVie Company.

Perinatal outcomes with isolated oligohydramnios at term pregnancy.

AIMS: To compare the outcomes of term gestations with oligohydramnios in the absence of other underlying disorders and term gestations with normal amniotic fluid. METHODS: A retrospective analysis of obstetric outcomes in 27,708 term pregnancies. We compared three groups: labor induced because of oligohydramnios, spontaneous onset of labor with normal amniotic fluid, and labor induced because of late term pregnancy with normal amniotic fluid. We excluded pregnancies with maternal or fetal diseases or disorders potentially related with amniotic fluid alterations. The main outcome measures were mode of delivery, neonatal birth weight, umbilical artery blood pH, Apgar scores and neonatal discharge status. RESULTS: Compared to spontaneous labor, induction of labor because of oligohydramnios was associated with a higher risk of cesarean delivery and small size of the fetus for gestational age (SGA). Compared to induction because of late term pregnancy there were no significant differences in neonatal, although neonates had a higher risk of being SGA. CONCLUSION: The only perinatal outcome for which the risk was higher in term pregnancies with isolated oligohydramnios was SGA. The systematic induction of labor in these pregnancies should be questioned.

The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma.

Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton's tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma. However, many patients relapse post CAR-T therapy with dismal outcomes. To dissect the underlying mechanisms of sequential resistance to BTKi and CAR-T therapy, we performed single-cell RNA sequencing analysis for 66 samples from 25 patients treated with BTKi and/or CAR-T therapy and conducted in-depth bioinformatics™ analysis. Our analysis revealed that MYC activity progressively increased with sequential resistance. HSP90AB1 (Heat shock protein 90 alpha family class B member 1), a MYC target, was identified as early driver of CAR-T resistance. CDK9 (Cyclin-dependent kinase 9), another MYC target, was significantly upregulated in Dual-R samples. Both HSP90AB1 and CDK9 expression were correlated with MYC activity levels. Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial.

BACKGROUND: The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. METHODS: Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632. FINDINGS: 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. INTERPRETATION: Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. FUNDING: Celgene.

Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma.

Bruton's tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11-knockout cells showed antitumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK/CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K/AKT/mTOR, and integrin signaling. Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.

Environmental and Anthropogenic Influences on Coliform Concentrations in the Octopus insularis Production Chain in the Veracruz Reef System, Gulf of Mexico.

Coliforms are relatively common in aquatic environments, but their concentrations can be increased by environmental changes and anthropogenic activities, thus impacting fisheries resources. To determine the microbiological quality in the octopus production chain (capture, post-capture, processing and commercialization), total (TC) and fecal (FC) coliforms were quantified in sea water, fresh octopus, fresh water, ice and octopus in two presentations: packed in ice and boiled. Samples came from fishing zones Enmedio, Chopa and La Gallega at the Veracruz Reef System (VRS) during dry, rainy and windy seasons. The coliforms were determined using the most probable number technique (MPN). The most relevant results indicated that octopus packed in ice coming from the commercialization stage had FC levels >540 MPN/100 g, which exceeded the permissible limits (230 MPN/100 g). Therefore, these products present a risk for human consumption. Differences in FC were observed in octopuses between the three fishing zones (H = 8.697; p = 0.0129) and among the three climatic seasons, increasing during the rainy season, highlighting La Gallega with 203.33 ± 63 MPN (H = 7.200; p = 0.0273). The results provide evidence of the environmental and anthropogenic influences on coliform concentrations and the urgent need to implement an efficient cold chain throughout octopus production stages with adequate handling practices to reverse this situation.

SARS-CoV-2 in eight municipalities of the Colombian tropics: high immunity, clinical and sociodemographic outcomes.

BACKGROUND: Serological evaluation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an alternative that allows us to determine the prevalence and dynamics of this infection in populations. The goal of this study was to determine the clinical and sociodemographic dynamics of SARS-CoV-2 infection in a region of the Colombian Caribbean. METHODS: Between July and November 2020, a cross-sectional observational study was carried out in Córdoba, located in northeast Colombia in the Caribbean area. Eight municipalities with the largest populations were chosen and 2564 blood samples were taken. A commercial enzyme-linked immunosorbent assay was used with the recombinant protein antigen N of SARS-CoV-2. The people included in the study were asked for sociodemographic and clinical data, which were analysed by statistical methods. RESULTS: A seroprevalence of 40.8% was obtained for SARS-CoV-2 in the Córdoba region. In the bivariate analysis, no differences were observed in seropositivity against SARS-CoV-2 for gender or age range (p>0.05). Higher seropositivity was found in low socio-economic status and symptomatic patients (p<0.0001). A total of 30.7% of the asymptomatic patients were seropositive for SARS-CoV-2, which could be linked to the spread of this infection. In the multivariate analysis, seroconversion was related to poverty and clinical manifestations such as anosmia and ageusia (p<0.05). CONCLUSIONS: The high seropositivity in Córdoba is due to widespread SARS-CoV-2 in this population. The relationship between seropositivity and socio-economic status suggests a higher exposure risk to the virus caused by informal economic activities in low-income groups. Clinical manifestations such as anosmia and ageusia could be clinical predictors of infection by the new emergent coronavirus.