[Effect of Chlorambucil Combined with Ibrutinib on Mantle Cell Lymphoma Cell Line Jeko-1 and Its Related Mechanism].

OBJECTIVE: To investigate the toxic effect of chlorambucil combined with ibrutinib on mantle cell lymphoma (MCL) cell line Jeko-1 and its related mechanism. METHODS: The MCL cell line Jeko-1 was incubated with different concentrations of chlorambucil or ibrutinib or the combination of the two drugs, respectively. CCK-8 assay was used to detect the proliferation of the cells, and Western blot was used to measure the protein expression levels of BCL-2, caspase-3, PI3K, AKT and P-AKT. RESULTS: After Jeko-1 cells were treated with chlorambucil (3.125, 6.25, 12.5, 25, 50 µmol/L) and ibrutinib (3.125, 6.25, 12.5, 25, 50 µmol /L) alone for 24, 48, 72h respectively, the cell proliferation was inhibited in a time- and dose-dependent manner. Moreover, the two drugs were applied in combination at low doses (single drug inhibition rate<50%), and the results showed that the combination of two drugs had a more significant inhibitory effect (all P < 0.05). Compared with the control group, the apoptosis rate of the single drug group of chlorambucil (3.125, 6.25, 12.5, 25, 50 µmol/L) and ibutinib (3.125, 6.25, 12.5, 25, 50 µmol/L) was increased in a dose-dependent manner. The combination of the two drugs at low concentrations (3.125, 6.25, 12.5 µmol/L) could significantly increase the apoptosis rate compared with the corresponding concentration of single drug groups (all P < 0.05). Compared with control group, the protein expression levels of caspase-3 in Jeko-1 cells were upregulated, while the protein expression levels of BCL-2, PI3K, and p-AKT/AKT were downregulated after treatment with chlorambucil or ibrutinib alone. The combination of the two drugs could produce a synergistic effect on the expressions of the above-mentioned proteins, and the differences between the combination group and the single drug groups were statistically significant (all P < 0.05). CONCLUSION: Chlorambucil and ibrutinib can promote the apoptosis of MCL cell line Jeko-1, and combined application of the two drugs shows a synergistic effect, the mechanism may be associated with the AKT-related signaling pathways.

Early complete response as a validated surrogate marker in extranodal marginal zone lymphoma systemic therapy.

ABSTRACT: Extranodal marginal zone lymphoma (EMZL) has a very indolent course, and the validation of surrogate markers could accelerate novel therapies. Although prognostic markers do exist, no surrogate markers have been validated in EMZL. We hypothesized that time to complete response within 24 months (TTCR24) and complete response (CR) at 24 months (CR24) could be valid surrogate markers of progression-free survival (PFS). The International Extranodal Lymphoma Study Group 19 phase 3 trial showed the advantage of double therapy (rituximab + chlorambucil) over single therapy (rituximab or chlorambucil) on PFS. We used 2 recently published single-trial approaches to assess whether TTCR24 and CR24 were good surrogate markers of 8-year PFS (8y-PFS). Among the 401 patients, 264 (66%) reached a CR in the first 24 months, of which 222 (84%) remained in CR at month 24. The cumulative incidence of CR over time was significantly higher in patients under double therapy (hazard ratio, 1.75; P < .001). The double therapy arm was associated with a higher CR24 rate, a shorter TTCR24, and a longer 8y-PFS. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% confidence interval [CI], 0.27-1.87). CR24 was also a strong surrogate marker because it mediated 90% (95% CI, 0.51-2.22) of the treatment effect on PFS and its natural indirect effect was significant throughout the follow-up. We found that TTCR24 predicted 95% and that CR24 mediated 90% of the treatment effect on long-term PFS. Therefore, TTCR24 and CR24 could be used in clinical trials as informative and valid early indicators of treatment effect on PFS. This trial was registered at www.clinicaltrials.gov as #NCT00210353.

Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up. METHODS: GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18-64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib-venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil-obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2-6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77). FINDINGS: Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib-venetoclax (n=106) or chlorambucil-obinutuzumab (n=105). At a median of 46 months (IQR 43-47) of follow-up, progression-free survival remained superior for the ibrutinib-venetoclax group (hazard ratio 0·214 [95% CI 0·138-0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0-82·0) for ibrutinib-venetoclax and 24·8% (16·5-34·1) for chlorambucil-obinutuzumab. Following the primary analysis, one patient in the chlorambucil-obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib-venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil-obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib-venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil-obinutuzumab group (of which 10 were due to post-treatment infections). INTERPRETATION: After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option. FUNDING: Janssen Research & Development and Pharmacyclics.

ROS/pH dual-sensitive emodin-chlorambucil co-loaded micelles enhance anti-tumor effect through combining oxidative damage and chemotherapy.

The high level of reactive oxygen species (ROS) at the tumor site has been widely used in the tumor targeted delivery. However, the ROS stimulus-responsive vector itself is also a ROS consumer, and the consumption of endogenous ROS may not be sufficient to maintain sustained drug release. In this study, we designed and synthesized ROS/pH dual-sensitive polymer micelles for the co-delivery of emodin (EMD) and chlorambucil (CLB). The release of quinone methides (QM) can consume glutathione (GSH), on the one hand, it can enhance the chemotoxicity of phenylbutyrate nitrogen mustard, on the other hand, emodin can induce oxidative damage of tumor cells and maintain the sustained targeted release of drugs.

Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia.

Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10-4) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10-6) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities.

Cost-effectiveness of acalabrutinib regimens in treatment-naïve chronic lymphocytic leukemia in the United States.

BACKGROUND: Clinical outcomes in chronic lymphocytic leukemia (CLL) have improved with targeted therapy, including Bruton tyrosine kinase inhibitors such as acalabrutinib. METHODS: A semi-Markov model with three health states (progression-free, progressed disease, and death) estimated cost per quality-adjusted life-year (QALY) gained for acalabrutinib ± obinutuzumab vs chlorambucil + obinutuzumab in treatment-naive CLL (based on ELEVATE-TN). The model used direct costs and resource utilization from the US Medicare perspective and utility values sourced from literature. Sensitivity analyses tested the robustness of the model. RESULTS: Over a 30-year lifetime horizon, the model base case analysis suggested that acalabrutinib monotherapy had an incremental cost of $206,329 and 2.52 QALYs gained versus chlorambucil + obinutuzumab, resulting in an incremental cost-effectiveness ratio (ICER) of $81,960/QALY. Acalabrutinib + obinutuzumab had an incremental cost of $423,747 and 2.79 QALYs gained (ICER: $152,153/QALY). Probabilistic sensitivity analysis showed the probability of acalabrutinib monotherapy being cost-effective as 59% to 73% at a $100,000-to-150,000/QALY willingness-to-pay threshold; the probability of acalabrutinib + obinutuzumab being cost-effective ranged from 34% to 51%. CONCLUSIONS: Although the analysis is limited by uncertainty in postprogression survival outcomes, acalabrutinib monotherapy is likely cost-effective vs chlorambucil + obinutuzumab in treatment-naive CLL in the US Medicare setting.

Pharmacological tumor PDL1 depletion with chlorambucil treats ovarian cancer and melanoma: improves antitumor immunity and renders anti-PDL1-resistant tumors anti-PDL1-sensitive through NK cell effects.

BACKGROUND: Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies. METHODS: We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1. RESULTS: PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced αPDL1 efficacy in tumors otherwise αPDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus αPDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3ß/ß-TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential. CONCLUSIONS: Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in αPDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including αPDL1-refractory cancers, and is rapidly clinically translatable.

Cost-Effectiveness of Venetoclax Plus Obinutuzumab Versus Chlorambucil Plus Obinutuzumab for the First-Line Treatment of Adult Patients With Chronic Lymphocytic Leukemia: An Extended Societal View.

OBJECTIVES: Efficacy of venetoclax plus obinutuzumab (VenO) compared with chlorambucil plus obinutuzumab (ClbO) for treatment-naïve adult patients with chronic lymphocytic leukemia (CLL) with coexisting medical conditions was investigated in CLL14 (NCT02242942). Our aim was to evaluate the cost-effectiveness of VenO versus ClbO for these patients from a Dutch societal perspective. METHODS: A 3-state partitioned survival model was constructed to evaluate the cost-effectiveness of VenO. The outcome of the analysis was the incremental cost-effectiveness ratio (ICER) with effectiveness measured in quality-adjusted life-years (QALYs) gained. Uncertainty was explored through deterministic and probabilistic sensitivity analyses, scenario analyses, and value of information analysis (VOI). RESULTS: The base case resulted in a discounted ICER -49 928 EUR/QALY gained (with incremental negative costs and positive effects). None of the ICERs resulted from deterministic sensitivity and scenario analyses exceeded the chosen willingness-to-pay threshold of 20 000 EUR/QALY, and > 99% of the iterations in the probabilistic sensitivity analysis were cost-effective. VOI analyses showed a maximum expected value of eliminating all model parameter uncertainty of 183 591 EUR. CONCLUSIONS: Our study demonstrated VenO being dominant over ClbO in treatment-naïve adult patients with CLL assuming a Dutch societal perspective. We concluded that our results are robust as tested through sensitivity and scenario analyses. Additionally, the VOI analyses confirmed that our current evidence base is strong enough to generate reliable results for our study. Nevertheless, further research based on real-world data or longer follow-up period could further contribute to the robustness of the current study's conclusions.

Long-term progression-free survival in patients with chronic lymphocytic leukemia treated with novel agents: An analysis based on indirect comparisons.

OBJECTIVE: In chronic lymphocytic leukemia, growing evidence has accumulated about long-term outcomes of first-line treatments. Our objective was to perform indirect comparisons across first-line treatments. METHODS: We applied the Shiny method, an artificial intelligence technique that analyses Kaplan-Meier curves and reconstructs patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and indirect head-to-head comparisons. The endpoint was progression-free survival (PFS). RESULTS: Seven first-line treatments were studied (1983 patients). Three treatments based on either ibrutinib or venetoclax (i.e., ibrutinib monotherapy, ibrutinib+ rituximab/obinutuzumab, and venetoclax+obinutuzumab) showed a very similar survival pattern. The PFS for these three treatments was significantly better than that of the remaining four treatments (fludarabine+cyclophosphamide+rituximab, chlorambucil+obinutuzumab, bendamustine+rituximab, and chlorambucil monotherapy). Regarding chlorambucil+ obinutuzumab, a significant between-trial variability was found. CONCLUSIONS: Long-term results are particularly favorable to ibrutinib (alone or in combination) and discourage further use of chlorambucil. As in other studies based on the Shiny method, the multi-treatment Kaplan-Meier graph summarized the available evidence in comparative terms. The evidence generated this way contributes to define the place in therapy of individual agents.

Use of oral chemotherapeutic agent, chlorambucil, as palliative treatment of thryoid adenocarcinoma in a golden-headed lion tamarin (Leontopithecus chrysomelas).

This case report describes the use of chlorambucil in a 7.5-year-old golden-headed lion tamarin (Leontopithecus chrysomelas) as palliative therapy for thyroid adenocarcinoma. Treatment was initiated at 0.1 mg/kg orally once daily. No physical abnormalities or substantial changes in complete blood cell counts and thyroid hormone levels from serial samples were detected.

Cost-utility analysis of venetoclax in combination with obinutuzumab as first-line treatment of chronic lymphocytic leukaemia in Spain.

OBJECTIVE: Venetoclax in combination with obinutuzumab has significantly improved efficacy versus immunochemotherapy (progression-free survival) in patients with chronic lymphocytic leukaemia who have not  received prior treatment. The objective of this study was to evaluate its efficiency in Spain using a cost-utility analysis. METHOD: Using a partitioned-survival analysis model adapted to the Spanish  context and based on three health states (progression-free survival, survival  after progression, and death), a simulation of the evolution of patients who  were candidates for initiating first-line treatment was conducted for a lifetime  time horizon. Venetoclax in combination with obinutuzumab was compared to  the most commonly used therapeutic options for these patients at the time of  study design: chlorambucil in combination with obinutuzumab, ibrutinib,  fludarabine in combination with cyclophosphamide and rituximab, and  bendamustine in combination with rituximab. In order to estimate survival  curves, efficacy data were derived from the CLL14 trial and a network meta- analysis. The  analysis was conducted from the perspective of the Spanish  National Healthcare System and included direct healthcare costs (i.e.  pharmacological costs and their administration), and those associated with the management of the disease and adverse events. The resource use was validated by an expert group. Quality of life data were used to estimate the  quality-adjusted life years obtained for each alternative. A threshold of  €25,000/quality-adjusted life years was used. The robustness of the model was evaluated using deterministic and probabilistic sensitivity analyses. RESULTS: Venetoclax in combination with obinutuzumab was shown to be a  dominant alternative compared to the rest of the treatment alternatives, with a  lower cost per patient (€-67,869 compared to chlorambucil in combination  with obinutuzumab, €-375,952 compared to ibrutinib, €-61,996 compared to  fludarabine in combination with cyclophosphamide and rituximab, and €- 77,398 compared to bendamustine in combination with rituximab). It also had  a greater gain in quality-adjusted life years (0.551 quality-adjusted life years  gained compared to chlorambucil in combination with obinutuzumab and  ibrutinib, 1.639 quality-adjusted life years gained compared to fludarabine in  combination with cyclophosphamide and rituximab, and 1.186 quality-adjusted  life years gained compared to bendamustine in combination with  rituximab). Between 68% and 85% of the simulations performed in the  sensitivity analysis showed that venetoclax in combination with obinutuzumab  had lower costs and more quality-adjusted life years gained. CONCLUSIONS: Venetoclax in combination with obinutuzumab is an efficient and  dominant alternative for treating previously untreated patients with chronic lymphocytic leukaemia compared to the available  alternatives and from the perspective of the Spanish National Health System.

OBJETIVO: Venetoclax en combinación con obinutuzumab ha mostrado frente a  la inmunoquimioterapia mejoras significativas en términos de eficacia (supervivencia libre de progresión) en pacientes con leucemia  infocítica crónica que no han recibido tratamiento previo. El objetivo de este  estudio fue evaluar su eficiencia en España a partir de un análisis de coste- utilidad.Método: A partir de un modelo de análisis de la supervivencia adaptado al  contexto español y basado en tres estados de salud (supervivencia libre de  progresión, supervivencia tras progresión y muerte), se llevó a cabo una  simulación de la evolución de los pacientes candidatos a iniciar una primera  línea de tratamiento para un horizonte temporal de toda la vida. Venetoclax en  combinación con obinutuzumab se comparó frente a las opciones terapéuticas  más utilizadas para estos pacientes en el momento del diseño del estudio:  clorambucilo en combinación con obinutuzumab, ibrutinib, fludarabina en  combinación con ciclofosfamida y rituximab, y bendamustina en combinación  con rituximab. Los datos de eficacia para estimar las curvas de supervivencia  fueron derivados del estudio CLL14 y de un metaanálisis en red. El análisis  consideró la perspectiva del Sistema Nacional de Salud incluyendo los costes  sanitarios directos, en concreto los farmacológicos y su administración, y los  asociados al manejo de la enfermedad y acontecimientos adversos. El uso de  recursos fue validado por un grupo de expertos. Se emplearon datos de calidad  de vida para estimar los años de vida ajustados por calidad obtenidos  para cada alternativa. Se consideró un umbral de 25.000 €/años de vida  ajustados por calidad. La robustez del modelo se evaluó mediante análisis de  sensibilidad determinísticos y probabilísticos. RESULTADOS: Venetoclax en combinación con obinutuzumab se mostró como  una alternativa dominante frente al resto de alternativas de tratamiento, con  un menor coste por paciente (­67.869 € frente a clorambucilo en combinación  con obinutuzumab, ­375.952 € frente a ibrutinib, ­61.996 € frente a  ludarabina en combinación con ciclofosfamida y rituximab, y ­77.398 € frente  a bendamustina en combinación con rituximab) y una mayor ganancia en años  de vida ajustados por calidad (0,551 años de vida ajustados por calidad  ganados frente a clorambucilo en combinación con obinutuzumab e ibrutinib,  1,639 años de vida ajustados por calidad ganados frente a fludarabina en  combinación con ciclofosfamida y rituximab, y 1,186 años de vida ajustados  por calidad ganados frente a bendamustina en combinación con rituximab).  Entre el 68% y el 85% de las simulaciones realizadas en el análisis de  sensibilidad mostraban a venetoclax en combinación con obinutuzumab con un  menor coste y un mayor número de años de vida ajustados por calidad  ganados. CONCLUSIONES: Venetoclax en combinación con obinutuzumab se muestra como una alternativa eficiente y dominante como tratamiento de  pacientes con leucemia linfocítica crónica no tratados previamente frente a las  alternativas disponibles y desde la perspectiva del Sistema Nacional de Salud.

Population pharmacokinetics identifies rapid gastrointestinal absorption and plasma clearance of oral chlorambucil administered to cats with indolent lymphoproliferative malignancies.

OBJECTIVE: To establish the pharmacokinetics of a single 2-mg oral dose of chlorambucil in cats with indolent lymphoproliferative malignancies. ANIMALS: 24 client-owned cats. PROCEDURES: Cats were assigned to 1 of 4 groups, with each group having a total of 3 sample collection time points over 12 hours after receiving a single 2-mg oral dose of chlorambucil. Each time point combined to generate 6 full patient plasma chlorambucil concentration-time curves from the 24 cats. Chlorambucil treatment was continued every other day and a single, variably timed sample collection was obtained on day 14. Population parameter estimates were obtained by nonlinear mixed-effects modeling. Covariates investigated included age, sex, baseline serum cobalamin, study location, weight, and body condition score. RESULTS: Chlorambucil administered orally to cats was found to have a peak plasma concentration of approximately 170 ng/mL (SE, 31.1 ng/mL), percent coefficient of variation (%CV) of 18.4% within 15 minutes, and a terminal half-life of 1.8 hours (SE, 0.21 hour; %CV, 12.4). At the 4-hour mark, a smaller secondary peak in plasma chlorambucil was found. Day 14 samples were similar to those of the initial dose. No covariates showed a significant effect in the population model. CLINICAL RELEVANCE: In these cats, chlorambucil at a 2-mg dose administered every other day undergoes rapid gastrointestinal absorption and plasma clearance with no drug accumulation between doses. These data are critical to inform future work investigating the association of chlorambucil drug exposure with adverse events and outcome of cats with lymphoproliferative diseases.

A Self-Reporting Fluorescent Salicylaldehyde-Chlorambucil Conjugate as a Type-II ICD Inducer for Cancer Vaccines.

Immunogenic cell death (ICD) can activate the anticancer immune response and is highly attractive to improve cancer treatment efficacy. ICD is closely related to endoplasmic reticulum (ER) stress, and a series of ICD inducers has recently been reported based on ER-targeted photodynamic/photothermal agents or metal complexes. However, these ER-targeted ICD inducers suffer from complicated synthesis and heavy-metal cytotoxicity. Inspired by the promising clinical potential of small organic molecules, herein, an ER-targeted fluorescent self-reporting ICD inducer, SA-Cbl, is developed by simple conjugation of the chemotherapeutic drug chlorambucil (Cbl) with salicylaldehyde (SA). SA-Cbl can selectively accumulate in the ER to induce rapid ROS generation and an unfolded protein response process, which leads to a fast release of damage-associated molecular patterns and efficient dendritic cells maturation. Meanwhile, the ER-targeted accumulation and ER-stress-inducing process can be in situ monitored based on the turn-on fluorescence of SA-Cbl, which is highly pH- and polarity-sensitive and can selectively interact with ER proteins. Compared with the traditional chemotherapy drug doxorubicin, the superior anticancer immunity effect of SA-Cbl is verified via an in vivo tumor model. This study thus provides a new strategy for developing fluorescent self-reporting ICD inducers by decoration of chemotherapeutic drugs with pH and polarity-sensitive organic fluorophores.

Feline non-erosive immune-mediated polyarthritis: a multicentre, retrospective study of 20 cases (2009-2020).

CASE SERIES SUMMARY: Cats with non-erosive immune-mediated polyarthritis (IMPA) were identified from seven referral hospitals between 2009 and 2020 for a multicentre retrospective case series. Data were obtained from hospital records and referring veterinarians were contacted for follow-up. Twenty cases were identified: 12 castrated males (60%), one entire male (5%) and seven spayed females (35%). Common clinical signs included lameness (n = 20/20) and pyrexia (n = 10/18). Three cats presented with and two cats developed ligament laxity during treatment. Thirteen cats (65%) were diagnosed with non-associative IMPA and seven (35%) with associative IMPA. Comorbidities identified included chronic enteropathy (n = x/7), feline immunodeficiency virus (n = x/7) feline herpesvirus (n = x/7), bronchopneumonia (n = x/7) and discospondylitis (n = x/7). Sampling of the tarsal joints most frequently identified an increased proportion of neutrophils, consistent with IMPA. Eighteen cats (90%) received immunosuppressants. Eleven cats were started on prednisolone; eight had a poor response resulting in the addition of a second agent, euthanasia or acceptance of the persisting signs. One cat received ciclosporin and required an alternative second agent owing to adverse effects. Five cats were started on prednisolone and ciclosporin; three had a poor response and required an alternative second agent. One cat received prednisolone and chlorambucil and had a good response. Two cats (10%) received meloxicam and had a good response, although the clinical signs recurred when medication was tapered. A good outcome was achieved in 14/20 cats (70%) with IMPA. In the cats with a poor outcome 4/6 were euthanased and 2/6 had chronic lameness. RELEVANCE AND NOVEL INFORMATION: Prognosis for feline IMPA can be good. Multimodal immunosuppression was often required. IMPA should be considered in lame cats, with or without pyrexia, when there is no evidence of trauma or infection. The tarsal joints should be included in the multiple joints chosen for sampling. Ligament laxity can occur in non-erosive feline IMPA.

Glucocorticoids, Cyclosporine, Azathioprine, Chlorambucil, and Mycophenolate in Dogs and Cats: Clinical Uses, Pharmacology, and Side Effects.

The treatment of immune-mediated disease in dogs and cats continues to evolve as new therapies are adapted from human medicine. Glucocorticoids remain the first-line treatment followed by second-line therapies including cyclosporine, azathioprine (dogs), chlorambucil, or mycophenolate. Second-line therapies are introduced due to the patient's lack of response or intolerable effects to glucocorticoids or may be introduced early in the disease treatment due to the patient's severe life-threatening clinical presentation. The goals of immunosuppressive treatment are to achieve disease remission while minimizing drug side effects. Ultimately, gradual drug tapering to the lowest dose to maintain disease remission or successful drug withdrawal.

Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies.

Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54-2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69-1.77); unmutated IGHV: 1.79 (0.99-3.24); and NOTCH1 mutated 1.05 (0.65-1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features.Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).