Při nutnosti řešit středně silnou a silnou bolest je téměř nemožné se obejít bez silných opioidů. Nové opioidní léčivé přípravky (atypické opioidy – buprenorfin, transdermální nebo transmukózní lékové formy) pomáhají zlepšit léčbu různých typů nádorové i nenádorové bolesti a zároveň snižují nežádoucí účinky silných opioidů, zejména zácpu. Fixní kombinace oxykodonu s naloxonem v poměru 2 : 1 zachovává výborný analgetický účinek silného opioidu oxykodonu a zároveň díky obsahu naloxonu předchází vzniku zácpy vyvolané opioidy.

When it is necessary to manage moderate to severe pain, it is nearly impossible to do so without the use of strong opioids. New opioid medications - referred to as atypical opioids, such as buprenorphine in transdermal or transmucosal formulations - contribute to improved treatment of various types of both cancer-related and non-cancer-related pain. At the same time, they help reduce the adverse effects commonly associated with strong opioids, particularly constipation. A fixed combination of oxycodone and naloxone in a 2:1 ratio maintains the excellent analgesic effect of the potent opioid oxycodone, while the inclusion of naloxone effectively prevents opioid-induced constipation.

Kazuistika popisuje případ 66letého pacienta s dlouhotrvajícím diabetem 2. typu (DM2T), u něhož byla léčba premixovaným inzulínem provázena opakovanými epizodami hypoglykemie včetně epizody závažné hypoglykemie s poruchou vědomí. Po přechodu na terapii fixní kombinace bazálního inzulínu glargin 100 a GLP-1 receptorového agonisty (GLP-1 RA) lixisenatidu v předplněném peru SoloStar došlo nejen k eliminaci závažných hypoglykemií, zlepšení glykemické kontroly, vyjádřené poklesem glykovaného hemoglobinu (HbA1c), ale i zlepšení kvality života pacienta. Tento případ ilustruje jak účinnost, tak i bezpečnost terapie fixní kombinací bazálního inzulínu a GLP-1 RA

This case report describes a 66-year-old patient with long-standing type 2 diabetes mellitus (T2DM). The patient experienced recurrent episodes of hypoglycaemia, including a severe hypoglycaemic event with impaired consciousness, while being treated with premixed insulin. After switching to a fixed-ratio combination therapy with basal insulin glargine 100 and the GLP-1 receptor agonist (GLP-1 RA) lixisenatide in the prefilled SoloStar pen, severe hypoglycaemic episodes were eliminated and glycaemic control improved. The improvement was reflected by a reduction in glycated haemoglobin (HbA1c), along with an overall enhancement in the patient’s quality of life. This case highlights both the efficacy and safety of fixed-ratio combination therapy with basal insulin and a GLP-1 RA.

Potřeba simplifikace (deintenzifikace) intenzifikovaného inzulínového režimu (IIR) je u pacientů s diabetes mellitus 2. typu důsledkem častého zahajování této terapie v minulosti, kdy nebyly k dispozici jiné alternativy. Deintenzifikace je v současné době umožněna dostupností fixních kombinací bazálního inzulinu a agonistů receptoru glukagonu podobného peptidu 1 (giukagon-iike peptide 1, GLP-1) (iGlarLixi, IDegLira). Studie IDEAL prokázala, že deintenzifikace IIR přechodem na iGlarLixi je u pacientů s diabetes mellitus 2. typu účinnou a bezpečnou možností simplifikace terapie, která poskytuje porovnatelnou glykemickou kompenzaci, benefity redukce tělesné hmotnosti, snížení množství inzulinových injekcí a celkové denní dávky inzulínu, zlepšení hodnot při kontinuálním monitorování glykemie (continuous glucose monitoring, CGM), a to bez zvýšeného rizika hypoglykemie a s vyšší spokojeností pacientů s léčbou.

The need for simplification (deintensification) of multiple daily injections (MDI) regimen in people with type 2 diabetes is a consequence of its frequent use in the past when no other relevant options were available. At present, this has become possible due to the availability of new medications and formulations, such as the fixed ratio combinations of basal insulin analogues and glucagon-like peptide 1 (GLP-1) receptor agonists (iGlarLixi, IDegLira). The IDEAL randomised controlled trial showed that insulin therapy deintensification from MDI regimen into once-daily administered iGlarLixi is an efficient and safe treatment option for people with type 2 diabetes that provides comparable glycaemic control with the benefits of reduction of body weight, total daily dose of insulin, number of insulin injections, lower proportion of visits as which hypoglycaemia was reported and increased patients’ satisfaction with the treatment.

• Keywords
• Suliqua, Xultophy,
• MeSH
• Glucagon-Like Peptide-1 Receptor Agonists pharmacology   therapeutic use   MeSH
• Diabetes Mellitus, Type 2 * diagnosis   drug therapy   MeSH
• Drug Combinations MeSH
• Hyperglycemia blood   prevention & control   MeSH
• Hypoglycemic Agents pharmacology   therapeutic use   MeSH
• Insulin * administration & dosage   pharmacology   classification   therapeutic use   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

AIMS: To assess the efficacy and safety of switching from premixed insulin to a once-daily, fixed-ratio combination of insulin glargine 100 U/mL + lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D). METHODS: In this phase 4, 24-week, single-arm study, participants switched from once-daily or twice-daily premixed insulin to iGlarLixi (EudraCT number 2021-003711-25). Key inclusion criteria: ≥18 years; premixed insulin therapy for ≥3 months and < 10 years; ± 1-2 oral antidiabetic drugs (OADs); HbA1c ≥7.5% to ≤10.0%. The primary endpoint was the change in HbA1c from baseline to Week 24. Secondary endpoints included: participants achieving HbA1c <7% and change in body weight at Week 24, and safety. RESULTS: Overall, 162 participants switched to iGlarLixi (89.5% from twice-daily premixed insulin); mean duration of diabetes was 15.7 (standard deviation [SD]: 8.3) years. Mean baseline HbA1c (8.5%) reduced by least squares (LS) mean of 1.2% (95% confidence interval [CI]: -1.4, -1.1) at Week 24, and 37.6% of participants had achieved an HbA1c target of <7% (95% CI: 30.0, 45.7). LS mean body weight change from baseline to Week 24 was -1.0 kg (95% CI: -1.6, -0.5). Fasting and post-prandial plasma glucose decreased from baseline to Week 24 by 45.6 mg/dL (SD ± 52.4) and 67.6 mg/dL (SD ± 65.1), respectively. Confirmed symptomatic hypoglycaemia occurred in 38.3% of participants (ADA level 1: 35.8%; level 2: 15.4%; level 3: 0.0%). CONCLUSIONS: iGlarLixi initiation was associated with improved glycaemic control, without body weight gain or increased hypoglycaemia over 24 weeks.

• MeSH
• Diabetes Mellitus, Type 2 * drug therapy   blood   MeSH
• Adult MeSH
• Drug Combinations MeSH
• Glycated Hemoglobin analysis   MeSH
• Hypoglycemia chemically induced   MeSH
• Hypoglycemic Agents * administration & dosage   adverse effects   therapeutic use   MeSH
• Insulin Glargine * administration & dosage   adverse effects   therapeutic use   MeSH
• Blood Glucose drug effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Drug Substitution * MeSH
• Peptides * administration & dosage   adverse effects   therapeutic use   MeSH
• Glucagon-Like Peptide-2 Receptor MeSH
• Drug Administration Schedule MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase IV MeSH
• Multicenter Study MeSH

BACKGROUND: Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown. METHODS: In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review. RESULTS: A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with chemoimmunotherapy. Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively; death from coronavirus disease 2019 was reported in 10, 25, and 21 patients in the three groups. CONCLUSIONS: Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.).

• MeSH
• Benzamides * adverse effects   administration & dosage   MeSH
• Bridged Bicyclo Compounds, Heterocyclic * administration & dosage   adverse effects   therapeutic use   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   mortality   MeSH
• Cyclophosphamide * administration & dosage   adverse effects   MeSH
• Progression-Free Survival * MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Pyrazines * adverse effects   administration & dosage   MeSH
• Rituximab * administration & dosage   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sulfonamides * administration & dosage   adverse effects   MeSH
• Vidarabine analogs & derivatives   administration & dosage   adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent. Four IBU-based combinations were studied: 1:4 M ratio with octanoic acid (OctA), 1:5 with nonanoic acid (NonA), 1:3 with decanoic acid (DeA) or 1:2 with dodecanoic acid (DoA). Fatty acids of different chain lengths were analyzed and discussed considering surface charge densities obtained via quantum chemistry. The THEDESs listed could apparently dissolve AbAc amounts up to 1311.0 ± 125.4 mg/g in IBU:OctA THEDES, 1151.7 ± 22.2 mg/g in IBU:NonA, 1160.4 ± 33.5 mg/g in IBU:DeA, and 231.3 ± 10.7 mg/g in IBU:DoA. In vitro dissolution of the simultaneously released drugs reached 37.8 ± 9.0 % to 64.2 ± 1.0 % for IBU and 5.0 ± 3.3 % to 19.4 ± 0.1 % for AbAc. This increased to between 60.4 ± 2.8 % and 79.4 ± 5.0 % of released IBU, and 23.6 ± 1.0 % to 57.3 ± 5.8 % of released AbAc, with 20 % (w/w) Tween 80 added to the formulations. This showed the significant potential of drug-containing THEDESs as solubilizing agents for poorly soluble drugs, in the form of fixed-dose combinations of synergistic APIs.

• MeSH
• Abiraterone Acetate * chemistry   administration & dosage   MeSH
• Chemistry, Pharmaceutical methods   MeSH
• Drug Combinations MeSH
• Ibuprofen * chemistry   administration & dosage   MeSH
• Fatty Acids chemistry   MeSH
• Drug Compounding methods   MeSH
• Antineoplastic Agents chemistry   administration & dosage   MeSH
• Solvents * chemistry   MeSH
• Solubility * MeSH
• Drug Liberation MeSH
• Publication type
• Journal Article MeSH

AIM: To evaluate the efficacy of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) using derived time-in-range (dTIR). METHODS: Participant-level data from LixiLan-L, LixiLan-O and LixiLan-G were pooled and dTIR (70-180 mg/dL), derived time-above-range (> 180 mg/dL) and derived time-below-range (dTBR; < 70 mg/dL) were calculated from participant seven-point self-monitored blood glucose profiles. RESULTS: This pooled analysis included data from 2420 participants receiving iGlarLixi (n = 1093), iGlar (n = 836), Lixi (n = 234) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) (n = 257). Numerically greater improvements in least square (LS) means dTIR were seen from baseline to end of treatment (EOT) with iGlarLixi (25.7%) versus iGlar (15.8%), Lixi (11.7%) or GLP-1 RA (16.2%). At EOT, the mean (standard deviation) dTBR was 0.71% ± 3.4%, 0.61% ± 3.2%, 0.08% ± 1.0% and 0.0% ± 0.0% for iGlarLixi, iGlar, Lixi and GLP-1 RA, respectively. In a subgroup analysis, participants aged younger than 65 years (n = 1690) and 65 years or older (n = 713) showed numerically greater improvements in LS means dTIR from baseline to EOT with iGlarLixi versus iGlar, Lixi or GLP-1 RA. CONCLUSIONS: iGlarLixi achieved improvements in dTIR, with low dTBR values, providing further evidence to inform clinical outcomes with the use of iGlarLixi.

• MeSH
• Glucagon-Like Peptide-1 Receptor Agonists MeSH
• Diabetes Mellitus, Type 2 * drug therapy   blood   MeSH
• Adult MeSH
• Drug Combinations MeSH
• Glycated Hemoglobin analysis   metabolism   drug effects   MeSH
• Hypoglycemic Agents * therapeutic use   MeSH
• Insulin Glargine * therapeutic use   MeSH
• Blood Glucose * drug effects   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Peptides * therapeutic use   administration & dosage   MeSH
• Randomized Controlled Trials as Topic MeSH
• Glucagon-Like Peptide-2 Receptor MeSH
• Blood Glucose Self-Monitoring MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

INTRODUCTION: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. METHODS: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. RESULTS: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. CONCLUSIONS: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. CLINICAL TRIAL REGISTRATION: NCT03749642.

• Publication type
• Journal Article MeSH

PURPOSE: Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). METHODS: Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. RESULTS: Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. CONCLUSION: RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

• MeSH
• Adenocarcinoma * drug therapy   pathology   mortality   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Esophagogastric Junction * pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Esophageal Neoplasms * drug therapy   pathology   mortality   MeSH
• Stomach Neoplasms * drug therapy   pathology   mortality   MeSH
• Nivolumab * therapeutic use   administration & dosage   adverse effects   MeSH
• Lymphocyte Activation Gene 3 Protein * MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.

• MeSH
• Adenine * analogs & derivatives   administration & dosage   therapeutic use   MeSH
• Transplantation, Autologous * MeSH
• Cyclophosphamide * administration & dosage   therapeutic use   MeSH
• Dexamethasone administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Doxorubicin administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell * therapy   drug therapy   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Piperidines * administration & dosage   therapeutic use   MeSH
• Prednisone administration & dosage   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Rituximab * administration & dosage   therapeutic use   MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation methods   MeSH
• Vincristine * administration & dosage   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• Europe MeSH
• Israel MeSH