Datasets:

dmariko

/

init_data

like 0

Results

LUNG METASTASES

Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (

PMC9823079

Conclusion

LUNG METASTASES

Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.

PMC9823079

Keywords

PMC9823079

Introduction

Cancer, breast cancer, malignancy, Breast cancer, lung cancer, HER2-positive metastatic breast cancer, malignant disease

BREAST CANCER, BRAIN METASTASES, BREAST CANCER, COMPLICATION, MALIGNANT DISEASE, LUNG CANCER, METASTASES, CANCER

Breast cancer (BC) has surpassed lung cancer as the most commonly diagnosed malignancy in women according to Global Cancer statistics 2020 [Brain metastases (BrM) is a common complication of advanced malignant disease and occurs in 1/3 of HER2-positive metastatic breast cancer [Studies have confirmed the activity of continued trastuzumab treatment beyond progression (TBP). The subgroup analysis of observational HERMINE study suggested that trastuzumab TBP offered a survival benefit to MBC patients treated with first-line trastuzumab [Dual HER2 blockade by trastuzumab plus TKI, simultaneously targeting the extra- and intra-cellular domains of HER2, showed encouraging anti-tumor activity in BC, including early breast cancer and MBC with intracranial metastases [

PMC9823079

Methods

PMC9823079

Patients and data collection

leptomeningeal disease, disability

ONCOLOGY, BRAIN METASTASIS, METASTATIC DISEASE

From November 1, 2018, to March 31, 2021, female patients aged ≥ 18 years old with histologically confirmed HER2-positive MBC at National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital (Shenzhen, Guangdong, China) were enrolled in this study. HER2 status was determined by central review based on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) examination using primary or metastatic lesion samples. Patients had been previously treated with trastuzumab, pertuzumab and/or lapatinib in the (neo)adjuvant/metastatic setting. Additional requirements included an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (on a 5-point scale by which greater scores reflect higher degree of disability); measurable lesions; and adequate organ function. Patients were excluded if they had previously received treatment with pyrotinib for metastatic disease; had symptomatic brain metastasis which necessitates immediate local intervention; or had leptomeningeal disease. All procedures performed involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was also approved by the institutional review board and ethics committee. All patients provided written informed consent for use of the medical information for research purpose.

PMC9823079

Treatment

All eligible patients were treated with pyrotinib (240–400 mg orally once daily), trastuzumab (6 mg per kilogram of body weight intravenously per 21 days, with an initial loading dose of 8 mg per kilogram) and single chemotherapeutic agent (nab-paclitaxel, 260 mg per square meter of body-surface area intravenously on day 1 of each 21-day cycle; or capecitabine, 1000 mg per square meter of body-surface area orally twice daily on days 1 to 14 of each 21-day cycle; or gemcitabine, 1000 mg per square meter of body-surface area intravenously on days 1 and 8 of each 21-day cycle; or vinorelbine, 60 mg per square meter of body-surface area orally on days 1 and 8 of each 21-day cycle and dose elevation to 80 mg per square meter of body-surface area was allowed if well tolerated).

PMC9823079

Follow-up and assessment

DISEASE

All patients were followed up until January 20, 2022. Disease response was evaluated according to imaging reports from serial clinical assessments. Patient/disease response assessments were performed at baseline, every 6 weeks for 24 weeks, and every 9 weeks thereafter, including performance status, history, laboratory examinations, electrocardiogram

PMC9823079

End points

death

DISEASE, DISEASE PROGRESSION, SECONDARY

The primary end point was PFS (calculated from the date of first treatment with double targeted therapy to the date of documented disease progression or death from any cause or the last follow-up visit) in TP. The secondary end points included PFS in the subgroup with BrM (Sub-BrM) at baseline; objective response rate (ORR, defined as the percentage of patients who had a confirmed complete response or partial response); clinical benefit rate (CBR, defined as the percentage of patients who had a confirmed complete response or partial response or stable disease for at least 24 weeks); disease control rate (DCR, defined as the percentage of patients who had a confirmed complete response or partial response or stable disease for at least 4 weeks); exploration of predictive factors of PFS; and safety.

PMC9823079

Statistical analysis

EVENT

All data were analyzed using SPSS 23.0 statistical software (SPSS, Inc., Chicago, IL, USA) and GraphPad Prism 5 software (GraphPad Software, Inc., La Jolla, CA, USA). Descriptive analysis was utilized to display clinicopathological features. The Kaplan–Meier method was used to estimate PFS and 95% confidence intervals (CIs) for the total population and the subgroups. Cox univariate and multivariate models were used to determine the predictive value of variables for PFS. In the analysis of progression-free survival, data from patients who did not have any documented event, were lost to follow-up or died from any cause were censored at the last date when the patient was known to be event-free. All reported

PMC9823079

Results

PMC9823079

Safety

ADVERSE EVENTS

All treatment-related adverse events (TRAEs) reported in the study were summarized in Table Treatment-related adverse events in total population

PMC9823079

Acknowledgements

The authors are grateful to the patients and all the researchers, including the physicians, pathologists, and technicians, who participated in this study.

PMC9823079

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by X-FX, Q-YZ, J-YH, L-PC, S-JG, S-LX, and X-FL. Writing-reviewing and editing were performed by X-XF, XB, LS. The first draft of the manuscript was written by X-FX and C-WD. Supervision and project administration was performed by C-WD. All authors are responsible for the contents and have read and approved the manuscript for submission.

PMC9823079

Funding

ONCOLOGY

This work was supported by the Chinese Society of Clinical Oncology (CSCO) Research Foundation in Beijing and fund from ShenZhen Science and Technology Program (2018, JCYJ20180306171227129). Cai-Wen Du has received researches supported from Beijing CSCO clinical Oncology Research Foundation and Shenzhen Science and Technology Innovation Commission.

PMC9823079

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

PMC9823079

Declarations

PMC9823079

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PMC9823079

Ethical approval

Cancer

CANCER

All procedures performed involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was also approved by institutional review boards and ethics committees (ethical code: 2019-35) of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

PMC9823079

Informed consent

Informed consent was obtained from all individual participants included in the study. The authors affirmed that human research participants provided informed consent for publication.

PMC9823079

References

PMC9823079

Subject terms

LBCL, toxicity, B-cell lymphoma, B cell lymphoma

REMISSIONS, B-CELL LYMPHOMA, CYTOKINE RELEASE SYNDROME, SECONDARY, B CELL LYMPHOMA, EVENTS

Axicabtagene ciloleucel (axi-cel) demonstrated superior efficacy compared to standard of care as second-line therapy in patients with high-risk relapsed/refractory (R/R) large B cell lymphoma (LBCL) considered eligible for autologous stem cell transplantation (ASCT); however, in clinical practice, roughly half of patients with R/R LBCL are deemed unsuitable candidates for ASCT. The efficacy of axi-cel remains to be ascertained in transplant-ineligible patients. ALYCANTE, an open-label, phase 2 study, evaluated axi-cel as a second-line therapy in 62 patients with R/R LBCL who were considered ineligible for ASCT. The primary end point was investigator-assessed complete metabolic response at 3 months from the axi-cel infusion. Key secondary end points included progression-free survival, overall survival and safety. The study met its primary end point with a complete metabolic response of 71.0% (95% confidence interval, 58.1–81.8%) at 3 months. With a median follow-up of 12.0 months (range, 2.1–17.9), median progression-free survival was 11.8 months (95% confidence interval, 8.4–not reached) and overall survival was not reached. There was no unexpected toxicity. Grade 3–4 cytokine release syndrome and neurologic events occurred in 8.1% and 14.5% of patients, respectively. These results support axi-cel as second-line therapy in patients with R/R LBCL ineligible for ASCT. ClinicalTrials.gov Identifier: In the ALYCANTE trial, second-line treatment with axicabtagene ciloleucel, a CD19-targeting CAR T-cell therapy, resulted in high response rates and durable remissions in patients with high-risk large B-cell lymphoma deemed ineligible for autologous stem cell transplantation.

PMC10579056

Main

LBCL, transplant-ineligible

B CELL LYMPHOMA

Large B cell lymphoma (LBCL) is successfully treated in approximately two-thirds of patients with rituximab-based chemoimmunotherapyIn patients with high-risk R/R LBCL considered eligible for ASCT, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T cell therapy, demonstrated superior efficacy over the SOC as a second-line therapy in the ZUMA-7 trialIn clinical practice, about half of patients with R/R LBCL are considered ineligible for HDCT/ASCTThe prognosis of patients with R/R LBCL who are ineligible for HDCT/ASCT is usually poor with standard salvage chemoimmunotherapyAlthough axi-cel has not been evaluated as a second-line therapy in patients with R/R LBCL who are ineligible for HDCT/ASCT, clinical trial data and real-world evidence have shown that CAR-T cell therapy is feasible in a subset of transplant-ineligible patients, notably in elderly and less-fit patients

PMC10579056

Results

aggressive B cell non-Hodgkin lymphoma

ADVERSE EVENTS, SECONDARY

The primary end point was investigator-assessed complete metabolic response (CMR) at 3 months from the axi-cel infusion. Secondary end points were objective response rate (ORR) at 3 months from the axi-cel infusion, CMR at 6 months from the axi-cel infusion, best ORR, best CMR, duration of response (DOR), EFS from leukapheresis, PFS from infusion, OS from infusion and the incidence, nature and severity of adverse events. Additional planned secondary end points not reported in this manuscript include health-related quality of life and the cell product characteristics and cellular kinetics of axi-cel.In the initial study protocol, we calculated that a sample size of 40 patients with aggressive B cell non-Hodgkin lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy and who were ineligible for HDCT/ASCT based on a physician’s assessment was sufficient to test the efficacy of axi-cel infusion. Our initial part of the study (

PMC10579056

Patients and treatment

follicular lymphoma

MAY, DISEASE, FOLLICULAR LYMPHOMA

Between 19 March 2021 and 4 May 2022, a total of 69 patients were enrolled and underwent leukapheresis, representing the full analysis set (FAS). Of these 69 patients, 62 (89.8%) received a single axi-cel infusion between 26 April 2021 and 16 June 2022 and were consequently included in the modified full analysis set (mFAS). There were five important protocol deviations from inclusion criteria: three related to a relapsed disease occurring beyond 12 months from completion of first-line chemoimmunotherapy and two related to patients with a histological diagnosis of grade 1–3A follicular lymphoma after central review. The patient disposition flow diagram is shown in Fig.

PMC10579056

Secondary efficacy outcomes

At 3 months from the axi-cel infusion, the investigator-assessed ORR was 75.8% (95% CI, 63.3–85.8%). In total, 37 patients (59.7%) remained in CMR, as assessed by the investigator, at 6 months from the axi-cel infusion (95% CI, 46.5–72.0%) (Extended Data Fig. At a median follow-up of 12.0 months, the median EFS from leukapheresis was 12.3 months (95% CI, 7.2–not reached; Fig.

PMC10579056

Subgroup analysis

We investigated whether the efficacy and safety of axi-cel were consistent among different patient populations, especially in patients aged ≥70 years and with comorbidities defined by a HCT-CI score ≥3. In patients aged ≥70 years (

PMC10579056

Discussion

LBCL

DISEASE, REMISSIONS

Patients with LBCL who are refractory or who relapse early after first-line chemoimmunotherapy are often chemorefractory and have a very limited cure rate after standard chemoimmunotherapyIn this patient population with poor prognostic features, including 54.8% with primary refractory disease and 63.4% who were refractory to bridging therapy, treatment with axi-cel resulted in high response rates and durable remissions. The investigator-assessed best ORR and best CMR were 90.3% and 79.0%, respectively. Median PFS was 11.8 months and median OS was not reached. Furthermore, the efficacy of axi-cel was maintained across key subgroups, including patients with high-risk features, such as age ≥70 years, HCT-CI score ≥3, IPI ≥ 3 and primary refractory disease. The only exception was in patients with a high TMTV at inclusion, as we observed a reduced CMR at 3 months among these patients. This observation is consistent with other studies evaluating CAR-T cell therapy for R/R LBCL, in which a high TMTV was associated with an increased risk of early relapse or progressionThe findings of ALYCANTE are overall consistent with the results of the phase 3 ZUMA-7 trialAnother CD19-directed CAR-T cell product, lisocabtagene maraleucel (liso-cel), has also been evaluated as a second-line therapy in the open-label, phase 2 PILOT study performed in 61 patients with R/R LBCL who are ineligible for ASCTDespite the comparable study designs and sample sizes of ALYCANTE and PILOTCurrently, there are no standard criteria nor consensus to determine whether a patient can undergo HDCT/ASCT. In most countries, a theoretical age limit for HDCT/ASCT is set to 65–70 years. The age cutoff to define ASCT ineligibility differed between ALYCANTE (65 years) and PILOT (70 years); however, in the present study, subgroup analysis demonstrated that efficacy and safety outcomes after axi-cel infusion were overall similar between patients aged <70 years and ≥70 years. Numerous investigations have additionally found that HCT-CI, a well-established prognostic model for comorbidities, can predict survival outcomes for both autologous and allogeneic stem cell transplantationThis study is limited by its single-arm design with no active control group. Therefore, selection bias cannot be ruled out. Although axi-cel compares favorably to second-line chemoimmunotherapy based on historical controlsIn conclusion, axi-cel as a second-line treatment resulted in high response rates and durable remissions in patients with high-risk R/R LBCL with poor prognostic features and who were not eligible for HDCT/ASCT. Moreover, despite advanced age and comorbidities, axi-cel had an acceptable safety profile in this population considered unfit for HDCT/ASCT. Together, these results support axi-cel as a second-line treatment in patients with R/R LBCL who are deemed ineligible for HDCT/ASCT.

PMC10579056

Methods

PMC10579056

Study design

ALYCANTE (ClinicalTrials.gov ID

PMC10579056

Inclusion and ethics

The study protocol was approved by French Ethics Committee Est I (Dijon) N°20.07.08.66206, in accordance with applicable French laws and regulations. The study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from each participant before any study procedure.

PMC10579056

Participants

pneumonitis, tumor, cardiovascular disease, Active hepatitis B, bowel obstruction, aggressive B cell non-Hodgkin lymphoma, renal disease, idiopathic pneumonitis, infection, B cell non-Hodgkin lymphoma, autoimmune disease

PLEURAL EFFUSION, TUMOR, PNEUMONITIS, CARDIOVASCULAR DISEASE, ORGANIZING PNEUMONIA, FOLLICULAR LYMPHOMA, DISEASE, BOWEL OBSTRUCTION, CENTRAL NERVOUS SYSTEM DISEASE, RENAL DISEASE, DRUG-INDUCED PNEUMONITIS, INFECTION, IDIOPATHIC PULMONARY FIBROSIS, AUTOIMMUNE DISEASE

Eligible patients were aged 18 years or older with histologically confirmed aggressive B cell non-Hodgkin lymphoma, diagnosed according to the 2016 World Health Organization classification criteriaThere were in total, three important protocol deviations from the inclusion criteria in the present study, which were all related to relapsed disease longer than 12 months after first-line chemoimmunotherapy. For two patients, the central histological diagnosis was not aggressive B cell non-Hodgkin lymphoma but grade 1–3A follicular lymphoma.Patients were deemed eligible for CAR-T cell therapy based on a physician’s assessment and all of the following:ECOG performance status of 0, 1 or 2.Adequate vascular access for leukapheresis (peripheral or central venous line).Absolute neutrophil count ≥1.0 × 10Platelet count ≥75 × 10Absolute lymphocyte count ≥0.1 × 10Creatinine clearance (according to the Cockcroft–Gault equation or the modification of diet in renal disease equation) ≥40 ml minSerum ALT/AST ≤ 2.5 × upper limit of normal.Total bilirubin ≤26 μmol lLeft ventricular ejection fraction ≥45%.Oxygen saturation ≥92% on room air.Key exclusion criteria included:Receipt of more than one prior line of systemic therapy.Previous CD19-targeted therapy.Cardiac involvement.Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.Clinically significant pleural effusion.Known central nervous system disease.History of cardiovascular disease within the past 6 months.History of autoimmune disease requiring systemic immunosuppression and/or disease-modifying agents within the last year.History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on a chest computed tomography scan at screening.Active hepatitis B or C infection or positive HIV serology at the time of screening.

PMC10579056

Procedures

toxicities, CRS

Extended Data Fig. Safety was monitored continuously throughout the study. CAR-T cell toxicities such as CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy grading system

PMC10579056

Outcomes

lymphoma, toxicities, death, CRS

DISEASE PROGRESSION, ADVERSE EFFECTS, DISEASE, EVENT, ADVERSE EFFECTS, SECONDARY, LYMPHOMA, PMR

The primary end point was investigator-assessed CMR at 3 months from the axi-cel infusion according to the Lugano response criteriaSecondary efficacy end points included investigator-assessed ORR at 3 months from the axi-cel infusion, investigator-assessed CMR at 6 months from the axi-cel infusion and the best investigator-assessed ORR and CMR. CMR and ORR at 3 months from the axi-cel infusion were also assessed by a central review panel formed by two readers and an adjudicator. Other secondary efficacy outcomes included the best ORR and best CMR as assessed by the central review panel, DOR, EFS from leukapheresis, PFS from infusion and OS from infusion. DOR, EFS and PFS were investigator-assessed. DOR was defined as the time from attainment of PMR or CMR to the date of first documented disease progression/relapse or death from any cause. EFS was defined as the time between leukapheresis and any event preventing axi-cel infusion if axi-cel was never infused, or death, disease progression or instauration of a new lymphoma therapy for lymphoma progression after axi-cel infusion. PFS was defined as the time from axi-cel infusion to disease progression or death from any cause. OS was defined as the time from axi-cel infusion to death from any cause. The estimated rates of EFS, PFS and OS at 6 and 12 months were further evaluated.Safety was evaluated as the incidence, nature and severity of adverse effects. Adverse effects of special interest were related to CAR-T cell toxicities and included CRS and ICANS. Mortality during the study was summarized by cause of death.

PMC10579056

Statistical analysis

DISEASE, EVENT

A one-sample binomial design was used to calculate the initial sample size. We hypothesized that axi-cel would yield a CMR at 3 months of 34% compared to 12% with a historical SOC estimated from a retrospective, real-world cohortEfficacy and safety analyses were performed on the mFAS, which included all patients who signed an informed consent and were infused with axi-cel. A sensitivity analysis of the primary end point was also conducted on all patients who signed an informed consent and had leukapheresis (FAS). We calculated CMR with exact Clopper–Pearson CI values, without adjustment for multiplicity. Patients without response assessment, due to any reason, were considered as nonresponders. We used the Kaplan–Meier method to estimate medians and 95% CI values for PFS, EFS, OS and DOR. If patients did not have an event at the time of the PFS, EFS and DOR analysis, they were censored at the date of the last disease assessment. For assessment of OS, alive patients were censored at their last follow-up date. Safety end points were assessed using descriptive statistics (counts and percentages). A subgroup analysis of CMR at 3 months was conducted for prespecified covariates (such as sex) and a Forest plot was provided.Collected data were entered using the Electronic Data Capture system from Ennov v.8.1 (Ennov). Sample size calculation was performed using EAST v.6.5 (Cytel). All statistical analyses were performed using SAS v.9.3 or higher (SAS Institute) and AdClin v.3.2.2 or higher (AdClin).

PMC10579056

Reporting summary

Further information on research design is available in the

PMC10579056

Online content

Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02572-5.

PMC10579056

Supplementary information

Supplementary Table 1 and Study Protocol.Reporting Summary

PMC10579056

Extended data

Study design and overview of study procedures.

PMC10579056

Causes of autologous stem cell transplantation (ASCT)-ineligibility in the modified full analysis set (N = 62).

comorbidity

Abbreviation: HCT-CI, hematopoietic cell transplantation-specific comorbidity index. Metabolic response over time in the modified full analysis set (mFAS) (N = 62).

PMC10579056

Extended data

is available for this paper at 10.1038/s41591-023-02572-5.

PMC10579056

Supplementary information

The online version contains supplementary material available at 10.1038/s41591-023-02572-5.

PMC10579056

Acknowledgements

P.

This study was funded by Kite, a Gilead company. We thank the patients, their families and the study personnel involved in this trial. We also thank the ALYCANTE investigators, P. Cony-Makhoul, E. Chareyre and the LYSARC study team (Supplementary Table

PMC10579056

Author contributions

R.H. and F.L. contributed to the conception, design and planning of the study. All authors contributed to the acquisition and analysis of data. All authors contributed to the critical review and revision of the manuscript. All authors approved the final version of the manuscript.

PMC10579056

Peer review

PMC10579056

Data availability

This trial is currently ongoing. Requests for access to aggregate data and supporting clinical documents will be reviewed and approved by an independent review panel on the basis of scientific merit. The datasets generated and/or analyzed during the current study are not publicly available due to proprietary considerations. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. Data requests pertaining to the manuscript may be made to the corresponding author (R.H.; [email protected]). Requests will be processed within 12 weeks.

PMC10579056

Competing interests

Monahan, Cancer

SACHS, CANCER

R.H. has received honoraria from Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda and Roche; and is a member on an entity’s Board of Directors or advisory committees of Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte and Miltenyi. E.B. has received honoraria from Kite/Gilead, Bristol-Myers Squibb, Novartis, Pfizer, Incyte, ADC Therapeutics, Roche and Takeda; travel reimbursement from Kite/Gilead, Bristol-Myers Squibb, Novartis and Pfizer; and research funding from Amgen and Bristol-Myers Squibb. G.C. has received consulting fees from Roche, AbbVie, Bristol-Myers Squibb, MedXCell, Mabqi and Onward Therapeutics; honoraria from Jansen, Gilead, Novartis, Roche, Bristol-Myers Squibb and Incyte; and travel and accommodation expenses from Gilead, Roche and Jansen. F.X.G. has received consulting fees from Gilead, Bristol-Myers Squibb, Miltenyi and Novartis; and travel and accommodation expenses from Gilead and Novartis. F.M. has received consulting fees from Roche, Gilead, Novartis, Bristol-Myers Squibb, Genmab and AbbVie; and honoraria for advisory boards from Roche, Gilead and Miltenyi. L.O. has received consulting fees from Roche; honoraria from Bristol-Myers Squibb, Kite/Gilead and Incyte; and travel and accommodation expenses from Roche and AstraZeneca. T.G. has received consulting fees from Takeda and Kite/Gilead; honoraria from Kite/Gilead; and travel and accommodation expenses from Roche, Takeda and Kite/Gilead. P.F. has received consulting fees from Gilead, AstraZeneca, BeiGene, AbbVie and Janssen; honoraria from Gilead, AstraZeneca, BeiGene, AbbVie and Janssen; and travel and accommodation expenses from Gilead, AstraZeneca, BeiGene, AbbVie and Janssen. R.D. has received honoraria from Novartis and Takeda; research funding from Ligue contre le Cancer, Arthur Sachs, Monahan Foundation, Servier Foundation, Philippe Foundation and DCP AP-HP; and non-financial support from Kite/Gilead. C.T. has received institutional research funding from Kite/Gilead and Roche; honoraria for advisory boards from Roche, Novartis, AstraZeneca, BeiGene, AbbVie, Takeda, Roche, Novartis, Kite/Gilead, Bristol-Myers Squibb; and travel and accommodation expenses from Roche, Novartis, AbbVie, Takeda, Roche, Kite/Gilead and Bristol-Myers Squibb. F.J. has received honoraria from Roche, Gilead, Janssen and Bristol-Myers Squibb; honoraria for advisory boards from Roche; and travel and accommodation expenses from Roche and Gilead. S.C. has received consulting fees from Atara, Novartis, Kite/Gilead, Pierre Fabre, Takeda, AbbVie and AstraZeneca; honoraria for advisory boards from Kite/Gilead, Novartis, AbbVie, Takeda and Viatris; institutional funding from Janssen; and travel and accommodation expenses from Novartis, AbbVie and Pierre Fabre. O.C. has received honoraria from Roche, Takeda, Bristol-Myers Squibb, Merck, Kite/Gilead, AbbVie and ADC Therapeutics; and research funding from Roche, Takeda and Kite/Gilead. G.B. has received honoraria for advisory boards from Novartis, Kite/Gilead, Bristol-Myers Squibb and Incyte; and travel and accommodation expenses from Novartis, Kite/Gilead, Bristol-Myers Squibb and Incyte. M.C. has received institutional research funding from AP-HP, INSERM, INCA, Fondation ARC pour la Recherche sur le Cancer and CALYM; honoraria from Amgen and CSL Behring; research funding from Innate Pharma and Servier; and travel and accommodation expenses from Pfizer, Grifols, CSL Behring and Gilead. F.L.G. has received honoraria from Rennes University Hospital. C.M. has received research funding from Kite Pharmaceuticals. C.P. is a LYSARC employee. E.I. has received honoraria from Janssen-Cilag and Pfizer. C.L. has received research funding from Ligue contre le Cancer and Labex Toucan; and travel and accommodation expenses from Roche and Janssen. All other authors declare no competing interests.

PMC10579056

References

PMC10579056

Highlights

depression, psychiatric, PTSD, G-TEP

Group Traumatic Episode Protocol (G-TEP) may be efficient to treat PTSD symptoms in migrants.G-TEP displayed a tendency toward a decrease in symptoms of depression in migrants. G-TEP is suitable to improve the access to psychiatric care for migrants.

PMC10093804

Abstract

psychiatric, PTSD, Stress Disorder, MDD, Trauma

DISEASES, MAJOR DEPRESSIVE DISORDER 2, EYE

Introduction: Post-Traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD) are commonly observed in migrants. Although Eye Movement Desensitization and Reprocessing (EMDR) can be helpful to treat these diseases, it remains difficult to propose EMDR as an individual intervention in help-seeking migrants. Group EMDR, like Group Traumatic Episode Protocol (G-TEP), which was built around the 8 phases of the original EMDR protocol, could offer an effective treatment to a large number of people. It may also be more resource-efficient to provide psychiatric care to migrants. Methods: In this open-label trial, the feasibility and the effectiveness of a 6-session G-TEP intervention was investigated in a group of 10 migrants. Results: The intervention was well tolerated by participants. The final attrition rate was 10%. After the intervention, there was a 28.2% significant decrease in PTSD and complex PTSD symptoms, as measured by the International Trauma Questionnaires (total_ITQ) scores (

PMC10093804

1. Introduction

PTE, traumatic, psychiatric, PTSD, Stress Disorder, MDD

EVENTS, MAJOR DEPRESSIVE DISORDER 2, EYE, DISORDERS

Migration is a complex and stressful experience. Migrants often experience potential traumatic events (PTE) either in their home country (pre-migration), during migration, and/or after their arrival in the host country (post-migration). Migration and resettlement have been associated with various mental-health problems and psychiatric conditions, the prevalence of which varies across studies. Among the most common psychiatric disorders associated with migration, Post-Traumatic Stress Disorder (PTSD) (prevalence varying between 9 and 36% across studies) and Major Depressive Disorder (MDD) (prevalence varying between 5 and 44% across studies) raise particular concern, as they are associated with long-lasting functional impairment [Eye Movement Desensitization and Reprocessing (EMDR) is a psychotherapeutic approach, which was designed on the basis of the so-called adaptive information processing (AIP) model [EMDR was designed and used as an individual intervention in all the above-mentioned studies. Since clinicians require complementary training to apply this treatment, individual EMDR may not be the most time- and cost-efficient psychotherapy when a high number of patients need treatment in a short time frame. This is a critical issue when considering access to mental health care for migrants, especially in Europe where a large proportion of migrants who have arrived over the last years have been exposed to PTE. The high volume of mental health care needed and the large number of potential patients among migrants are challenging the access to mental health care systems in host countries [Thus, group EMDR, which could offer an effective treatment to a large number of people, may be more resource-efficient. Up to now, several EMDR group protocols have been developed, including Group Traumatic Episoderotocol (G-TEP) [Therefore, group EMDR has been gaining attention in the scientific literature in the past few years [

PMC10093804

2. Methods

G-TEP, borderline personality disorder, eating or obsessive-compulsive disorder, traumatic, bipolar disorder, PTSD, schizophrenia, schizoaffective disorder, MDD, Trauma, DSM-5

DISORDER, NEUROLOGICAL DISORDER

This open-label pilot study investigated the clinical effects of G-TEP in help-seeking migrants. First, all participants had an interview with a psychiatrist (P.V.) to control for group eligibility. The inclusion criteria were: PTSD and/or MDD (according to the DSM-5 criteria), the possibility of attending all sessions of the G-TEP protocol, and sufficient emotional stability to process traumatic memories. The exclusion criteria were: comorbid diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, eating or obsessive-compulsive disorder, substance use disorder, borderline personality disorder, or any neurological disorder. Participants were asked to complete two self-assessment questionnaires: the 12-item International Trauma Questionnaire (ITQ) and the 9-item version of the Patient Health Questionnaire (PHQ-9). During the last session of the G-TEP intervention, ITQ and PHQ-9 were assessed again to evaluate changes.

PMC10093804

2.1. Participants

MDD, PTSD

The participants were migrants identified as suffering from symptoms of PTSD and/or MDD and referred to our department. We have established a partnership with a charity that helps migrants solve their administrative issues and offers them social support. The sample included 10 migrants coming from various continents (Europe, Asia, and Africa): 7 women and 3 men (mean age 31.3 years old; standard deviation SD = 11.9; range 17–53) (

PMC10093804

2.2. Clinical Assessment

MDD, CPTSD, P7–P9, PTSD

The ITQ is a self-reported short and simply-worded measure, focusing on the key symptoms of PTSD and complex-PTSD (CPTSD). The total_ITQ score is composed of a PTSD score and a Disturbances in Self-Organization (DSO) score. The PTSD score is a Likert scale composed of 6 items (P1–P6); the P1 and P2 items represent the re-experiencing-in-the-here-and-now score, P3 and P4 the avoidance score, and P5 and P6 the sense of a current threat. The DSO score is a Likert scale also composed of 6 items (C1–C6); C1 and C2 represent affective dysregulation, C3 and C4 negative self-perception, and C5 and C6 disturbances in relationships. The functional impact of these symptoms was also measured using the sum of the P7–P9 and C7–C9 items of the ITQ (functional_ITQ).The Patient Health Questionnaire (PHQ-9) is composed of 9 items on a Likert scale, assessing symptoms of MDD. Each participant was accompanied by a volunteer of the charity. For the non- or partial-French-speaking migrants, the volunteer translated, or at least helped the participant understand the inclusion interview.

PMC10093804

2.3. G-TEP Intervention

G-TEP

The G-TEP intervention consisted of 6 weekly 2-hour sessions. The first 2 sessions were used to train participants on stabilization exercises and for the detailed presentation of the G-TEP worksheet. The following 3 sessions were dedicated to the desensitization process. The last session was dedicated to the self-assessment questionnaires, to a general feedback about the intervention and to a reminder of the stabilization exercises. The group was moderated by two psychiatrists (E.C. and P.V.) and a psychologist (S.R.). While one moderator was effectively leading the group intervention, the two other moderators checked that every participant understood the instructions and remained active. They could also more intensively support a participant in case of abreaction. Non-French-speaking participants were given a worksheet translated in their native language (1 in English, 1 in Arabic).

PMC10093804

2.4. Statistical Analysis

PTSD

The primary outcome measures were the ITQ sub-scores (total_ITQ scores and functional_ITQ scores) and the PHQ-9 scores completed at baseline and after the completion of the 6 sessions. The Wilcoxon signed rank test was used to compare the pre- and post-intervention scores. Statistical analyses were performed using JASP (Version 0.16.3) [Computer software] (JASP Team (2022), Amsterdam, The Netherlands). The PTSD and DSO scores measured using the ITQ were also compared pre- and post-intervention.

PMC10093804

3. Results

CPTSD, PTSD

All participants except three attended all six sessions of the G-TEP intervention. The two 17-year-old women from Cameroon (Participants 6 and 7) missed the 4th session. Another participant, a 22-year-old man from Guinea (Participant 10), missed the last session and had to be excluded from the analysis because of missing post-intervention data. Participants tolerated the intervention well, with the exception of one patient (Participant 7) who reported several abreactions during the procedure. Detailed results are given in At the end of the G-TEP intervention, there was a 28.2% significant decrease in PTSD and CPTSD symptoms, as measured by the total_ITQ scores (W = 44.0; z = 2.547;

PMC10093804

4. Discussion

MDD, PTSD

In this open-label pilot study, G-TEP was found to significantly decrease symptoms of PTSD, especially those relating to disturbances in self-organization, in a group of migrant participants who completed the intervention. This improvement was accompanied by a significant decrease in the functional impact of PTSD symptoms. Symptoms of MDD also decreased, although non-significantly. Notably, this decrease almost reached statistical significance (The proposed intervention consisted of 6 weekly 2-hour sessions. This framework is consistent with the one used in other studies investigating the clinical interest of G-TEP EMDR (for a review, see [Two specificities of the intervention proposed herein should be discussed. First, the sessions were conducted with a high number of practitioners, two psychiatrists and a psychologist. It may have been possible to deliver this intervention with only two practitioners. Secondly, each participant was accompanied by a volunteer who was always the same throughout the intervention. This was done to provide social support during the difficult desensitization process and to encourage session attendance. Since only three participants missed only one session each, these objectives can be considered as having been achieved, and the final attrition rate was 10%. The support provided by the volunteers was intensive, and this may have influenced the results concerning the GTEP intervention. Nevertheless, because of social, administrative, and cultural issues they face, migrants have more difficulties in accessing health care, and stronger support is necessary.There are some limitations to the present study. The analyzed sample was small, which drastically decreased the statistical power of the study. Because of the limited number of participants, the diagnostic features of the ITQ could not be used. Moreover, this study did not include a control group, and there was no follow-up assessment after the intervention. Thus, the expectancy bias and the natural evolution of the symptoms were not controlled. There was a large heterogeneity concerning the clinical responses to G-TEP, with clear beneficial effects in some participants (e.g., participants 5 and 9) but no benefits at all for other participants (e.g., participant 3). The size of the sample did not allow us to investigate potentially predictive markers of response.

PMC10093804

Author Contributions

The GTEP intervention was administered by P.V., S.R. and E.C.; P.V. wrote the manuscript with the support of N.C. and J.B. and C.V.; J.B. performed the statistical analysis. N.P. supervised the project. All authors have read and agreed to the published version of the manuscript.

PMC10093804

Institutional Review Board Statement

No ethical committee approval was obtained for this study involving only validated, and usual psychological treatments.

PMC10093804

Informed Consent Statement

Informed consent was obtained from all subjects participating in the study after a fair description of the study objectives.

PMC10093804

Data Availability Statement

For privacy reasons, the data that support the findings of this study cannot be made publicly available. However, they remain available from the corresponding author, PV, upon reasonable request.

PMC10093804

Conflicts of Interest

The authors don’t have any conflict of interest to declare related to this work.

PMC10093804

References

depression, post-traumatic stress disorder, PTSD

EVENT

Demographic characteristics of the included participants.Changes in symptoms of post-traumatic stress disorder (PTSD) and depression in participants receiving the 6-session Group Traumatic Event Protocol (G-TEP).

PMC10093804

Supplementary Information

toxicities, NHL

INDOLENT NON-HODGKIN LYMPHOMA, NHL

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (The online version contains supplementary material available at 10.1007/s12185-022-03455-0.

PMC9813077

Keywords

PMC9813077

Introduction

NHLs, Non-Hodgkin lymphomas, malignant lymphomas, NHL

PROLIFERATION, NON-HODGKIN LYMPHOMA, NHL, TUMOR GROWTH, MALIGNANT LYMPHOMAS

Non-Hodgkin lymphomas (NHLs) comprise about 95% of the malignant lymphomas diagnosed in Japan [Phosphatidylinositol 3 kinases (PI3K) are a family of membrane-bound kinases involved in the growth and survival of healthy cells that are implicated in tumor growth and proliferation when they are dysregulated or aberrantly activated [This article describes a phase Ib/II study in Japanese patients with relapsed/refractory indolent NHL. The aims of the study were to identify the recommended dose of copanlisib in this patient group and assess the safety and antitumor activity of the copanlisib recommended dose.

PMC9813077

Methods

PMC9813077

Study design

This was an open-label, single-arm, phase Ib/II study conducted at 13 centers in Japan. The study was in two parts: the dose-escalation part (phase Ib) to determine the recommended dose and the expansion part (phase II) to evaluate the antitumor activity and safety of the recommended dose of copanlisib.The protocol was reviewed and approved by each study site’s Independent Ethics Committee/Institutional Review Board before the start of the study, as were all protocol amendments at the time of their implementation. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonisation guideline E6: Good Clinical Practice. All patients voluntarily provided written informed consent prior to any study procedures being undertaken.

PMC9813077

Patients

inadequate liver, tumor, myocardial infarction, angina, impaired pulmonary function, toxicity, human immunodeficiency virus infection, B-cell NHL, cardiac disease, interstitial lung disease, alopecia

TUMOR, UNCONTROLLED HYPERTENSION, MYOCARDIAL INFARCTION, HEART DISEASE, CHRONIC HEPATITIS, DIABETES MELLITUS, ALOPECIA, HUMAN IMMUNODEFICIENCY VIRUS INFECTION, SMALL LYMPHOCYTIC LYMPHOMA, SEIZURE DISORDERS, B-CELL NHL, CONGESTIVE HEART FAILURE, CARDIAC DISEASE, JC VIRUS INFECTION, ONCOLOGY, INTERSTITIAL LUNG DISEASE, PATHOLOGY, BLEEDING DIATHESIS

The study included Japanese patients aged ≥ 20 years with a histologically confirmed diagnosis (central pathology review) of one of the following types of indolent B-cell NHL: FL grade 1, 2, or 3a, small lymphocytic lymphoma with absolute lymphocyte count < 5 × 10Other inclusion criteria were: Eastern Cooperative Oncology Group (ECOG) performance status 0–2, life expectancy of 3 months or longer, adequate bone marrow, liver, and renal function as assessed within 7 days before starting study treatment, left ventricular ejection fraction ≥ lower limit of normal for the study center, and the availability of fresh or archival tumor tissue.Key exclusion criteria were: uncontrolled hypertension (blood pressure > 150/90 mmHg despite optimal medical management), type I or II diabetes mellitus (glycated hemoglobin > 8.5% or fasting blood glucose > 160 mg/dL at screening), history of cardiac disease or congestive heart failure, myocardial infarction within 6 months of study entry, active heart disease, new-onset angina within 3 months before study entry, treatment (chemotherapy, immunotherapy, radiotherapy, or investigational drug) targeting lesions within 4 weeks before study entry, evidence or history of a bleeding diathesis, history or concurrent conditions or interstitial lung disease or impaired pulmonary function, ongoing systemic corticosteroid therapy, unresolved toxicity attributed to prior treatment (other than alopecia), prior treatment with a PI3K inhibitor or strong cytochrome P450 3A4 inhibitors, known history of human immunodeficiency virus infection or chronic hepatitis B or C virus infection requiring treatment, seizure disorders, inadequate liver, renal, or bone marrow function (assessed as per laboratory values), and pregnant or lactating women.

PMC9813077

Study methodology

DLTs, toxicity, toxicities, hyperglycemia, PD

HYPERGLYCEMIA, DISEASE PROGRESSION, ADVERSE EVENT

After a screening period of up to 28 days, three eligible patients began treatment with copanlisib at 45 mg (dose level 1) by 1 h intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Tolerability was assessed at the end of the first cycle, and if no dose-limiting toxicities (DLTs) occurred, three additional patients were enrolled and treated with copanlisib at 60 mg (dose level 2). If one DLT developed, an additional three patients were enrolled and treated at each dose level. Copanlisib was considered not to be tolerated and the study stopped if two or more out of three patients or two or more out of six patients showed DLTs.Once the recommended dose level was established, 20 patients were enrolled in the expansion part (phase II) of the study, which included patients from the dose-escalation phase. During the expansion part, patients were treated with copanlisib until disease progression (PD), clinical progression (e.g., deterioration of ECOG performance status to ≥ 3), unacceptable toxicity, or other reasons for treatment withdrawal.As transient post-infusion hyperglycemia is a known adverse event (AE) with copanlisib, a low carbohydrate diet was recommended for the first 48 h after copanlisib infusion.

PMC9813077

Outcomes and assessments

tumor, DLTs, neutropenia, toxicity, Malignant Lymphoma, hyperglycemia, Cancer

ADVERSE EVENT, TUMOR, NEUTROPENIA, ADVERSE DRUG REACTION, DISEASE, MALIGNANT LYMPHOMA, HYPERGLYCEMIA, PANCREATITIS, EVENTS, HYPERTENSION, CANCER

Patients were assessed for AEs, and blood samples were taken for laboratory assessments at screening, on day 1 of cycle 1, at each visit during treatment, and at the safety follow-up visit 28–35 days after the last administration of copanlisib. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4), and assessed as related or not related to copanlisib by the investigator. Treatment-emergent AEs (TEAEs) were any AEs arising or worsening after the start of drug administration until 28–35 days after the last dose of copanlisib, and an adverse drug reaction (ADR) was an AE considered to be related to copanlisib treatment.A DLT was defined as any grade 3 or 4 non-hematologic toxicity that did not improve within 21 days despite optimal supportive care, excluding the following events: transient post-infusion grade 3 hypertension, grade 3 or 4 hyperglycemia that improves with insulin treatment, and any grade 3 or 4 lipase and/or amylase elevation without signs of pancreatitis. Hematologic DLTs were defined as grade 4 neutropenia lasting for ≥ 7 days despite adequate treatment (including granulocyte colony stimulating factor), an absolute neutrophil count < 1000/mmThe primary endpoint was to assess the safety profile of copanlisib at the recommended dose. Contrast-enhanced computed tomography or magnetic resonance imaging of all suspected disease sites was performed at screening, every 2 cycle during study treatment during Year 1, every 3 cycle during Year 2, and every 6 cycle during Year 3. An independent, blinded evaluation of the tumor status was conducted using the Revised Response Criteria for Malignant Lymphoma [

PMC9813077

Statistical analysis

DLTs

Since the study was primarily a descriptive safety and tolerability assessment, no formal sample size estimate was performed, but we included at least three patients at each dose level to identify any DLTs and 20 patients to determine antitumor activity. Both efficacy and safety were assessed in the full analysis set (FAS), which included all patients who were assigned to treatment in the dose-escalation part (FAS 1) or dose-expansion part (FAS 2). Demographics and baseline characteristics were summarized using descriptive statistics and/or frequency as appropriate. Efficacy variables were summarized using descriptive statistics, with 95% confidence intervals (CIs) calculated for ORR. Time-to-event endpoints were assessed using frequency, median, quartiles, range, and rate within each 90-day period, as well as by Kaplan–Meier curves. Missing data were not imputed.

PMC9813077

Results

PMC9813077

Treatment exposure

At the time of data cut-off, the median duration of study treatment was 19.3 weeks (4.8 cycles), and the median number of copanlisib infusions was 12. The median total dose per patient was 720 mg, and the median percentage of planned dose was 83.3%.

PMC9813077

Pharmacokinetics

The maximum plasma concentration and area under the concentration–time curve to 168 h from copanlisib infusion in Japanese patients were both similar to those values determined in non-Japanese patients (Supplementary Fig. S3).

PMC9813077

Discussion

hypertension, NHL

HYPERGLYCEMIA, HYPERTENSION, NHL

This phase Ib/II study demonstrated that the recommended dose of copanlisib is 60 mg in Japanese patients with relapsed/refractory indolent NHL, and that the safety and tolerability of copanlisib, as well as the antitumor activity, in this population are similar to those reported in the CHRONOS-1 study [In our study, copanlisib was associated with an ORR of 68.0% and median duration of response of almost 1 year (330 days or 10.8 months), compared with an ORR of 60.6% and median duration of response of 14.1 months in CHRONOS-1 [Hyperglycemia and hypertension were common AEs with copanlisib in our study, consistent with previous data for copanlisib monotherapy [Of the five patients with hypertension who were able to continue copanlisib for more than 1 year, three patients developed hypertension within the first month of treatment (grade 3, Our study has some limitations which need to be acknowledged. As a phase Ib/II study, a small number of patients were enrolled. Almost all of these patients had FL, so the results should be confirmed in larger studies in patients with other types of indolent NHL.In conclusion, this study indicates that copanlisib, at a recommended dose of 60 mg, has an acceptable safety and tolerability profile, and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.

PMC9813077

Acknowledgements

Mitali Choudhury of inScience Communications

We would like to thank Catherine Rees and Mitali Choudhury of inScience Communications, Springer Healthcare who wrote the outline and the subsequent drafts of this manuscript, respectively. This medical writing assistance was funded by Bayer Yakuhin, Ltd.

PMC9813077

Author contributions

JGV and BHC: conceptualized and designed the study. NF, DM, KH, HN, SM, KK, TU, SK, JK, CI, MY, NT, YS, HM, and KT: collected and assembled the data. MY, SM, TT, and YT: interpreted the data. All authors critically reviewed the manuscript and approved the final draft for submission.

PMC9813077

Funding

Bayer Yakuhin

PMC9813077

Declarations

PMC9813077

Conflict of interest

Shinichi, Barrett, honoraria/lecture

BARRETT

Noriko Fukuhara has received research grants from AbbVie, Bayer, Eisai, Gilead Sciences, Ono Pharmaceutical, and Solasia Pharma and honoraria from Chugai and Kyowa Kirin. Dai Maruyama has received research grants from Celgene, Novartis, Chugai, Ono Pharmaceutical, Takeda, Janssen, and MSD and honoraria from Janssen, Mundipharma, Eisai, and Chugai. Kiyohiko Hatake has received honoraria/lecture fees from Takeda, Chugai, Celgene, Otsuka, Towa, Kyowa Kirin, Daiichi Sankyo, Eisai, Yakult Honsha, and Meiji Seika Pharma and consulting fees from Eisai. Hirokazu Nagai has received research grants from AstraZeneca, Celgene, Mundipharma, Zenyaku Kogyo, Takeda, Chugai, Bayer, Bristol Myers Squibb, Janssen, Kyowa Kirin, Ono Pharmaceutical, MSD, and SymBio Pharmaceuticals and honoraria/lecture fees from Eisai, Chugai, Takeda, Celgene, Mundipharma, Kyowa Kirin, Ono Pharmaceutical, AstraZeneca, Sanofi, Bristol Myers Squibb, Novartis, Janssen, SymBio Pharmaceuticals, Chordia Therapeutics, and Nihon Medi-Physics. Shinichi Makita has received honoraria from Celgene, Bristol Myers Squibb, Chugai, CSL Behring, Daiichi Sankyo, Eisai, Novartis, SymBio Pharmaceuticals, and Takeda and advisory board fees from Takeda, Celgene, Bristol Myers Squibb, Daiichi Sankyo, and Novartis. Shigeru Kusumoto has received research grants from Chugai, Daiichi Sankyo, Kyowa Kirin, Janssen, Bristol Myers Squibb, and Bayer and honoraria/lecture fees from Chugai, Daiichi Sankyo, Kyowa Kirin, Janssen, and Bristol Myers Squibb. Junya Kuroda has received research grants from Kyowa Kirin, Chugai, Ono Pharmaceutical, Sanofi, Eisai, Bristol Myers Squibb, Sysmex, Sumitomo Dainippon Pharma, Nippon Shinyaku, AbbVie, Teijin, and Otsuka Pharmaceutical; honoraria from Janssen K.K., Kyowa Kirin, Chugai, Ono Pharmaceutical, Sanofi, Eisai, SymBio, Bristol Myers Squibb, Astellas Pharma, Pfizer, Nippon Shinyaku, Daiichi Sankyo, Sumitomo Dainippon Pharma, AbbVie, Novartis, and Otsuka Pharmaceutical; and consultant fees from Janssen K.K. and Bristol Myers Squibb. Masamitsu Yanada has received research grants from AbbVie, AstraZeneca, Bayer, Celgene, Chugai, Eisai, IQVIA, Genmab, Incyte, Mundipharma, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Solasia Pharma, SymBio, Takeda, Yakult, and Zenyaku Kogyo. Youko Suehiro has received research grants from Chugai, Genmab, Kyowa Kirin, Incyte, Amgen, Ono Pharmaceutical, Otsuka Pharmaceutical, and Teijin and honoraria from Chugai, Ono Pharmaceutical, Takeda, Eisai, Kyowa Kirin, Celgene, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Bristol Myers Squibb, AbbVie, Meiji Seika Pharma, Pfizer, and Sanofi. Hironobu Minami has received research grants from Asahi Kasei Pharma, Astellas, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, CSL Behring, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eisai, Kyowa Kirin, Lilly, Merck Serono, Mitsubishi Tanabe, MSD, Nippon Kayaku, Nippon Shinyaku, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Shionogi, Takeda, Taiho, Teijin, and Tsumura; honoraria from AbbVie, Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eisai, Genomic Health, Kyowa Kirin, Lilly, Meiji Seika Pharma, Merck Serono, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Sanofi, Taiho, and Takeda; and grants for clinical trials from AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, MSD, Ono Pharmaceutical, Pfizer, Taiho, Amgen, Novartis, and Insight Bioscience Japan. Jose Garcia-Vargas and Barrett H. Childs are employees of Bayer Healthcare Pharmaceuticals Inc. Masanobu Yasuda, Shigeo Masuda, Toshiaki Tsujino, and Yui Terao are employees of Bayer Yakuhin Ltd. Kenjiro Kamezaki, Toshiki Uchida, Chisako Iriyama, and Norifumi Tsukamoto declare no conflict of interest. Kensei Tobinai has received honoraria from Zenyaku Kogyo and HUYA Bioscience.

PMC9813077

References

PMC9813077

Objectives

aneurysm

ANEURYSM

Differences in indication and technique make a randomised comparison between valve-sparing root replacement (VSRR) and personalised external aortic root support (PEARS) challenging. We performed a propensity score (PS)-matched comparison of PEARS and VSRR for syndromic root aneurysm.

PMC10313978

Methods

Aneurysm, connective tissue disease, aortic regurgitation, aneurysm

ANEURYSM, ANEURYSM, AORTIC REGURGITATION, AORTIC VALVE INSUFFICIENCY, CONNECTIVE TISSUE DISEASE

Patients in the PEARS 200 Database and Aortic Valve Insufficiency and ascending aorta Aneurysm InternATiOnal Registry (undergoing VSRR) with connective tissue disease operated electively for root aneurysm <60 mm with aortic regurgitation (AR) <1/4 were included. Using a PS analysis, 80 patients in each cohort were matched. Survival, freedom from reintervention and from AR ≥2/4 were estimated using a Kaplan-Meier analysis.

PMC10313978

Results

death, bleeding, impingement, coronary injury, deaths

BLEEDING

Median follow-up was 25 and 55 months for 159 PEARS and 142 VSRR patients. Seven (4.4%) patients undergoing PEARS required an intervention for coronary injury or impingement, resulting in one death (0.6%). After VSRR, there were no early deaths, 10 (7%) reinterventions for bleeding and 1 coronary intervention. Survival for matched cohorts at 5 years was similar (PEARS 98% vs VSRR 99%, p=0.99). There was no difference in freedom from valve or ascending aortic/arch reintervention between matched groups. Freedom from AR ≥2/4 at 5 years in the matched cohorts was 97% for PEARS vs 92% for VSRR (p=0.55). There were no type A dissections.

PMC10313978

Conclusions

’s disease stage

VSRR and PEARS offer favourable mid-term survival, freedom from reintervention and preservation of valve function. Both treatments deserve their place in the surgical repertoire, depending on a patient’s disease stage. This study is limited by its retrospective nature and different follow-ups in both cohorts.

PMC10313978

WHAT IS ALREADY KNOWN ON THIS TOPIC

aneurysm, aortic valve reintervention

ANEURYSM

While valve-sparing root replacement (VSRR) is the established treatment for syndromic root aneurysm, there remains a cumulative risk of aortic valve reintervention. In personalised external aortic root support (PEARS), the dilated aorta is supported using a bespoke mesh, optimally respecting valve anatomy. To date, no type A dissections have been observed after PEARS.

PMC10313978

WHAT THIS STUDY ADDS

aneurysm

DISEASE PROGRESSION, EVENTS, ANEURYSM

VSRR and PEARS both seem to offer favourable mid-term survival, freedom from reintervention and preservation of valve function in syndromic root aneurysm with near-normal valve function. Our study indicates that an earlier intervention in the disease progression via PEARS may be justified with a low probability of developing aortic events if the necessary attention goes to the coronary anatomy.

PMC10313978

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

aneurysm

DISEASE PROGRESSION, EVENTS, ANEURYSM, COMPLICATIONS

Long-term data are needed to determine the role of all possible treatments in the surgical repertoire. Improved prediction of aortic complications will further help guide patient selection. A shared decision-making process should involve weighing the risk of watchful waiting against the potential risks of all available surgical treatments.VSRR and PEARS both seem to offer favourable mid-term survival, freedom from reintervention and preservation of valve function in syndromic root aneurysm with near-normal valve function. Our study indicates that an earlier intervention in the disease progression via PEARS may be justified with a low probability of developing aortic events if the necessary attention goes to the coronary anatomy.

PMC10313978

Introduction

aneurysm

ANEURYSM

Valve-sparing root replacement (VSRR) is an established surgical treatment for aortic root aneurysm.(A) ExoVasc implant used to stabilise the ascending aorta during personalised external aortic root support surgery. (B) Intraoperative photograph of valve-sparing root replacement. The corrugations of the relatively rigid structure of the low-porosity vascular graft can be seen. Illustration provided by Exstent.

PMC10313978

Methods

PMC10313978

Study design

Aneurysm

ANEURYSM, AORTIC VALVE INSUFFICIENCY

We present a multicentre study using two existing databases: the ‘PEARS 200’ and ‘AVIATOR’ Database (Aortic Valve Insufficiency and ascending aorta Aneurysm InternATiOnal Registry), both containing prospectively and retrospectively collected data.

PMC10313978

Data collection and study endpoints

bleeding, aneurysm, endocarditis, stroke, Loeys-Dietz syndrome, MFS

BLEEDING, MYOCARDIAL INFARCTION, ANEURYSM, ENDOCARDITIS, POSTOPERATIVE COMPLICATIONS, STROKE, LOEYS-DIETZ SYNDROME, ASCENDING AORTIC DISSECTION

From both databases, patients with CTD (MFS, Loeys-Dietz syndrome and ACTA2 mutations) undergoing elective surgery for aortic root aneurysm <60 mm diameter with at most mild AR (grade 0/4 or 1/4) were extracted. Patients with ascending aortic dissection or endocarditis were excluded. The primary endpoint was mid-term survival. Secondary endpoints were in-hospital mortality and the occurrence of postoperative complications (reintervention for bleeding, myocardial infarction, need for coronary revascularisation, stroke, perioperative dissection). Secondary endpoints during follow-up were the occurrence of type A and type B dissections, freedom from valve reintervention, freedom from valve or aortic intervention (ascending aorta and arch) and freedom from AR grade ≥2/4.

PMC10313978

Data analysis

Continuous variables were tested for normality with the Shapiro-Wilk test, shown as median (IQR) and compared using Mann-Whitney U test. Categorical variables were shown as n (%) and compared via Χ

PMC10313978

Patient and public involvement

No patients were involved in the design, conduct or reporting of this study.

PMC10313978

Results

PMC10313978

Baseline demographics

AORTIC REGURGITATION

The 159 included PEARS patients were operated at 20 centres between 2004 and 2019, while the 142 patients undergoing VSRR from the AVIATOR underwent surgery at 13 centres between 1996 and 2021. Eighty patients in each cohort were matched using a PS analysis. Before matching, patients undergoing VSRR were significantly older, more likely to have mild AR or a history of cardiac surgery, had a higher EuroSCORE II and larger aortic root. After matching, covariates were balanced (Demographics for the total population and matched populationUnderlying aetiology was not used to match. Continuous variables were compared using Mann-Whitney U test, categorical variables via ΧSMD was used to evaluate balance between groups.AR, aortic regurgitation; LVEF, left ventricular ejection fraction; PEARS, personalised external aortic root support; SMD, standardised mean difference; VSRR, valve-sparing root replacement.

PMC10313978

Operative variables and in-hospital outcomes

coronary injury, aortic annuloplasty, impingement, patent foramen ovale

CARDIOPULMONARY, AORTIC REGURGITATION

In both groups, concomitant procedures predominantly involved the mitral valve (12.3%, 20 of 159 for PEARS and 11.3%, 16 of 142 for VSRR). Cardiopulmonary bypass was used in 18.3% (24 of 131) of uncomplicated isolated aortic PEARS cases. For patients undergoing VSRR, 57% were operated via the reimplantation/David technique and 37.4% underwent remodelling with aortic annuloplasty. Average aortic cross-clamp time was 138±33 min with nine patients requiring an additional clamping session. Nearly two-thirds (65.5%) of patients undergoing VSRR did not require cusp repair, while one cusp was repaired in 21.1%, most commonly via central free-margin plication. An overview of operative variables is shown in Operative variablesCABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; PEARS, personalised external aortic root support; PFO, patent foramen ovale; VSRR, valve-sparing root replacement.In two patients scheduled for PEARS, an intraoperative conversion to VSRR was performed as the aorta was deemed too fragile (n=1), or after coronary injury occurred (n=1). As patients are entered into the AVIATOR Database by completed procedure, we did not capture conversions during intended VSRR. Seven (4.4%) patients undergoing PEARS needed an intraoperative or postoperative intervention for coronary injury or impingement (In-hospital and postoperative outcomes for total and matched populationContinuous variables compared using Mann-Whitney U test, categorical variables via χAR, aortic regurgitation; Asc, ascending aorta; AV, aortic valve; PEARS, personalised external aortic root support; VSRR, valve-sparing root replacement.

PMC10313978

Survival

death

POSTOPERATIVE COMPLICATIONS

Median follow-up duration for PEARS patients was 25 months (IQR 12–52, total of 542 postoperative patient years), while for VSRR patients, it was 55 months (IQR 23–89, 713 postoperative years). No follow-up after discharge could be collected for two (1.3%) PEARS and four (2.8%) VSRR patients. Overall survival at 5 years was similar for PEARS and VSRR at 95.8% vs 99.2% (p=0.27). In the matched cohorts, survival was also similar at 5 years: 98.3% vs 98.6% (p=0.99) for PEARS and VSRR, respectively. Underlying causes of death and details on postoperative complications are shown in

PMC10313978