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Rituximab

Retrospective study (n=80) : Patient who underwent HSCT, in Saint-Antoine hospital, between 2010-2015, treated by rituximab for high level EBV-DNAemia (above 3.3 log copies/mL).

Prospective study (n=58) : Patients who underwent HSCT, in Saint-Antoine hospital and la Pitié-Salpêtrière, in 2016-2017, treated by rituximab for high level EBV-DNAemia (above 10 000c/mL), And/or having post-transplant lymphoproliferative diseases(PTLD) Concerned population Allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients with a high Epstein-Barr virus (EBV) viral load

At D0:

* blood samples
* saliva sample

At D8: blood sample

the results will be compared to the analysis of EBV transcripts that are specific for the latent or replicative phase of the virus by reverse transcription-quantitative PCR (RT-qPCR), and to the detection of free virus in the saliva, which is associated with viral reactivation

biological collection

Eolia Brissot, Associate Professor

Scientific context

Epstein-Barr virus has a causal role in the pathogenesis of multiple distinct lymphomas. Post-transplant lymphoproliferative diseases (PTLD) are the most frequent EBV-induced proliferations. PTLD after allogeneic stem cell transplantation has an incidence lower than 5% but may increase up to 10-20% in patients with established risk factors. EBV-DNAemia is predictive of EBV-PTLD and is routinely performed using qPCR on whole blood. Preemptive therapeutic strategies with anti-CD20 antibody are used when patients are above a defined EBV-DNAemia threshold. This approach remains limited since it does not discriminate between an EBV-induced lymphoproliferation (latent cycle) and/or a replicating virus (replicative cycle).

Epigenetic modifications plays a central role in regulating the switch from latent to lytic gene expression. Specific DNA modifications can be regarded as molecular signatures for EBV genomes associated with the status of the viral infection (latent vs lytic). Accordingly, these signatures may be envisioned as a potent tool to characterize the state of the viral infection in vivo.

Description of the project Our primary objective is to estimate the respective percentages of EBV-lytic and EBV-latent genomes (proliferating cells) in patients presenting with a high EBV-DNAemia after allogeneic stem cell transplantation HSCT by analysing the epigenetic modifications of EBV genome on specific sites. Our secondary objectives are i) to determine risk factors associated with each "latent versus lytic EBV" profiles and ii) to correlate the "latent versus lytic EBV" profiles with response to rituximab infusion and patient outcomes.

For this purpose, a retrospective study (n=80) and a prospective study (estimation n=58) will be established. The different steps of this project are:

1. To study epigenetic modifications. The laboratory is developing a new approach to distinguish between latent and lytic genomes.
2. To realize quantitative analysis by RT-PCR of different EBV transcripts specific of the latent or of the lytic phase of the virus This method will be applied on RNA extracted from patient blood samples with elevated EBV viral load, under condition preserving RNA integrity. The results will be validated on a prospective cohort of HSCT patients (n=58) (Saint-Antoine Hospital and La Pitié-Salpêtrière Hospital).
3. To perform quantitative analysis of EBV genomes in plasma, saliva and total blood samples by current routine procedures In addition to total blood samples, plasma and saliva will be collected since free viral particles are known to accumulate in these biological fluids upon EBV reactivation. These samples will be treated by normalized procedures that are routinely used in the medical virology laboratory to quantify EBV in human samples.

Expected results By establishing a simple method for studying epigenetic modifications of EBV genomes, we expect to understand the significance of high EBV viral load and the pathophysiology of post-HSCT PTLD. We aim to distinguish between the latent / lytic profiles of HSCT patients and to correlate their respective risks for developing PTLD. Establishing the epigenetic EBV profile in the post-HSCT setting when facing increase viral load and PTLD will improve our understanding of the biological mechanisms determining EBV-status in post-HSCT. This should improve major medical and economical issues. These results could have a major therapeutic

Study duration :

Total study duration: 37 months Duration of recruitment: 24 months Duration of participation for each patient: 13 months

Inclusion criteria:

Retrospective study: Patient who underwent HSCT, in Saint-Antoine hospital, between 2010-2015, treated by rituximab for high level EBV-DNAemia (above 3.3 log copies/mL).

Prospective study: Patients who underwent HSCT, in Saint-Antoine hospital and la Pitié-Salpêtrière, in 2016-2017, treated by rituximab for high level EBV-DNAemia (above 10 000c/mL), And/or having post-transplant lymphoproliferative diseases(PTLD) Concerned population Allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients with a high Epstein-Barr virus (EBV) viral load

Study endpoints:

Primary endpoint (linked to the primary objective) Respective percentages of latent versus replicative EBV profiles, defined by the methylation level of specific sites of EBV genome, in a cohort of HSCT patients with a high EBV viral load (above 3.3 log copies/ml) before the initiation of treatment per rituximab. A methylation index will be calculated from the respective differences of the "Cycle thresholds" of the methyl-qPCR performed on patients blood samples Secondary endpoints (linked to the secondary objectives)

1. Characteristics of the patients according to the EBV q-PCR results
2. Patients' outcome according to the EBV profile defined by the methyl-qPCR :

   * Response to Rituximab infusion (EBV DNA-emia \< 3.3 log copies/mL) after a maximum of 4 infusions)
   * Disease-free survival (DFS) at 12 months defined as survival without relapse
   * Overall survival (OS) at 12 months
   * Relapse incidence (RI) at 12 months
   * Non-relapse mortality (NRM) at 12 months
   * Number of post-HSCT infections within 12 months

Statistical Analysis :

1. Comparison between characteristics of latent and lytic genomes will be performed using parametric (Student t-test) or non-parametric (Mann Whitney test) when appropriate for continuous variables, Chi-Square test for qualitative variables.

   Multivariate analysis for determination of risk factors associated with "lytic EBV" profiles will be performed using logistic regression.
2. Correlation between "latent versus lytic EBV" profiles" and response to rituximab infusion will be performed using logistic regression including in the model all other factors potentially associated to the response to rituximab. OS and DFS will be estimated by using the Kaplan-Meier method. Cumulative incidences of RI and NRM will be calculated from the date of inclusion to the date of relapse or death in remission, respectively, with the other event being the competing risk. Death or progression will be considered as a competing events for estimating the incidence of acute GVHD. Multivariate analyses for survival endpoints will be performed using the Cox proportional hazards model. The type I error rate is fixed at 0.05 for determination of factors associated with time to event outcomes. All statistical analyses will be performed with R software packages (R Foundation for Statistical Computing, Vienna, Austria)

1 population divided in 2 groups: Retrospective study (n=80): Patient who underwent HSCT, in Saint-Antoine hospital, between 2010-2015, treated by rituximab for high level EBV-DNAemia (above 3.3 log copies/mL).

Prospective study (n=58): Patients who underwent HSCT, in Saint-Antoine hospital and la Pitié-Salpêtrière, in 2016-2017, treated by rituximab for high level EBV-DNAemia (above 10 000c/mL), And/or having post-transplant lymphoproliferative diseases(PTLD) Concerned population Allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients with a high Epstein-Barr virus (EBV) viral load

Methyl-qPCR : a New Predictive Marker for Epstein-Barr Virus-associated Lymphoproliferations During Allogeneic Hematopoietic Stem Cell Transplantation

Defined by epigenetic modifications of EBV genome, in a cohort of HSCT patients with a high EBV viral load (above 10 000 c/ml) before the initiation of treatment per rituximab.

To determine the risk factors associated with latent versus replicative EBV profiles, in allo-HSCT with a high viral load.

- Response to Rituximab infusion (EBV DNA-emia \< 3 log copies/mL after a maximum of 4 infusions)

Institut National de la Santé Et de la Recherche Médicale, France

Assistance Publique - Hôpitaux de Paris

Neoplasms

Hematologic Neoplasms

No change to patient's usual care at Princess Margaret Cancer Centre.

a longitudinal 6-month rehabilitation program that uses a person- centred strategy and a multidimensional approach targeting physical activity, nutrition, psychosocial distress and promoting self-management skills.

CaRE-4-alloBMT uses emerging eHealth technologies to reduce barriers to accessing and providing cancer rehabilitation which includes: 1) Individualized progressive exercise prescriptions that allows customizable exercise prescriptions, tracking of exercise completion, and video tutorials; 2) Individualized nutrition plans and stepped stratified care such as education, counselling, intervention based on nutritional status and delivered by registered dietitians; 3) On-line e-modules provide interactive education to promote self-management skills for stress management, nutrition, managing common symptoms, etc.; 4) Remote monitoring using FitbitTM devices to monitor patients physical activity, caloric intake, and sleep for duration of the program. CRS and alloBMT clinicians will have access to real-time Fitbit data through our clinical dashboard; 5) Remote clinical support: check-ins and health coaching sessions with a member of the CRS team (phone or MS Teams video).

CaRE-4-alloBMT plus usual care group

Jennifer M Jones, PhD

Currently, transplantation centers across North America generally do not offer longitudinal rehabilitation programs and research is urgently needed to test the acceptability and effectiveness of these programs using innovative delivery strategies that have the potential for future scalability and to understand the associated costs. Through a strong collaboration between the PM Cancer Rehabilitation and Survivorship (CRS) and alloBMT teams, the principal investigators developed an innovative multicomponent rehabilitation intervention for patients undergoing alloBMT (CaRE-4-alloBMT).

CaRE-4-alloBMT uses a person- centred strategy and a multidimensional approach targeting physical activity, nutrition, psychosocial distress and promoting self-management skills. Innovative components of CaRE-4-alloBMT include:1) Individualized progressive exercise prescriptions developed and monitored by CRS registered kinesiologists and supported with a web/mobile application (Physitrack) that allows customizable exercise prescriptions, tracking of exercise completion, and video tutorials; 2) Individualized nutrition plans and stepped stratified care (education, counselling, intervention) based on nutritional status and delivered by registered dietitians (alloBMT and CRS). 3) On-line e-modules (developed in collaboration with PM Oncology Education) provide interactive education to promote self-management skills on crucial topics; 4) Remote monitoring using FitbitTM devices to monitor patients physical activity, caloric intake, and sleep for duration of the program; 5) Remote clinical support: Pre/Post discharge, patients will have scheduled (PHS) remote check-ins and health coaching sessions with a member of the CRS team (phone or MS Teams video).

Objectives: i) To test the feasibility and safety of CaRE-4-alloBMT plus standard best practice cancer care compared to standard best practice cancer care alone; ii) To assess the preliminary efficacy of CaRE-4-alloBMT on physical function, disability, nutritional status, distress, QoL, healthcare utilization, and survival and estimate program return on investment.

1.0 BACKGROUND: Allogeneic blood and marrow transplantation (alloBMT) is a curative treatment for many hematologic cancers and its use has increased rapidly over the past decade. While effective, alloBMT is associated with numerous treatment-related physical and psychosocial side effects, reduced physical functioning, and worsening nutritional status which are associated with increased risk of complications (i.e. infections, drug toxicity, weight loss, graft failure \& graft-versus-host disease), significant early and late treatment related mortality, and can profoundly affect quality of life (QoL).

As a result, there have been calls for increased attention to the management of adverse effects associated with alloBMT with the goal to minimize dysfunction, maximize well-being and QoL, and reduce treatment-related mortality.

Cancer rehabilitation is now considered an essential component of cancer care and focuses on prevention and treatment of the adverse effects of cancer and treatment and to optimize functional status and QoL. Embedding multidimensional longitudinal (pre to post transplant) rehabilitation programs that focus on exercise, nutrition and teaching self-management skills as a standard part of treatment for individuals undergoing alloBMT has potential to mediate the significant adverse effects, improve survival, and reduce burden on the healthcare system. While patients typically receive some in-patient rehabilitation, this is a small part of the alloBMT pathway and services are quite limited. Currently, transplantation centers across North America generally do not offer longitudinal rehabilitation programs and research is urgently needed to test the acceptability and effectiveness of these programs using innovative delivery strategies that have the potential for future scalability and to understand the associated costs. In response, through a strong collaboration between the PM Cancer Rehabilitation and Survivorship (CRS) and alloBMT teams, the principal investigators developed an innovative multicomponent rehabilitation intervention for patients undergoing alloBMT (CaRE-4-alloBMT).

2.0 PROGRAM DESCRIPTION (see Appendix 1): CaRE-4-alloBMT is a longitudinal 6-month rehabilitation program (peri to post transplant) adapted from an existing evidence-based and effective model developed by the CRS team (CaRE@ELLICSR and CaRE@Home). The program is informed by established behaviour change theory and harnesses current and emerging eHealth technologies to reduce barriers to accessing and providing cancer rehabilitation. CaRE-4-alloBMT uses a person- centred strategy and a multidimensional approach targeting physical activity, nutrition, psychosocial distress and promoting self-management skills. Innovative components of CaRE-4-alloBMT include:

1. Individualized progressive exercise prescriptions developed and monitored by CRS registered kinesiologists and supported with a web/mobile application (Physitrack) that allows customizable exercise prescriptions, tracking of exercise completion, and video tutorials. The initial personalized exercise program will be given to a participant following the initial assessment. A program will be created based on the specific needs and physical condition of each participant. The participant will receive the detailed exercise program via Physitrack (includes exercise description and videos of each exercise). Each exercise program will contain cardiovascular and strength training as well as stretching exercises. The exercise program will be revised and progressions will be added based on the individual's needs after the follow-up assessments or during the scheduled check-ins between assessments. Check-ins are scheduled as follows:

   * At 2 and 4 weeks after initial assessment
   * 8 weekly check-ins following discharge
   * At 10 and 12 weeks following discharge The participant can contact the Kinesiologist by e-mail at any point during the program.
2. Individualized nutrition plans and stepped stratified care (education, counselling, intervention) based on nutritional status and delivered by registered dietitians (alloBMT and CRS). As part of standard of care, all patients receive a nutrition assessment and their caloric intake goals are set. Those in the INT arm (CaRE-4-alloBMT plus usual care group) will receive additional nutritional education through the e-modules and monitoring of caloric intake through the Fitbit. They will also have access to meal preparation and recipes through ellicsrkitche.ca. Patients can track their nutritional intake on their Fitbit device and this data will be monitored weekly by the RKin. Patients who falls below 50% of their goals (based on intake assessment) will flagged to the RD for follow up.
3. On-line e-modules (developed in collaboration with PM Oncology Education) provide interactive education to promote self-management skills on crucial topics (i.e. stress management, nutrition, managing common symptoms). There will be 9 online e-modules:

   * Introduction: Getting started
   * Eat and Cook for Wellness
   * Exercise
   * Manage Your Emotions
   * Reduce Fatigue
   * Being Mindful
   * Boost Your Brain Health
   * Stay Connected
   * Planning for the Future Participants will be asked to complete all 9 modules. Each module should take between 20-30 minutes to complete. Participants can go through these modules at their own pace. Patients will receive a link for the online modules. Patients will be able to access the module by entering their e-mail address and creating their own unique password.
4. Remote monitoring using FitbitTM devices to monitor patients physical activity, caloric intake, and sleep for duration of the program. CRS and alloBMT clinicians will have access to real-time Fitbit data through the clinical dashboard (developed in collaboration with TECHNA). The Fitbit is also known to promote behaviours change and allows for self-monitoring and feedback. Participants will be asked to wear the Fitbit for the duration of the study. Participants will only need to add their meals to monitor their nutrition. No other action is required from the participants once the account has been created. This will replace the paper based food diary they must keep (standard of care). The account for the participant will be created by the RA or RKin and the participant will then be able to access the app via an email link. The RA or RKin can assist/provide support to the participant as needed to access the app. If the participant is unable to download or use the app a detailed print out of their exercise program will be provided.

   The following information will be required to create an account:
   * First name
   * Last name (participant study number will be entered in this field
   * Year of birth
   * Email address Both the participant and Kinesiology team will have access to this information but the account information is not visible to third parties. Physitrack provides links to the privacy policy and terms of use/agreement and is available for the participant to review as needed.
5. Remote clinical support: Pre/Post discharge, patients will have scheduled (PHS) remote check-ins and health coaching sessions with a member of the CRS team (phone or MS Teams video). These occur in week 2,4 (pre) and 1-8,10,12 (post-discharge).

Frequency of check-ins and what will be discussed: Check-ins are by telephone or MSteams video and scheduled as follows:

* At 2 and 4 weeks after initial assessment (pre-BMT admission)
* Weeks 1-8, 10 and 12 post-discharge (post-BMT dischange)

  - Check-ins discussion using motivational interviewing techniques and focus on
* Adherence to exercise program
* Changes to exercise program based on participant's needs
* Module completion
* Answering participants questions The program strongly aligns with the SUNDAE framework

Participants will be informed when consented that they will be grouped into one of two (control or intervenion) study groups for the duration of the study. Following their baseline assessment, patients will be randomized (1:1 stratified by age and clinical frailty score at pre-transplant consultation).

biostatician will provide the randomized grouping for each of the participants.

Cancer Rehab Program for Allogenic Bone and Marrow Transplant Patients - CaRE-4-alloBMT

A Longitudinal Multidimensional Cancer Rehab Program for Patients Undergoing Allogenic Bone and Marrow Transplantation (CaRE-4-alloBMT)

Number of patients who complete the study/ drop-out will be used to identify feasibility of the intervenion.

Check-ins with health coach during assessments will be used to identify intervention acceptability/preference.

Patients will be checking-in at specific timepoints with a health coach to discuss their preference/challenges with intervention.

World Health Organization Disability Assessment Schedule 2.0. The scale is (0-4) for a total score from 0-48 and the larger the value the worse the outcome.

self reported measure of overall health - total score: 0-100 and the higher the score, the better the health state (less disability)

using data from fitbit worn by patient to record their daily caloric intake.

Patient-reported instrument for assessment of nutrition status in patients with cancer - Typical scores range from 0-35 with a higher score reflecting a greater risk of malnutrition and scores ≥9 indicating a critical need for nutrition intervention and symptom management.

Measure of General Anxiety and distress - total score: 0-21 and the cut-offs are: 0-4: minimal anxiety 5-9: mild anxiety 10-14: moderate anxiety 15-21: severe anxiety

a measure of quality of life - total score of 0-196 with a higher scores for the scales and subscales indicate better quality of life.

clinic chart details for days in hospital, readmission

will be interpretted from the quantitative and qualitative date extracted

Health related quality of life - The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems.

measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface

measures the muscular strength or the maximum force/tension generated by one's forearm muscles

measurement that assesses functional lower extremity strength in older adults

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Methyl-qPCR : a New Predictive Marker for Epstein-Barr Virus-associated Lymphoproliferations During Allogeneic Hematopoietic Stem Cell Transplantation	NCT03343834	Epstein-Barr Vi... Hematologic Dis... Allogeneic Dise...	biological coll...	18 Years -	Assistance Publique - Hôpitaux de Paris
Cancer Rehab Program for Allogenic Bone and Marrow Transplant Patients - CaRE-4-alloBMT	NCT04966156	Allogeneic Dise... Hematologic Can... Cancer Rehabili...	CaRE-4-alloBMT ...	18 Years -	University Health Network, Toronto

Spots Global Cancer Trial Database for allogeneic disease