AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients (NAViRe)

Real-life Observatory of Efficacy and Resistance to Anti CMV Molecules in Stem Cell Recipients

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that represent a major cause of morbidity in haematopoietic stem cell transplants (HSCT) recipients, mostly through reactivation of the recipient's virus.

If left untreated, 40 to 80% of patients will develop CMV infection, leading to CMV disease in 30 to 35 % patients, and associated with considerable morbi-mortality. Interstitial pneumonia is the most severe and specific manifestation, although CMV replication by itself has also indirect effects such as triggering graft versus host disease and increasing immunosuppression. The current burden of CMV infection increases by 25 to 30% the cost of the graft in France. This also includes the burden for refractory - infections, that represent up to 13% of recipients with CMV infection, including 3% of cases with virological resistance in France (data from the Reference Center cohorts).

Ganciclovir, or valganciclovir preemptive treatment, guided by CMV viral load follow-up allowed significant reduction of CMV disease to 2-6% but did not prevent CMV indirect effects. In addition, hematotoxicity can compromise post-transplant haematological reconstitution, thus preventing its use as prophylaxis in France. Foscarnet, iv-administered and nephrotoxic, remains less used. There is thus a high expectation from less toxic molecules for prophylaxis The development letermovir recently available for prophylaxis of CMV infection in high risk patients will modify the patients care and follow-up. This new molecule targeting CMV terminases (developed by Merck) was recently marketed in France (Jan 2020). However, the analysis of the letermovir phase III study and further publications show that the risk of emergence of resistance is low, but may occur in case of breakthrough and thus post AMM monitoring is required.

A "real-life" evaluation of these new molecules in terms of efficacy, emergence of resistance, tolerance and morbimortality related to CMV infection, is useful, to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients. To this purpose, the National Reference Center in collaboration with the French Society for marrow graft and cell therapy (SFGMTC) set up a cohort of surveillance of allografted patients, receiving, in prevention or treatment, old and new molecules.

Study Overview

• Status: Completed
• Conditions: Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Antivirals; Antiviral Drug Resistance
• Intervention / Treatment: Other: Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients

Detailed Description

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that represent a major cause of morbidity in haematopoietic stem cell transplants (HSCT) recipients, mostly through reactivation of the recipient's virus.

If left untreated, 40 to 80% of patients will develop CMV infection, leading to CMV disease in 30 to 35 % patients, and associated with considerable morbi-mortality. Interstitial pneumonia is the most severe and specific manifestation, although CMV replication by itself has also indirect effects such as triggering graft versus host disease and increasing immunosuppression. The current burden of CMV infection increases by 25 to 30% the cost of the graft in France. This also includes the burden for refractory - infections, that represent up to 13% of recipients with CMV infection, including 3% of cases with virological resistance in France (data from the Reference Center cohorts).

Ganciclovir, or valganciclovir preemptive treatment, guided by CMV viral load follow-up allowed significant reduction of CMV disease to 2-6% but did not prevent CMV indirect effects. In addition, hematotoxicity can compromise post-transplant haematological reconstitution, thus preventing its use as prophylaxis in France. Foscarnet, iv-administered and nephrotoxic, remains less used. There is thus a high expectation from less toxic molecules for prophylaxis The development letermovir recently available for prophylaxis of CMV infection in high risk patients will modify the patients care and follow-up. This new molecule targeting CMV terminases (developed by Merck) was recently marketed in France (Jan 2020). However, the analysis of the letermovir phase III study and further publications show that the risk of emergence of resistance is low, but may occur in case of breakthrough and thus post AMM monitoring is required.

A "real-life" evaluation of these new molecules in terms of efficacy, emergence of resistance, tolerance and morbimortality related to CMV infection, is useful, to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients. To this purpose, the National Reference Center in collaboration with the French Society for marrow graft and cell therapy (SFGMTC) set up a cohort of surveillance of allografted patients, receiving, in prevention or treatment, old and new molecules.

• Study Type: Observational
• Enrollment (Actual): 400

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • CHU
  • Angers, France
    • CHU
  • Besançon, France
    • CHU
  • Bordeaux, France
    • CHU
  • Caen, France
    • CHU
  • Clermont-Ferrand, France
    • CHU
  • Grenoble, France
    • CHU
  • Lyon, France
    • HCL
  • Montpellier, France
    • CHU
  • Nancy, France
    • CHU
  • Paris, France
    • APHP
  • Poitiers, France
    • CHU
  • Rouen, France
    • CHU
  • Saint-Etienne, France
    • CHU
  • Strasbourg, France
    • CHU
  • Limoges
    • Limoges, Limoges, France, 87045
      • CHU de Limoges

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Candidate (adult) for an allograft of hematopoietic stem cells for which a decision of transplant is made and willing to participate in the cohort.

Description

Inclusion Criteria :

• Candidate (adult) for an allograft of hematopoietic stem cells for which a decision of transplant is made and willing to participate in the cohort.

Exclusion Criteria :

• CMV-seronegative patient receiving a negative CMV donor graft ;
• Patient having signed the consent but not grafted ;
• Patient included in a clinical study on an anti-CMV molecule ;
• Non-insured social patient ;

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Multicentric NAViRe cohort with biocollection; The National Reference Center (CNR) for cytomegalovirus with the French Society for Medullary Transplantation and Cell Therapy (SFGM-TC) has set up a surveillance cohort of allografted patients (NAViRe cohort) receiving, as prevention or treatment, Anti-Cytomegalovirus (Anti-CMV) molecules, "new or less recent", thus allowing the development of a new observatory evaluating in real life the potentials of these drugs in terms of efficacy, emergence of resistance, tolerance and morbidity and mortality associated with CMV infection.This work is useful to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients and allows the emergence of an real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients.

Other: Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients; Signing of consent at the time of the pre-transplant consultation (1 month before grafting). Inclusion of patients during conditioning (around D-8 of transplantation). Samples related to the cohort:one blood sample from the donor (only familial donors) for genetic SNPs analysis. 5 samples: D-8, D20, D100, D200 (+/-10 days), 1 year : 1 tube of 7ml of whole blood on EDTA: Biobanking of whole blood for genetic SNPs analysis (D-8) of specific transporters for GCV, and of plasma for TTV viral load at all times. In routine care:samples taken in the event of a therapeutic escape (2 x 7 ml EDTA tubes, for resistance genotype, and ganciclovir dosage, 3 x 1 ml for Quantiferon CMV, according to CNR Herpesvirus recommendations. 1 x Paxgene tube (2.5 ml) for subsequent CMV genomic and transcriptomic studies. Cell preservation plasma and whole blood for biocollection (2 tubes EDTA de 7ml). Samples stored by the centers' virology laboratories are periodically sent to the CNR for analysis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	between Day-30 and Day -8
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	between Day-8 and Day 0
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	at Day20
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	at Day100
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	at Day 200 (Month 6)
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	Month12
CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).	CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen	Month24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uses of anti-CMV molecules : preemptive treatment	% of patients having received preemptive treatment	at Day200
Uses of anti-CMV molecules : prophylaxis	% of patients having received prophylaxis	at Day200
Uses of anti-CMV molecules : curative treatment	% of patients having received curative treatment	at Day200
Uses of anti-CMV molecules	Cumulative duration of exposure (number of day) for each drug administered	at Day200
Uses of anti-CMV molecules : preemptive treatment	% of patients having received preemptive treatment	at Month12
Uses of anti-CMV molecules : prophylaxis	% of patients having received prophylaxis	at Month12
Uses of anti-CMV molecules : curative treatment	% of patients having received curative treatment	at Month12
Uses of anti-CMV molecules	Cumulative duration of exposure (number of day) for each drug administered	at Month12
Uses of anti-CMV molecules : preemptive treatment	% of patients having received preemptive treatment	at Month24
Uses of anti-CMV molecules : prophylaxis	% of patients having received prophylaxis	at Month24
Uses of anti-CMV molecules : curative treatment	% of patients having received curative treatment	at Month24
Uses of anti-CMV molecules	Cumulative duration of exposure (number of day) for each drug administered	at Month24
Incidence of the non-response and resistance to antivirals with risk factors associated (virological, pharmacological, immunological). Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in	Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in : Refractory CMV infection CMV viremia that increases after at least 2 wk of appropriately dosed antiviral therapy.; Probable refractory CMV infection : persistent viral load after at least 2 wk of appropriately dosed antiviral therapy.; Refractory CMV end organ disease : worsening in signs and symptoms or progression into end-organ disease after at least 2 wk of appropriately dosed antiviral therapy.; Probable refractory CMV end-organ disease : lack of improvement in signs and symptoms after at least 2 wk of appropriately dosed antiviral drugs.; Antiviral drug resistance : viral genetic alteration that decreases susceptibility to one or more antiviral drugs. Resistance : presence of a resistance-related mutation by resistance genotyping of UL97, UL54, UL56, UL89, UL27 genes, carried out or validated by the Limoges Herpesviruses reference laboratory. In blood or any other sample.	at Month12
Incidence of the non-response and resistance to antivirals with risk factors associated (virological, pharmacological, immunological). Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in	Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in : Refractory CMV infection CMV viremia that increases after at least 2 wk of appropriately dosed antiviral therapy.; Probable refractory CMV infection : persistent viral load after at least 2 wk of appropriately dosed antiviral therapy.; Refractory CMV end organ disease : worsening in signs and symptoms or progression into end-organ disease after at least 2 wk of appropriately dosed antiviral therapy.; Probable refractory CMV end-organ disease : lack of improvement in signs and symptoms after at least 2 wk of appropriately dosed antiviral drugs.; Antiviral drug resistance : viral genetic alteration that decreases susceptibility to one or more antiviral drugs. Resistance : presence of a resistance-related mutation by resistance genotyping of UL97, UL54, UL56, UL89, UL27 genes, carried out or validated by the Limoges Herpesviruses reference laboratory. In blood or any other sample.	at Month24
Adverse effects leading to interruption of treatment	Incidence of treatment emergent adverse event as assessed by interruption of treatment	at Month12
Adverse effects leading to interruption of treatment	Incidence of treatment emergent adverse event as assessed by interruption of treatment	at Month24
CMV related mortality	Number of patients who died from CMV related desease	at Month12
CMV related mortality	Number of patients who died from CMV related desease	at Month24
CMV associated morbidity : delay engraftment	number of days bettwen graft and engraftment	at Month12
CMV associated morbidity : GVHD	Incidence of GVHD	at Month12
CMV associated morbidity : CMV infection/disease	Incidence of CMV infection/disease (infection or disease will be combined to report this outcome). CMV infection : positive diagnostic test (CMV culture, antigen detection or CMV PCR), in any body fluid or tissue, in the absence of symptoms. CMV disease : CMV infection associated with end-organ disease (clinical signs and oriented virological diagnosis).	at Month12
CMV associated morbidity : delay engraftment	number of days bettwen graft and engraftment	at Month24
CMV associated morbidity : GVHD	Incidence of GVHD	at Month24
CMV associated morbidity : CMV infection/disease	Incidence of CMV infection/disease (infection or disease will be combined to report this outcome). CMV infection : positive diagnostic test (CMV culture, antigen detection or CMV PCR), in any body fluid or tissue, in the absence of symptoms. CMV disease : CMV infection associated with end-organ disease (clinical signs and oriented virological diagnosis).	at Month24

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Investigators: Principal Investigator: Pascal TURLURE, Service d'Hématologie Clinique et de Thérapie Cellulaire

Publications and helpful links

General Publications

• Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28.
• Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019 Apr 8;68(8):1420-1426. doi: 10.1093/cid/ciy696.
• Billat PA, Ossman T, Saint-Marcoux F, Essig M, Rerolle JP, Kamar N, Rostaing L, Kaminski H, Fabre G, Otyepka M, Woillard JB, Marquet P, Trouillas P, Picard N. Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients. Pharmacol Res. 2016 Sep;111:501-508. doi: 10.1016/j.phrs.2016.07.012. Epub 2016 Jul 9.
• Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.
• Robin C, Hemery F, Dindorf C, Thillard J, Cabanne L, Redjoul R, Beckerich F, Rodriguez C, Pautas C, Toma A, Maury S, Durand-Zaleski I, Cordonnier C. Economic burden of preemptive treatment of CMV infection after allogeneic stem cell transplantation: a retrospective study of 208 consecutive patients. BMC Infect Dis. 2017 Dec 5;17(1):747. doi: 10.1186/s12879-017-2854-2.
• Billat PA, Woillard JB, Essig M, Sauvage FL, Picard N, Alain S, Neely M, Marquet P, Saint-Marcoux F. Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity? J Antimicrob Chemother. 2016 Feb;71(2):484-9. doi: 10.1093/jac/dkv342. Epub 2015 Nov 3.
• Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191.

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2020
• Primary Completion (Actual): September 24, 2025
• Study Completion (Actual): November 30, 2025

Study Registration Dates

• First Submitted: September 14, 2020
• First Submitted That Met QC Criteria: December 30, 2020
• First Posted (Actual): December 31, 2020

Study Record Updates

• Last Update Posted (Estimated): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Antivirals; Antiviral Drug Resistance
• Additional Relevant MeSH Terms: Infections; Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections
• Other Study ID Numbers: 87RI18_0011 (NAViRe)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No