AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients

NCT04690933 | Completed

• 1 other identifier: 87RI18_0011 (NAViRe)
• Study Type: observational
• Target: 400
• Locations: 1 country
• Sites: 16

Brief Summary

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.

Conditions

Hematopoietic Stem Cell Transplantation; Antivirals; Antiviral Drug Resistance; Cytomegalovirus Infections

Keywords

Hematopoietic Stem Cell Transplantation; Cytomegalovirus Infections; Antivirals; Antiviral Drug Resistance

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (24)

• Uses of anti-CMV molecules : preemptive treatment

  at Day200

• Uses of anti-CMV molecules : prophylaxis

  at Day200

• Uses of anti-CMV molecules : curative treatment

  at Day200

• Uses of anti-CMV molecules

  at Day200

• Uses of anti-CMV molecules : preemptive treatment

  at Month12

Study Arms (1)

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

Interventions

Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients OTHER

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.

Multicentric NAViRe cohort with biocollection

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• 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 ;

Sponsors & Collaborators

• University Hospital, Limoges: lead

Study Sites (16)

CHU de LIMOGES

Limoges, Limoges, 87045, France

Location

CHU

Amiens, France

Location

CHU

Angers, France

Location

CHU

Besançon, France

Location

CHU

Bordeaux, France

Location

CHU

Caen, France

Location

CHU

Clermont-Ferrand, France

Location

CHU

Grenoble, France

Location

HCL

Lyon, France

Location

CHU

Montpellier, France

Location

CHU

Nancy, France

Location

APHP

Paris, France

Location

CHU

Poitiers, France

Location

CHU

Rouen, France

Location

CHU

Saint-Etienne, France

Location

CHU

Strasbourg, France

Location

Related Publications (7)

• 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.

  PMID: 27682069 BACKGROUND

• 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.

  PMID: 30137245 BACKGROUND

• 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.

  PMID: 27402191 BACKGROUND

• 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.

  PMID: 29211658 BACKGROUND

• 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.

  PMID: 29207952 BACKGROUND

• 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.

  PMID: 26538506 RESULT

• 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.

  PMID: 29596116 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Samples related to the cohort : One blood sample from the donor (only familial donors) for genetic SNPs analysis. 5 samples: D-8 (conditioning), D20, D100 (+/- 10 days), 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. Conservation of viral load monitoring remnants at the center's virology laboratory.

MeSH Terms

Conditions

Cytomegalovirus Infections

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Study Officials

• Pascal TURLURE

  Service d'Hématologie Clinique et de Thérapie Cellulaire

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2020
• First Posted: December 31, 2020
• Study Start: September 24, 2020
• Primary Completion: September 24, 2025
• Study Completion: November 30, 2025
• Last Updated: December 15, 2025

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (16)