Clinical trial NCT04690933: AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients
Official title: Real-life Observatory of Efficacy and Resistance to Anti CMV Molecules in Stem Cell Recipients
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Hematopoietic Stem Cell Transplantation
Cytomegalovirus Infections
Antivirals
Antiviral Drug Resistance
Keywords: Hematopoietic Stem Cell Transplantation
Cytomegalovirus Infections
Antivirals
Antiviral Drug Resistance
Lead sponsor: University Hospital, Limoges
Sponsor class: OTHER
First posted: 2020-12-31
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility criteria: 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 ;

Primary outcomes:
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: between Day-30 and Day -8
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: between Day-8 and Day 0
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: at Day20
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: at Day100
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: at Day 200 (Month 6)
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: Month12
measure: CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017).
timeFrame: Month24
Secondary outcomes:
measure: Uses of anti-CMV molecules : preemptive treatment
timeFrame: at Day200
measure: Uses of anti-CMV molecules : prophylaxis
timeFrame: at Day200
measure: Uses of anti-CMV molecules : curative treatment
timeFrame: at Day200
measure: Uses of anti-CMV molecules
timeFrame: at Day200
measure: Uses of anti-CMV molecules : preemptive treatment
timeFrame: at Month12
measure: Uses of anti-CMV molecules : prophylaxis
timeFrame: at Month12
measure: Uses of anti-CMV molecules : curative treatment
timeFrame: at Month12
measure: Uses of anti-CMV molecules
timeFrame: at Month12
measure: Uses of anti-CMV molecules : preemptive treatment
timeFrame: at Month24
measure: Uses of anti-CMV molecules : prophylaxis
timeFrame: at Month24
measure: Uses of anti-CMV molecules : curative treatment
timeFrame: at Month24
measure: Uses of anti-CMV molecules
timeFrame: at Month24
measure: 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
timeFrame: at Month12
measure: 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
timeFrame: at Month24
measure: Adverse effects leading to interruption of treatment
timeFrame: at Month12
measure: Adverse effects leading to interruption of treatment
timeFrame: at Month24
measure: CMV related mortality
timeFrame: at Month12
measure: CMV related mortality
timeFrame: at Month24
measure: CMV associated morbidity : delay engraftment
timeFrame: at Month12
measure: CMV associated morbidity : GVHD
timeFrame: at Month12
measure: CMV associated morbidity : CMV infection/disease
timeFrame: at Month12
measure: CMV associated morbidity : delay engraftment
timeFrame: at Month24
measure: CMV associated morbidity : GVHD
timeFrame: at Month24
measure: CMV associated morbidity : CMV infection/disease
timeFrame: at Month24
Other outcomes:
Locations:
city: Limoges
country: France
facility: CHU de LIMOGES
Study officials:
affiliation: Service d'Hématologie Clinique et de Thérapie Cellulaire
name: Pascal TURLURE
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.