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Patients receiving an allogeneic hematopoietic stem cell transplant (allo-CSH) are at high risk of infection, particularly of fungal origin. Until the 2018 recommendations of the 6th European Conference on Infections in Leukemia (ECIL6), primary prophylaxis of invasive fungal infections (IFI), in allograft patients, was based on the administration of fluconazole until D100. Due to changes in transplantation practices (alternative donor transplantation, sequential transplantation, etc.) and changes in microbiological ecology (increased incidence of IFIs caused by filamentous germs such as aspergillosis and mycormycosis), fluconazole prophylaxis is now sometimes suboptimal. It is therefore recommended that patients at high risk of developing IFIs should be given azole molecules with activity against filamentous agents as primary prophylaxis during the first 3 months after transplantation.
Posaconazole is often under-dosed (below the minimum effective concentration). It therefore seems essential to carry out a prospective study with close [C]min dosing in the specific situation of allograft patients, a population that appears to be at risk of underdosing in the light of initial retrospective analysis results.
There are several treatments based on azole molecules: voriconazole, posaconazole, isavuconazole... To date, none of these treatments has been approved for primary post-allograft prophylaxis. Posaconazole is indicated in cases of graft-versus-host disease (GVHD) (requiring systemic corticosteroid therapy after allo-CSH), and as primary prophylaxis during aplasia in patients with acute myeloblastic leukemia/myelodysplasia (AML/MDS). Other azole molecules are not approved for primary prophylaxis, and may give rise to drug interactions with certain treatments prescribed for allograft patients (e.g. ciclosporin, letermovir).
Although recommendations for the administration of posaconazole as primary prophylaxis post allo-CSH have been in place for 4 years, few studies are available to date. The adult hematology department of Nantes University Hospital conducted a retrospective study of 70 allograft patients at high risk of IFI between 04/2020 and 12/2021. Posaconazole treatment was administered from D0 (or the day after the 2nd dose of post-transplant cyclophosphamide) to D100. Treatment was generally well tolerated, with discontinuation due to possible treatment toxicity in 12.6% of cases, mainly of hepatic origin (n=7). Posaconazole was resumed in 2 cases without recurrence of toxicity. In 84.2% of patients, no IFI was observed. One of the limitations of this study was the low number of determinations of residual posaconazole concentration ([C]min). In fact, [C]min was carried out in only 59 patients/70, with a median delay of 9 days. In 43% of cases, the [C]min was insufficient (< 0.5 mg/L), which is significantly lower than the [C]min obtained in patients with AML/MDS undergoing induction ([C]min< 0.5 mg/L: 5% of patients). It therefore seems essential to carry out a prospective study with close [C]min measurement in the specific situation of allograft patients, a population that appears to be at risk of underdosing in the light of the initial retrospective results of analyses.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Posaconazole | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Posaconazole | Drug | Per Os, on Day 0 of allo-CSH if the patient's condition permits, or after the last dose of immunosuppressor (post-transplant cyclophosphamide) (Day+5 or Day+6 depending on protocols). On the first day of treatment: 300 mg in the morning (= 3 x 100 mg tablets) and 300 mg in the evening (= 3 x 100 mg tablets), then from day 2 of treatment: 300 mg per day (= 3 x 100 mg tablets) in a single dose |
| Measure | Description | Time Frame |
|---|---|---|
| Effective residual concentration of posaconazole | The main objective is to study, in the early phase after allo-CSH, the percentage of patients who have an effective residual concentration of posaconazole. The primary endpoint is plasma residual posaconazole concentration ([C]min), measured on day 8 of posaconazole initiation. A [C]min > 0.7mg/l is considered effective. | On the 8th day of treatment (i.e. after 7 days of treatment) |
| Measure | Description | Time Frame |
|---|---|---|
| Monitoring of residual plasma concentrations [C]min | Weekly residual plasma concentrations of posaconazole | From posaconazole baseline up to Day100 |
| Description of circumstances leading to posaconazole underdosing |
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Inclusion Criteria:
Patient ≥ 18 years of age. There is no maximum age for inclusion
Allo-CSH transplant for hematologic malignancy or benign hemopathy of any type with one or more high risk IFI criteria:
Written informed consent prior to protocol initiation
ECOG <=2
Female of childbearing age with negative pregnancy test and on highly effective contraception during treatment and for 12 months after posaconazole discontinuation
Men of childbearing age with effective contraception during treatment and for 6 months after stopping posaconazole.
Hepatitis B, C and HIV serologies negative.
Social security affiliation
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Amandine LE BOURGEOIS, MD | Contact | 02 40 08 32 71 | +33 | amandine.lebourgeois@chu-nantes.fr |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Nantes | Recruiting | Nantes | France | 44000 | France |
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A clinical record will be taken twice a week during hospitalization and then once a week to describe clinical symptoms leading to malabsorption: nausea, vomiting, diarrhea, mucositis, colitis. Symptom intensity will be assessed according to the NCI CTCAE v5 classification
| From posaconazole baseline up to Day100 |
| Description of circumstances leading to posaconazole underdosing | Adherence to treatment will be monitored daily during hospitalization by paramedical staff. Once home, adherence will be assessed once a week by the doctor in charge of the patient | From posaconazole baseline up to Day100 |
| Description of circumstances leading to posaconazole underdosing | All co-medications should be recorded throughout the course of posaconazole treatment, based on data from the patient's medical record | From posaconazole baseline up to Day100 |
| Description of the reasons for administering posaconazole intravenously (IV) | The physician in charge of the patient should specify the reason(s) for IV administration of the treatment | From posaconazole baseline up to Day100 |
| Description of situations leading to initial non-administration or early discontinuation of posaconazole | The physician in charge of the patient should specify the situation(s) that led to non-administration or early discontinuation of treatment. | From posaconazole baseline up to Day100 |
| Description of situations leading to initial non-administration or early discontinuation of posaconazole | Description of posaconazole-related toxicities according to NCI CTCAE v5 classification | From posaconazole baseline up to Day 100 |
| Description of invasive fungal infections occurring | Description of IFI cases according to EORTC classification | From posaconazole baseline up to 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) |
| Description of patient outcome: incidence of engraftment | Engraftment assessed on hematological reconstitution (number of days of aplasia with PNN <0.5 G/L and platelets < 20, number of platelet and packed cell transfusions) | Month 1 post-transplant |
| Description of patient outcome: overall survival (OS) | Survival between day 0 of transplantation and date of death or last follow-up | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) or death |
| Description of patient outcome: disease-free survival (DFS) | Survival between day 0 of transplant and date of relapse, death or last follow-up | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) or documented relapse or death whicvever came first |
| Description of patient outcome: non-relapse mortality (NRM) | Any death unrelated to relapse or disease progression | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) or death, whichever came first |
| Description of patient outcome: incidence of relapse (IR) | Any documented disease recurrence | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) or any documented disease recurrence, whichever came first |
| Description of patient outcome: cumulative incidence of acute GVHD | Acute GVH grade 2-4 according to Mount Sinai criteria | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) |
| Description of patient outcome: cumulative incidence of chronic GVHD | Extensive chronic GVH according to NCI criteria | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) |
| Description of patient outcome: GVHD-free relapse-free survival (GRFS) | Median relapse-free survival without grade 3-4 acute GVHD or chronic GVHD requiring systemic treatment | Up to Day100 and 1 year post-transplant and/or through study completion (end of follow-up at the last visit of the last patient included in the study) or death |
| Grade 3 and 4 post-transplant adverse events | Post-transplant grade 3 and 4 adverse events (dates of occurrence) (NCI CTCAE version 5 criteria) | Up to Day100 and 1 year post-transplant |
| ID | Term |
|---|---|
| D019337 | Hematologic Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C101425 | posaconazole |
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