Impact of Pre-existing Invasive Aspergillosis on Allogeneic Stem Cell Transplantation

NCT ID: NCT03014934

Last Updated: 2021-01-14

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 2100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2021-12-31

Brief Summary

Via a prospective non-interventional study clinical outcome of patients with - and without - history of pre-existing invasive aspergillosis undergoing allo-HSCT will be assessed, in terms of non-relapse mortality overall mortality and fungal infectious morbidity.

Aim. Assessment of 1-year outcome of patients undergoing allo-HSCT with history of pre-existing IA vs. no pre-existing IA.

Hypothesis. NRM in patients with pre-existing IA is not higher (by a specified margin of 10%) than patients without pre-existing IA.

Study population. First allo-HSCT in patients with acute leukaemia and MDS given stem cell grafts.

Cohort 1: History of probable or proven invasive aspergillosis Cohort 2: No History of probable or proven invasive aspergillosis: this cohort includes also the patient with a history of possible mycosis not documented microbiologically.

Detailed Description

Background & Rationale. In patients with pre-existing invasive aspergillosis allo-HSCT is feasible without progression of fungal infection. However, the influence of invasive pulmonary aspergillosis (IA) on transplant related complications and on long term survival has not been investigated in a larger patient cohort under current conditions.

Recently the IDWP and ALWP performed a retrospective analysis on the impact of preexisting aspergillosis on allo-HSCT outcome.2 In summary, there was a trend towards impaired outcome of allo-HSCT in patients with prior IA but there was no significant impact on important allo-HSCT transplant outcomes, such as survival, GVHD and relapse. The data suggest that a history of IA should not generally be considered a contraindication for allo-HSCT. To be able to more precisely investigate the impact of IA on allo-HSCT, a non-interventional prospective study is needed.

Primary objective:

To determine if pre-existing IA influences non-relapse mortality after allo-HSCT

Secondary objectives:

• To determine if pre-existing IA influences:

• relapse free survival
• overall survival
• incidence and severity of GVHD
• incidence of relapse
• incidence of IA post allo-HSCT

for the subgroup of transplant with previous IA

• progression of IA

Research design:

Prospective study. Study recruitment is expected to start by May 1st, 2016. It is expected that recruitment will be closed by October 31st 2017. Follow up will be till one year after transplant.

Items:

Data from Med A form, Med C form for all patients, Aspergillus form for patients with probable/proven IA.

Endpoint(s):

Primary endpoint: 1-year non-relapse mortality cumulative incidence

Secondary endpoints:

• 1-year relapse free survival
• 1-year overall survival
• 1-year incidence and severity of GVHD
• 1-year incidence of relapse
• status of IA (before conditioning and at 1 year)

Study population

• First allo-HSCT in patients with AML or
• First allo-HSCT in patients with ALL or
• First allo-HSCT in patients with MDS

Cohort 1: History of probable or proven invasive aspergillosis Cohort 2: No History of probable or proven invasive aspergillosis

Cases: Prior IA = probable/proven IA according EORTC 2008 criteria (Cohort 1) Controls: No prior proven probable IA = all other patients = those really negative for IA and those with possible IA (Cohort 2)

Sample size Assuming a 20% incidence of non relapse mortality in patients without proven or probable history of IA, a total of 2100 HSCTs will be needed in order to test the hypothesis that the incidence of non relapse mortality in cohort 1 (HSCTs with previous history of proven or probable IA) is not higher than cohort 2 (HSCTs without history of IA or with previous history of possible IA) by more than a specified margin of 10%. The estimated proportion of HSCTs in cohort 1 is 5%, thus 105 and 1995 HSCTs will be needed in cohort 1 and cohort 2, respectively, considering an alpha=0.05, a beta=0.2.

Data Collection & Statistical Analysis Plan:

(List all research variables to be collected and list all outcome variables to be analysed, give a brief description of the method of analysis (in collaboration with the EBMT statistician) All data collection will be performed by the IDWP Data Office (Leiden) according to EBMT guidelines.

Primary endpoint: non relapse mortality The non relapse mortality will be estimated using the cumulative incidence method. Death due to transplant will be considered as an event, whilst relapse of the underlying disease will be considered as competing events. Patients alive at the end of the follow-up will be censored at this date. Cohort 1, vs. Cohort 2 will be compared by the Gray test.

A cause specific Cox model will be performed in order to estimate the risk of dying for Cohort 1 respect Cohort 2.

The following variables will enter the multivariate model as possible confounders: age (as continuous variable), gender (M vs. F), underlying disease (ALL vs. AML/MDS), status at SCT (1st CR vs. ≥ 2 CR vs. Prim Refr/noCR), time from diagnosis to SCT (as continuous variable), donor type (sibling vs. UD vs. Haplo), source of SCT (BM vs. PB vs. CB), donor age, d/r gender match, d/r CMV status, conditioning regimens (MAC vs. RIC vs. TBI), type of immunosuppression (in vivo T depletion y/n, in vitro T-depletion y/n), DLI post SCT (y/n), centre.

Secondary endpoints Relapse free survival and overall survival will be estimated by the Kaplan-Meier methods. Incidence of GvHD and incidence of relapse will be estimated by the cumulative incidence methods. A cause specific Cox model will be estimated to compare Cohort 1 and Cohort 2; it will be adjusted by the confounders analyzed also in the primary endpoint.

The severity of GvHD will be described by descriptive statistics. Frequencies and percentages will be use for categorical variables, whilst median, range, mean and standard deviation will be computed for continuous variables.

Additional descriptive statistic will be separately performed in cohort 2. Main characteristics of patients will be also described.

Conditions

Invasive Aspergillosis

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Cases: Prior Invasive Aspergillosis

History of probable or proven Invasive Aspergillosis according to EORTC 2008 criteria

No interventions assigned to this group

Controls: No prior proven Invasive Aspergillosis

Patients really negative for Invasive Aspergillosis and those with possible Invasive Aspergillosis

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• First allo-HSCT
• Acute leukaemia or MDS
• Received stem cell grafts

Exclusion Criteria

• History, in the 6 months preceding HSCT, or documented presence of Invasive candida or mould infections other than IA (Mucor, Fusariosis).

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Society for Blood and Marrow Transplantation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Olaf Penack, MD

Role: PRINCIPAL_INVESTIGATOR

Charite University, Berlin, Germany

Jan Styczynski

Role: STUDY_CHAIR

University Hospital, Collegium Medicum UMK

Locations

Charité Universitätsmedizin Berlin

Berlin, , Germany

Site Status: RECRUITING

Institute G. Gaslini

Genova, , Italy

Site Status: RECRUITING

Clinica di Oncoematologia Pediatrica

Padua, , Italy

Site Status: RECRUITING

Ospedale Infantile Regina Margherita

Torino, , Italy

Site Status: RECRUITING

King Faisal Specialist Hospital & Research Centre

Riyadh, , Saudi Arabia

Site Status: RECRUITING

Hospital Santa Creu i Sant Pau

Barcelona, , Spain

Site Status: RECRUITING

University Hospital

Basel, , Switzerland

Site Status: RECRUITING

Gazi University School of Medicine

Ankara, , Turkey (Türkiye)

Site Status: RECRUITING

Countries

Germany; Italy; Saudi Arabia; Spain; Switzerland; Turkey (Türkiye)

Central Contacts

Jennifer Hoek, MD

Role: CONTACT

j.d.c.hoek@lumc.nl

+31715265668

Facility Contacts

Renate Arnold

Role: primary

renate.arnold@charite.de

49-30-450-553-302

Edoardo Lanino, MD

Role: primary

edoardolanino@gaslini.org

39-010-5636-2405

Giuseppe Basso

Role: primary

giuseppe.basso@unipd.it

39-049-821-3579

Franca Fagioli, MD

Role: primary

franca.fagioli@unito.it

+39-011-313-5360

Mahmoud Aljurf

Role: primary

maljurf@kfshrc.edu.sa

(996-1) 442-4586

Jorge Sierra, MD

Role: primary

tolius@santpau.cat

34-93-556-5649

Helen Baldomero

Role: primary

Helen.Baldomero@usb.ch

+41 61 265 3203

Ulker Kocak, MD

Role: primary

ulkerkocak@gazi.edu.tr

+90 0312-202-60-15

Other Identifiers

EBMT-8414113

Identifier Type: -

Identifier Source: org_study_id