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JOURNAL ONKOLOGIE – STUDIE

Central Nervous System Disorders Following Hematopoietic Stem Cell Transplantation

Rekrutierend

NCT-Nummer:
NCT04737785

Studienbeginn:
Januar 2021

Letztes Update:
06.07.2021

Wirkstoff:
-

Indikation (Clinical Trials):
Infection, Communicable Diseases, Central Nervous System Infections, Nervous System Diseases, Central Nervous System Diseases, Hematologic Diseases, Hematologic Neoplasms

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
European Group for Blood and Marrow Transplantation

Collaborator:
-

Studienleiter

Martin Schmidt-Hieber, Dr
Principal Investigator
Carl-Thiem-Klinikum, Clinic for Hematology and Oncology, Cottbus, Germany

Kontakt

Studienlocations
(3 von 13)

Pankreaskarzinomzentrum im Carl-Thiem-Klinikum Cottbus
Thiemstraße 111
3048 Cottbus
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Martin Schmidt-Hieber
E-Mail: M.Schmidt_Hieber@ctk.de
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

For each case patient (i.e. HSCT recipient with a CNS disorder) two control patients (1:2

allocation) should be analysed prospectively with the aim to get more insights into risk

factors for CNS disorders. Hereby, the two patients transplanted subsequently to the

corresponding case patient should be included as controls if they survive and do not develop

a CNS disorder until the inclusion time point. Inclusion time points of controls should be

determined by using the same delay between transplant and the onset of the CNS disorder of

the corresponding case patient. Controls should also be stratified by centre, HSCT type (i.e.

allogeneic vs. autologous) and age (adults vs. paediatrics). As for cases with CNS disorders,

controls should also be evaluated regularly until last follow-up. To avoid bias and to

estimate the incidence of infectious vs. non-infectious CNS disorders in autologous and

allogeneic HSCT recipients accurately centres should also report patients with CNS disorders

not included in this study (e.g. due to lack of informed consent or essential Med-A data).

Centres are additionally asked by the data management office in Leiden/Netherlands for these

data on a regularly basis.

Primary objectives

- Clinical and diagnostic characteristics of infectious and non-infectious CNS disorders

following allogeneic or autologous HSCT

- Outcome 30 days after CNS disorder onset (cured vs. improved vs. stabilized vs. worsened

vs. died due to CNS disorder vs. died by other cause)

Secondary objectives

- Incidence, timing, and distribution of infectious and non-infectious CNS disorders after

HSCT

- Impact of development of CNS disorders on overall survival

- Risk factors for CNS disorders after allogeneic and autologous HSCT using a

prospectively assessed matched control group

- Efficacy of treatment for different types of CNS disorders

Data Collection & Statistical Analysis Plan Data collection will be performed by the IDWP

data office (Leiden/Netherlands). Hereby, patient and transplant data are reported directly

from the centres to the data office according to EBMT guidelines.

Important basic data for analysis (collected from Med-A and Med-C for both case patients and

controls):

- Recipient/donor sex

- Recipient/donor age (at HSCT)

- Primary diagnosis (leading to HSCT)

- Status of the primary disease at the time of HSCT - remission (partial or

complete)/relapse/relapse including CNS involvement/progression, stable disease,

unknown)

- Prior CNS radiotherapy

- Prior intrathecal (antineoplastic) treatment

- Prior (antineoplastic) treatment (especially 'novel drugs´)

- Pre-existing medical conditions, e.g. chronic kidney disease, liver disease

- Recipient/donor serostatus of CMV, EBV, HHV-6, HSV, VZV, Toxoplasma spp.

- Type of transplant (allogeneic vs. autologous)

- Type of donor (MRD vs. haploidentical donor vs. other donor type)

- Stem cell source (CB vs. BM vs. PB)

- Type of conditioning (e.g. MAC vs. RIC, fludarabine-containing vs. other, TBI incl.

dose), including details on absolute dose and dose adjustments of fludarabine

- TCD (yes vs. no), ATG (yes vs. no), alemtuzumab (yes vs. no) in conditioning and at

study inclusion (day 0)

- Acute and chronic GvHD (at day 0, including grade)

- ECOG performance status at different time points

- Concomitant infections: e.g. paranasal sinusitis, results of blood cultures performed

during the episode of CNS disorder, galactomannan, beta-D-glucan (peripheral blood, BAL

etc.)

- Selected peripheral blood parameters, e.g. white blood cell count, absolute neutrophil

count, duration of neutropenia <0.5x109/L, absolute lymphocyte count, platelet count,

sodium, potassium, calcium, phosphate, creatinine, urea nitrogen, ammonia, bilirubin,

IgG concentration, creatinine, GFR

Specific data to be collected for patients with CNS disorders (see also Med-C for cases and

appendix), e.g.:

- Recipient´s age at onset of the CNS disorder (day 0)

- Date of symptom onset of the CNS disorder

- Type of symptoms (e.g. seizures, hemiplegia, paraplegia, paresis, psychosis, vomiting,

confusion/altered consciousness, fever)

- Date of diagnosis of the CNS disorder (e.g. CSF analysis)

- Clinical diagnosis of CNS infection (e.g. encephalitis, meningitis, meningoencephalitis,

myelitis, abscess, leukoencephalopathy)

- Clinical diagnosis of non-infectious CNS disorder (e.g. metabolic/drug-induced disorder,

posterior reversible encephalopathy syndrome, bleeding, thrombosis, ischemic stroke, CNS

relapse of a underlying malignancy)

- Time interval between HSCT and symptom onset

- Time interval between symptom onset and diagnosis of CNS disorder

- Antimicrobial prophylaxis prior to onset of a CNS disorder

- Level of likelihood of the type of CNS disorder - the centres report the diagnostic

tests performed to make a diagnosis of CNS disorder including i.e.: magnetic resonance

imaging (MRI), MRI spectrometry, positron emission tomography/computed tomography

(PET/CT), CT, electroencephalography (EEG), CSF analyses, microbiological studies (e.g.,

cultures, PCR, galactomannan, Candida mannan, beta-D-glucan, antibodies in peripheral

blood, CSF or other materials such as brain biopsy), autopsy results

- Type and efficacy of treatment for the CNS disorder 30 days after onset (cured vs.

improved vs. stabilized vs. worsened vs. died due to CNS disorder vs. died by other

cause)

- Outcome (alive or death, including date, cause of death, CNS disorder-related death vs.

other death cause) at the different study points

Specific data to be collected for patients without CNS disorder (see also Med-C for

controls), e.g.:

- Time interval between HSCT and day 0 (inclusion time point, same delay between

transplant and CNS disorder onset of the corresponding case)

- Date of study inclusion (i.e. day 0)

- Recipient´s age at study inclusion

- Occurrence of a CNS disorder after study inclusion

- Antimicrobial prophylaxis prior to study inclusion

- Outcome (alive or death, including date, cause of death) at the different study points

Statistical analysis Statistical methods used to compare groups for primary and secondary

outcomes Primary endpoints: descriptive statistics will be performed to report the main

characteristics (and 30 day outcome) of patients with infectious and non-infectious CNS

disorders: absolute and percentage frequencies will be reported for categorical variables;

median, IQR and range will be used for continuous variables.

Secondary endpoints: the cumulative incidence of infectious and non-infectious CNS disorders

after HSCT will be estimated by the cumulative incidence method: infectious and

non-infectious CNS disorders will be considered as events, whilst non-CNS relapse, non-CNS

secondary malignancy and non-CNS death will be considered as competing event. Overall

survival will be assessed using Kaplan-Meier curves, and the impact of the development of CNS

disorders on overall survival will be assessed using time-dependent Cox models. To compute

these endpoints, the data of all patients after HSCT will be obtained from the EBMT patient

databases (e.g. ProMISe).

The risk factor analysis will be performed by a conditional logistic regression model.

P-values <0.05 will be considered statistically significant. The analyses will be performed

using the software SAS/R v 9.4 or higher (SAS Institute Inc., Cary, NC, USA).

Methods for additional analyses, such as subgroup analyses and adjusted analyses The

cumulative incidence of infectious and non-infectious CNS disorders after HSCT will be

computed and reported separately for different transplant types (autologous vs. allogeneic -

matched related donor vs. haploidentical donor vs. other donor type), and stem cell source

(cord blood vs. bone marrow vs. peripheral blood) of HSCT and for different age categories

(adults vs. paediatrics). These comparisons will be presented in terms of crude cumulative

incidence curves, and differences between groups will be assessed using Gray's test.

Multivariable analyses will be performed using cause-specific hazard models. Cox models for

overall survival will include CNS disorders as time-dependent covariates. Candidate variables

for these analyses will be obtained from a list of predefined variables, including (but not

limited to) type of transplant (allogeneic vs. autologous HSCT), age, stem cell source, donor

relationship, and use of T cell depletion. Potential effects of centres will be examined

using random effects.

Risk factors for CNS disorders after allogeneic and autologous HSCT will be assessed using

multivariable conditional logistic regression. Candidate variables for this analysis will be

obtained from a list of predefined variables, including the stratification variables.

Model building will proceed as follows: each variable will be preliminarily assessed using

univariable analyses. Factors associated with the response and significant at the 20% level

in univariable analyses will be considered for inclusion in a multivariable model. Factors

will be retained if significant at the 5% level, and interaction terms included (after

assessment of main effects) if significant at a 10% level (with possible corresponding

subgroup analyses used to illustrate differential effects).

Ein-/Ausschlusskriterien

Inclusion Criteria:

Case group:

- received allogeneic or autologous HSCT between January 1st, 2021 and December 31st,

2022

- develop an infectious (any CTCAE grade) or relevant (CTCAE >1°) non-infectious CNS

disorder after HSCT in this period.

Control group:

- received allogeneic or autologous HSCT between January 1st, 2021 and February 28th,

2023

- who survive and do not develop a CNS disorder until the inclusion time point (day 0,

defined as the same delay between transplantation and CNS disorder onset of the

corresponding case)

Exclusion Criteria:

- Patients with missing essential Med-A data

- Patients not giving informed consent to report data to EBMT prior to initiation of

transplant procedures

Studien-Rationale

Primary outcome:

1. Clinical characteristics of infectious and non-infectious CNS disorders following allogeneic or autologous HSCT (Time Frame - 32 months):
Clinical characteristics to be analysed: Recipient/donor sex Recipient/donor age (at HSCT) Primary diagnosis Status of the primary disease at the time of HSCT - remission (partial or complete) /relapse /relapse including CNS involvement/progression, stable disease, unknown) Prior CNS radiotherapy Prior intrathecal (antineoplastic) treatment Prior (antineoplastic) treatment (especially 'novel drugs´) Pre-existing medical conditions Recipient/donor serostatus of CMV, EBV, HHV-6, HSV, VZV, Toxoplasma spp. Type of transplant (allogeneic vs. autologous) Type of donor (MRD vs. haploidentical donor vs. other donor type) Stem cell source (CB vs. BM vs. PB) Type of conditioning (RIC vs MAC) TCD (yes vs. no), ATG (yes vs. no), alemtuzumab (yes vs. no) Acute and chronic GvHD (at day 0, including grade) ECOG performance status at different time points Concomitant infections Selected peripheral blood parameters

2. Diagnostic characteristics of infectious and non-infectious CNS disorders following allogeneic or autologous HSCT (Time Frame - 32 months):
Diagnostic characteristics analyzed: Recipient´s age at onset of the CNS disorder (day 0) Date of symptom onset of the CNS disorder Type of symptoms (e.g. seizures, hemiplegia, paraplegia, paresis, psychosis, vomiting, confusion/altered consciousness, fever) Date of diagnosis of the CNS disorder (e.g. CSF analysis) Clinical diagnosis of CNS infection (e.g. encephalitis, meningitis, meningoencephalitis, myelitis, abscess, leukoencephalopathy) Clinical diagnosis of non-infectious CNS disorder (e.g. metabolic/drug-induced disorder, posterior reversible encephalopathy syndrome, bleeding, thrombosis, ischemic stroke, CNS relapse of a underlying malignancy) Time interval between HSCT and symptom onset Time interval between symptom onset and diagnosis Antimicrobial prophylaxis prior to onset of CNS disorder Level of likelihood of the type of CNS disorder:

3. Efficacy of CNS treatment for different types of CNS disorders (Time Frame - 30 days):
Efficacy measured as: CNS cured with neurological sequelae CNS cured without neurological sequelae CNS symptoms improved CNS symptoms stabilized deteriorating death because of CNS disorder death because of other cause Treatments analyzed: Antimicrobials Steroids Surgical treatment Reduction of immunosuppression Other treatment Types of CNS disorders: infectious non-infectious

4. Survival (Time Frame - 32 months):
alive or death, including date, cause of death, CNS disorder-related death vs. other death cause at the different study points

Secondary outcome:

1. Incidence of infectious and non-infectious CNS disorders after HSCT (Time Frame - 32 months):
To identify the Incidence of infectious and non-infectious CNS disorders after HSCT

2. Timing of infectious and non-infectious CNS disorders after HSCT (Time Frame - 32 months):
To identify the timing of infectious and non-infectious CNS disorders after HSCT

3. Distribution of infectious and non-infectious CNS disorders after HSCT (Time Frame - 32 months):
To identify the distribution of infectious and non-infectious CNS disorders after HSCT

4. Impact of development of CNS disorders on overall survival (Time Frame - 32 months):
to identify the Impact of development of CNS disorders (yes/no) on overall survival (alive/dead) using a prospectively assessed matched control group without CNS

5. Risk factors for CNS disorders after allogeneic and autologous HSCT using a prospectively assessed matched control group (Time Frame - 32 months):
Risk factors assed: Recipient/donor sex Recipient/donor age (at HSCT) Primary diagnosis Status of the primary disease at the time of HSCT Prior CNS radiotherapy Prior intrathecal (antineoplastic) treatment Prior (antineoplastic) treatment (especially 'novel drugs´) Pre-existing medical conditions Recipient/donor serostatus of CMV, EBV, HHV-6, HSV, VZV, Toxoplasma spp. Type of transplant (allogeneic vs. autologous) Type of donor (MRD vs. haploidentical donor vs. other donor type) Stem cell source (CB vs. BM vs. PB) Type of conditioning (RIC vs MAC) TCD (yes vs. no), ATG (yes vs. no), alemtuzumab (yes vs. no) Acute and chronic GvHD (at day 0, including grade) ECOG performance status at different time points Concomitant infections Selected peripheral blood parameters

6. Efficacy of treatment for different types of CNS disorders (Time Frame - 32 months):
Efficacy of treatment measured as: CNS cured with neurological sequelae CNS cured without neurological sequelae CNS symptoms improved CNS symptoms stabilized deteriorating death because of CNS disorder death because of other cause

Studien-Arme

  • Case group
    HSCT recipients who developed a CNS disorder after HSCT
  • Control group
    HSCT recipients whom did not develop a CNS disorder

Quelle: ClinicalTrials.gov


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