Primary objectiveTo evaluate current clinical practice and develop a population based Campath® (Alemtuzumab) pharmacokinetics model for predicting total Alemtuzumab exposure after i.v. administration before allogeneic stem cell transplantation in…
ID
Source
Brief title
Condition
- Haemoglobinopathies
- Immune system disorders congenital
- Immunodeficiency syndromes
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Campath® (Alemtuzumab) levels measured 15-30 minutes before (please note: no
sample will be taken before the first Alemtuzumab dose) and after each Campath®
(Alemtuzumab) administration as well as at day 0 (= day HSCT), +1, +7, +14, +21
and at week +4 and +6 after alloHSCT.
Secondary outcome
Explorative secondary Endpoints (outcome parameters)
• Immune reconstitution:
-- Lymphocytes / neutrophils / monocytes / T cells (total, CD4+ and CD8+
subsets, CD4+/CD8+ ratio) / NK cells / B cells count are measured at week +2
(if peripheral leucocytes are measurable yet), +3, +4, +6, +8, +10 and +12
after alloHSCT;
-- Neutrophil (CD15+ cells) engraftment
-- Recovery of CD4+ T cells
-- Recovery of CD8+ T cells
- Chimerism analysis of total peripheral blood mononuclear cells (PBMC) at week
+4, +8, +12 and at +6, +9 and +12 months after alloHSCT;
• Incidence of acute and chronic graft-versus-host-disease (GvHD) and grading
according to classic Glucksberg-Seattle scale and NIH criteria respectively;
• Overall survival (OS);
• Event free survival (defined as without death or retransplantation);
• Cumulative incidence of treatment-related mortality (TRM);
• Cumulative incidence of graft failure (defined as non-engraftment or
rejection);
• Incidence of viral primary infections or reactivations (e.g. cytomegalovirus,
Epstein-Barr-virus, human herpesvirus 6, adenovirus) within the first 100 days;
• Incidence of Donor Lymphocyte Infusion (DLI) within the first 100 days;
• Incidence of bacterial, parasitic and fungal primary infections within the
first 100 days;
• Incidence of autoimmune reactions (e.g. autoimmune cytopenia, autoimmune
haemolytic anemia) within 10 years after alloHSCT (serum samples will be taken
if indicated);
• Incidence of secondary immune-mediated endocrine disorders (e.g. gonadal
dysfunction, hypothyreosis).
Background summary
Children with severe congenital immunological and non-malignant hematological
disorders (e.g. primary immunodeficiencies and hemoglobinopathies) have a poor
quality of life and a markedly reduced life expectancy. They carry a huge
health economic burden due to frequent hospitalization, progressive organ
damage and disabilities that tend to increase during adolescence and adulthood
with major socio-economic implications on the affected patients, their
families, and on the society. Despite a variable clinical course, feasible
systematic transfusion program and infection prophylaxis, many patients develop
life-threatening infections and end-organ complications. For these patients
allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only
established curative treatment aiming at reconstitution of healthy donor-type
immuno- and hematopoiesis. Early transplant related morbidity and mortality due
to severe infections, graft failure and graft-versus-host-disease (GvHD) remain
serious complications of this otherwise curative therapy modality.
Campath® (Alemtuzumab) is a humanized IgG monoclonal antibody targeting the
CD52-antigen, a membrane protein expressed on the surface of several peripheral
blood immune cells (e.g. B cells, monocytes, NK cells) and in particular on
T-lymphocytes, but not on hematopoietic stem cells. Prior to alloHSCT, Campath
is prescribed to eliminate a.o. T-cells, thereby preventing GvHD and graft
rejection. However, Campath® (Alemtuzumab) persistence in blood usually causes
a prolonged immune depletion and a delayed immune recovery, thereby increasing
the risk of infection and autoimmune reactions.
In children, Campath® is considered standard of care prior to alloHSCT
(off-label use) following the recommendation of the European Society for Blood
and Marrow Transplantation and of the European Society for Immunodeficiencies
as well as according to relevant peer-reviewed literature.
Recent publications on pediatric Campath® (Alemtuzumab) pharmacokinetics (PK)
suggest large inter-patient variability and consequent repetitive overdosing,
thus significantly impacting biological efficacy and clinical outcome. However,
neither the proper identification of Campath® (Alemtuzumab) PK determinants nor
an accurate evaluation of the current (reduced) Campath® dose recommendation of
0.4-1.0mg/kg was possible up to now.
Primary hypothesis
High interindividual variability of Campath® (Alemtuzumab) PK in children
transplanted for severe non-malignant diseases crucially impacts the cumulative
exposure to Alemtuzumab given intravenously as part of a treosulfan- or
busulfan-based reduced intensity conditioning (RIC) regimen pre and post
alloHSCT.
Secondary Hypothesis
The exposure to Campath® (Alemtuzumab) correlates significantly with immune
reconstitution, risk of acute and chronic GvHD and primary clinical outcome
defined as incidence of infectious complications, reactive autoimmunity and
secondary immune-endocrine disorders in children with non-malignant diseases
undergoing alloHSCT.
Study objective
Primary objective
To evaluate current clinical practice and develop a population based Campath®
(Alemtuzumab) pharmacokinetics model for predicting total Alemtuzumab exposure
after i.v. administration before allogeneic stem cell transplantation in
children with non-malignant diseases treated with treosulfan- or busulfan-based
reduced intensity conditioning regimens.
Secondary objectives
• To evaluate whether variation in exposure to Campath® (Alemtuzumab)
correlates significantly with immune reconstitution, mixed chimerism incidence
as well as acute and chronic GvHD incidence and grade.
• To investigate whether variation in Alemtuzumab exposure correlates
significantly with the incidence of infectious complications, autoimmune
reactions and secondary immune-endocrine disorders.
Study design
International multicenter observational study.
Study burden and risks
Our observational study focuses on children with congenital severe
immunological or haematological disorders prior to stem cell transplantation
and, therefore, on vulnerable participants. Considering the severe clinical
course and prognosis of these particular primary diseases that our study is
analysing, no adult cohort could be eligible for this clinical research.
Children with congenital severe immunological or haematological disorders carry
the heaviest burden of disease and without definitive treatment, the condition
is mostly fatal. Allogeneic hematopoietic stem cell transplantation is an
extremely effective way of restoring the immuno- and hematopoiesis, but a high
level of expertise and innovative individualized treatment approaches available
at all participating centers are mandatory.
In this study, the impact of Campath® (Alemtuzumab) on clinical outcome in
children will be accurately investigated providing fundamental data for precise
dosing recommendations, thereby allowing further crucial therapeutic
improvements to benefit future patients. To protect our study participants,
this observational study will be conducted at national reference centers for
pediatric immune-hematological disorders. Only investigators and medical
personal who are experienced in working with children will be directly involved
in patients care.
Special attention was accorded to the schedule of assessments to minimize
burden and time effort for participants. Patients care, comprehension of
informed consent and voluntary participation will be of high priority. The
study will neither extend the duration of the hospitalisation nor increase the
frequency of consultations on the outpatient clinic. Since a central venous
line is mandatory for stem cell transplantation, the blood samples collection
will be pain- and stress-less and only performed by experienced pediatric
nurses to minimize the risk of complications (e.g. infections). The extra
collection of a limited number (5 to maximal 9) of blood samples for
pharmacokinetics analyses may eventually lead to a slightly increased risk of
developing a central venous line infection. However, we consider this risk to
be very low.
The risk of unauthorized data access and/or unwanted identification of project
participants will be assured.
We conclude that the potential benefit of our observational study far outweighs
the possible risks of our additional measurements.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
• diagnosis of severe congenital immune deficiency or of congenital
hematological disorder with an indication for HSCT, e.g. (severe) combined
immunodeficiency ((S)CID), hemophagocytic lymphohistiocytosis (HLH), chronic
granulomatous disease (CGD), thalassemia major, sickle cell disease (SCD);
• age at diagnosis and at the time of HSCT <= 18 years;
• Alemtuzumab treatment intravenously (iv) is given as part of a treosulfan- or
a busulfan-based reduced intensity conditioning regimen prior to alloHSCT;
• all donor types and hematopoietic stem cell sources will be considered;
• allogeneic hematopoietic stem cell transplantation is performed in a study
participating center; written consent of the parents (legal guardian) and of
the patient herself or himself if >=14 years old (>=12 years old in the
Netherlands);
• in case of multiple alloHSCT per patient, further transplantations will only
be considered if a minimal serotherapy-free interval of 3 months is preceding
the second transplant
Exclusion criteria
• patients who do not fulfill the inclusion criteria;
• patients with known hypersensitivity to Alemtuzumab;
• patients treated with other serotherapy drugs (e.g. anti-thymocyte globulin -
ATG) within the same conditioning regimen prior to HSCT;
• patients who received any other serotherapy in the last 3 months before
starting this observational study;
• known HIV-positivity;
• severe uncontrolled infections before alloHSCT;
• active malignancies;
• pregnancy/lactation.
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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In other registers
| Register | ID |
|---|---|
| CCMO | NL68506.058.19 |