Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04575779 |
| Other study ID # |
70 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 10, 2018 |
| Est. completion date |
May 30, 2022 |
Study information
| Verified date |
January 2023 |
| Source |
Ain Shams University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This study focuses on the basis for current immunosuppressive strategies in patients
undergoing allogeneic haematopoietic stem cell transplantation at the bone marrow
transplantation unit in Ain Shams university hospitals. It discusses whether there is room
for improving both the monitoring and the delivery of pharmacologically mediated
immunosuppression in this population of patients. Our study will try to determine whether CsA
administration at a daily dose of 3 mg/kg/day intravenously (IV) in 2 hrs (short infusion)
twice-daily will achieve C2 blood levels of at least 800 mg/l and whether it will be feasible
and safe or not.
Description:
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is considered as a curative
treatment for patients with haematological malignancies like leukaemia, myelodysplasia,
lymphoma, and multiple myeloma. However, graft-versus-host disease (GvHD) both in its acute
and chronic forms, has limited the benefits of allogeneic HSCT by significant morbidity and
mortality.
Pharmacological suppression of the donor-derived alloreactive immune response has played a
central role in reducing the morbidity and mortality of graft-versus-host disease (GvHD),
which remains the major cause of toxicity after allogeneic stem cell transplantation (SCT).
Graft versus host disease (GvHD) is a condition that might occur after an allogenic
transplant, In GvHD, the donated bone marrow or peripheral blood stem cells view the
recipient's body as foreign, and the donated cells/bone marrow attack the body. There are two
forms of GvHD: Acute graft versus host disease (aGvHD) and Chronic graft versus host disease
(cGvHD). As an allogeneic transplant recipient, the patient might experience either form of
GvHD, both forms, or neither.
Acute GvHD, which results from an interaction of donor T lymphocytes with the recipient's
antigens, occurs in approximately 30%-60% of patients after allogeneic Hematopoietic Stem
Cell Transplantation (HSCT). At the same time, it has become clear that the intensity of
post-transplant immunosuppression is one of the most important determinants of relapse risk
through its impact on the potency of an immunologically mediated graft-versus leukaemia (GVL)
effect.
Among the variety of immunosuppressants available, cyclosporin A (CsA) has been the most
extensively used drug to prevent or treat graft-versus-host disease (GvHD) in hematopoietic
stem cell transplant (HSCT) recipients, since its introduction in the 1970s. It has been
shown that CsA is effective in preventing and controlling acute and chronic GvHD.
Cyclosporine is an immunosuppressive agent, a metabolite extracted from the fungus
Tolypocladium. It is a potent suppressor of the immune system, particularly T-lymphocytes.
Cyclosporine binds to the intracellular receptor cyclophilin, subsequently inhibiting
cytokine production, including interleukin-2 and 4, tumour necrosis factor-alpha, and
interferon-gamma, which leads to impairment of normal lymphoid cell activation.
Other mechanisms may contribute to immunosuppression. Cyclosporine is cell cycle
phase-specific; lymphocytes in the G0 or G1 phase of the cell cycle are specifically and
reversibly inhibited. Direct cytotoxic effects on T- and B-lymphocytes have also been
demonstrated.
The cyclosporine (CsA) acts in a concentration-dependent rather than a time-dependent
fashion. It has been shown that the most significant pharmacodynamic effect occurs within the
first two h of exposure (C2) at peak CsA levels of 800-2285 mg/l which result in 70-96%
calcineurin inhibition and maximum suppression of IL-2 release from T cells.
Pharmacokinetics of cyclosporine (CsA) is highly complex and affected by many factors like
demographics, concurrent medications and type of primary disease for which transplantation
was indicated. Moreover, the complexity of CsA pharmacokinetics is increasing in critically
ill patients in acute post-transplantation phase due to the presence of additional several
clinical factors simultaneously affecting the in-vivo behaviour of CsA. This made very little
research investigating the pharmacokinetic behaviour of CsA in acute post-transplantation
period.
This study will focus on the basis for current immunosuppressive strategies in patients
undergoing allogeneic haematopoietic stem cell transplantation at the bone marrow
transplantation unit in Ain Shams university hospitals and discuss whether there is room for
improving both the monitoring and the delivery of pharmacologically mediated
immunosuppression in this population of patients.
Although it has already been known that the clinical effect of the cyclosporine (CsA) depends
on the reached concentration levels in the blood, the best way of therapeutic monitoring of
this drug is not universally accepted. The measurement of the drug concentration. level in
the blood prior to the administration of the next successive dose (C0) and dosing of the drug
on the basis of this drug concentration, represents the more common way of CsA therapeutic
monitoring. Recently, it has been shown that C0 does not correlate well with the episodes of
acute rejection, and undesirable drug effects as well.
Many studies showed that the absorption, but not the elimination phase, is primarily
significant for the cyclosporine (CsA) effectiveness and that the area under the
concentration-time curve in the first 4 hours after the drug administration (AUC0-4)
adequately reflects the exposure of the organism to the drug and correlates well with
clinical events. It was also shown that out of all drug concentration levels separately
measured at some points of time during the absorption phase; the drug concentration level
determined 2 hours after the administration (C2) correlates the best with the area under the
concentration-time curve in the first 4 hours after the drug administration (AUC0-4).
In the past few years, considerable refinement has occurred in the pharmacologically mediated
immunosuppressive strategies utilized in recipients of solid organ transplants. This has
occurred through the use of more precise methods of monitoring established agents,
principally cyclosporin (CsA), which have been shown to reduce the risk of graft rejection in
the setting of both kidney and liver transplantation. This experience suggests that there may
be scope for translating the advances that have been made in the field of solid organ
transplantation to recipients of allogeneic haematopoietic stem cells.
The drug concentration level determined 2 hours after the administration (C2) monitoring has
been adopted for renal, liver and heart transplant recipients as the two h peak concentration
correlates well with the area under the concentration-time curve (AUC) from 0 to 4 h after
giving the drug and that this predicts the occurrence of acute rejection and nephrotoxicity.
The drug concentration level determined 2 hours after the administration (C2) monitoring is
also associated with clinical benefits as a reduction in graft rejections after solid organ
transplantation. Amazingly, data on pharmacokinetics and target C2 levels are lacking in
Hematopoietic Stem Cell Transplantation (HSCT) patients. Moreover, there is no consensus
about how cyclosporin (CsA) should be administered with some centres giving 1 or 2
intermittent infusions and others continuous 24 h infusion. Hence, our study will try to
determine whether administering CsA at a daily dose of 3 mg/kg/day intravenously(i.v.) in 2
hrs (short infusion) twice-daily will achieve C2 blood levels of at least 800 mg/l and
whether it will be feasible and safe or not.
