Evaluation of the Clinical Outcome of Cyclosporine Short Infusion Versus Continuous Infusion Post Allogenic Stem Cell Transplantation

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.