Cyclosporine Dose Adjustment According to Calcineurin Activity After Allogeneic Hematopoietic Stem-cell Transplantation

Study Overview
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Brief Summary
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The purpose of this trial is to assess whether an adaptation of cyclosporine (CsA) dose according to a longitudinal calcineurin (CN) activity monitoring would prevent the onset of graft-versus-host disease (GVHD).

Detailed Description
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Our previous studies established a correlation between increased calcineurin (CN) activity and the risk of developing severe acute GVHD in allogeneic stem cell transplant recipients receiving immunosuppressive therapy with calcineurin inhibitors. This proof-of-concept trial is aiming at evaluating CALCIneurin activity as a monitoring biomarker of efficacy of cyCLOsporine - (CALCICLO) - for the prophylaxis of acute GVHD. Our aim is to assess whether a longitudinal monitoring of CN activity would permit to adapt and optimize the dose of CsA that would prevent the onset of severe acute GVHD, yet still maintaining an acceptable tolerability profile.

Official Title
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Reduction of Acute and Chronic Graft-versus-host Disease After Allogeneic Hematopoietic Stem-cell Transplantation by Adapting Cyclosporine Doses According to Calcineurin Activity : a Proof-of-concept Trial

Conditions
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Hematopoietic Stem Cell Transplantation, Graft Versus Host Disease

Intervention / Treatment
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* Behavioral: Dose adaptation according to CN activity monitoring
* Drug: Cyclosporine (CsA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients were between the age of 12 and 60 years Patients planned to receive an allogeneic HSCT following a myeloablative conditioning regimen Exclusion Criteria: Transplant from a syngeneic donor Evidence of refractory disease Nonmyeloablative conditioning Any participation to a study with a new investigational drug within the previous 3 months

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose adjustment according CN activity<br> | Behavioral: Dose adaptation according to CN activity monitoring<br>* The protocol of the CALCICLO trial consisted in a CsA dose adaptation during the first 100 days following transplantation. This dose adaptation was performed according to both residual CsA blood and CN activity levels only if the safety of vital functions - especially renal, liver, and neurological - was preserved as assessed by clinical evaluations and laboratory analyses such as creatinine clearance higher than 40 ml/min, serum bilirubin lower than 40 µM and absence of neurological signs. According to the protocol, CsA blood levels and CN activity were measured concomitantly at least once a week from day 0 to day 15, twice a week from day 16 to day 35 and then once a week until day 100.<br>Drug: Cyclosporine (CsA)<br>* Cyclosporine (CsA)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary end point is the acute grade II to IV GVHD-free survival 100 days after transplantation. |  | 100 days after transplantation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety was a secondary endpoint. It was assessed through clinical assessments including vital signs, creatinine clearance, the presence or not of neurological signs evocative of, or consistent with CsA toxicity, creatinine clearance and serum bilirubin. |  | 100 days after transplantation |