Use of Leflunomide as Primary Prophylaxis against Cytomegalovirus (CMV) Reactivation in Haploidentical Haematopoietic Stem Cell Transplant (HIT) Single arm Phase 2 Clinical Trial
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Tata Memorial Hospital
- Enrollment
- 22
- Locations
- 1
- Primary Endpoint
- To determine the rate of clinically significant CMV infection on prophylactic leflunomide in
Overview
Brief Summary
Background
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established therapy for a variety of malignancies, congenital and acquired hematological diseases as well as immunodeficiencies . Allo-HSCT can be broadly classified into 3 types – matched related donor (MRD) (includes matched sibling donor) transplants, unrelated donors and haploidentical (haplo) transplants. Severe viral infections are more common after unrelated donor allo-HSCT, and after haplo-HSCT. Viral infections account for a large part of complications and even fatalities after HSCT. While hygienic measures and patient isolation protect against some pathogens, a special risk originates from viruses that silently persist within the patient or the transplanted cells. After primary infection, viruses like Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), adenovirus (ADV), herpes simplex virus (HSV) and varicella zoster virus (VZV) can reactivate especially in the context of immunodeficiency and immunosuppression . B-cell function and specific antibodies are important for defence against infection with exogenous viruses, while cytotoxic T-cells are important for preventing severe viral disease and against latent viruses. The immune defects in HSCT-patients are frequently complex with defects in cytotoxic T-lymphocyte, helper T-lymphocyte, NK-cell, and B-lymphocyte functions
Rationale for dose
Dose of leflunomide used in this study will be 100mg OD for 3 days followed by 20mg OD. This is based on the standard approved dose of leflunomide used in Rheumatoid arthritis and our prior experience with leflunomide in treatment of CMV
Rationale for duration
Most haplo-HSCT patients have CMV reactivation within first 3 months (day +100) posttransplant. Marty et al also used letermovir prophylaxis for 100 days post-transplant. However, there is a concern for delayed CMV disease after stoppage of prophylaxis . As leflunomide is a safe drug and can be used for prolonged duration, we will use leflunomide for 180 days post-transplant or until the patient is on immunosuppression i.e., calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), Etanercept, Ruxolitinib or steroid (above the replacement dose of 7.5 mg prednisolone), whichever is later
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Masking
- None
Eligibility Criteria
- Ages
- 18.00 Year(s) to 70.00 Year(s) (—)
- Sex
- All
Inclusion Criteria
- •Males or females undergoing Haplo-identical haematopoetic stem cell transplant. -Undetectable CMV from plasma sample in preceding 7 days -Patient who has WBC engraftment ANC More than 500 per cu mm for 3 or more consecutive days. -Within 7 days of WBC engraftment -Adequate liver functions ALT or AST less than 5 times upper limit of normal and Bilirubin less than 3 times upper limit of normal at time of starting leflunomide -Understands the study procedures, alternative treatment available and risks involved with the study and voluntarily agree to participate by giving written informed consent.
Exclusion Criteria
- •Known hypersensitivity to Leflunomide -History of clinically significant CMV reactivation in past 1 year -Patient is receiving or has received drug known to have anti CMV activity within in last 7 days Ganciclovir, valganciclovir, foscarnet, letermovir, acyclovir at doses more than 3200 mg PO per day or more than 25 mg/kg IV per day), valacyclovir (at doses More than 3000 mg PO per day -Inadequate renal function creatinine clearance less than 30 ml per min -Chronic active hepatitis B (HBsAg+ or any HBV DNA+), hepatitis C, or/& HIV -Any psychiatric condition that might limit the ability of the patient to comply with the protocol.
Outcomes
Primary Outcomes
To determine the rate of clinically significant CMV infection on prophylactic leflunomide in
Time Frame: 25 weeks
haplo-HSCT patients till day+180 post HSCT
Time Frame: 25 weeks
Secondary Outcomes
- -To evaluate the safety of post-transplant leflunomide using(-To evaluate the incidence of clinically significant BK virus)
Investigators
Lingaraj Nayak
ACTREC Tata Memorial Centre