A Safety and Feasibility Trial of Leflunomide in Patients With Steroid Dependent Chronic Graft-Versus-Host Disease

  • End date
    Aug 2, 2023
  • participants needed
  • sponsor
    City of Hope Medical Center
Updated on 18 October 2022
bone marrow transplant
serum pregnancy test
human immunodeficiency virus
cell transplantation
myeloablative conditioning
neutrophil count
urine test
platelet transfusions
growth factors


This phase I trial studies the side effects of leflunomide in treating patients with steroid dependent chronic graft versus host disease (cGVHD). cGVHD is a common complication of bone marrow transplant. GVHD occurs when immune cells transplanted from a donor (the graft) recognize the transplant recipient (the host) as foreign, and cause damage to the skin, gastrointestinal tract or other organs. Steroids are the first line of therapy and benefits are seen in about one-third of patients with cGVHD. Prolonged use of steroids is associated with multiple complications. Leflunomide may decrease the body's immune response and reduce inflammation associated with cGVHD.



I. Evaluate safety and tolerability of leflunomide in hematopoietic cell transplant (HCT) patients with steroid dependent chronic GvHD (cGvHD).


I. Characterize the toxicity profile of leflunomide in patients with steroid dependent cGVHD.

II. Obtain preliminary evidence of leflunomide activity against GVHD by estimating the response rate (as defined by 2014 National Institutes of Health [NIH] consensus development project on clinical trials in cGVHD) in an expansion cohort of 12 patients with steroid dependent cGVHD.

III. Evaluate changes in cGVHD severity using physician-reported cGVHD activity assessment form.

IV. Evaluate changes in symptom activity using cGVHD activity assessment patient self-report.

V. Evaluate failure-free survival and GVHD free survival. VI. Evaluate changes in steroid doses while on therapy. VII. Evaluate rate of infectious complications during leflunomide administration.


I. Assess the presence and percentage of immune cell subsets (including but not limited to Th17 and Treg cells) in whole blood after leflunomide administration.

II. Assess the changes in the presence and levels of GVHD inflammatory biomarkers and cytokines (including but not limited to IL-17A, IL-21, and IL-2) in plasma after leflunomide administration.

III. Assess the plasma pharmacokinetics of teriflunomide (active metabolite of leflunomide).


Patients receive leflunomide orally (PO) once daily (QD) for days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally continue leflunomide for an additional 6 cycles as long as response or stable disease is maintained.

After completion of study treatment, patients are followed up at 30 days, and then periodically thereafter.

Condition Chronic Graft Versus Host Disease, Steroid Refractory Graft Versus Host Disease
Treatment leflunomide
Clinical Study IdentifierNCT04212416
SponsorCity of Hope Medical Center
Last Modified on18 October 2022


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Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
If unavailable, exceptions may be granted with study principal investigator (PI) approval
Karnofsky performance status of >= 70 %
Ability to read and understand English or Spanish for questionnaires
Recipients of allogeneic stem cell transplantation (sibling/unrelated/umbilical cord blood [UCB]/Haplo) with myeloablative or non-myeloablative conditioning regimens
Participants must have steroid-dependent cGVHD. Steroid dependent cGVHD is defined as having persistent signs and symptoms of cGVHD despite the use of prednisone for 2 months without complete resolution of signs and symptoms. Both classic cGVHD and overlap syndromes will be allowed to participate
Estimated life expectancy greater than 3 months
No more than 4 prior lines of treatment. Sirolimus and tacrolimus used for prophylaxis will not be counted as line of therapy
Stable dose of corticosteroids for 2 weeks prior to enrollment
Able to swallow pills
Absolute neutrophil count (ANC) >= 1,000/mm^3 (without myeloid growth factors within 1 week of study entry) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
Platelets >= 50,000/mm^3 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
Total bilirubin =< 2 mg/dl (exception permitted in patients with Gilbert's syndrome
aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
Abnormal liver function tests (LFTs) (liver function panel) in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal LFTs as being consistent with hepatic cGVHD and a liver biopsy will not be mandated in this situation
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
ALT =< 2.0 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
[SGPT]) =< 2 x upper limit of normal [ULN]), unless hepatic dysfunction is a
manifestation of presumed cGVHD (performed within 28 days prior to day 1 of
Creatinine clearance of >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal. or calculated by Cockcroft-Gault equation (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
protocol therapy unless otherwise stated)
Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR]) (performed within 28 days prior to day 1 of protocol therapy)
If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed
AST =< 2.0 x ULN (performed within 28 days prior to day 1 of protocol therapy unless
otherwise stated)
Note: Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
Meets other institutional and federal requirements for infectious disease titer
requirements (to be performed within 28 days prior to day 1 of protocol
therapy unless otherwise stated)
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (to be
performed within 28 days prior to day 1 of protocol therapy unless otherwise
Agreement by females and males of childbearing potential to use an effective method of
birth control or abstain from heterosexual activity for the course of the
study through at least 3 months after the last dose of protocol therapy. The
effects of study treatment on a developing fetus have the potential for
teratogenic or abortifacient effects. Should a woman become pregnant or
suspect that she is pregnant while participating on the trial, she should
inform her treating physician immediately

Exclusion Criteria

Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment
Donor lymphocyte infusion within 100 days prior to enrollment
Patients may not be receiving any other investigational agents concurrently. Oral chemotherapeutic agents or biologics -for example ruxolitinib or rituximab therapy and ibrutinib / imatinib (either past or current exposure) - is allowed
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
Active infection requiring antibiotics. An active uncontrolled infection is defined as hemodynamic instability attributed to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection
Uncontrolled cardiac angina or symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV)
Pregnant women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with leflunomide
Patients should not have any uncontrolled illness including ongoing or active infection
Active malignant relapse
Patients with other active malignancies are ineligible for this study, other than superficial localized skin cancer (basal or squamous cell carcinoma)
Active diarrhea, not related to cGVHD
Clinically significant uncontrolled illness
Patients on dialysis
Patients requiring ventilator support
Patients with acute GvHD
Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Inability to comply with protocol therapy and follow up visits
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
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