| Eligibility |
Inclusion Criteria:
- Age 18 years or older and able to provide informed consent
- ECOG 0-2
- Compensated Child-Pugh class A of any etiology with the exception of chronic hepatitis
B with one or more of the following cytopenias
1. Leukopenia defined as white blood cell count <2000/mm3 or absolute neutrophil
count <1000/mm3 along with thrombocytopenia <150,000/mm3 measured on two separate
occasions at least 3 months apart within 6 months of enrollment
2. Thrombocytopenia defined as platelet count <50,000/mm3 along with white blood
cell count <4000/mm3 measured on two separate occasions at least 3 months apart
within 6 months of enrollment
- Compensated Child-Pugh class B cirrhosis of any etiology with the exception of chronic
hepatitis B with one or more of the following cytopenias:
1. Leukopenia defined as white blood cell count = 3500/mm3 measured on two separate
occasions at least 3 months apart within 6 months of enrollment 3. Thrombocytopenia
defined as platelet count = 100,000/mm3 measured on two separate occasions at least 3
months apart within 6 months of enrollment
- Enrolled patients must have one or more of the following:
- Presence of a genetic variant (defined as a known mutation, variant likely to be
pathogenic or variant of undetermined significance with likely deleterious effect
on transcription or translation) in at least one of the following genes: TERT,
TERC, RTEL1, DKC, NOP10, NHP2, TINF2, WRAP53
- Shortened telomere length in peripheral blood mononuclear cells (defined as
age-adjusted telomere length at or below the 5th percentile)
- Of note, patient's found to have telomere mutations know to confer a gain of
function will be excluded
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate
of < 1% per year during the treatment period
- A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (>= 12 continuous months of amenorrhea
with no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus)
- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, proper use of hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or post
ovulation methods) and withdrawal are not acceptable methods of contraception
- Women of childbearing potential (WOCBP) must have a negative serum test (minimum
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
72 hours prior to the start of treatment
Exclusion Criteria:
- Cirrhosis secondary to chronic hepatitis B or any history of hepatitis B
- Patients with telomere related mutations know to confer gain of function will be
excluded
- Patients known to be infected with HIV
- History of any hormone sensitive malignancy, including breast cancer, prostate cancer,
hepatocellular carcinoma or liver adenoma as well as any patient considered high risk
for developing malignancy (i.e. history of familial cancers including a first degree
relative)
- Patients who are actively receiving anti-cancer therapy
- Liver decompensation event within the last 6 months (i.e. variceal bleed, ascites
requiring paracentesis, hepatic encephalopathy)
- Active thrombosis or history of unprovoked thromboembolic disease, including
cardiovascular events. If a patient has received and completed adequate
anticoagulation for a provoked thrombosis, they can be included in the study.
- Pregnant or planning to become pregnant
- Females patients who are breast feeding
- Any contraindication to danazol use
- Uncontrolled co-morbid condition which would make the administration of danazol
unsafe, including decompensated heart failure or known EF less than 40%, unstable
angina pectoris, uncontrolled cardiac arrhythmia, decompensated liver failure, renal
failure defined as creatinine greater than >1.6 or psychiatric illness that would
limit compliance with study requirements
- Alanine aminotransferase and/or aspartate aminotransferase >3x upper limit of normal
- Alkaline phosphatase >2.5 x upper limit of normal
- Total bilirubin or direct bilirubin >2.5 x upper limit of normal
- Patients with known alcohol or drug abuse within the last year
- Concomitant use of hormone stimulants or hormone blocking agents.
- Concomitant use of other bone marrow stimulating agents that may affect white blood
cell and platelet counts (i.e. G-CSF, romiplostim, eltrombopag, corticosteroids).
Short term use of growth factors per standard of care in preparation for procedure or
for other medical indications is acceptable. Patients taking corticosteroids above 5
mg of prednisone or the equivalent who are on a stable dose for at least 8 weeks prior
to enrollment can be included.
- Concomitant treatment with systemic immunosuppressive medications (including but not
limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents)
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