Early Initiation of Oral Therapy With Cyclosporine and Eltrombopag for Treatment Naive Severe Aplastic Anemia (SAA)
Early Initiation of Oral Therapy With Cyclosporine and Eltrombopag for Treatment Naive Severe Aplastic Anemia (SAA)
Background:

 Severe aplastic anemia (SAA) is a rare and serious blood disorder. It causes the immune
 system to turn against bone marrow cells. Standard treatment for SSA is a combination of 3
 drugs (Cyclosporine [CsA], Eltrombopag [EPAG], and horse anti-thymocyte globulin [h-ATG]).
 Researchers want to see if starting people at a lower dose of CsA with EPAG before giving
 them h-ATG is helpful.

 Objective:

 To learn if early initiation of oral therapy with CsA and EPAG is safe and effective in
 people who have SAA and have not been treated with a course of immunosuppressive therapy and
 EPAG.

 Eligibility:

 People ages 3 and older with SAA

 Design:

 Participants will be screened with:

 medical history

 physical exam

 electrocardiogram

 blood tests

 family history

 bone marrow biopsy

 current medicines.

 Participants may be screened remotely via telephone conference.

 Participants will take a lower oral dose of CsA and EPAG. They will take CsA twice a day for
 6 months. They will take EPAG for 6 months. Those who cannot visit the NIH Clinical Center
 within 72 hours will start taking the drugs at home. They will have weekly telephone calls
 with NIH staff until they visit the Clinical Center.

 Participants may get h-ATG at the Clinical Center for 4 days. For this, they will have a
 central line placed. It is a plastic tube inserted into a neck, chest, or arm vein.

 Participants will repeat most screening tests throughout the study.

 Participants will have follow-up visits at the Clinical Center at 3 months, 6 months, and
 annually for 5 years after the start of the study.
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure characterized by
 pancytopenia and a hypocellular marrow. Allogeneic bone marrow transplantation is curative in
 younger patients, but older age and/or lack of a suitable donor have limited application of
 this procedure. As an alternative to transplant, immunosuppressive treatment (IST) has
 provided durable remissions and similar long term survival. Approximately 2/3 of patients who
 receive IST with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA) have blood
 count recovery, but 25-30% do not respond and 30-40% will relapse. A likely explanation for
 partial recovery and relapse is incomplete elimination of auto-reactive T cells and
 insufficient stem cell reserve.

 Thrombopoietin (TPO) is a key regulator of hematopoietic stem cell renewal and survival. To
 improve the hematologic response rate, our group assessed the addition of eltrombopag (EPAG),
 a synthetic mimetic of TPO, to IST in treatment na(SqrRoot) ve SAA. This combination achieved
 a higher complete response rate to about 50% and an overall response rate to 80%, both
 superior to historic controls. This regimen received FDA approval in November 2018. Combined
 therapy is now being tested in a European randomized study. Furthermore, protocols have been
 developed internationally to determine whether EPAG and CsA, without ATG, are sufficient to
 improve blood counts, in countries where ATG is not available.

 The long-term complications, relapse and clonal evolution, were no worse with the addition of
 EPAG than in our historical cohort, but still remain a problem. Clonal evolution occurs in
 10-15% of patients and is defined as development of myelodysplastic syndrome or acute myeloid
 leukemia with characteristic cytogenetic abnormalities of aneuploidy, especially monosomy 7
 or deletion 7q. There are no predictive tools to identify patients at higher risk for either
 of these two long term events.

 Because SAA is a rare disease, treatment has been recommended to take place at a specialized
 center. However, delays in reaching such centers and initiating therapy are common. From
 current understanding of the disease, immune destruction of cells is ongoing during this
 period, likely impacting on both short and long term outcomes. We propose early initiation of
 lower dose CsA (2mg/kg/day) and EPAG to decrease ongoing immune destruction and stimulate
 HSPC while awaiting full work up and transfer to the Clinical Center (CC).

 The aim of this study is to test feasibility and safety of initiating oral therapy before
 arriving to the NIH, based on diagnostic tests performed by local physicians and
 interpretation from experts here. Treatment will be initiated remotely but under complete
 guidance and supervision of the research team at the Hematology Branch. All patients except
 the ones who achieve complete response will receive standard three drug regimen upon
 completion of work up here at the CC. Primary endpoint of the study will be to assess
 feasibility and safety as a composite measure of misdiagnosis, noncompliance with the regimen
 or failure to establish care at the Clinical Center within 8 weeks of initiating treatment,
 and TRSAE (treatment related serious adverse events). Initial treatment period of 8 weeks may
 be extended in special circumstances. Secondary endpoints are response rates at landmark time
 points, relapse, overall survival, and clonal evolution.
-  INCLUSION CRITERIA:

 1. Age >= 3 years old

 2. Weight >12Kg

 3. Severe aplastic anemia:

 -  Bone marrow cellularity <30% (excluding lymphocytes) AND At least two of the
 following:

 -  Absolute neutrophil count <500/microliter

 -  Platelet count <20,000/microliter

 -  Absolute reticulocyte count <60,000/microliter

 EXCLUSION CRITERIA:

 1. Known diagnosis or high suspicion of Fanconi anemia or other constitutional marrow
 failure syndrome

 2. Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry
 involving chromosome 7 or complex karyotype. Patient will not be excluded if
 cytogenetics are not done or are pending

 3. A course of prior immunosuppressive therapy (ATG, cyclosporine, alemtuzumab, and high
 dose cyclophosphamide), or eltrombopag

 4. SGOT or SGPT >2.5 times the upper limit of normal or total bilirubin >1.5 x upper
 limit of normal

 5. Subjects with liver cirrhosis (as determined by the investigator).

 6. Subjects with human immunodeficiency virus (HIV) who are not receiving antiretroviral
 therapy, have detectable HIV RNA viral load and have CD4 cell count <200/microliter,
 or are on anti-retroviral therapy that interacts with the study drugs. subjects will
 not be excluded if HIV testing is pending or unavailable.

 7. Glomerular filtration rate (GFR) <40 mL/min/1.73m^2

 8. Hypersensitivity to EPAG or its components

 9. Infection not adequately responding to appropriate therapy

 10. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,
 infectious, or metabolic disease of such severity that it would preclude the patient's
 ability to tolerate protocol therapy, or that death within 7-10 days is likely

 11. Potential subjects with cancer who are on active chemotherapeutic treatment or who
 take drugs with hematological effects will not be eligible

 12. Inability to understand the investigational nature of the study or to give informed
 consent or does not have a legally authorized representative or surrogate that can
 provide informed consent.

 13. Inability to swallow

 14. Unable to participate in audio/video telecommunication

 15. Inability to ship the study drug to participant

 16. History or current diagnosis of cardiac disease indicating significant risk of safety
 for patients participating in the study such as uncontrolled or significant cardiac
 disease,

 including any of the following: Recent myocardial infarction (within last 6 months),
 uncontrolled congestive heart failure, unstable angina (within last 6 months),
 clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular
 tachycardia, and clinically significant second or third degree AV block without a
 pacemaker.), long QT

 syndrome, family history of idiopathic sudden death, congenital long QT syndrome or
 additional risk factors for cardiac repolarization abnormality, as determined by the
 investigator.

 17. Impaired cardiac function, such as: Corrected QTc >450 msec using Fridericia
 correction (QTcF) on the screening ECG (using triplicate ECGs), other clinically
 significant cardiovascular disease (e.g., uncontrolled hypertension, history of labile
 hypertension), history of known structural abnormalities (e.g. cardiomyopathy).

 18. Concurrent participation in an investigational study within 30 days prior to
 enrollment or within 5-half-lives of the investigational product, whichever is longer.
 Note: parallel enrollment in a disease registry is permitted.

 19. Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits
 of participating in the study outweigh the potential risks of thromboembolic events,
 as determined by the investigator.

 20. Women of child-bearing potential, defined as all women physiologically capable of
 becoming pregnant, unless they are using basic methods of contraception during dosing
 of study treatment. Basic contraception methods include:

 - Total abstinence (when this is in line with the preferred and usual lifestyle of the
 subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation

 methods) and withdrawal are not acceptable methods of contraception

 -  Female sterilization (have had surgical bilateral oophorectomy with or without
 hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
 taking study treatment. In case of oophorectomy alone, only when the reproductive
 status of the woman has been confirmed by follow up hormone level assessment

 -  Male sterilization (at least 6 months prior to screening). The vasectomized male
 partner should be the sole partner for that subject

 -  Barrier methods of contraception: Condom or Occlusive cap. For the UK: with
 spermicidal foam/gel/film/cream/ vaginal suppository

 -  Use of oral, injected or implanted hormonal methods of contraception or placement
 of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
 hormonal contraception that have comparable efficacy (failure rate <1%), for
 example hormone vaginal ring or transdermal hormone contraception.

 -  In case of use of oral contraception women should have been stable on the
 same pill for a minimum of 3 months before taking study treatment.

 21. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic
 gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1

 22. Sexually active males unless they use a condom during intercourse while taking the
 drug during treatment, and for 7 days after stopping treatment (and for an additional
 12 weeks [for genotoxic compounds]) and should not father a child in this period. A
 condom is required to be used also by vasectomized men as well as during intercourse
 with a male partner in order to prevent delivery of the drug via semen.