NIH RUNX1-FPD Clinical Research Study

The purpose of this study is to conduct dedicated, systematic, and long-term clinical research of patients with germline RUNX1 mutations and their families in order to achieve better understanding of the disease progression and underlying mechanisms, which will lead to better clinical management and hopefully develop new therapies.

People with germline RUNX1 mutations develop a genetic disease called familial platelet disorder with associated myeloid malignancies (FPDMM, or simply FPD), which is characterized with frequent bleeding or bruising problems due to low platelet counts (quantitative disorder) and the inability of their platelets to work exactly as they should (qualitative disorder). Many patients also have skin disorders such as eczema and a subset of the patients are at risk of developing cancer, especially cancers of blood cells. With close monitoring and follow-up, we are hoping to learn more about our patient’s risk factors for cancer development so that we can tailor our preventive and treatment strategies accordingly.

Related Publication:

Deuitch N, Broadbridge E, Cunningham L, et al. RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. 2021 Mar 4. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. [GeneReviews]

Cunningham L, Merguerian MD, Calvo KR, Davis J, Deuitch NT, Dulau-Florea AE, Patel N, Yu K, Sacco K, Bhattacharya S, Passi M, Ozkaya N, De Leon SV, Chong SN, Craft KM, Diemer JL, Bresciani E, O'Brien KJ, Andrews EJ, Park N, Hathaway L, Cowen EW, Heller T, Ryan K, Barochia A, Nghiem K, Niemela JE, Rosenzweig SD, Young DJ, Frischmeyer-Guerrerio P, Braylan RC, Liu PP. Natural History Study of Patients with Familial Platelet Disorder with Myeloid Malignancy. Blood. 2023 Sep 22:blood.2023019746. doi: 10.1182/blood.2023019746. Epub ahead of print. [PubMed]

Yu K, Deuitch NT, Merguerian MD, Cunningham L, Davis J, Bresciani E, Diemer JL, Andrews EJ, Young A, Donovan FX, Sood R, Craft KM, Chong SN, Chandrasekharappa SC, Mullikin J, Liu PP. Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy. Blood Adv. 2023 Nov 21:bloodadvances.2023011165. doi: 10.1182/bloodadvances.2023011165. Epub ahead of print. [PubMed]

This study has the potential for significant impact on the fields of hematology and oncology because of the rare opportunity to monitor the genomic evolution of cancer from a pre-cancer population in real time. The aim is to better understand how germline RUNX1- predisposes to cancer development in some people and not in others. Today we know that the lifetime risk of developing cancer is not the same for each RUNX1patient. Analyses across many RUNX1 families show that some have 10% of affected family members go on to develop cancer, while others have closer to 100%. This natural history study may be able to focus upon the factors associated with cancer risk.

For example, some of the questions that are being addressed in the study include:

• Does the type of RUNX1 mutation play a role in defining risk?
• Do the platelet counts have an impact on risk?
• Do certain secondary mutations, such as those acquired in the blood, confer a higher risk than other mutations?
• Can secondary mutations help us understand the timing of cancer onset, severity or type of cancer?
• What about other signs and symptoms, like eczema? Could this be linked to germline RUNX1 mutations?
• Are there other symptoms in people with germline RUNX1 mutation that have yet to be fully characterized?

The NIH is the largest research hospital and public funder of biomedical research in the world. The NIH mission is to: ‘enhance health, lengthen life, and reduce illness and disability’. 

Do I have to pay anything for participating in the study?
No, as an enrolled patient on an NIH protocol, all your care at the NIH clinic is free of charge. Your insurance will not be billed for anything. Medical care at home does not change as a result of being enrolled on the study.

Will I (or my child) have to provide a bone marrow sample or a peripheral blood sample? 
The care provided on the protocol is determined by the tests that are clinically indicated. It is easiest to schedule your visit to NIH at a time when a bone marrow or a peripheral blood sample would have been scheduled locally anyway. Any research testing would be performed at the same time as any clinical testing. If the timing of clinical and research samples doesn’t align or isn’t indicated, you or your child can still enroll on the study and we can obtain additional samples at the next visit if needed. At each annual check-up, you (or your child) will have a physical exam and your blood drawn. The study team will request bone marrow biopsies at study entry and at disease progression. The frequency of bone marrow biopsies in between will be determined based on a number of individual clinical factors, such as changing blood counts.

How many times a year do I need to physically visit the NIH clinic?
Ideally, patients will visit the NIH clinic for an annual check-up with the RUNX1 medical team and NIH subspecialists as needed. We ask to be kept up to date with any new medical information while patients are at home during the year. It is also possibly to come to NIH more frequently than yearly if needed. We understand that sometimes life circumstances and logistics will make yearly visits the NIH difficult. If so, we can work with local clinicians in these circumstances to obtain as much useful data as possible.

Will I be able to visit a local doctor to participate in the clinical study or do I need to travel to the NIH Clinical Center in Bethesda, MD? 
To participate in the clinical study, we highly encourage each study participant to travel to the NIH clinical center annually. The data for the study is most consistent and thus comparable between patients when the annual physical and history is performed by the same clinical teams. Furthermore, many of the tests are specialized and require fresh samples. Therefore, samples drawn at other institutions and sent to us will not be able to have the full panel of testing performed. Nonetheless, we understand that life and logistics will sometimes preclude the annual visit to the NIH, and so we can work with local clinicians in these circumstances to obtain clinical data and samples.

Is my doctor going to be my primary doctor or the doctors at the NIH? 
You will remain under the care of your primary doctor and/or primary hematologist (as indicated). As long as you approve, the doctors at the NIH will be in close contact with your doctor and will share all your medical data with each other.

What is the relationship between my primary doctor and the NIH? 
Your primary doctor and the NIH will be in collaboration with each other. If your primary doctor is not interested in communicating with the NIH, you can still participate in this study.
If you don’t have a primary hematologist, we encourage you to establish care with one as soon as possible.

How will my data and my participation in the clinical study be kept anonymous? 
Under the law, and under NIH policy, it is strictly enforced that all of your data is kept anonymous when sharing for the purposes of the study and any additional research. The only people who will know you and your data are those staff members that are directly taking care of you or who are investigator on the protocol. Those staff members, like all in the medical profession, are trained and bound by law in keeping clinical and research data confidential. Any collaborators only receive deidentified information.

If I develop leukemia and require a bone marrow transplant can I have the transplant done at the NIH and how much will it cost? 
If you develop a hematologic malignancy, your primary doctor and the doctors at the NIH will work with you to decide what options are best for your care. If a bone marrow transplantation is indeed required, you can receive one at the NIH if you are a candidate for the transplantation protocol. There are many factors you will want to take into consideration when deciding where you have your treatment.

How will my participation help the study team better understand how RUNX1 mutations cause illness?
Your medical history, physical exam and biological samples will allow the clinical research team to track how your blood system changes over time along with all of the other RUNX1 participants. By being able to compare across many patients at the same time, using the same tests, we hope to uncover which factors are protecting some patients from developing cancer and which factors work to accelerate the process towards developing cancer. Our goal is to learn how to develop tools to identify who is at high-risk of cancer how best to monitor and treat high-risk patients. We are also performing research to try to correct RUNX1 mutations. This work is in early pre-clinical development at this time.

What information will the NIH clinic share with me about my health and the results of the overall study? 
The NIH will share with you all of your data. There is an online patient portal so that you can access your clinical data at your convenience. Once there are enough participants to meaningfully address the research questions, the research team will prepare a result report for publication. This publication will be openly accessible to the public and all data will be deidentified, meaning each participant in the study will remain anonymous.

What does the itinerary for my trip to the NIH clinic look like? 
For a complete clinical work up, plan on a total of at least 2 days, including U.S.-based travel to Bethesda, Maryland. If traveling from farther away, and if several family members are scheduling appointments together, additional time will likely be necessary. However, each patient can determine how much time they are willing and able to give, and the NIH clinical team can adjust accordingly.

Example long NIH Itinerary:

• Weeks prior to arrival: Sign study consents (this is usually done by phone/mail) and send your medical records to the NIH ahead of your appointment. If you need information on how to do this, please email runx1@nih.gov for a secure email link or fax number.
   
• Afternoon or evening prior to first visit:
  Travel to Bethesda, register in NIH designated hotel, register in outpatient admissions
   
• NIH Day 1:
  Meet the RUNX1 clinical team. Undergo a routine physical exam, blood-draw and have a detailed discussion about your and your family’s medical history. Meet with preanesthesia clinic (if a sedated bone marrow biopsy is needed) or any other needed subspecialists such as gastroenterology, dermatology, allergy/immunology, child life/recreation therapy. It is important that the NIH clinical team does a thorough examination of any and all of your health conditions.
   
• NIH Day 2:
  Bone marrow biopsy and/or skin biopsy in the morning (this can be done at the same location so there is only one procedure site) and allow recovery time in the afternoon.
  
  In general, a bone marrow biopsy is done with conscious sedation (versed & fentanyl) or Monitored Anesthesia Care (MAC) for adults. Some adults chose to only have local anesthesia with lidocaine. All children have Monitored Anesthesia Care. Children (and some adults) who will receive MAC should not eat or drink liquids at least 8 hours prior to their procedure. The decision regarding anesthesia will be made with you well before your arrival at the NIH.  
  
  A small skin biopsy (2-4 mm less; than the diameter of a pencil eraser) will also be taken, likely during the same time of your bone marrow biopsy. Since some patients with germline RUNX1 also have dermatologic diagnoses such as eczema or psoriasis, you may spend some time with a dermatologist to review your history and any potentially related skin symptoms.
   
• NIH Day 3: On the last day you will have a brief post-op check and ‘wrap-up’ meeting with the NIH clinical team. This means you will sit down with the clinical team to discuss all of the results that have come back in this 1-3 day time interval.  Some results may take 14 weeks or longer and will be communicated to you later by phone.  During your wrap-up meeting, we will also discuss your overall experience at NIH, plans for follow up visits with your local clinician(s) and future visits to the NIH. You will spend time discussing what to look out for and when to call your local clinician/NIH should anything change with your health status. Upon departure you will be provided an information packet including contact information and resources that will guide you should you have any questions or need medical attention.
   
• NIH Short Visit example itinerary: We can accomplish the vast majority of the above itinerary in 36 hour for an adult who only requires local anesthesia for their bone marrow biopsy. The bone marrow biopsy is performed on the first day. The post op check and wrap-up meeting occur early on the second day with subsequent travel home.
   

What are the NIH researchers doing with my blood?
Analyzing your blood allows clinicians and scientists to monitor and track a number of different elements about the health of your blood system and your overall health. In this study, your blood sample will be processed through many different laboratory assessments, several that are far more advanced than what is routinely done in clinical practice. For example, the number of your different blood cell types, their structure and functionality can all be evaluated. Your blood sample, when processed for next generations sequencing, can reveal changes in the DNA of your blood cells. Your blood sample can also provide information about inflammation by measuring the level of inflammatory cytokines in your blood serum.

What are the NIH researchers doing with my bone marrow? 
Just like your blood sample, there are a series of laboratory evaluations that we can evaluate to obtain as much information about your blood precursor cells as possible. The goal is to understand what changes occur in patients who progress to leukemia as compared to those who don’t, since it is believed that leukemia is developed from the blood precursor cells in the bone marrow. This knowledge not only helps us identify patients who are at high risk for progression to leukemia but may also help us understand why the changes are happening and how to block them with therapy or another type of intervention.

What are the NIH researchers doing with my skin biopsy?
Your skin biopsy will serve as a control sample. Mutations that we find in the DNA of your skin cells will help the NIH team define germline mutations, meaning mutations you were born with. All RUNX1 patients will have a RUNX1 mutation in their skin. Therefore, we will find the same mutations in your blood cells as well. However, any mutations we find in your blood but not in your skin are considered “somatic” mutations, meaning they happened after birth and originated in one cell that divided and created daughter cells, but such mutations will not pass on to your children. Somatic mutations happen in every human being, in every tissue type and increase as we age. But, somatic mutations in genes that are vital to your blood health can lead to myelodysplastic syndrome (MDS) and certain types of leukemias and lymphomas, and this is what the NIH research team is tracking and looking out for.

Who will I be in contact with prior to visiting the NIH, and how can I get more information?
You will have at least one phone call with the NIH clinical team. A nurse or study coordinator will provide you with all of the necessary information prior to your trip. 

Is it possible to participate in the NIH study without coming to the Clinical Center? 

Coming to the NIH Clinical Center allows us to get more detailed and consistent data for the study, and provide more tailored results to you. However, we also recognize that not everyone will be able to physically travel to Bethesda, especially during the COVID-19 pandemic. We are able to complete some elements of the study evaluation using a combination of telehealth, medical record collection, remote blood draw (via ExamOne) and collaboration with your local providers. Please let our team know if you are interested in participating remotely. 

Who should be referred to the NIH team?

Any patient (age 1 month or above) with proven or highly suspected RUNX1 mutation. This includes patients with chronic thrombocytopenia and family history of thrombocytopenia, chronic/refractory ITP, von willebrand disease, bleeding problems, cancer including myelodysplastic syndrome or leukemia.

Would I be transferring care of my patient to the NIH?

No. The patient will continue to follow with their primary care doctor and hematologist. The NIH study is meant to supplement the care that they are already receiving. Patients who do go on to develop leukemia should receive treatment at their home institution, though we would continue to follow the patients in tandem. There may be options to receive hematologic malignancy or transplant care at NIH if needed.

Who is the primary point of contact at the NIH for clinicians that refer patients? 

All of the RUNX1 study staff listed above share one email: runx1@nih.gov. We can send individuals secure links for medically secure communication needs.

What data would be captured? What type of samples would be required?

Bone marrow aspirates and biopsies will be collected for in-depth testing: Whole exome or whole genome sequencing, RNA sequencing on blood precursors, a SNP array for detection of copy number variations, a targeted somatic mutation panel, cytogenetic analysis, FACS analysis, histological/pathological evaluations, and megakaryocyte/platelet electron microscopy. Peripheral blood samples will be collected for standard panels of hematologic, chemical, and immunologic testing. Skin biopsy will be performed to generate fibroblasts to provide germline DNA controls. We time the NIH visit for when the bone marrow sample is clinically indicated.

What are the goals of the NIH clinic? 

This is a natural history study that aims to follow patients with germline RUNX1 mutations longitudinally to learn as much as possible about risk factors for progression to hematologic malignancies and comorbidities (including non-hematological) that should be screened for. We seek to identify secondary mutations in clonal hematopoietic cell populations that may be useful for prognosis and that may also guide future research on mechanisms of leukemia development. We are also examining preclinical models of Runx1 mutations and investigating novel mechanisms of mutation correction. We hope that these efforts will result in better clinical management and improved treatment outcome and may lead to clinically applicable targeted therapies someday.

What information will the NIH share with referring clinicians about patients sent to the NIH clinic? 

Referring clinicians will be sent all CLIA-certified lab results and clinical notes generated at the NIH for their patient(s).

Can patients have the option to be seen at a local clinic for [annual] updates for the natural history study?

The data for the study is most consistent (and thus comparable between patents) when the annual physical and history is performed by the same team. Furthermore, many of the tests are specialized and require fresh samples. Therefore, samples drawn at other institutions and sent to us will not be able to have the full panel of testing performed. Nonetheless, we understand that life circumstances and logistics will sometimes preclude the annual visit to the NIH, and so we can work with local clinicians in these circumstances to obtain as much useful data as possible.

Will there be annual updates on overall progress of the clinic?

Results from the study will be published in a peer-reviewed journal that will be accessible in full via PubMed.

How will data from the clinic be disseminated to the patients’ local clinical care team?

The patient will have access to their clinical data via an NIH patient portal. They can download their medical records to share with their local clinical care team. In addition, the NIH clinical team will also print medical records upon patient request.

What if my patient needs a bone marrow transplant?

This treatment decision will be made by their local, primary clinical team.  The NIH clinical team can offer recommendations or consultation if requested. If needed, the patient will have the option of having the bone marrow transplant performed at the NIH at no cost to them or their insurance. Of course, they still may have it performed elsewhere if they prefer.

If I am a research investigator, how can I apply to have access to tissue samples?

There will be a web portal, available soon, that will display an application form. The form will require a basic professional biosketch and short research proposal.