Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Diseases and Abnormalities at or Before Birth

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Syndrome

Hematologic Neoplasms

Cytopenia

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Failure Disorders

Pancytopenia

Neoplastic Syndromes, Hereditary

Congenital Bone Marrow Failure Syndromes

Anemia

Leukopenia

Thrombocytopenia

Anemia, Aplastic

Hemoglobinuria

Hemoglobinuria, Paroxysmal

Bone Marrow Diseases

Hematologic Diseases

Leukocyte Disorders

Blood Platelet Disorders

Hemolysis

Anemia, Hemolytic

Infant, Newborn, Diseases

Genetic Diseases, Inborn

Participants may undergo blood sample collection, a bone marrow biopsy, a skin punch biopsy, hair follicle collection, a buccal swab, and/or saliva collection for NGS analysis on study. Patients may additionally undergo clinical assessment and may receive genetic counseling on study.

Undergo blood sample, hair follicle, and saliva collection

Biospecimen Collection

Bone Marrow Biopsy

Punch Biopsy

Buccal Swab

Clinical Evaluation

Genetic Counseling

Quality-of-Life Assessment

Electronic Health Record Review

Brittany Burnap

Clinical Trials Referral Office

Cecilia Y. Arana Yi, M.D.

James M. Foran, M.D.

Mrinal S. Patnaik, MBBS

This clinical trial tests next generation sequencing (NGS) for the detection of precursor features of pre-myeloid cancers and bone marrow failure syndromes. NGS is a procedure that looks at relevant cancer associated genes and what they do. Finding genetic markers for pre-malignant conditions may help identify patients who are at risk of pre-myeloid cancers and bone marrow failure syndromes and lead to earlier intervention.

PRIMARY OBJECTIVES:

I. To use genomics and functional translational studies to diagnose, prognosticate and potentially offer therapeutic directives for patients with precursor features of myeloid neoplasms (myelodysplastic syndrome \[MDS\], myeloproliferative neoplasms \[MPN\], MDS/MPN overlap syndrome) and germline predisposition/bone marrow failure states, who do not meet the criteria for the diagnosis of these cancers as of yet.

II. To identify patients with precursor myeloid malignancies and bone marrow failure syndromes.

III. To examine the utility of NGS methods for discovery of targets or pathways involved in precursor features of myeloid cancer and bone marrow failure.

IV. To use clinomics/genomics to better understand pathobiology and risk of disease progression.

V. To help better understand the implications of variants of unknown significance using computational biology and functional studies.

VI. To utilize normal, age and sex matched controls to validate genetic and epigenetic testing carried out under this protocol (essential for accurate data analysis).

VII. To assess frailty in patients with clonal hematopoiesis in order to validate genetic and epigenetic testing completed under this protocol as objective assessments of frailty and aging in comparison to standard of care frailty and geriatric assessments.

OUTLINE:

Participants may undergo blood sample collection, a bone marrow biopsy, a skin punch biopsy, hair follicle collection, a buccal swab, and/or saliva collection for NGS analysis on study. Patients may additionally undergo clinical assessment and may receive genetic counseling on study.

Pre-myeloid Cancer and Bone Marrow Failure Clinic Study

Assessed by the number of subjects whose cytopenias are persistent or progressive over the course of the study

Assessed by the number of subjects who have evolved to MDS over the course of the study

Assessed by the number of subjects who have evolved to AML over the course of the study

Mayo Clinic

Principal Investigator

Nutritional and Metabolic Diseases

Carcinoma

Carcinoma, Squamous Cell

Fanconi Syndrome

Fanconi Anemia

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Anemia, Hypoplastic, Congenital

DNA Repair-Deficiency Disorders

Metabolic Diseases

Renal Tubular Transport, Inborn Errors

Kidney Diseases

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Congenital Aplastic Anemia

A prospective cohort of individuals with Fanconi anemia (FA) at very high risk of squamous cell carcinoma (SCC)

NCI Family Study Referrals

Neelam Giri, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Fanconi anemia (FA) is an inherited disorder. People with FA are more likely to get certain cancers, especially squamous cell carcinoma (SCC). These cancers usually appear first in the mouth, esophagus, and genital and anal areas. Early detection of SCCs may help improve survival rates for people with FA.

Objective:

This natural history study will regularly screen people with FA for SCC.

Eligibility:

People aged 12 years and older with FA or a prior cancer diagnosis. Children aged 8 to 11 years with FA may also be eligible.

Design:

Participants will receive a comprehensive screening for cancer or early signs of cancer.

Participants will have a physical exam. They will provide blood and saliva samples. Cells will be collected by rubbing a swab on the inside of the cheeks. A skin sample may be removed from the back, buttocks, or inside of the upper arm.

Participants will have pictures taken of their mouth. Any mouth sores will be mapped. Cells will be collected from the sores with a small brush.

Specialists will examine the participant s ears, nose, throat, teeth, and skin.

Adult participants may have a gastrointestinal exam or pelvic exam. Participants may have an endoscopy. A long tube with a camera and a light will be inserted through the mouth and down into the stomach.

Participants may have a liver ultrasound. A wand will be pressed against their belly to get pictures of the organs inside the body.

Participants will have screenings every year for up to 10 years. Each visit will last up to 3 days. They will have remote follow-up visits every 6 - 8 months....

Study Description:

This is a natural history study involving questionnaires, clinical and research evaluations, clinical and research laboratory tests, review of medical records, and cancer surveillance. A prospective cohort of individuals with Fanconi anemia (FA) at very high risk of squamous cell carcinoma (SCC) will be screened and provide new information on oral potentially malignant lesion (OPML) development and robustly quantify the risk of progression of OPML to cancer in FA.

Objectives:

Primary Objectives:

1. To establish a central program and a team of expert clinicians and scientists at the NIH Clinical Center to conduct a comprehensive longitudinal study of cancer screening in adolescent and young adults (AYA) with FA at high risk of SCC through detailed clinical evaluation and biospecimen collection.
2. To characterize the clinical and pathological natural history of OPMLs in AYAs with FA using brush biopsies for cytopathologic diagnosis and DNA aneuploidy and correlate those findings with tissue biopsies and genomic analyses of oral epithelial dysplasia (OED) and SCC.
3. To prospectively screen individuals with FA for early indicators for the development of esophageal and anogenital SCC.

Secondary Objectives:

1. To identify genetic, epigenetic, and immunologic mechanisms underlying tumorigenesis and immune escape in individuals with FA.
2. To facilitate the enrollment of individuals with FA with high-grade dysplasia or SCC in intra- and extra-mural precision intervention trials.

Endpoints:

Primary Endpoints:

1. Characterize the natural history of OPMLs in FA, rates of progression, regression, and development of new lesions
2. Determine the utility of brush biopsy to identify oral dysplasia and SCC in FA
3. Identify potential precursor states for esophageal and anogenital cancers in FA
4. Develop screening guidelines for esophageal and anogenital cancer in FA

Secondary Endpoints:

1. Identify predictive biomarkers of oral SCC development
2. Characterize genetic and epigenetic changes that lead to SCC development
3. Facilitate patient enrollment in intervention trials

Defining the Natural History of Squamous Cell Carcinoma in Fanconi Anemia

Prospectively screen individuals with FA for early indicators for the development of esophageal and anogenital SCC.

Characterize the clinical and pathological natural history of OPMLs in AYAs with FA using brush biopsies for cytopathologic diagnosis and aneuploidy and correlate those findings with tissue biopsies and genomic analyses of oral epithelial dysplasia (OED) and SCC.

National Cancer Institute (NCI)

Disease Susceptibility

Disease Attributes

Familial Platelet Disorder With Associated Myeloid Malignancy

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Escalating doses of imatinib to determine the MTD

Collection of blood or marrow only. No treatment.

Imatinib at 100-400 mg PO QD based on arm assignment/dose level

imatinib

Assay sequencing platform to identify pathogenic genetic mutations in DNA and RNA

TruSight Oncology

Rebecca Alexander

Lea C Cunningham, M.D.

National Cancer Institute Referral Office

Background:

Runt-related transcription factor 1 (RUNX1) gene regulates the formation of blood cells. People with mutations of this gene may bleed or bruise easily; they are also at higher risk of getting cancers of the blood, bone marrow, and lymph nodes.

Objective:

To test a drug (imatinib) in people with RUNX1 mutations that cause symptoms.

Eligibility:

Adults aged 18 and older with RUNX1 mutations. Healthy people without this mutation, including family members of affected participants, are also needed.

Design:

Participants with the RUNX1 mutation will be screened. They will have a physical exam with blood and urine tests. They will have a test of their heart function. They may need a new bone marrow biopsy: A sample of soft tissue will be removed from inside a bone.

Imatinib is a tablet taken by mouth once a day, every day, at home. Affected participants in different parts of the study will take imatinib for either 28 days or up to 84 days.

Participants will visit the clinic once a week for the first 28 days that they are taking the imatinib. Then they will come once every 2 weeks if they are taking the drug for 84 days. Blood, urine, and tests of heart function will be repeated. They may opt to have the bone marrow biopsy repeated after they finish their course of imatinib.

Participants will have a follow-up visit 30 days after they stop taking imatinib.

Participants who do not have the RUNX1 mutation will have 1 clinic visit. They will have blood tests. They will fill out questionnaires. They may opt to have a bone marrow biopsy....

Background:

* Runt-related transcription factor 1 (RUNX1) gene is located on chromosome 21 and encodes an important regulator of hematopoiesis. People normally inherit one functional copy from each parent.
* RUNX1 function is highly dose dependent as both too little as well as too much RUNX1 activity is associated with development of hematologic malignancy. The focus of this protocol is participants with germline RUNX1 mutations resulting in too little RUNX1 activity.
* Germline heterozygous RUNX1 mutations are inherited in an autosomal dominant manner and cause a disorder called Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM). Patients with one deleterious germline RUNX1 mutation often have haploinsufficiency although some mutations are associated with a dominant negative effect.
* Clinically, patients with germline RUNX1 mutations have aberrant megakaryocytic development, which often results in quantitative and/or qualitative platelet defects. Patients often have easy bleeding or bruising, although some cases are subclinical, and they may present to clinicians with hematologic malignancy.
* Patients with germline RUNX1 mutations have 35-45% lifetime risk of developing myeloid hematologic malignancies including MDS and AML. Increased risk of B-ALL, T-ALL and other hematologic malignancies is also associated with deleterious germline RUNX1 mutations.
* Deleterious RUNX1 mutations are known to be associated with high-risk malignancy with poor response to upfront chemotherapy and require hematopoietic stem cell transplantation (HSCT).
* Imatinib is a dual SFK and ABL inhibitor that is FDA approved and indicated for treatment of CML, ALL, MDS/MPD, aggressive systemic mastocytosis (ASM) as well as hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL).
* ABL physically associates with RUNX1, phosphorylates key tyrosines within the RUNX1 inhibitory domain and negatively regulates RUNX1 transcriptional activity.
* We hypothesize that imatinib will decrease RUNX1 tyrosine phosphorylation thereby increasing RUNX1 protein activity to a level closer to that expected for 2 normal copies of RUNX1. We also hypothesize that normal levels of RUNX1 protein activity will ameliorate platelet dysfunction and bleeding symptoms via objective measures.
* We expect this study to inform the biologically relevant endpoints for a subsequent phase II efficacy study, which would also seek to determine if longer term imatinib administration could prevent malignant transformation.

Objectives:

* To determine the dose of imatinib for dose expansion in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose escalation phase
* To determine the safety of imatinib in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose expansion phase

Eligibility:

* Age \>=18 years
* Participants with deleterious germline RUNX1 mutations as defined by ClinGen with adequate organ function and no history of hematologic malignancy.

Design:

* This is a phase Ib study with 2 cohorts (participants with and without pathogenic or likely pathogenic RUNX1 mutations) and 3 arms (2 for imatinib administration and 1 for biobanking control).
* A standard 3+3 non-randomized dose-escalation design will be used in the first arm, with orally administered imatinib tested at 4 dose levels from 100 to 400 mg daily for 28 days for participants with pathogenic or likely pathogenic germline RUNX1 mutations.
* Participants will have PK/PD evaluations at all dose levels.
* An expansion cohort will be treated at the maximum tolerated dose (MTD) in Arm 2, daily for 12 weeks. Participants who are treated on the dose escalation phase may also be treated in the expansion phase after an appropriate wash out period of 28 days.
* The third arm is for unaffected family control participants with wildtype RUNX1 or healthy volunteers who may choose to enroll to donate blood or marrow but will not be treated.
* 12-24 participants will be enrolled for dose escalation, 12 participants in the expansion cohort, and up to 80 unaffected controls contemporaneously whenever feasible.

Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

Phase Ib Study of Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@

Safety will be evaluated by the number of DLTs identified at each dose level. The number of DLTs at each dose level will be reported and used to determine the RP2D.

Safety will be evaluated by the number of DLTs identified at each dose level.

AEs are reported by type and grade, and frequency.

Change in measurement; assessed for statistical significance by an appropriate paired test.

Change in measurement of drug levels in blood; assessed for statistical significance by an appropriate paired test.

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Decitabine

Lenograstim

Adjuvants, Immunologic

Immunologic Factors

Antimetabolites

Participants with MDS, AML, AML/MDS, treatment related myeloid neoplasm (tAML/MDS) with either idiopathic disease or inherited bone marrow failure syndrome (iBMF) with standard risk for treatment related toxicities will be enrolled and will undergo study procedures as outlined:

* Cycles 1: Study treatment start must occur 40 - 120 days post allogenic HCT.

  * Day 2 - 6 of 28-day cycle: Predetermined dose of Decitabine.
  * Day 1 - 6 of 28-day cycle: Predetermined dose of Filgrastim.
* Cycles 2 - 6:

  * Day 2 - 6 of 28-day cycle: Predetermined dose of Decitabine.
  * Day 1 - 6 of 28-day cycle: Predetermined dose of Filgrastim.
* Follow up visit every 6 months for 24 months post allogenic HCT.

Participants with MDS, AML, AML/MDS, tAML/MDS with iBMF with increased risk for treatment related toxicities will be enrolled and will undergo study procedures as outlined:

* Cycles 1: Study treatment must occur 40 - 120 days post allogenic HCT.

  * Day 2 - 6 of 28-day cycle: Predetermined dose of Decitabine.
  * Day 1 - 6 of 28-day cycle: Predetermined dose of Filgrastim.
* Cycles 2 - 6:

  * Day 2 - 6 of 28-day cycle: Predetermined dose of Decitabine.
  * Day 1 - 6 of 28-day cycle: Predetermined dose of Filgrastim.
* Follow up visit every 6 months for 24 months post allogenic HCT.

Nucleoside metabolic inhibitor, via IV infusion.

Recombinant granulocyte colony-stimulating factor (G-CSF), via subcutaneous injection.

Filgrastim

Franziska Wachter, MD

Franziska Wachter

The purpose of this study is to examine if it is feasible to administer decitabine and filgrastim after allogenic hematopoietic stem cell transplant (HCT) in children and young adults with myelodysplastic syndrome, acute myeloid leukemia and related myeloid disorders, and if the treatment is effective in preventing relapse after HCT.

The names of the study drugs involved in this study are:

* Decitabine (a nucleoside metabolic inhibitor)
* Filgrastim (a recombinant granulocyte colony-stimulating factor (G-CSF)

This is a single arm, pilot study to determine if sequential cycles of maintenance therapy with decitabine and filgrastim post allogenic hematopoietic cell transplant (HCT) are feasible and effective in preventing relapse after HCT in pediatric and young adult patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and treatment related myeloid malignancies (tAML/MDS) with either idiopathic disease or underlying germline disorders, including a subset that may be at higher risk for toxicity from treatment.

Decitabine in combination with filgrastim after stem cell transplant has been shown to be effective in a large study that included mainly adult patients with acute myeloid leukemia.

The research study procedures include screening for eligibility, study treatment including evaluations and follow up visits and blood tests. Bone marrow biopsies and aspirates will be performed as standard of care.

Participants will receive study treatment for 6 months if tolerated and will be followed for 24 months after stem cell transplant.

It is expected about 37 people will take part in this research study.

This research study is supported by Dana-Farber Cancer Institute philanthropy and institutional grants from the Dana-Farber Cancer Institute and Boston Children's Hospital.

A Pilot Study to Evaluate the Feasibility of Post-Hematopoietic Stem Cell Transplant Prophylaxis With Decitabine Combined With Filgrastim for Children and Young Adults With AML, MDS and Related Myeloid Malignancies

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Feasibility failure relates to decitabine exposure in the setting of post-hematopoietic stem cell transplant (HCT) maintenance and in combination with filgrastim; FFR is defined as the proportion of participants that do not initiate at least 5 of 6 planned cycles and/or receive fewer than 22/30 overall planned decitabine doses during maintenance phase.

EFS based on the Kaplan-Meier method is defined as the time from HCT until evidence of relapse of myelodysplastic syndrome (MDS) or leukemia, or death from any cause. Participants without an event are censored at the date of last follow-up.

OS based on the Kaplan-Meier method is defined as the time from HCT to death or censored at date of last follow-up

Tolerability is based on select adverse events (AE) deemed probably of definitely related to decitabine; TTR is the proportion of participants with grade 4 non-hematologic (NH) AEs except infection and febrile neutropenia, grade 3 NH AEs causing a delay in treatment by \>14 days, and hematologic AEs including ANC\<500 cells/uL or platelet count\<10,000 cells for \>1 week despite supportive care as well as day 28 ANC and platelet target levels or graft failure.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pre-myeloid Cancer and Bone Marrow Failure Clinic Study	NCT02958462	Myeloid Maligna... Inherited Bone ... Clonal Expansio... Cytopenia Bone Marrow Fai... Clonal Cytopeni... Clonal Hematopo... Hematologic Neo... Hematopoietic a... Hereditary Neop... Idiopathic Cyto... Idiopathic Dysp... Low Risk Myelod...	Biospecimen Col... Bone Marrow Bio... Punch Biopsy Buccal Swab Clinical Evalua... Genetic Counsel... Quality-of-Life... Electronic Heal...	18 Years -	Mayo Clinic
Defining the Natural History of Squamous Cell Carcinoma in Fanconi Anemia	NCT05687149	Fanconi Anemia Inherited Bone ...		8 Years -	National Institutes of Health Clinical Center (CC)
Defining the Natural History of Squamous Cell Carcinoma in Fanconi Anemia	NCT05687149	Fanconi Anemia Inherited Bone ...		8 Years -	National Institutes of Health Clinical Center (CC)
Pre-myeloid Cancer and Bone Marrow Failure Clinic Study	NCT02958462	Myeloid Maligna... Inherited Bone ... Clonal Expansio... Cytopenia Bone Marrow Fai... Clonal Cytopeni... Clonal Hematopo... Hematologic Neo... Hematopoietic a... Hereditary Neop... Idiopathic Cyto... Idiopathic Dysp... Low Risk Myelod...	Biospecimen Col... Bone Marrow Bio... Punch Biopsy Buccal Swab Clinical Evalua... Genetic Counsel... Quality-of-Life... Electronic Heal...	18 Years -	Mayo Clinic
Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency	NCT06090669	Inherited Bone ... Familial Platel...	imatinib TruSight Oncolo...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Pilot Study to Evaluate the Feasibility of Post-Hematopoietic Stem Cell Transplant Prophylaxis With Decitabine Combined With Filgrastim for Children and Young Adults With AML, MDS and Related Myeloid Malignancies	NCT05796570	Acute Myeloid L... Myelodysplastic... Myeloid Maligna... MDS Inherited Bone ... Myeloid Neoplas... Aml	Decitabine Filgrastim	1 Year - 39 Years	Dana-Farber Cancer Institute
A Pilot Study to Evaluate the Feasibility of Post-Hematopoietic Stem Cell Transplant Prophylaxis With Decitabine Combined With Filgrastim for Children and Young Adults With AML, MDS and Related Myeloid Malignancies	NCT05796570	Acute Myeloid L... Myelodysplastic... Myeloid Maligna... MDS Inherited Bone ... Myeloid Neoplas... Aml	Decitabine Filgrastim	1 Year - 39 Years	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for inherited bone marrow failure syndrome