Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

The investigators will analyze the genomic features of clonal dominance and ineffective hematopoiesis in elderly subjects enrolled in two population-based studies: "Health and Anemia" study \[Haematologica 2010;95:1849\], and "Monzino 80-plus" study \[BMC Neurol.2011;11:54, validation cohort\]. Overall in 5000 subjects aged \>65y peripheral blood samples (in some cases collected at different time points) will be available for biological investigations.

The investigators will base on large retrospectove adult MDS population with comprehensive genomic and clinical data available within EuroBloodNet network (data on 3000 patients will be available), to accurately predict clinical outcomes in MDS at individual-patient level.

The investigators plan to define 2 homogenous clinical cohorts (learning and testing cohort at 2:1 ratio) in order to define distinct patterns and genetic groups within MDS and to independently validate their predictive value.

The investigators will analyze MDS patients enrolled in prospective clinical trials conducted within the EuroBloodNet network. Overall 350 patients treated with azacitidine from prospective studies (VidazaAllotrial, RELAZA02 trial, AZA-Ida study, intensive AZA study) will be available for biological investigations to define biomarkers associated with clinical response. Validation of biomarkers will then be performed in an independent cohort including 320 patients (AZA-PLUS trial). In all these studies, biobanking of bone marrow (BM) and peripheral blood (PB) samples has been systematically performed, providing a unique resource to be investigated within this proposal.

Matteo Della Porta, MD

Maria Elena Bicchieri, PhD

Pierre Fenaux, MD

Uwe Platzbecker, MD

Francesc Sole, MD

Rationale Myelodysplastic syndromes (MDS) are rare cancers with unmet medical needs. Study of MDS has been rapidly transformed by genome characterization.

The investigators hypothesize that comprehensive analyses of large patient population will allow to correctly estimate the effect of each mutation on clinical outcomes, and that niche factors and immune dysfunctions may influence the development of MDS, clonal evolution and response to treatments

Aims

1- Investigate gene mutations, niche factors and immune dysfunctions influencing the development of MDS, and define biomarkers for early identification of individuals at risk; 2- Develop prognostic models for MDS patients through integration of comprehensive genomic/clinical information; 3- Define biomarkers to better stratify the individual probability of response to specific treatments

Methods EuroBloodNet, the European Reference Network in rare hematological diseases, will provide a basis for research activities. Study of genomic features of clonal dominance in elderly subjects enrolled in large population-based studies and description of the dynamics of clonal establishment and evolution; study of bone marrow microenvironment to identify immune dysfunctions influencing MDS development. Development of inclusive statistical models to accurately predict clinical outcome at individual level, based on large MDS populations with comprehensive genomic/clinical data. Finally, analysis of mutational screening and immune profiles from patients enrolled in prospective trials, to provide evidence on genetic/immunologic profiles associated with probability of response to specific compounds

Expected results To characterize how clonal hematopoiesis relates to the induction of MDS clinical phenotype, and to test the utility of gene sequencing to detect subjects at risk of developing MDS. To define effective prognostic systems and biomarkers to stratify the individual probability of response to treatment

MDS typically occurs in elderly people and a portion of these subjects evolve into acute myeloid leukemia (AML). The natural history of MDS is highly heterogeneous, and therefore a risk-adapted treatment strategy is mandatory.

The presence of mutations in a given individual has only limited predictive power, as conversion to MDS is rare regardless of mutation status. In addition, in patients with overt MDS, genetic abnormalities explain only a proportion of the total hazard for survival, meaning that a large percentage is still associated with clinical and non-mutational factors. Comprehensive analyses of large patient populations are warranted to correctly estimate the independent effect of each mutation on clinical outcome and response to treatment.

Moreover, environmental factors influencing the development of MDS and the probability of response to specific treatments are to be characterized. They include alterations in the immune system. In this context, a significant association was found between autoimmune disorders and MDS, and activation of the inflammasome may contribute to MDS development

AIMS 1- Investigate gene mutations, niche factors and immune dysfunctions influencing the development of MDS, and define biomarkers for early identification of individuals at risk; 2- Develop prognostic models for MDS patients through integration of comprehensive genomic/clinical information; 3- Define biomarkers to better stratify the individual probability of response to specific treatments

EXPERIMENTAL DESIGN

AIM1

1a) The investigators will analyze the genomic features of clonal dominance and ineffective hematopoiesis in elderly subjects enrolled in different population-based studies.

Peripheral blood samples will be available for biological investigations. A low-cost, high-throughput platform for mutation screening of 72 genes known to be relevant in MDS will be used.

1b) In order to gain further insight into the MDS genetic heterogeneity, the investigators will perform DNA sequencing in hematopoietic progenitors single cells to clarify the clonal architecture of marrow dysplasia in HSC, the dynamics of clonal establishment and expansion during hematopoietic differentiation, and their relationship with the disease phenotype and evolution

1c) In selected elderly individuals, the investigators will study the transcriptome (RNA sequencing) of isolated mesenchymal stromal cells (MSC) and marrow microenvironment (i.e., innate ad adaptive immunity) with the aim to identify niche factors that may influence the development of a MDS phenotype in elderly subjects with clonal hematopoiesis. Moreover, in patients suffering from both MDS and autoimmune disorder, the investigators will analyze immunological parameters. They will be compared with those of patients with MDS but without immune disorder, and patients with immune disorders without MDS

AIM2

In myeloid malignancies, it was shown that large knowledge banks of matched genomic-clinical data can improve clinical decision-making.

In the present project, basing on large MDS populations with comprehensive genomic and clinical data available within EuroBloodNet network (data on \>3000 patients will be available), the investigators will develop inclusive, multistage statistical models (Bayesian network analysis and clustering) to accurately predict clinical outcomes in MDS at individual-patient level. The investigators plan to define 2 homogenous clinical cohorts in order to define distinct patterns and genetic groups within MDS and to independently validate their predictive value. As a research tool, the investigators plan to create a prototype portal within our EuroBloodNet website that allows outcome predictions to be generated based on this data set for user-defined constellations of genomic features and clinical variables. The reliability of this tool on clinical decision making will be tested in a prospective observational trial in the context of EuroBloodNet

AIM3

The investigators will analyze the mutational status and immune landscape associated with response to HMA in MDS patients enrolled in prospective clinical trials conducted within the EuroBloodNet network. Patients treated with azacitidine from prospective studies will be available for biological investigations to define biomarkers associated with clinical response. Validation of biomarkers will then be performed in an independent cohort. In all these studies, biobanking of bone marrow (BM) and peripheral blood (PB) samples has been systematically performed, providing a unique resource to be investigated within this proposal. Data on mutational screening and immune profiles are already available in most patients, and were obtained by comparable methods. For mutation screening, a NGS approach covering key genes involved in myeloid malignancies and the response to HMA was used. For a comprehensive immunological characterization of T lymphocytes, NK cells and ILC cells, standardized flow cytometric protocols were used, which will provide novel insights into frequency, differentiation and activity of these cells in response to therapy. Complementary immunoassays based on Luminex technology will be used to quantify secretory proteins (cytokines, chemokines, growth factors) in BM and PB plasma samples.

An European Platform for Translational Research in Myelodysplastic Syndromes

An Integrated European Platform to Conduct Translational Studies in Myelodysplastic Syndromes Based on the EuroBloodNet Infrastructure

The investigotors will study the prevalence and type of somatic mutations by a low-cost, high-throughput platform including 72 genes, relevant in myeloid neoplasms.

The investigators will study the genes diffentially expressed between cell populations of interest and normal controls

The investigators will define, by innovative bayesian and clustering models, independent clinical and molecular factors associated to the probability of survival and response to specific treatments.

The investigators will analyse by flow-cytometry the frequency of T lymphocytes, NK cells and ILC cells during different disease stages and in response to therapy.

Complementary immunoassays based on Luminex technology will be used to quantify secretory proteins (cytokines, chemokines, growth factors).

Istituto Clinico Humanitas

Anemia

Anemia, Aplastic

Myeloproliferative Disorders

Pancytopenia

Myelodysplastic-Myeloproliferative Diseases

Aplastic Anemia

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Chromosome 5q Deletion

Escalating doses of pacritinib (cohort 1)

Low-risk cohort (cohort 2): Initiated on pacritinib 100 mg BID. After three cycles, pacritinib dose escalated to 200 mg BID, the adult phase II recommended dose, if not in complete remission.High-risk cohort (cohort 3): Initiated on pacritnib 200 mg BID, the adult phase II recommended dose.

Pacritinib will be administered orally on a continuous basis for 28 day cycles without a rest period between cycles. Dose assigned by dose level/phase.

pacritinib

Rosandra N Kaplan, M.D.

National Cancer Institute Referral Office

Background:

Myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are blood disorders that can cause serious complications in children and adults. MDS and MDS/MPN can also progress to acute myeloid leukemia. Treatments for these disorders are risky and not always effective. Better treatments are needed.

Objective:

To test a study drug (pacritinib) in adults and children with MDS or MDS/MPN.

Eligibility:

Children (aged 12 to 17 years) and adults (aged 18 years and older) with MDS or MDS/MPN.

Design:

Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart function. They may have a bone marrow biopsy: An area over the hip will be numbed; a needle will be inserted to remove a sample of soft tissue from inside the hipbone.

Pacritinib is a capsule taken by mouth. All participants will take the study drug 2 times a day, every day, in 28-day cycles. They will write down the date and time they take each capsule. Doctors will assign varying dosages of the drug to different participants.

Participants will have clinic visits each week during cycle 1; every 2 weeks during cycle 2; and gradually increasing to every 3 months after cycle 13. Treatment will continue for up to 8 years.

Bone marrow biopsies, heart tests, and other tests will be repeated at intervals throughout the study. Participants will also fill out questionnaires about their quality of life, the symptoms of their disease, and other topics.

Background:

-Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral cytopenia, ineffective and dysplastic hematopoiesis, and increased risk of progression to acute myeloid leukemia (AML).

-The significant genetic heterogeneity of MDS contributes to the challenges in treatment.

* Targeting the bone marrow microenvironment (BMME) may allow for treatments that bypass the genetic complexity of MDS.
* MDS studies support a role for changes within the BMME and support the emerging concept that interdependency between the MDS clone and diverse cell populations in the BMME contributes to disease pathophysiology.
* CSF1R is a receptor tyrosine kinase involved in myeloid-lineage cell survival, proliferation, and differentiation.
* The presence of CSF1R-expressing cells in the AML BMME has been shown with evidence that these cells support leukemic cells through cytokine secretion, and the ligand for CSF1R, CSF1, has been shown to be increased in peripheral blood and bone marrow of some patients with MDS, together supporting CSF1R inhibition as a plausible therapeutic target in myeloid malignancies.
* IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in patients with MDS, supporting IRAK1 inhibition as a plausible therapeutic target in MDS.
* A small percentage of patients with MDS have activating mutations in JAK2 or FLT3, and in these patients, JAK2 or FLT3 inhibition may allow for direct anti-tumor effect.
* Pacritinib is a multi-kinase inhibitor of CSF1R, IRAK1, JAK2, and FLT3, all of which are of therapeutic interest in MDS as discussed above and has been overall well tolerated in clinical trials and has shown efficacy in the treatment of myelofibrosis.

Objectives:

-Phase I:

* To determine the safety and confirm the recommended phase II dose of pacritinib in participants who are 12-17 years of age with MDS or MDS/MPN (myelodysplastic/myeloproliferative neoplasms).

  -Phase II:
* To determine the efficacy of pacritinib in participants who are \>= 18 years of age with MDS or MDS/MPN, as measured by overall response rate, separately by risk-based cohort.

Eligibility:

-Participants with MDS or MDS/MPN, including therapy-related MDS or MDS/MPN, and MDS or MDS/MPN with germline predisposition, as defined according to the 2016 WHO criteria, 2022 WHO criteria, or 2022 International Consensus Classification

* Age 12-17 years for phase I and age \>= 18 years for phase II
* Participants \>= 18 years of age with higher-risk MDS (HR-MDS) must have resistance to hypomethylating agents as defined as failure to show improvement after at least 4 cycles of treatment (primary resistance) or relapse in participants with initial response to long-term treatment (secondary resistance) OR have intolerance to hypomethylating agents OR have a contraindication to hypomethylating agents
* Participants \>= 18 years of age with LR-MDS must be refractory to OR ineligible to receive standard of care therapies (i.e., erythropoietin-stimulating agents, lenalidomide, luspatercept), and present with one of the following characteristics:

  * Severe neutropenia defined by absolute neutrophils count \<=0.5x10\^9/L without the use of granulocyte colony-stimulating factors
  * Symptomatic anemia defined by hemoglobin 16-week average \<10 g/dL and symptoms that may include fatigue, weakness, reduced exercise tolerance, dyspnea on exertion, palpitations, (orthostatic) hypotension, near syncope and restless legs
  * Thrombocytopenia defined as platelets \<20x10\^9/L or platelets \<50x10\^9/L and a history of clinically relevant non-major or major bleeding according to the ISTH classification
* Participants 12-17 years of age with MDS: must be relapsed/refractory OR ineligible to receive immunosuppressive therapy and hematopoietic stem cell transplantation

  * Ineligibility to receive hematopoietic stem cell transplantation will include participants who are not anticipated to be candidates to receive transplantation within the next 3 months due to medical comorbidities, lack of appropriate donor, or logistical barriers

to transplant

* Participants 12-17 years of age must weigh \>= 35 kg
* Participants with MDS/MPN must be relapsed/refractory (failed a minimum of 1 standard of care therapy) OR ineligible to receive standard of care OR without known life-prolonging therapy options OR have a diagnosis for which no known standard of care exists

Design:

-This study consists of two phases, which will enroll concurrently:

--Phase I: 3 plus 3 dose-escalation of pacritinib in participants 12-17 years of age with two planned dose levels per group: Group 1 = weight 35 kg to \< 50 kg \[DL1 = 100 mg BID, DL2 = 200 mg BID\], Group 2 = weight \>= 50 kg \[DL1 = alternating days of 100 mg

BID and 200 mg BID, DL2 = 200 mg BID\]

--Phase II: activity evaluation of pacritinib in participants \>= 18 years of age, separated into two cohorts:

* Low risk cohort: Initiate on pacritinib 100 mg BID, after completion of 3 cycles, participants will undergo dose escalation to 200 mg BID, the adult phase II recommended dose, unless they meet criteria for complete remission, in which case lower dose pacritinib will be continued without escalation
* High risk cohort: Initiate on pacritinib 200 mg BID, the adult phase II recommended dose

  * In all participants, pacritinib will be administered orally on a continuous basis for cycles of 28 days.

Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms

Phase I/II Trial of Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms

.All IPD recorded in the medical record will be shared with intramural investigators upon request. 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.

Determined by the number of participants with dose-limiting toxicities (DLTs) reported at each dose level studied

Clinical responses evaluated by CBC and bone marrow biopsy/aspirate reported separately by cohort, with a separate 95% confidence interval for each cohort

AUC, half-life, and steady state concentration of pactritinib evaluated separately by dose level using descriptive statistics

Grades and types of toxicity noted for the agent at each dose level, separately by cohort

National Cancer Institute (NCI)

Immune System Diseases

Lymphoma

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Hodgkin Lymphoma

Patients undergo collection of blood samples, complete surveys, and undergo cardiac MRI on study. Patients also have their medical records reviewed.

Biospecimen Collection

Electronic Health Record Review

Magnetic Resonance Imaging

Survey Administration

Site Public Contact

Don E. Eslin

Emily B. Walling

Robert J. Hayashi

Katharine R. Lange

Kara M. Kelly

Ellen K. Chang

Mark A. Ranalli

Susan J. Lindemulder

Jill P. Ginsberg

Jean M. Tersak

Donald T. Beam

Timothy C. Griffin

Robert J Hayashi

This study assesses how blood cell growth patterns (clonal hematopoiesis), relates to heart health or cardiovascular disease (CVD) after treatment in patients with Hodgkin lymphoma. In some patients, cancer treatment at a young age may lead to later complications, including problems with heart health. Checking for blood cell growth patterns called therapy-related clonal hematopoiesis (t-CH) can help predict who might be at risk for heart health problems after Hodgkin lymphoma treatment. If doctors know who may be at greater risk for developing later heart complications, then they can more closely monitor those patients to prevent or detect heart complications early.

PRIMARY OBJECTIVES:

I. To assess the prevalence of participants in AHOD1331 with therapy-related clonal hematopoiesis (t-CH) possessing somatic mutations associated with cardiovascular disease (CVD) which are detected after Hodgkin Lymphoma therapy.

II. To assess participants of AHOD1331 with t-CH for the presence or absence of objective signs of CVD using cardiac magnetic resonance imaging (MRI).

SECONDARY OBJECTIVES:

I. To assess whether participants in AHOD1331 with t-CH expand this population over time and possess objective findings of CVD.

II. To assess whether patients both with and without objective findings of CVD using cardiac MRI possess clinical risk factors for CVD.

EXPLORATORY OBJECTIVES:

I. To assess the prevalence of patients receiving mediastinal radiation who have objective findings of CVD using cardiac MRI, that also possess t-CH with mutations associated with CVD.

II. To assess whether specific patient characteristics and treatment (age, gender, race, dexrazoxane usage, etc.) correlate with a higher incidence of t-CH with mutations associated with CVD.

III. To assess the effects of t-CH on CVD by considering other factors such as patient characteristics and clinical conditions associated with an elevated risk for CVD.

OUTLINE: This is an observational study.

Patients undergo collection of blood samples, complete surveys, and undergo cardiac MRI on study. Patients also have their medical records reviewed.

A Study About How Blood Cell Growth Patterns Relate to Heart Health After Treatment for Hodgkin Lymphoma

Assessment of Clonal Hematopoiesis and Its Relationship to Cardiovascular Disease in Hodgkin Lymphoma Survivors

The outcome is the expansion of the CH, which will be expressed as the variant allele fraction (VAF) (CH verses the total normal DNA in the sample). The VAFs and their exact 90% (Clopper-Pearson) confidence intervals are used to summarize the prevalence and nature of CVD, CH and CH with mutations associated with CVD for patients receiving mediastinal radiation.

The outcome here is the incidence of t-CH with mutation. The specific patient characteristic and treatments (age, gender, race, dexrazoxane usage etc.) will be used to predict the incidence of t-CH with mutation rate. Regression model will be constructed to evaluate the effect of these patient characteristics and treatments on the incidence of t-CH with mutation rate, which will be presented by p-values, coefficients and their confidence intervals.

The outcome is the cardiovascular disease defined by cMRI. This aim is to evaluate the effect of other covariates such as patient characteristics (age, gender, race, etc.) and clinical conditions (radiation treatment with cardiac dosimetry, follow-up duration, etc.) on cardiovascular disease.

The proportions will be compared with one-sided Z-Test with normal approximation and significance level 0.05 for primary.

The proportions of t-CH mutation for patients without CVD after Hodgkin Lymphoma therapy. The proportions will be compared with one-sided Z-Test with normal approximation and significance level 0.05 for primary.

Left Ventricular Ejection Fraction (LVEF), \< 55%

Global Longitudinal Strain (GLS) less negative than -18%

Left Ventricular End Diastolic Volume indexed to body surface are (LVEDVi) \> 85 mL:/meter\^2.

The outcome is the expansion of the CH, which will be expressed as the variant allele fraction (VAF) (CH verses the total normal DNA in the sample). Graphic analysis to reveal the time varying trend in the association between the expansion of CH over time and the presence/worsening of CVD signs and apply generalized estimating equation method (with each patient as cluster unit) to quantify this association while controlling for the potential correlation of repeated measurements within each patient.

The outcome is the presence of CVD. This aim is to determine if there is an association between the presence of CVD and the individual variables constituting the clinical profile, either parametric (e.g., independent t-test, Chi\^2-test, Pearson correlation coefficients) or nonparametric (e.g., Wilcoxon rank sum tests, Spearman's rank correlation coefficients) methods will be applied. Bootstrapping techniques might be used as a method of inference which does not rely on a specific underlying distribution. The statistical significance level will be set to 0.05 and all data analysis will be done using SAS statistical software (version 9.4).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An European Platform for Translational Research in Myelodysplastic Syndromes	NCT04174547	Myelodysplastic...		18 Years -	Istituto Clinico Humanitas
Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms	NCT06303193	Myelodysplastic...	pacritinib	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Study About How Blood Cell Growth Patterns Relate to Heart Health After Treatment for Hodgkin Lymphoma	NCT05705531	Cardiovascular ... Clonal Hematopo... Hodgkin Lymphom...	Biospecimen Col... Electronic Heal... Magnetic Resona... Survey Administ...	7 Years - 40 Years	Children's Oncology Group

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