Blood and Lymph Conditions

All Conditions

Rare Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Chronic Myeloproliferative Disorders

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Interferons

Interferon-alpha

isabelle Plo, PhD

Léa Durix, MD,PhD

Isabelle Plo, PhD

Léa Durix

Florence Pasquier, MD, PhD

Florence Pasquier, MD,PhD

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are myeloid malignancies resulting from the transformation of a multipotent hematopoietic stem cell (HSC) caused by mutations activating the JAK2/STAT pathway. The most prevalent mutation is JAK2V617F. Type 1 and Type 2 calreticulin (CALR) and thrombopoietin receptor (MPL) mutations are also observed in ET and PMF. Additional non-MPN mutations affecting different pathways are also found, particularly in PMF, and are involved in disease initiation and/or in phenotypic changes and /or disease progression and/or response to therapy.

There is an obvious and urgent need for an efficient therapy for MPN. In particular, PMF remain without curative treatment, except allogeneic HSC transplantation and JAK inhibitors have limited effects on the disease outcome. Among novel therapeutic approaches, Peg-IFNα2a (IFN) is the most efficient harboring both high rates of hematological responses in JAK2V617F and CALRmut MPN patients and some molecular responses mainly in JAK2V617F patients including deep molecular response (DMR). Nevertheless, several studies, including our own, have demonstrated that the IFN molecular response in CALRmut patients is heterogeneous and overall much lower than in JAK2V617F patients. Moreover, some JAK2V617F MPN patients do not respond to IFN, and DMR is only observed in around 20% of JAK2V617F patients. Finally, long-term treatments are needed (2-5 years) to obtain a DMR, jeopardizing its success due to possible long-term toxicity.

The underlying reasons for failure, drug resistance, heterogeneous molecular response in CALRmut patients and the long delays for DMR in JAK2V617F patients remain unclear, largely because the mechanisms by which IFNα targets MPN malignant clones remain elusive.

Significant improvement of IFN efficacy cannot be achieved without basic and clinical research. Hence our two lines of research are to

* Understand how IFNα specifically targets neoplastic HSCs
* Predicting and improving patient response during IFNα therapy

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are myeloid malignancies resulting from the transformation of a multipotent hematopoietic stem cell (HSC) caused by mutations activating the JAK2/STAT pathway. The most prevalent mutation is JAK2V617F. Type 1 and Type 2 calreticulin (CALR) and thrombopoietin receptor (MPL) mutations are also observed in ET and PMF. Additional non-MPN mutations affecting different pathways are also found, particularly in PMF, and are involved in disease initiation and/or in phenotypic changes and /or disease progression and/or response to therapy.

There is an obvious and urgent need for an efficient therapy for MPN. In particular, PMF remain without curative treatment, except allogeneic HSC transplantation and JAK inhibitors have limited effects on the disease outcome. Among novel therapeutic approaches, Peg-IFNα2a (IFN) is the most efficient harboring both high rates of hematological responses in JAK2V617F and CALRmut MPN patients and some molecular responses mainly in JAK2V617F patients including deep molecular response (DMR). Nevertheless, several studies, including our own, have demonstrated that the IFN molecular response in CALRmut patients is heterogeneous and overall much lower than in JAK2V617F patients. Moreover, some JAK2V617F MPN patients do not respond to IFN, and DMR is only observed in around 20% of JAK2V617F patients. Finally, long-term treatments are needed (2-5 years) to obtain a DMR, jeopardizing its success due to possible long-term toxicity.

The underlying reasons for failure, drug resistance, heterogeneous molecular response in CALRmut patients and the long delays for DMR in JAK2V617F patients remain unclear, largely because the mechanisms by which IFNα targets MPN malignant clones remain elusive.

Significant improvement of IFN efficacy cannot be achieved without basic and clinical research. Hence our two lines of research are to

* Understand how IFNα specifically targets neoplastic HSCs
* Predicting and improving patient response during IFNα therapy

The main objective from the basic point of view is to draw the clonal architecture of the mutated cells of the patients during IFN treatment to provide a better understanding of the mechanism of action of IFN in MPN: namely how and at what level of hematopoietic differentiation the IFN specifically targets JAK2V617F HSCs and if and why it does not have the same effect on CALRm patients.

Our previous clinical study using clonal architecture data combined with a mathematical model indicates that depletion of JAK2V617F HSC by differentiation into progenitors and thus loss of self-renewal may be the critical mechanism for eradication of JAK2V617F disease by IFN. We hope to confirm this hypothesis in a larger number of patients and to understand the basis of the differential effects of JAK2V617F and CALRm mutations on disease-initiating stem cells.

The secondary objectives are to:

* Validate the resistance of CALRm patients to IFN treatment in a larger number of patients. Moreover, high IFN doses, in contrast to JAK2V617F patients, are deleterious to the molecular response for reasons that remain to be understood.
* Investigate the role of associated mutations in IFN-induced molecular responses.

IFN treatments have been shown to promote the appearance of clones (JAK2V617F positive or JAK2V617F negative) with additional mutations, such as Tet2 or DNMT3a, which could be responsible for resistance to IFN treatment . We would like to increase the number of patients and their follow-up to analyze the role of these mutations in treatment success. Moreover, these additional mutations (new or selected by the treatment) could favor the development of more severe pathologies (MF, MDS, AML) than PV or TE and would be important to monitor on the follow-up of IFN-treated patients.

-Explore in vitro the effect of IFN in combination with other molecules on primary patients' cells. Indeed, our basic study already showed the involvement of PML in the mechanism of action of IFN and we found that arsenic greatly potentiates the effect of IFN. We will deeply investigate by which exact mechanisms.

All the data will be collected in patients before IFN treatment or during the IFN treatment and data will be collected by single cell genotyping of colonies and/or by single cell RNA sequencing coupled to genotyping of mutations and/or in vitro assays.

Blood will be sampled and fractionated into different types of progenitors based on CD34, CD38 and CD90 markers, granulocytes, platelets,plasma.

The progenitor cells will be single cell sequenced or genotyped. Alternatively the progenitor cells will be cultured in vitro. The DNA and RNA will be extracted from granulocytes and platelets respectively

Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms

Blood samples are processed to separate mature cells (granulocytes) from progenitors (CD34+ marker). Progenitors are isolated and separated by FACS according to their more or less mature CD34+/CD38±/CD90± phenotype and then cultured for 14 days at the single-cell level. The cells resulting from their differentiation in culture are lysed and their DNA is isolated and stored for PCR or NGS analysis in order to define their mutational profile. Once the genotyping of these cells is established, the DNA is destroyed and nothing remains of the initial biological sample.

Blood samples are processed to separate mature cells (granulocytes) from progenitors (CD34+ marker). Progenitors are isolated and subjected to scRNA-seq using long-read techniques (PromethION). The trajectories of hematopoietic differentiation and RNA sequencing will be analyzed in each cell

Blood samples are processed to separate mature cells (granulocytes) from progenitors (CD34+ marker). Progenitors (CD34+) are then cultured in serum free medium with cytokines or in semisolid medium in the presence of IFN alone or in association.

Institut National de la Santé Et de la Recherche Médicale, France

Neoplasms

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Lenograstim

high dose of donor granulocyte colony-stimulating factor（G-CSF）mobilized peripheral blood hematopoietic stem cell are infused to patient received normal chemotherapy

high dose of donor G-CSF mobilized peripheral blood hematopoietic stem cell are infused to patient received normal chemotherapy

hematopoietic stem cell

HUISHENG AI

Huisheng Ai, MD

The purpose of this study is to evaluate the safety and efficiency of high dose allogeneic mismatched hematopoietic stem cells infusions after normal chemotherapy in patients with relapsed/refractory acute myeloid leukemia（AML）.

The relapsed/refractory AML patients will receive IA/DA/MA(I,Idamycin，D，Daunorubicin，M，Mitoxantrone，A，cytosine arabinoside) chemotherapy followed by infusion of high dose allogeneic mismatched hematopoietic stem cells.

no graft-versus-host disease (GVHD) prevention will be conducted before transplantation. Cytokine storm,GVHD snd donor graft will be detected post-transplantation.

High Dose Donor Hematopoietic Stem Cell Infusion for Relapsed/Refractory AML

Treatment of Relapsed/Refractory Acute Myeloblastic Leukemia(AML) by Infusion of Donor High Dose Allogeneic Mismatched Hematopoietic Stem Cells After Chemotherapy

defined as \>= Grade 3 signs/symptoms, laboratory toxicities, and clinical events) that are possibly, likely, or definitely related to study treatment

The Affiliated Hospital of the Chinese Academy of Military Medical Sciences

Immune System Diseases

Hematologic Neoplasms

Graft vs Host Disease

Homologous Wasting Disease

Antirheumatic Agents

Dermatologic Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Cyclosporine

Cyclosporins

Mycophenolic Acid

Busulfan

Thiotepa

Antilymphocyte Serum

All adults patients with hematological malignancies, lacking a HLA matched donor but with a HLA compatible CB unit, fulfilling the inclusion criteria, will undergo to intrabone HSC infusion of CB.

Myeloablative conditioning regimen (MAC):

i.v. Busulfan 12.8 mg/kg, Cyclophosphamide 120 mg/kg, ATG-Fresenius 30 mg/kg

Reduced intensity conditioning regimen (RIC):

Tiothepa 10 mg/kg, Fludarabine 100 mg/kg, Cyclophosphamide 100 mg/kg, ATG-Fresenius 30 mg/kg

GVHD prophylaxis:

Cyclosporine 1 mg/kg since day -7 to +120, Mycophenolate 15 mg kg x 2 since day +1 to +27

Intrabone cord blood infusion

Francesca Bonifazi, MD

The purpose of this study is to evaluate the engraftment of donor hemopoiesis (proportion of transplanted patients with successful engraftment at day +42) in adult patients affected by high risk hematological malignancies after intrabone infusion of cord blood.

For many hematological malignancies, hemopoietic stem cell (HSC) transplant is the only possible treatment. The source of HSC is often bone marrow (BM) or, in the past 10 years, peripheral blood cell (PBSC) mobilized by granulocyte growth factor. Transplant needs a HLA compatible (related or unrelated) donor. Around 10-30% of patients with indication for allogeneic HSC transplant are not able to undergo the procedure because of the lack of a HLA compatible donor. Cord blood (CB) cells represent another possible source, which needs a lower degree of HLA compatibility, this type of transplant, however, offers a lower number of HSC. For this reason, adult patients, until now, could not use this source, because of the not suitable number of cell per kg, of recipient body weight. Recently, in experimental animal models it was observed that intrabone HSC transplant allows, in the recipient, engraftment of donor hemopoiesis by using a 1Log (10-1) lower number of cells compared to the intravenous way (Yahata 2003, Castello 2004). Safety and feasibility of intrabone infusion was verified by two clinical studies on humans: the first was conducted by Ringden O. et al. in 18 patients without any evidence of collateral effects and with complete engraftment of donor hemopoiesis with BM as a source of HSC (Hagglund 1998); the second one was conducted by Frassoni et al. (Frassoni 2008) with CB as the source of HSC.

The aim of this study is to evaluate the intrabone infusion instead of the intravenous one, for the HSC transplant from CB in patients with haematological malignancies when it is not possible to find a HLA matched donor.

We will perform:

* evaluation of the engraftment kinetics;
* evaluation of the chimerism degree at 30, 60, 100 days, 6 months and 1 year after transplant;
* studies on immunological reconstitution and the role of the NK compartment.

Intrabone Infusion of Cord Blood in Adults With Hematological Malignancies

Intrabone Infusion of Cord Blood Hemopoietic Stem Cells in Adult Patients With High Risk Haematological Malignancies.

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Infections

Symptoms and General Pathology

Communicable Diseases

Virus Diseases

Disease Attributes

Antibodies

Immunoglobulins

Antibodies, Blocking

Samira FAFI-KREMER, PharmD

Samira FAFI-KREMER, PharmD, PhD

Catherine PAILLARD, MD, PhD

Aurélie VELAY, MD

François SEVERAC, Statistician

The BK virus (BKV) belongs to the Polyomaviridae family. The primary infection, generally asymptomatic, occurs during childhood. The virus then persists in latent form in the body, mainly in the epithelial cells of the kidney and urinary tract. Cellular immunosuppression favors BKV replication. It is responsible for pathologies of the renal-urinary tract such as BKV-associated nephropathy (BKVAN) in kidney transplant recipients, hemorrhagic cystitis (HC) in hematopoietic stem cell (HSC) recipients or ureteral stenosis.

To date, there is no specific antiviral treatment against BKV. The management of patients is essentially symptomatic and requires a multidisciplinary approach. It is therefore necessary to identify early prognostic markers for the occurrence of CH and to develop new therapeutic strategies.

Role of Neutralizing Antibodies in the Prediction and Treatment of BK Virus Infection in Hematopoietic Stem Cell Allograft Patients at the Pediatric Oncology-hematology Department of the HUS

Role of Neutralizing Antibodies in the Prediction and Treatment of BK Virus Infection in Hematopoietic Stem Cell Allograft Patients at the Pediatric Oncology-hematology Department of the University Hospital of Strasbourg (HUS)

University Hospital, Strasbourg, France

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms	NCT05850273	Myeloproliferat...		18 Years -	Institut National de la Santé Et de la Recherche Médicale, France
High Dose Donor Hematopoietic Stem Cell Infusion for Relapsed/Refractory AML	NCT03080922	Leukemia, Myelo...	hematopoietic s...	15 Years - 85 Years	The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
Intrabone Infusion of Cord Blood in Adults With Hematological Malignancies	NCT00886522	Hematological M...	Intrabone cord ...	18 Years - 65 Years	IRCCS Azienda Ospedaliero-Universitaria di Bologna
Intrabone Infusion of Cord Blood in Adults With Hematological Malignancies	NCT00886522	Hematological M...	Intrabone cord ...	18 Years - 65 Years	IRCCS Azienda Ospedaliero-Universitaria di Bologna
High Dose Donor Hematopoietic Stem Cell Infusion for Relapsed/Refractory AML	NCT03080922	Leukemia, Myelo...	hematopoietic s...	15 Years - 85 Years	The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
Role of Neutralizing Antibodies in the Prediction and Treatment of BK Virus Infection in Hematopoietic Stem Cell Allograft Patients at the Pediatric Oncology-hematology Department of the HUS	NCT05618275	BK Virus Infect...		1 Year - 19 Years	University Hospital, Strasbourg, France
Role of Neutralizing Antibodies in the Prediction and Treatment of BK Virus Infection in Hematopoietic Stem Cell Allograft Patients at the Pediatric Oncology-hematology Department of the HUS	NCT05618275	BK Virus Infect...		1 Year - 19 Years	University Hospital, Strasbourg, France

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