Infections

All Conditions

Neoplasms

Blood and Lymph Conditions

Symptoms and General Pathology

Immune System Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Leukemia

Communicable Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Mycoses

Invasive Fungal Infections

Neutropenia

Aspergillosis

Invasive Pulmonary Aspergillosis

Pulmonary Aspergillosis

Lymphoma

Leukemia, Myeloid

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bacterial Infections

Bacterial Infections and Mycoses

Lung Diseases

Lung Diseases, Fungal

Respiratory Tract Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Granulocytopenia

Acute Graft Versus Host Disease

Lymphosarcoma

Anti-Infective Agents

All Drugs and Chemicals

Amphotericin B

Liposomal amphotericin B

Clotrimazole

Miconazole

Antifungal Agents

Amebicides

Antiprotozoal Agents

Antiparasitic Agents

Anti-Bacterial Agents

Drug: AMPHOTERICIN B Dosage form: Abelcet® 5mg/ml administered by inhalation. Dosage: 10 ml (50 mg) for the first week with a frequency twice a week. Dosage: from the second week onwards 5 ml (25 mg) with a frequency of a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.

Duration: 4-5 prophylaxis courses defined as each administration period during a neutropenia period, with a 4-6 weeks length considering the duration of neutropenia.

The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.

AMPHOTERICIN B

Jesus Estella, PhMD

The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive chemotherapy.

In recent years the incidence of invasive fungal infection (IFI) especially when caused by filamentous fungi has increased in patients with haematological malignancies and there exists an international consensus on diagnostic criteria. Despite diagnostic and therapeutic progress, invasive aspergillosis remains a major clinical problem of haematological patients, given the still high mortality rates and the huge economic cost of hospitalization of patients, which is attributable to aspergillosis. In addition to the morbidity and mortality rates, these infections interfere with the chemotherapy treatment plan with the risk of compromising the outcome of the antileukemic treatment.

In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some benefit in haematological patients, however it was not effective in a large multicenter study with neutropenic patients. Based on the outcome of that clinical trial, the use of aerosolised amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a decade. During this time the use of azole agents as drugs of choice for antifungal prophylaxis in high risk patients was consolidated. However, one of the main problems in the use of triazoles with activity against filamentous fungi (itraconazole, voriconazole, posaconazole) is drug-drug interactions due to their CYP3A4 inhibitory activity. One of the most serious interactions is that which occurs with vincristine, used throughout the treatment of acute lymphoblastic leukemia, and which has lead to reports of neurotoxicity due to metabolic inhibition.

ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad spectrum of fungal species, including Aspergillus spp. The active component of ABELCET®, amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action.

Abelcet® is recommended for the intravenous treatment of a broad spectrum of systemic fungal infections in adult patients. Although it has a pediatric indication, there are numerous studies published regarding the safety levels of Abelcet® administered intravenously in children and in haematological adults patients which look very promising. In this context, the working hypothesis proposed in this project is that the administration of aerosolised ABLC for pediatric patients with acute leukemia treated with intensive chemotherapy will be an effective alternative as a prophylaxis of pulmonary fungal infections in these patients.

In the treatment of pediatric patients with haematological malignancies the use of intensive chemotherapy is required, which is immunosuppressive and therefore significantly increases the risk of IFI, especially filamentous fungi. IPA is associated with high mortality (\>50%) in those patients, making it imperative to adopt effective, preventive, prophylactic measures. Drug interactions occur frequently with triazole antifungal drugs; cases of clinically significant interactions with vincristine, an anchor drug in the treatment of the majority of pediatric leukemia, are documented. On the other hand, there are promising data from previous studies regarding the safety and efficacy of the intravenous ABLC formulation (Abelcet®) in the treatment of pediatric patients with fungal infections.

If the working hypothesis is confirmed, the aerosolised ABLC treatment would be an effective, safe and reliable prophylactic option for IPA. It would offer an alternative to the systemic administration of antifungal triazoles without affecting the antileukemic treatment in pediatric patients with AL.

Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia

A Phase II Trial to Evaluate the Safety and Tolerability of Nebulised Amphotericin B Lipid Complex (ABELCET®) in the Prophylaxis of Invasive Pulmonary Aspergillosis During Prolonged Neutropenia in Paediatric Patients With Acute Leukaemia

Anonymized individual data of participants will be shared with Authorities at the end of the Clinical Development Plan by the CTD (Common Technical Document). Results will be published in a scientific publication.

is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each).

The incidence of invasive pulmonary aspergillosis during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with invasive pulmonary aspergillosis and the number of paediatric patients on prophylaxis with Acute Leukaemia (AL) undergoing intensive chemotherapy.

Percentage of deaths related to Invasive Pulmonary Aspergillosis during the prophylactic treatment period with Abelcet® in paediatric patients with Acute Leukaemia undergoing intensive chemotherapy.

Ministry of Health, Spain

Fundació Sant Joan de Déu

Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).

AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.

Amphotericin B (ABELCET®)

Patients fulfilling inclusion criteria and those giving the general informed consent for the study initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).

AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization was 10 ml (50 mg) twice a week for the first week, and then from the second week onwards was reduced to 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count demonstrated to be greater than or equal to 1500 cells/mm3.

>= 3 years to <=18 years

Age, Customized

Sex: Female, Male

caucasian

amerindian

african

gypsies

patients ethnicity percentage : caucasian (84.4%), Amerindian (6.3%), African (3.1%) and gypsies (6.3%).

Race/Ethnicity, Customized

Spain

Region of Enrollment

Rosa Maria morales Palau

Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability

At baseline, none of the 32 pediatric patients with acute leukemia included in the clinical trial had API. During the trial period there were 3 patients who developed API

Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis

Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®.

Overall Study

Syndrome

Graft vs Host Disease

Preleukemia

Myelodysplastic Syndromes

Leukemia, Myelomonocytic, Juvenile

Leukemia, Biphenotypic, Acute

Bone Marrow Diseases

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Homologous Wasting Disease

Acute Leukemia of Ambiguous Lineage

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antineoplastic Agents

Antirheumatic Agents

Gastrointestinal Agents

Cyclophosphamide

Abatacept

Vedolizumab

Calcineurin Inhibitors

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Enzyme Inhibitors

Cyclophosphamide 100 mg/kg/course on the days +3, +4 Abatacept 10 mg/kg/day on the days +5, +14, +28, +45, +60, +90, +120 Vedolizumab 10 mg/kg/day, max. 300 mg on the days -1, +14, +28

GVHD prevention: post-transplantation cyclophosphamide, abatacept, vedolizumab, calcineurin inhibitor

GVHD prevention using a combination of post-transplantation cyclophosphamide in combination with abatacept, vedolizumab and calcineurin inhibitor in children and young adults with hematoloblastosis after myeloablative conditioning regimen with treosulfan/TBI, cyclophosphamide/etoposide, fludarabine after HSCT from matched unrelated and haploidentical donors

Conditioning regimen:

Treosulfan 42 g/m2/course on the days -5, -4, -3 or total body irradiation 12 Gray/course on the days -8, -7, -6 Cyclophosphamide 50 mg/kg/course on the days -3, -2 or Etoposide 60 mg/kg on the days -6, -5 Fludarabine 150 mg/m2/course on the days -6, -5, -4, -3, -2

Prevention of GVHD:

Cyclophosphamide 100 mg/kg/course on the days +3, +4 Abatacept 10 mg/kg/day on the days +5, +14, +28, +45, +60, +90, +120 Vedolizumab 10 mg/kg/day, max. 300 mg on the days -1, +14, +28 Cyclosporine A or Tacrolimus 3 mg/kg/day from -1 to 120 (in case of high risk of relapse: patients with JMML, without of remission o positive MRD after HSCT)/180 days or Ruxolitinib (in case of intolerance to calcineurin inhibitors) 5m/day for patients \<12 years old and 10 mg/day for patients \>12 years old by scheme of CNI.

Donor selection criteria

In case of detection of two or more suitable donors, the choice is made in favor of:

* CMV Compliance
* Sex of donor and recipient
* medical and psychological suitability and desire of the donor
* Compatibility by blood type

Duration of therapy

* 120 days (for patients with high risk of recurrence: positive minimal residual disease before HSCT, non-remission status after HSCT, patients diagnosed with juvenile myelomonocytic leukemia)
* 180 days (for the rest) Time of observation
* follow up during 3 years after HSCT

Criteria for premature stopping of the study

1. The probability of developing acute GVHD II-IV is above 40%, of which III-IV - above 15%
2. The probability of 100-day transplant-associated mortality is higher than 20%. Goal Evaluation Date Intermediate analysis after 1 year from the beginning. The final analysis is scheduled to take place 100 days after the last patient is included.

Data Monitoring and Management

1. Plan of initial examination of the patient

After signing the informed consent and registration, the patient undergoes an examination in accordance with the standard plan of pre-transplantation examination and additional examinations, including:

* Confirmation of remission status, determination of MRD, chimerism according to the protocol 1. Monitoring of donor chimerism in patients with acute leukemia Point Days Lines

  1 +30 day general, CD34
* Only if a relapse of the disease is suspected, cm can be sent to study chimerism:

  * General
  * Chimerism in the sorted MRD fraction 2. Minimal residual disease (MRD) monitoring in patients with ALL +30, +100 days after HSCT - for all patients: MRD (immunophenotyping), Cytogenetics (if it presence)

    + 60, +180 days after HSCT - for patients with MRD + or refractory before HSCT: MRD (immunophenotyping), Cytogenetics (if it presence) 3. Minimal residual disease (MRD) monitoring in patients with AML

    +100 days after HSCT - for all patients: MRD (immunophenotyping), Cytogenetics (if it presence)

    + 30, +180 days after HSCT - for patients with MRD + or refractory before HSCT: MRD (immunophenotyping), Cytogenetics (if it presence)

    4. Biobanking (KM, blood)

In this protocol, in addition to routine post-transplantation monitoring, the following studies are carried out:

• Study of the subpopulation composition of peripheral blood lymphocytes: B-cells: CD19

T-cells:

CD3/4/8/ TCR/gd CD3/4/8/45RA/CCR7 (CD197) CD3/4/31/45RA CD4/25/127

NK-compartment:

CD3/CD56

TCR repertoire:

Analysis multiplicity: +30, +60, +100, +180, +360 day The amount of blood for analysis is 5 ml in a test tube with EDTA.

* Pathogen-specific immunoreconstitution research - ELISPOT method for evaluating the production of gamma-interferon by peripheral blood mononuclears after incubation with microbial antigens. The main antigens studied are (CMV pp65, EBV, Adenovirus (AdvHexon), BK virus) Multiplicity of analysis of recipients: +30, +60, +100, +180, +360. The amount of blood for analysis on +30 days is 10 ml, subsequently - 5 ml in a test tube with EDTA.
* Virological monitoring by PCR weekly:

Blood: CMV, EBV, ADV by PCR method Chair: ADV MONITORING by PCR is carried out up to 100 days after CGSC. The exception is patients with viremia, or receiving immunosuppressive therapy on day 100.

in case of suspected visceral lesion: cerebrospinal fluid / bal / stool / urine / biopsy / other material

* Biobanking Multiplicity: + 30, +60, +100, +180, +360 Blood in a test tube with EDTA, used 2. Toxicity monitoring:
* Diagnosis and therapy of acute GVHD Clinical diagnosis and staging of acute GVHD is carried out in accordance with standard criteria (Appendix No. 3).

When an isolated rash appears, a skin biopsy is mandatory. When a clinic of acute GVHD appears with damage to the upper and lower gastrointestinal tract (nausea, vomiting, enterocolitis), gastroscopy with a biopsy of the gastric mucosa and colonoscopy with a floor biopsy is reokended.

The biopsy material should also be sent for virological examination. Before starting therapy, a consultation is held with the head of the protocol / appointed expert.

• Criteria for prescribing systemic immunosuppressive therapy: Acute GVHD stage I - therapy is not carried out Acute GVHF stage II-IV - methylprednisolone 1-2 mg / kg / day IV The period for assessing the response to first-line therapy: 72 hours, 7 days, 14 days from the start of therapy.

• Criteria for prescribing second-line therapy: progression of manifestations of O.RTPH after 72 hours or no improvement after 7 days or incomplete resolution of clinical and laboratory manifestations after 14 days

• Diagnosis and therapy of chronic GVHD: Diagnosis and staging of chronic GVHD are performed in accordance with THE NIH criteria (Appendix No. 4). Due to the fact that the development of chronic GVHD is one of the main parameters for the evaluation of the study, the diagnosis and staging of chronic GVHD are performed prospectively, monthly from the day +100, using a structured examination in accordance with Appendix No. 2.

Therapy of chronic GVHD is carried out in accordance with the standard adopted in the clinic

Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis

Prospective Pilot Study of the Clinical Efficacy and Safety of the Method for Preventing a Graft-versus-host Disease Through the Agency of Using the Combination of Post-transplantation Cyclophosphamide With Abatacept, Vedolizumab and Calcineurin Inhibitor at Children and Young Adults With Hemoblastosis After Hematopoietic Stem Cell Transplantation From an Unrelated or Haploidentic Donor

Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Leukemia, Myeloid, Acute

Neoplasm, Residual

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Immunomodulating Agents

NK cells infusion after immunosuppressive chemotherapy

NK cells

Roberto M Lemoli, MD

Antonio Curti, MD

AML patients with de-novo or secondary disease with age greater than 18 years not eligible for stem cell transplantation for medical contraindications, lack of donor or lack of stem cells,are eligible. Leukemias other than AML and M3 FAB subtype will be excluded from the study. Immunosuppressive chemotherapy prior to NK cell infusion will include: fludarabine and cyclophosphamide 4g/m2 (Flu/Cy). The therapy will be administered over 6 days on inpatient basis. Haploidentical NK cells will be selected from a steady-state large volume leukapheresis product from a suitable KIR ligand incompatible donor. Donor-recipients pairs will be selected on the basis of known KIR ligands. In particular, haploidentical donors will be included if present at least one allele mismatch at a class I locus among the following ones: HLA-C alleles with Asn77-Lys80, HLA-C alleles with Ser77-Asn80, HLA-Bw4 alleles. Immunomagnetic enrichment of NK cells will follow two subsequent steps: 1) depletion of CD3+ T cells followed by 2) positive selection of CD56+ NK cells. Contaminating CD3+ T cells will be carefully evaluated.

When previously cryproserved NK cells are still available, further re-infusions may be performed, according to PI's evaluation. The number of remaining NK cells must be sufficient for the reinfusion of at least the minimum dose of cells (106/kg). At least two months should elapse between two consecutive infusion procedures.

Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells

University of Bologna

prof. Roberto M. Lemoli

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia	NCT01615809	Invasive Pulmon... Lymphoblastic L... Myeloblastic Le... Lymphoblastic L... Myeloblastic Le...	AMPHOTERICIN B	3 Years - 17 Years	Fundació Sant Joan de Déu
Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis	NCT05515029	Acute Lymphobla... Myeloblastic Le... Biphenotypic Ac... Malignant Lymph... Myelodysplastic... Juvenile Myelom...	GVHD prevention...	1 Day - 21 Years	Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells	NCT00799799	Myeloblastic Le...	NK cells	18 Years -	University of Bologna
Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis	NCT05515029	Acute Lymphobla... Myeloblastic Le... Biphenotypic Ac... Malignant Lymph... Myelodysplastic... Juvenile Myelom...	GVHD prevention...	1 Day - 21 Years	Federal Research Institute of Pediatric Hematology, Oncology and Immunology

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