Irradiation-based Myeloablative Conditioning Followed by Treg/Tcon Immunotherapy in HSCT

Antileukemic Activity of Allogeneic Hematopoietic Stem Cell Transplantation With Fractionated Total Body Irradiation or Total Marrow and Lymph Node Irradiation Followed by Adoptive Immunotherapy With Regulatory and Conventional T Cells

To evaluate if hyper-fractionated TBI or TMLI followed by Treg/Tcon adoptive immunotherapy improve cGvHD/disease free survival after allogeneic HSCT in patients affected by high-risk acute leukemias or other hematologic malignancy where HSCT is indicated.

Study Overview

• Status: Recruiting
• Conditions: Lymphoma; Acute Myeloid Leukemia; Myeloproliferative Disorders; Multiple Myeloma; Acute Lymphoid Leukemia; Other Hematologic Malignant Neoplasms
• Intervention / Treatment: Biological: High dose irradiation conditioning + Treg/Tcon

Detailed Description

Improving cGvHD/disease free survival in patients with high-risk acute leukemias or other hematologic malignancy where HSCT is indicated with the use of a regulatory T cell based protocol. Hyper-fractionated Total Body Irradiation or Total Marrow and Lymphoid Irradiation based conditioning will be followed by the infusion of T regulatory and T conventional cell adoptive immunotherapy and a purified CD34+ hematopoietic stem cell graft. Incidence of Non Relapse Mortality, Relapse, acute Graft versus Host Disease, chronic Graft versus Host Disease, as well as probability of cGvHD/disease free survival will be assessed in patient subpopulations separated according to HLA-matching with the donor (HLA-matched HSCT and HLA-haploidentical HSCT) and type of disease (acute myeloid leukemia, acute lymphoid leukemia, lymphoma, multiple myeloma, myeloproliferative disease, and other).

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mara Merluzzi, MBioTech; Phone Number: +393482200239; Email: maramerluzzi@libero.it
• Study Contact Backup: Name: Antonio Pierini, MD, PhD; Phone Number: +390755784147; Email: antonio.pierini@unipg.it

Study Locations

• Italy
  • PG
    • Perugia, PG, Italy, 06132
      • Recruiting
      • University Of Perugia
      • Contact: Mara Merluzzi, MBioTech; Phone Number: +393482200239; Email: maramerluzzi@libero.it
      • Principal Investigator: Cynthia Aristei, MD
      • Sub-Investigator: Loredana Ruggeri, MD
      • Sub-Investigator: Adelmo Terenzi, MD
      • Sub-Investigator: Simonetta Saldi, MD
      • Contact: Antonio Pierini, MD, PhD; Phone Number: +390755784147; Email: antonio.pierini@unipg.it
      • Principal Investigator: Maurizio Caniglia, MD
      • Sub-Investigator: Alessandra Carotti, MD
      • Sub-Investigator: Franca Falzetti, MD
      • Sub-Investigator: Antonio Pierini, MD
      • Sub-Investigator: Ilaria Capolsini, MD
      • Sub-Investigator: Elena Mastrodicasa, MD
      • Sub-Investigator: Maria Speranza Massei, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• AML and ALL in complete remission and with high-risk of relapse
• AML and ALL primarily chemoresistant or relapsed;
• Chronic Myeloid Leukemia in accelerated or blastic phase;

• Patients affected by

  • Multiple myeloma,
  • Non Hodgkin lymphoma,
  • Hodgkin lymphoma,
  • Chronic myeloproliferative syndrome,
  • Chronic Lymphoid Leukemia,
  • Other Hematological malignancy at high-risk of relapse or detectable disease and where a HSCT is indicated.
• Age <75 years
• ECOG ≤ 2
• Acceptable lung, liver, kidney, and heart function and absence of relevant psichiatric diseases
• Signature of the informed consent

Exclusion Criteria:

• Age >75 years
• ECOG > 2
• Not acceptable lung, liver, kidney, and heart function and presence of relevant psichiatric diseases
• Pregnancy
• No signature of the informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose irradiation conditioning + Treg/Tcon; High dose irradiation based conditioning regimens followed by infusion of donor regulatory and conventional T cells and purified CD34+ hematopoietic stem cell transplantation	Biological: High dose irradiation conditioning + Treg/Tcon; High dose irradiation based conditioning regimens followed by infusion of donor regulatory and conventional T cells and purified CD34+ hematopoietic stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
chronic GvHD/relapse-free survival	To evaluate if irradiation based myeloablative conditioning followed by Treg/Tcon adoptive immunotherapy improve chronic GvHD/relapse-free survival (GRFS) after allogeneic HSCT in patients affected by acute leukemias or other hematologic malignancies where HSCT is indicated. GRFS will be assessed in subgroups of patients separated according to HLA-matching with the donor and type of disease (acute myeloid lekemia, acute lymphoid leukemia, other)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
full donor-type engraftment	neutrophil and platelet engraftment measured by neutrophil counts >500/mmc for 3 consecutive days and platelets count >20000/mmc with 7 consecutive without platelet transfusion	30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative incidence of grades ≥ 2 acute GvHD	cumulative incidence of grades ≥ 2 acute GvHD according to NIH consesus criteria	6 months
cumulative incidence of extensive chronic GvHD	cumulative incidence of extensive chronic GvHD according to revised NIH consesus criteria (Jagasia et al. BBMT 2015)	2 years
cumulative incidence of non-relapse mortality	cumulative incidence of non-relapse mortality, defined as death by any cause in the absence of relapse, as competitive risk versus relapse	2 years
cumulative incidence of relapse	cumulative incidence of relapse, defined as disease recurrence according to marrow morphology, flow cytometry, cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction, as competitive risk versus non-relapse mortality	2 years

Collaborators and Investigators

• Sponsor: University Of Perugia
• Investigators: Principal Investigator: Andrea Velardi, MD, PhD, University Of Perugia

Publications and helpful links

General Publications

• Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, Del Papa B, Zei T, Ostini RI, Cecchini D, Aloisi T, Perruccio K, Ruggeri L, Balucani C, Pierini A, Sportoletti P, Aristei C, Falini B, Reisner Y, Velardi A, Aversa F, Martelli MF. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011 Apr 7;117(14):3921-8. doi: 10.1182/blood-2010-10-311894. Epub 2011 Feb 3.
• Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A, Pierini A, Massei MS, Amico L, Urbani E, Del Papa B, Zei T, Iacucci Ostini R, Cecchini D, Tognellini R, Reisner Y, Aversa F, Falini B, Velardi A. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014 Jul 24;124(4):638-44. doi: 10.1182/blood-2014-03-564401. Epub 2014 Jun 12.
• Pierini A, Ruggeri L, Carotti A, Falzetti F, Saldi S, Terenzi A, Zucchetti C, Ingrosso G, Zei T, Iacucci Ostini R, Piccinelli S, Bonato S, Tricarico S, Mancusi A, Ciardelli S, Limongello R, Merluzzi M, Di Ianni M, Tognellini R, Minelli O, Mecucci C, Martelli MP, Falini B, Martelli MF, Aristei C, Velardi A. Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia. Blood Adv. 2021 Mar 9;5(5):1199-1208. doi: 10.1182/bloodadvances.2020003739.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Anticipated): February 28, 2023
• Study Completion (Anticipated): February 28, 2023

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 4, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 8, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Multiple Myeloma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Myeloproliferative Disorders
• Other Study ID Numbers: 02/14

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No