Post Transplant High-Dose Cy as GvHD Prophylaxis in 1 HLA Mismatched Unrelated HSCT for Myeloid Malignancies

NCT ID: NCT03270748

Last Updated: 2023-03-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-15
• Study Completion Date: 2022-11-20

Brief Summary

The experimental treatment consists in the application of a therapeutic strategy with post Transplant High-Dose Cyclophosphamide as GvHD Prophylaxis in Patients Receiving 1-Antigen/Allele HLA Mismatched (7/8 matched) Unrelated Hemopoietic Stem Cell Transplantation for Myeloid Malignancies.

Detailed Description

The experimental treatment consists in the application of a therapeutic strategy with post Transplant High-Dose Cyclophosphamide as GvHD Prophylaxis in Patients Receiving 1-Antigen/Allele HLA Mismatched (7/8 matched) Unrelated Hemopoietic Stem Cell Transplantation for Myeloid Malignancies Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for a variety of hematologic malignancies due to two separate components: chemo/radiotherapy administered before the transplant (conditioning regimen) and the presence of immunocompetent cells in the graft, capable of inducing a "graft-versus-malignancy effect" also known as "GvL" effect. However, this immune-reaction usually carries the risk of detrimental effects seen as a multi-organ syndrome known as graft-versus-host disease (GvHD), which remains the most feared complication of Allogeneic hematopoietic stem cell transplantation. GvHD may be given to disparities between donor and recipient in presence of gene mismatches in the Major Histocompatibility Complex, also known as Human Leucocyte Antigen (HLA) system, or in any minor histocompatibility antigen. Thus, GvHD is obviously more common (and possibly more severe) in patients transplanted from HLA-mismatched donors as compared with those receiving grafts from HLA-matched donors.

A major limitation of allo-HSCT is the availability of a donor given that only a small percentage of patients has a HLA identical family donor. For the majority of patients (approximately 70%) who lack a HLA-identical sibling, alternative donors include HLA-matched unrelated donors and cord blood units. The chance of identifying a suitable marrow unrelated donor (MUD) in the international voluntary donor registries is limited by the frequency of a certain HLA genotype in the general population.

One of the alternative options in such cases is the use of a HLA-mismatched unrelated donor (MMUD). HLA-mismatching is defined as the presence of unshared antigens/alleles in recipient-donor pairs for HLA-A, -B, -C or DRB1 loci.

Patients undergoing MUD or MMUD transplants usually receive an intensified three-drug immunosuppressive regimen: anti-thymocyte globulin in addition to the standard platform of a calcineurine-inhibitor and an anti-metabolite.

The effect of HLA mismatches on clinical outcomes has been investigated in several studies. Single HLA mismatches at HLA-A, -B, -C, or -DRB1 locus (7/8 HLA-matched) were associated with lower overall survival and disease free survival, higher non-relapse mortality, and higher incidence of acute GvHD as compared with 8/8 HLA-matched pairs.

Many clinical trials suggest that high-dose Cy administrated after allogeneic HSCT didn't cause prolonged aplasia due toxicity on donor stem cells; could prevent rejection due to HLA-disparity and could be effective in preventing GvHD, allowing adequate immune-reconstitution.

With this study the investigators plan to investigate if post-transplant high-dose Cy, with a calcineurine inhibitor and mycophenolate, could reduce acute GvHD rates and infectious complications improving clinical outcomes of MMUD transplants in patients with acute myeloid leukemia and myelodysplastic syndrome.

Conditions

Myeloid Malignancies

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental

Experimental: Experimental The experimental consists in the application of a therapeutic strategy: post Transplant High-Dose Cyclophosphamide as GvHD Prophylaxis in Patients Receiving 1-Antigen/Allele HLA Mismatched (7/8 matched) Unrelated Hemopoietic Stem Cell Transplantation for Myeloid Malignancies Therapeutic intervention, namely conditioning regimen and GVHD prophylaxis, are based on standard current regimens: Busulfan 0,8 mg/kg 4 times per day during 2 h infusions for 4 consecutive days (from day -6 through day -3) Fludarabine 40 mg/m2 per day for 4 days (from day -6 through day -3); GvHD prophylaxis: Cyclosporine or Tacrolimus beginning day+5 up to at least 100 days. Micofenolate 15mg/kg twice a day from day +5 to +35.

Group Type: EXPERIMENTAL

GvHD prophylaxis

Intervention Type: DRUG

Cyclophosphamide 50 mg/kg intravenously day+3 and +4 (total dose:100 mg/kg).

Interventions

GvHD prophylaxis

Cyclophosphamide 50 mg/kg intravenously day+3 and +4 (total dose:100 mg/kg).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Acute myeloid leukemia in complete remission Myelodysplastic syndrome Indication for allo-HCT No available HLA identical sibling donor or HLA matched unrelated donor Activation of an alternative donor search Presence of a 1 antigen/allele mismatched (7/8 HLA matched) unrelated donor ECOG performance status <2 Written and signed informed consent

Exclusion Criteria

left ventricular ejection fraction < 40% FEV1, FVC, DLCO <50% of predicted LFT > 5 times the upper limit of normal creatinine clearance < 40 ml/min Previous allogeneic Hemopoietic Stem Cell Transplantation

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gruppo Italiano Trapianto di Midollo Osseo

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Annamaria Raiola, MD

Role: PRINCIPAL_INVESTIGATOR

Ospedale Policlinico San Martino-IST

Locations

Azienda Ospedaliera SS Antonio e Biagio

Alessandria, , Italy

Ospedali Riuniti

Ancona, , Italy

Ospedale Moscati

Avellino, , Italy

Policlinico di Bari-Ematologia con trapianti

Bari, , Italy

Divisione di Ematologia - Ospedali Papa Giovanni XXIII

Bergamo, , Italy

Ospedale San Orsola

Bologna, , Italy

Ospedale Regionale Generale- Divisione Ematologia

Bolzano, , Italy

ASST Spedali Civili

Brescia, , Italy

Ospedale Binaghi

Cagliari, , Italy

S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle

Cuneo, , Italy

Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza

Foggia, , Italy

AOU-IRCCS San Martino-IST

Genova, , Italy

Osp. Card. Panico

Lecce, , Italy

AOU Integrata

Mestre, , Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Ospedale Niguarda Ca' Grande

Milan, , Italy

Divisione Ematologia - Azienda Ospedaliera Universitaria - Policlinico -

Modena, , Italy

ASST Ospedale S. Gerardo de' i Tintori - Università degli Studi di Milano

Monza, , Italy

A.O.U. Policlinico Federico II

Napoli, , Italy

Azienda ospedaliera Universitaria di Parma

Parma, , Italy

Fondazione IRCCS San Matteo

Pavia, , Italy

Ospedale G. Da Saliceto di Piacenza

Piacenza, , Italy

Azienda Ospedaliero Universitaria Pisana

Pisa, , Italy

Centro Unico Regionale Trapianti di Midollo Osseo - Ospedale Bianchi-Melacino-Morelli

Reggio Calabria, , Italy

A.O. San Camillo Forlanini

Roma, , Italy

Divisione di Ematologia - Istituto di Semeiotica Medica - Policlinico A. Gemelli

Roma, , Italy

Policlinico Umberto I

Roma, , Italy

Az. Ospedaliera Universitaria Senese - Divisione Ematologia e Trapianti

Siena, , Italy

Ospedale Moscati

Taranto, , Italy

A.O.U. Citta della Salute e della Scienza

Torino, , Italy

Ospedale Gonzaga

Torino, , Italy

A.O. Santa Maria della Misericordia

Udine, , Italy

Ospedale S. Bortolo-Divisione Ematologia

Vicenza, , Italy

Countries

Italy

References

Raiola AM, Bruno B, Risitano AM, Mosna F, Cavattoni IM, Onida F, Saporiti G, Patriarca F, Battista ML, Pavone V, Mele A, Chiusolo P, Sica S, Loteta B, di Grazia C, Carella AM, Salvatore D, Morello E, Leoni A, Giaccone L, Bernasconi P, Terruzzi E, Mordini N, Borghero C, Zallio F, Luppi M, Grassi A, Olivieri A, Piras E, Sacchi N, Ciccone G, Castiglione A, Degrandi E, Angelucci E, Martino M, Bonifazi F. Posttransplant cyclophosphamide as GVHD prophylaxis in patients receiving mismatched unrelated HCT: the PHYLOS trial. Blood Adv. 2025 Apr 22;9(8):1966-1975. doi: 10.1182/bloodadvances.2024015173.

Reference Type: DERIVED

PMID: 39928954 (View on PubMed)

Other Identifiers

GITMO-PHYLOS

Identifier Type: -

Identifier Source: org_study_id