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

Myeloid Malignancies Clinical Trial

— GITMO-PHYLOS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03270748
• Other study ID #: GITMO-PHYLOS
• Status: Completed
• Phase: Phase 2
• Start date: January 15, 2020
• Est. completion date: November 20, 2022

Study information

• Verified date: March 2023
• Source: Gruppo Italiano Trapianto di Midollo Osseo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: November 20, 2022
• Est. primary completion date: November 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Myeloid Malignancies
• Neoplasms

Intervention

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

Locations

Country	Name	City	State
Italy	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	Milano
Italy	Ospedale Niguarda Ca' Grande	Milano
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

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Trapianto di Midollo Osseo

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	incidence of acute GvHD	cumulative incidence of acute GvHD (grade II-IV) at 100 days post Unrelated Hemopoietic Stem Cell Transplantation	day +100 post-transplant
Secondary	Overall survival	is defined as the time from transplant to the date of death due to any cause or to the last date the patient was known to be alive (censored observation) or to the date of the data cut-off for final analysis	1 year post transplantation
Secondary	GRFS (GvHD free, relapse free survival)	are defined as occurrence of grade III-IV acute GvHD, chronic GvHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause	first 12 months after transplantation
Secondary	chronic graft-versus-host disease	Cumulative incidence and severity of chronic graft-versus-host disease (by NIH criteria)	3 years from transplantation
Secondary	Graft failure	failure a) Primary graft failure is defined as < 5% donor chimerism. Secondary graft failure (graft rejection) is defined as initial recovery followed by neutropenia with <5% donor chimerism. b) Rate of graft rejection and graft failure	day +100 and 1 year after transplantation
Secondary	Haematopoietic Recovery	Time to reach an absolute neutrophil count > 0.5 109/L from day of HSCT. Neutrophil recovery end-point will be defined as the first of 3 consecutive days with an absolute neutrophil count > 0.5 x109/L. Time to reach platelet engraftment, defined as the number of days after HSCT (Day 0) for patients to maintain an un-transfused platelet count of > 20.0 x 109/L.	participants will be followed for the duration of hospital stay, an expected average of 30 days
Secondary	Non Relapse Mortality	The cumulative incidence of Non Relapse Mortality is defined as death due to any other cause than progression of malignancy after allogeneic stem cell transplantation. Cumulative incidence	at 100 days, at 180days and at 1 year from transplantation
Secondary	Relapse and Residual Disease	Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of acute myeloid leukemia or myelodisplastic syndrome consistent with pre-transplant features. Molecular relapse will be defined where available as any evidence of a pre-transplant defined abnormality using conventional cytogenetics or FISH techniques or cytofluorimetric analysis or molecular probes	at 1 year from transplantation
Secondary	Incidence of infectious complications and kinetics of immune-reconstitution	the rate of proven and probable invasive fungal infections and viral reactivation/disease (CMV, HHV6,Adenovirus, EBV). Immune-reconstitution will be evaluated with lymphocyte sub-populations counts (CD3+, CD4+, CD8+, CD16+, CD20+) and IgG, IgA, IgM titer	one year after transplant