Clinical trial NCT03270748: Post Transplant High-Dose Cy as GvHD Prophylaxis in 1 HLA Mismatched Unrelated HSCT for Myeloid Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myeloid Malignancies
Keywords: Allogeneic hematopoietic stem cell transplantation
acute graft-versus-host disease
Unrelated donors
Post-transplant cyclophosphamide
Myeloid Malignancies
unrelated hematopoietic cell transplantation
GITMO
Lead sponsor: Gruppo Italiano Trapianto di Midollo Osseo
Sponsor class: OTHER
First posted: 2017-09-01
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: incidence of acute GvHD
timeFrame: day +100 post-transplant
Secondary outcomes:
measure: Overall survival
timeFrame: 1 year post transplantation
measure: GRFS (GvHD free, relapse free survival)
timeFrame: first 12 months after transplantation
measure: chronic graft-versus-host disease
timeFrame: 3 years from transplantation
measure: Graft failure
timeFrame: day +100 and 1 year after transplantation
measure: Haematopoietic Recovery
timeFrame: participants will be followed for the duration of hospital stay, an expected average of 30 days
measure: Non Relapse Mortality
timeFrame: at 100 days, at 180days and at 1 year from transplantation
measure: Relapse and Residual Disease
timeFrame: at 1 year from transplantation
measure: Incidence of infectious complications and kinetics of immune-reconstitution
timeFrame: one year after transplant
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Azienda Ospedaliera SS Antonio e Biagio
city: Ancona
country: Italy
facility: Ospedali Riuniti
city: Avellino
country: Italy
facility: Ospedale Moscati
city: Bari
country: Italy
facility: Policlinico di Bari-Ematologia con trapianti
city: Bergamo
country: Italy
facility: Divisione di Ematologia - Ospedali Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Ospedale San Orsola
city: Bolzano
country: Italy
facility: Ospedale Regionale Generale- Divisione Ematologia
city: Brescia
country: Italy
facility: ASST Spedali Civili
city: Cagliari
country: Italy
facility: Ospedale Binaghi
city: Cuneo
country: Italy
facility: S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
city: Foggia
country: Italy
facility: Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza
city: Genova
country: Italy
facility: AOU-IRCCS San Martino-IST
city: Lecce
country: Italy
facility: Osp. Card. Panico
city: Mestre
country: Italy
facility: AOU Integrata
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Ospedale Niguarda Ca' Grande
city: Modena
country: Italy
facility: Divisione Ematologia - Azienda Ospedaliera Universitaria - Policlinico -
city: Monza
country: Italy
facility: ASST Ospedale S. Gerardo de' i Tintori - Università degli Studi di Milano
city: Napoli
country: Italy
facility: A.O.U. Policlinico Federico II
city: Parma
country: Italy
facility: Azienda ospedaliera Universitaria di Parma
city: Pavia
country: Italy
facility: Fondazione IRCCS San Matteo
city: Piacenza
country: Italy
facility: Ospedale G. Da Saliceto di Piacenza
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Reggio Calabria
country: Italy
facility: Centro Unico Regionale Trapianti di Midollo Osseo - Ospedale Bianchi-Melacino-Morelli
city: Roma
country: Italy
facility: A.O. San Camillo Forlanini
city: Roma
country: Italy
facility: Divisione di Ematologia - Istituto di Semeiotica Medica - Policlinico A. Gemelli
city: Roma
country: Italy
facility: Policlinico Umberto I
city: Siena
country: Italy
facility: Az. Ospedaliera Universitaria Senese - Divisione Ematologia e Trapianti
city: Taranto
country: Italy
facility: Ospedale Moscati
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza
city: Torino
country: Italy
facility: Ospedale Gonzaga
city: Udine
country: Italy
facility: A.O. Santa Maria della Misericordia
city: Vicenza
country: Italy
facility: Ospedale S. Bortolo-Divisione Ematologia
Study officials:
affiliation: Ospedale Policlinico San Martino-IST
name: Annamaria Raiola, MD
role: PRINCIPAL_INVESTIGATOR
References: