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

Sponsor

Gruppo Italiano Trapianto di Midollo Osseo (Other)

Overall Status

Recruiting

CT.gov ID

NCT03270748

Collaborator

(none)

Enrollment

Locations

Arm

34.5

Anticipated Duration (Months)

2.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Myeloid Malignancies	Drug: GvHD prophylaxis	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

78 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 15, 2020

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: 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.

Drug: GvHD prophylaxis

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

Outcome Measures

Primary Outcome Measures

incidence of acute GvHD [day +100 post-transplant]
cumulative incidence of acute GvHD (grade II-IV) at 100 days post Unrelated Hemopoietic Stem Cell Transplantation

Secondary Outcome Measures

Overall survival [1 year post transplantation]
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
GRFS (GvHD free, relapse free survival) [first 12 months after transplantation]
are defined as occurrence of grade III-IV acute GvHD, chronic GvHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause
chronic graft-versus-host disease [3 years from transplantation]
Cumulative incidence and severity of chronic graft-versus-host disease (by NIH criteria)
Graft failure [day +100 and 1 year after transplantation]
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
Haematopoietic Recovery [participants will be followed for the duration of hospital stay, an expected average of 30 days]
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.
Non Relapse Mortality [at 100 days, at 180days and at 1 year from transplantation]
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
Relapse and Residual Disease [at 1 year from transplantation]
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
Incidence of infectious complications and kinetics of immune-reconstitution [one year after transplant]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Azienda Ospedaliera SS Antonio e Biagio	Alessandria	Italy
2	Ospedali Riuniti	Ancona	Italy
3	Ospedale Moscati	Avellino	Italy
4	Policlinico di Bari-Ematologia con trapianti	Bari	Italy
5	Divisione di Ematologia - Ospedali Papa Giovanni XXIII	Bergamo	Italy
6	Ospedale San Orsola	Bologna	Italy
7	Ospedale Regionale Generale- Divisione Ematologia	Bolzano	Italy
8	ASST Spedali Civili	Brescia	Italy
9	Ospedale Binaghi	Cagliari	Italy
10	S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle	Cuneo	Italy
11	Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza	Foggia	Italy
12	AOU-IRCCS San Martino-IST	Genova	Italy
13	Osp. Card. Panico	Lecce	Italy
14	AOU Integrata	Mestre	Italy
15	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano	Italy
16	Ospedale Niguarda Ca' Grande	Milano	Italy
17	Divisione Ematologia - Azienda Ospedaliera Universitaria - Policlinico -	Modena	Italy
18	ASST Ospedale S. Gerardo de' i Tintori - Università degli Studi di Milano	Monza	Italy
19	A.O.U. Policlinico Federico II	Napoli	Italy
20	Azienda ospedaliera Universitaria di Parma	Parma	Italy
21	Fondazione IRCCS San Matteo	Pavia	Italy	27100
22	Ospedale G. Da Saliceto di Piacenza	Piacenza	Italy
23	Azienda Ospedaliero Universitaria Pisana	Pisa	Italy
24	Centro Unico Regionale Trapianti di Midollo Osseo - Ospedale Bianchi-Melacino-Morelli	Reggio Calabria	Italy
25	A.O. San Camillo Forlanini	Roma	Italy
26	Divisione di Ematologia - Istituto di Semeiotica Medica - Policlinico A. Gemelli	Roma	Italy
27	Policlinico Umberto I	Roma	Italy
28	Az. Ospedaliera Universitaria Senese - Divisione Ematologia e Trapianti	Siena	Italy
29	Ospedale Moscati	Taranto	Italy
30	A.O.U. Citta della Salute e della Scienza	Torino	Italy
31	Ospedale Gonzaga	Torino	Italy
32	A.O. Santa Maria della Misericordia	Udine	Italy
33	Ospedale S. Bortolo-Divisione Ematologia	Vicenza	Italy