Clinical trial NCT02827149: High Resolution Donor Recipient HLA Matching Level in Unrelated HSCT
Official title: High Resolution Donor Recipient HLA Matching Level in Unrelated Hematopoietic Stem Cell Transplantation and Impact on the Transplant Outcome: the Italian Experience
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hematologic Diseases
Keywords: HSCT
high resolution HLA typing
unrelated donor
Lead sponsor: Gruppo Italiano Trapianto di Midollo Osseo
Sponsor class: OTHER
Collaborators: name: Associazione Italiana di Immunogenetica e Biologia dei Trapianti (AIBT)
name: National Marrow Donor Program
name: University of Rome Tor Vergata
First posted: 2016-07-11
Enrollment: 1838
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: PROBABILITY_SAMPLE
Study population: This study will enrol adult patients who received hematopoietic stem cell transplantation (HSCT) from unrelated adult donor between 1° January 2012 and 31 December 2015.

Brief summary: Italian, retrospective, prospective, observational, multicentre, spontaneous, non-interventional, non-pharmacological The study aims to analyze in the national Italian experience

1. The compatibility level selected by the Italian Transplant Centres using an high resolution HLA typing at the start of search process for hematopoietic stem cell transplantation from volunteer unrelated donor
2. The transplant outcomes in terms of Overall Survival, Disease Free Survival, Relapse Rate and Transplant Related Mortality and the correlation with the level of HLA matching pairs of donor/recipient included in the Italian Bone Marrow Donor Registry and Promise registry.
3. The possible identification of allelic mismatching combinations characterized by increased cross-reactivity associated with higher incidence of acute or chronic graft-versus-host disease .
4. The possible identification of combinations of allelic mismatching characterized by higher permissiveness.

Detailed description: Haematopoietic allogeneic stem cell transplantation (HSCT) represents a potentially curative treatment for several haematological disorders, but its application depends on the availability of a suitable donor. Some data show that in US population the likelihood of finding HR 8/8 HLA A, B, C, DRB1 matched donor in NMDP registry is about 75% for white Europeans but only 46% for white patients of Middle Eastern or North African descents. Moreover, this probability decreases for patients belonging to African or Black South/Central American group at 18% and 16%, respectively. Furtherly, recent data have reported a significant improvement in the unrelated donor identification over the years. In particular, they have conducted the unrelated donor searches for 1344 ideal patients in the "Be The Match Registry" database at 2 time points: 2009 and 2012. Their results have shown that 8/8 high resolution HLA match rate (A, B, Cw and DRB1) for White raised from 68% in 2009 to 72% in 2012. Corresponding match rates were 41% to 44% for Hispanic, 44% to 46% for Asian/Pacific Islander), and 27% to 30% for African American/Black race and ethnic groups for 2009 and 2012, respectively. The 2012 10/10 match rates were 67% for White, 38% for Hispanic, 41% for Asian/Pacific Islander, and 23% for African American/Black.

Current available data confer to HLA mismatch (6-7/8) a significant increased risk for grades II to IV and III to IV acute graft versus host disease, chronic graft versus host disease, transplant-related mortality (TRM) and overall mortality compared with HLA-matched cases (8/8). However, it is not yet clear if type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch are associated with overall mortality. In order to improve the outcome of the unrelated HSCT, many efforts are ongoing for identifying permissive and non permissive HLA disparity both for I and II classes HLA. Recently, several authors have highlighted the crucial role of allelic mismatching Cw combinations in supporting GVL/ graft versus host disease effect with a consequent decreased risk of relapse (p\<0.003). On the contrary, Cw disparities as Cw03:03 vs Cw03:04 or Cw07:01 vs Cw07:02 seem to be permissiveness in terms of HSCT clinical outcome. Contemporarily, Japanese meta-analysis on 6967 unrelated HSCT has shown that the presence of HLA-B\*51:01 in the donor/recipient pairs is associated with acute graft versus host disease not only for the strong linkage disequilibrium of HLA-C\*14:02 and -B\*51:01 but also for the effect of HLA-B\*51:01 itself. Based on these data, mismatched HLA-C\*14:02 should be considered a non-permissive HLA-C mismatch in donor selection because it seems to be a potent risk factor for severe acute graft versus host disease and mortality.

Concerning DPB1 HLA loci, an algorithm for non-permissive HLA-DPB1 disparities has been described, based on T-cell alloreactivity patients, with potential clinical implications. To confirm this data, GITMO analysis has reported an increased but similar overall mortality by non-permissive HLADPB1 disparity in 10 of 10 (HR 2.12; CI, 1.23-3.64; P .006) and 9 of 10 allele-matched transplantations (HR 2.21; CI, 1.28-3.80; P .004), both in early-stage and in advanced-stage disease. Additionally, recent data have reported that among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute graft versus host disease and HLA-DPB1 mismatch is associated with decreased relapse. Non-permissive HLA-DPB1 allele mismatch was also associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Based on all these reports, the current suggestions concerning the unrelated donor selection consists of a full matching at HLA-A, -B, -C, and -DRB1 unrelated donor for optimal HSCT survival, and avoiding non-permissive HLA-DPB1 mismatches in otherwise HLA-matched pairs.

In 2009, a previous retrospective Italian analysis, performed on 805 couples, reported that globally there are no differences in terms of outcomes (Overall Survival, Disease Free Survival, Relapse Rate and Transplant Related Mortality and Graft Versus Host Disease) in adult patients with neoplastic diseases transplanted with HLA-matched donor 10/10 or 9/10. However, stratifying patients by stage of disease at transplant, a single HLA incompatibility significantly increases the risk of mortality in patients who received HSCT in early stage whereas this data is not confirmed for patients transplanted in advanced stage of disease. This previous Italian analysis included only 10/10 high-resolution typed pairs from 1999 to 2006, excluding all the others couple without a full HLA typing for avoiding confounding results. According to Italian Bone Marrow Donor Registry standard, extended HR HLA was not a mandatory requirement from 1999 to 2006.

From January 2012, all Italian recipients have been typed with HR-HLA typing at the starting of the unrelated donor search process with a consequent advantage in terms of "non selected population" as object of the present observational trial. Moreover, the larger size of cohort of patients who underwent unrelated HSCT during a smaller study period of 2 years should lead to a more effective analysis including the assessments of permissive and non-permissive I and II class HLA incompatibilities. Finally, in order to give a stronger statistical power to this trial, particular efforts have been drawn in order to recovery data about the graft versus host disease prophylaxis.

Eligibility criteria: Inclusion Criteria:

Haematological disease

Written and signed PROMISE informed consent

Patient undergoing unrelated HSCT

Exclusion Criteria:

Unavailability of HR-HLA pairs typing including at least A, B, C, DRB1 loci

Primary outcomes:
measure: compatibility level
timeFrame: 4 months by Activation of the donor search
measure: Overall survival from transplant
timeFrame: 100 days, 1 year and 2 years from transplant
measure: Disease Free Survival
timeFrame: 100 days, 1 year and 2 years from transplant
measure: Relapse Rate
timeFrame: 100 days, 1 year and 2 years from transplant
measure: Transplant Related Mortality
timeFrame: 100 days, 1 year and 2 years from transplant
Secondary outcomes:
measure: identification of allelic mismatching
timeFrame: 2 years from transplant
measure: identification of allelic mismatching
timeFrame: 2 years from transplant
measure: Acute Graft-versus-Host Disease (aGvHD)
timeFrame: from date of transplant to until the date of first event of aCGVD assessed up to 100 days post transplant]
measure: Chronic Graft-versus-Host Disease (cGvHD)
timeFrame: from day +100 post transplant to until the date of first event to cGVHD assessed up to 2 years post enrolment]
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Azienda Ospedaliera SS Antonio e Biagio
city: Ancona
country: Italy
facility: Clinica di Ematologia - Ospedali Riuniti di Ancona
city: Ascoli Piceno
country: Italy
facility: Ospedale Mazzoni
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: Brescia
country: Italy
facility: AO Spedali Civili di Brescia- USD - TMO Adulti
city: Cagliari
country: Italy
facility: Ospedale Binaghi
city: Catania
country: Italy
facility: Ospedale Ferrarotto - Ematologia
city: Cuneo
country: Italy
facility: S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
city: Firenze
country: Italy
facility: Cattedra di Ematologia - Azienda Ospedaliera di Careggi
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: Milano
country: Italy
facility: Divisione di Ematologia - Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: IEO
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Modena
country: Italy
facility: Divisione Ematologia - Azienda Ospedaliera Universitaria - Policlinico -
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Napoli
country: Italy
facility: A.O.U. Policlinico Federico II
city: Palermo
country: Italy
facility: AO Ospedali Riuniti Villa Sofia - Cervello
city: Palermo
country: Italy
facility: Dipartimento Oncologico La Maddalena
city: Pavia
country: Italy
facility: Fondazione IRCCS San Matteo
city: Pavia
country: Italy
facility: Policlinico San Matteo
city: Perugia
country: Italy
facility: Dip. Medicina Clinica e Sperimentale
city: Pescara
country: Italy
facility: Ospedale Civile
city: Piacenza
country: Italy
facility: Ospedale G. Da Saliceto di Piacenza
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: Cattedra di Ematologia - Policlinico
city: Roma
country: Italy
facility: Divisione di Ematologia - Istituto di Semeiotica Medica - Policlinico A. Gemelli
city: Roma
country: Italy
facility: Policlinico Universitario Tor Vergata
city: Rozzano (MI)
country: Italy
facility: Dipartimento di Oncologia Medica ed Ematologia - Istituto Clinico Humanitas
city: Taranto
country: Italy
facility: Ospedale Moscati
city: Torino
country: Italy
facility: AOU CIttà della Salute e della Scienza
city: Torino
country: Italy
facility: Ospedale Regina Margherita
city: Udine
country: Italy
facility: Clinica Ematologica - AOU Santa Maria Della Misericordia
city: Verona
country: Italy
facility: AOU Integrat
city: Vicenza
country: Italy
facility: Ospedale S. Bortolo-Divisione Ematologia
Study officials:
affiliation: Policlinico Università Tor Vergata - Rome
name: Alessandra Picardi, MD
role: PRINCIPAL_INVESTIGATOR
References: