Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02827149 |
| Other study ID # |
GITMO-HLA-HR |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2017 |
| Est. completion date |
September 21, 2018 |
Study information
| Verified date |
August 2021 |
| Source |
Gruppo Italiano Trapianto di Midollo Osseo |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial 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.
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.
