High Resolution Donor Recipient HLA Matching Level in Unrelated HSCT
Condition: Hematologic Diseases
MeSH terms: Hematologic Diseases
Study type: Observational [Patient Registry]

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.
    

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.
      
Keywords: HSCT; high resolution HLA typing; unrelated donor