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Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors

Leukemia volume 22, pages 2119–2122 (2008)Cite this article

Partially human leukocyte antigen (HLA)-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT) from haploidentical family, unrelated and cord blood donors, has during recent years become an important and feasible therapeutic option for the almost 50% of patients affected by high-risk hematologic malignancies lacking an HLA-identical sibling donor.1 In these patients, the curative efficacy of allo-HSCT is critically dependent on timely detection of recurrent disease, necessary for undertaking pre-emptive therapeutic measurements, such as down-tapering of immune suppressive drugs or administration of donor lymphocyte infusions (DLI) to promote graft versus leukemia (GvL) activity.2 Tumor-specific molecular markers such as oncogene rearrangements for detection of minimal residual disease (MRD) are only available for approximately 30% of patients.3 For the remaining 70%, the status of host chimerism (HC) after allo-HSCT can be a useful surrogate marker for MRD.4 Currently, the standard reference method for HC analysis is the genomic detection of patient and donor-specific short tandem repeats (STR), a reliable method suitable for quantitative HC analysis with a reported sensitivity of around 5%, which limits its efficacy in the determination of low levels of HC as surrogate marker for MRD.5

To test whether detection of patient-specific HLA alleles by standard genomic typing could increase the sensitivity of HC analysis after allo-HSCT from alternative donors, we first validated hybridization-based PCR sequence-specific oligonucleotide probing (SSO) using the Dynal RELI SSO kit for HLA-A, B, C, DRB, DQB1, and sequence-specific priming (SSP) using the Olerup SSP kit for HLA-DPB1, on a reference standard curve (details on Materials and methods can be viewed in the Supplementary Material). SSO and SSP were shown to have a sensitivity of 1 and 5%, respectively (Supplementary Figure 1 in Supplementary Material and data not shown). Next, we comparatively evaluated HC analysis by STR and HLA typing in bone marrow (BM) follow-up samples of allo-HSCT from alternative, at least one HLA allele-mismatched donors, with a total of 183 and 100 parallel tests for STR and SSO or STR and SSP, respectively. The overall concordance was 81.4% for STR and SSO, and 80% for STR and SSP (Table 1). In 3.3 and 4% of the analyses, respectively, negative results of SSO and SSP contrasted a positive STR. All of these cases were subsequently shown to be false positive STR results, as none of them was followed by a clinical event explaining a positive HC, such as relapse, graft rejection or persistent mixed chimerism (PMC). Conversely, 15.3 and 16% of positive SSO and SSP results, respectively, contrasted a negative STR (Table 1). Overall, 42.9% of these SSO and 12.5% of these SSP results were true positive, as evidenced by subsequent onset of a clinical event explaining a positive HC, such as relapse, graft rejection or PMC (data not shown).

Table 1 Concordance and discordance between HC results obtained by SSO or SSP with the STR reference method
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References

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Authors and Affiliations

  1. Unit of Molecular Immunology of Transplantation, Immunohematology and Transfusion Medicine Service, San Raffaele Scientific Institute, Milano, Italy

    B Mazzi, L Vago, E Sironi, A Palini, S Rossini & K Fleischhauer

  2. Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano, Italy

    T D Clerici, M T Lupo Stanghellini, J Peccatori, M Bernardi, C Bordignon & F Ciceri

  3. Diagnostica e Ricerca S.p.A., San Raffaele Scientific Institute, Milano, Italy

    M Zanussi, P Carrera & M Ferrari

  4. Unit of Genomics for Diagnosis of Human Pathologies, San Raffaele Scientific Institute, Milano, Italy

    P Carrera & M Ferrari

  5. University ‘Vita e Salute San Raffaele’, San Raffaele Scientific Institute, Milano, Italy

    C Bordignon & M Ferrari

  6. Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Milano, Italy

    C Bonini

  7. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET),

    K Fleischhauer

  8. San Raffaele Scientific Institute, Milano, Italy

    K Fleischhauer

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  1. B Mazzi
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  2. T D Clerici
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Corresponding author

Correspondence to F Ciceri.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Mazzi, B., Clerici, T., Zanussi, M. et al. Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors. Leukemia 22, 2119–2122 (2008). https://doi.org/10.1038/leu.2008.98

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