Platelet donor selection for HLA-immunised patients; the impact of donor-specific HLA antibody levels.

BACKGROUND: Approximately 20% of patients with a recurrently poor platelet transfusion increment show human leukocyte antigen (HLA) alloantibodies. The aim of this study was to analyse the impact of mean fluorescence intensity (MFI) levels of donor-specific HLA antibodies and the feasibility of the HLAMatchmaker algorithm in donor selection. STUDY DESIGN AND METHODS: A total of 270 HLA-typed platelet transfusion responses of 40 patients were included in the study. The patients' immunisation status was determined with Luminex-based methods, and HLA alloantibody strengths were defined as the MFI. For the Matchmaker eplet matching, the HLA-ABC Eplet Matching Version 2.1 was used. RESULTS: In 62% of the 270 transfusions, HLA antibodies against the transfused platelets were present, with a median cumulative MFI level of 2026 (range: 299-29 203). In multivariate analysis, a cumulative MFI level higher than 1000 emerged as an independent risk factor for a poor platelet transfusion increment, along with infection and the age of the product. CONCLUSION: The HLAMatchmaker algorithm alone is not a sufficient tool for donor selection. Donor selection based primarily on the levels of donor-specific HLA antibodies is a preferable practice.

Trends in allogeneic haematopoietic cell transplantation for myelofibrosis in Europe between 1995 and 2018: a CMWP of EBMT retrospective analysis.

We performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis between 1995 and 2018 across 278 centres. Activity increased steadily across the four analysed eras (<2006, 2006-2010, 2011-2014 and 2015-2018). Median recipient age increased over time between the earliest and most recent cohort (49.4 years (range, 20.1-68) versus 59.3 years (range, 18.1-78.1). Increasing number of patients with a Karnofsky performance status <90 underwent transplant over time. Increased utilisation of matched unrelated donors was apparent (<2006, 22.5% versus 2015-18, 45.2%; p < 0.001). Decreased use of myeloablative conditioning, increased use of busulphan-based platforms and anti-thymocyte globulin was evident. Of note, rates of acute (a)GVHD grade II-IV by day +100 decreased over time (p = 0.027) as did rates of chronic (c) GVHD, predominantly extensive cGVHD (<2006, 36% (31-41%) versus 2015-18, 23% (21-25%); p = 0.001). Overall, significant factors associated with worse overall survival and non-relapse mortality (NRM) remained older age, use of donors other than matched sibling, recipient CMV seropositivity and a lower Karnofsky performance status (<90). Multivariable analysis demonstrated improvements in overall survival and reductions in relapse risk over time with stable NRM rates despite increasing numbers of older, less fit patients and use of unrelated donors.

Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.

Conflicting HLA assignment by three different typing methods due to the apparent loss of heterozygosity in the MHC region.

Loss of heterozygosity (LOH) has been reported to cause false human leukocyte antigen (HLA) homozygous typing results in pre-transplant patients suffering from haematological malignancies, who in fact are HLA heterozygous. This poses a challenge for histocompatibility testing, as a stem cell graft from a genuinely HLA homozygous donor to a mistyped patient may lead to acute life-threatening graft-vs-host disease. LOH in the HLA region on chromosome 6 is known to be quite common in solid tumours, helping malignant cells to escape T-cell surveillance, but the incidence in haematological malignancies is less well known and the estimates vary. Here we report LOH in the HLA region of five patients with haematological malignancy. We found considerable differences in sensitivity between the three different HLA typing methods used in our laboratory: SSP was clearly the most sensitive method for detecting the lost haplotype, followed by rSSO, while SBT was the least sensitive technique. A subsequent, retrospective genotyping of 65 HLA homozygous haematological patients by SSP method showed no mistyped LOH cases in our laboratory in the past 10 years. The frequency of HLA homozygosity was found to be similar between haematological patients and control groups. It is important for an HLA laboratory to be aware of the differences in various HLA typing techniques' sensitivity for detecting an under-represented haplotype between HLA typing techniques when genotyping patients with haematological diseases. It is advisable for HLA laboratories to have at least two different methods with different sensitivities in their repertoire to be able to retype samples when a false homozygous result is suspected.