No abstract

Haematopoietic stem cell transplantation was proposed as a treatment strategy just over 60 years ago. Owing to great advances in the field, haematopoietic stem cell transplantation has become an established method for the treatment of many haemato-oncological, immunological and hereditary conditions with the potential of cure. The number of haematopoietic stem cell transplants performed worldwide reached one million by 2012. This review provides an overview of autologous and allogeneic haematopoietic stem cell transplantation including disease indications, the individual steps of the procedure and outcome, and highlights achievements in the treatment of autoimmune diseases. Although autoimmune conditions account for only 1% of indications for autologous haematopoietic stem cell transplant, this is increasingly used to treat high-risk autoimmune diseases. Haematopoietic stem cell transplantation can induce long-term remission by resetting the immune system via eradication of autoreactive immune cells and the generation of a de novo self-tolerant immune system. Data seem most encouraging in multiple sclerosis and systemic sclerosis and it is likely that the number of procedures performed to treat these conditions will rise in the future.

Background: The germline telomerase reverse transcriptase (TERT) rs2736100_C variant was identified as a susceptibility factor for a variety of solid tumors and recently for myeloproliferative neoplasms (MPN).Methods: LightCycler melting curve analysis was applied to detect risk alleles of TERT rs2736100_C and Janus kinase 2 (JAK2) rs12343867_C tagging 46/1 haplotype in 584 BCR-ABL1-negative MPN, 308 acute, and 86 chronic myeloid leukemia (AML and CML) patients and 400 healthy individuals.Results: TERT rs2736100_C showed an increased allele frequency in BCR-ABL1-negative MPN patients compared with controls (62.7%AE2.8% vs. 48.8%AE3.5%, P < 0.0001) regardless of molecular background or disease type, but not in CML or AML. Combined TERT and JAK2 hetero-or homozygosity conferred even higher risk for classic MPN. Common complications (throm-

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) with high mortality rate. We retrospectively studied the frequency, clinical and genetic associations and prognostic effect of TA-TMA, in a total of 425 consecutive adult patients, who underwent allo-HSCT for a malignant haematological condition between 2007 and 2013 at our single centre. TA-TMA developed in 19% of the patients. Unrelated donor type (P o 0.001), acute GvHD grades II-IV (P o0.001), myeloablative conditioning regimens (P = 0.003), tacrolimus-based GvHD prophylaxis (P = 0.003), CMV infection (P = 0.003) and carriership for HLA-DRB1*11 (P = 0.034) were associated with the development of TA-TMA. Survival was adversely affected by the presence of TA-TMA (P o 0.001). Among patients with TA-TMA, the outcome of HLA-DRB1*11 carriers was significantly better compared with non-carriers (P = 0.003). As a new finding, our observations suggest that the presence of HLA-DRB1*11 antigen contributes to the development of TA-TMA and affects the outcome.

The lack of highly effective drugs in many malignancies has prompted scientific interest in the development of alternative treatment strategies. Cellular immunotherapy involving the adoptive transfer of immune cells that potently recognize and eliminate malignantly transformed cells has become a promising new tool in the anticancer armory. Studies suggest that the unique biological properties of umbilical cord blood (UCB) cells could precipitate enhanced anticancer activity; hence, UCB could be an optimal source for immunotherapy with the potential to provide products with 'off-the-shelf' availability. Areas covered: In this review, the authors summarize data on the transfer of naturally occurring or genetically modified UCB cells to treat cancer. The focus within is on the phenotypic and functional differences compared to other sources, the alloreactive and anticancer properties, and manufacturing of these products. Therapies utilizing cytokine-induced killer (CIK) cells, natural killer (NK) cells and chimeric antigen receptor (CAR) T-cells, are discussed. Expert opinion: The cellular immunotherapy field has become a growing, exciting area that has generated much enthusiasm. There is evidence that anticancer immunotherapy with UCB-derived products is feasible and safe; however, considering the limited number of clinical trials using UCB-derived products, further studies are warranted to facilitate translation into clinical practice.

No abstract

SUMMARY Objectives To investigate attrition at the finally selected donor stage among British Bone Marrow Registry (BBMR) donors, all recruited from blood donors. Background The success of searches for unrelated stem cell donors relies on the existence of large international donor registries and the availability of registered donors when matched with a patient. Withdrawal of donors may adversely affect patient outcomes. Materials/Methods Data on 2942 planned donations were analysed to assess donor‐related deferral rates and associated factors. Results Overall, 20·2% of requests were cancelled. Transplant centres activated more than half of the cancellations (52·6%). Donor reasons accounted for 46·7% of cancellations (9·4% of requests), of which 61·7% happened for medical and 38·3% for personal reasons. Medical ineligibility of the donor was associated with increasing age (odds ratio [OR] = 1·36, P = 0·011) and peripheral blood stem cell source (OR = 2·22, P = 0·006), and there was some evidence of association with low blood donation reliability (OR = 1·52, P = 0·054). The blood donor reliability score relates to blood donation, and the score worsens if donors consistently fail to attend a donation session when invited. Withdrawal on personal grounds showed associations with donor age (OR = 1·72, P = 0·017, 30–40 years vs other ages), peripheral blood stem cell source (OR = 2·43, P = 0·010) and low blood donor reliability (OR = 1·94, P = 0·007). Conclusions To our knowledge, this is the first report on all‐cause cancellation at the finally‐selected donor stage for international stem cell donor provision, showing 9·4% donor‐related cancellation rate. Scores associated with blood donation reliability may be useful to predict stem cell donor withdrawal.

We retrospectively analyzed the prognostic impact of Proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression free survival. In proteasomes of individuals with G/G genotype we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase-and trypsin-like activity. 4Abstract Background: Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, an SNP with unknown functional effect, was recently reported to influence response to bortezomib based therapy in follicular lymphoma. Patients and Methods: We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results: On univariate analysis patients carrying the variant G allele showed significantly shorter progression free survival (PFS) with a pattern suggestive of a gene dose effect (PFS 26.4, 22.3,and 16.4 months in C/C, C/G, and G/G patients, respectively, p=0.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (HR 2.29, p<0.001) with a similar trend in C/G carriers (HR 1.33, p=0.097) when compared to the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared to that of C/C carriers, despite the fact that the PSMB1 expression and the proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase-and trypsin-like activity of proteasomes from G/G individuals. Conclusion: Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes which are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanism to cope with the abundance of misfolded proteins.