Impact of β-Globin Mutations on Outcome of Matched Related Donor Hematopoietic Stem Cell Transplantation for Patients with β-Thalassemia Major

AbstractThe clinical outcome of hematopoietic stem cell transplantation (HSCT) for patients with β-thalassemia major (β-TM) can be affected by several factors. We investigated the influence of β-globin gene mutation in patients with β-TM on the clinical outcome of HSCT and conducted a prospective study of consecutive β-TM patients who underwent allogeneic HSCT at our center. Among 87 included patients, 62 (71%) had homozygous and 25 (29%) had compound heterozygous β-globin gene mutations. Intervening sequence II-1 appeared to be the most common mutation, with an occurrence rate of 33% in β-globin alleles. With a median follow-up of 12 months, the thalassemia-free survival and overall survival probabilities were 83% (standard error, 4%) and 90% (standard error, 3%), respectively. Overall survival was not found to be associated with the β-globin gene mutation status, but thalassemia-free survival was significantly improved in patients with homozygous mutations compared with patients with compound heterozygous mutations in univariate (91.2% versus 64.0%, P = .009) and multivariable (hazard ratio, 3.83; P = .014) analyses. This is the first report on the impact of β-globin mutation status on the outcome of β-TM after allogeneic HSCT and helps to better illustrate the course and prognosis of β-TM after transplantation

CTLA-4 Blockade of Natural Killer Cells Increases Cytotoxicity against Acute Lymphoid Leukaemia Cells Neda

Objective: There is interest in using cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy to treat blood cancers.Unfortunately, patients with acute lymphoblastic leukaemia (ALL) frequently exhibit resistance to treatment and naturalkiller (NK) cell exhaustion. This study aims to increase the cytotoxic potency of natural killer cells by using CTLA-4 toblock the Nalm-6 leukaemia cell line.Materials and Methods: In this experimental study, NK cells were purified from the peripheral blood mononuclear cells(PBMCs) of 10 healthy people and assessed by flow cytometry for purity and viability. The purified cells were activatedovernight at 37°C and 5% CO2 with interleukin-15 (IL-15, 10 ng/ml) followed by evaluation of expressions of CTLA-4,activating and inhibitory receptors, and the release of interferon gamma (IFN-γ) and granzyme B (GZM B). CTLA-4expression on NK cells from recurrent ALL patients was also evaluated. Finally, the cytotoxic activity of NK cells wasassessed after the CTLA-4 blockade.Results: The purity of the isolated cells was 96.58 ± 2.57%. Isolated NK cells activated with IL-15 resulted in significantlyhigher CTLA-4 expression (8.75%, P<0.05). Similarly, CTLA-4 expression on the surface of NK cells from patientswith ALL was higher (7.46%) compared to healthy individuals (1.46%, P<0.05). IL-15 reduced NKG2A expression(P<0.01), and increased expressions of NKP30 (P<0.05) and NKP46 (P<0.01). The activated NK cells released moreIFN-γ (P<0.5) and GZM B (P<0.01) compared to unactivated NK cells. Blockade of CTLA-4 enhanced the NK cellkilling potential against Nalm-6 cells (56.3%, P<0.05); however, IFN-γ and GZM B levels were not statistically differentbetween the blocked and non-blocked groups.Conclusion: Our findings suggest that CTLA-4 blockage of Nalm-6 cells causes an increase in antitumour activity ofNK cells against these cells. Our study also provides evidence for the potential of cancer immunotherapy treatmentusing blocking anti-CTLA-4 mAbs

Strategic priorities for hematopoietic stem cell transplantation in the EMRO region

The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region

Is platelet gel safe enough for neutropenic patients?

Our group recently described a case of life-threatening oral mucositis (OM) following highdose conditioning chemotherapy for peripheral blood stem cell transplantation (PBSCT), which was successfully treated with cord blood platelet gel (CBPG

Evaluation of Candida colonization index, molecular identification, and antifungal susceptibility pattern of Candida species isolated from critically ill pediatric patients: A singlecenter study in Iran

Background and Purpose: Given the high mortality rate of invasive candidiasis inhospitalized pediatric patients, it is crucial to establish a predictive system to achieveearly diagnosis and treatment of patients who are likely to benefit from early antifungal treatment. This study aimed to assess the Candida colonization index, species distribution, and antifungal susceptibility pattern of Candida strains isolated frompediatric patients with high Candida colonization index (CI)Materials and Methods: This study was carried out at the Children’s Medical Center inTehran-Iran. In total, 661 samples were collected from 83 patients. The Candida CI wascalculated according to the descriptions of previous studies. The isolates were identified using polymerase chain reaction-based techniques. The Clinical and Laboratory Standard Institute protocol M60 was used to conduct the antifungal susceptibility test.Results: A colonization index greater than 0.5 was confirmed in 29 cases (58% ofpositive samples) with two children developing candidemia. Candida albicans (n=53,49.5%) was the most common Candida species in patients with CI > 0.5. Except foracute lymphoblastic leukemia, no risk factors were linked to a high index in colonizedchildren (P > 0.05). Twelve isolates (7.01%) were multi-azole resistant with high MICsagainst both isavuconazole and ravuconazole and seven strains (4.09%) wereechinocandins resistant.Conclusion: In pediatric intensive care units, patients are at risk of fungal infection,particularly candidemia. In this study, more than half of the children with positive yeastcultures had CI > 0.5, and 6.8% developed candidemia

Cost and quality issues in establishing hematopoietic cell transplant program in developing countries

The hematopoietic cell transplant (HCT) activity has grown significantly over the past two decades in both developing and developed countries. Many challenges arise in establishing new HCT programs in developing countries, due to scarcity of resources and manpower in expertise in HCT. While cost issues can potentially hinder establishment of new HCT programs in certain regions, the focus on quality and value should be included in the general vision of leadership before establishing an HCT program. The main challenge in most developing countries is the lack of trained/qualified personnel, enormous start-up costs for a tertiary care center, and quality maintenance. Herein, we discuss the main challenges from a cost and quality perspective which occur at initiation of a new HCT program. We give real world examples of two developing countries that have recently started new HCT programs despite significant financial constraints. We also portray recommendations from the Worldwide Network of Blood and Marrow Transplantation for levels of requirements for a new HCT program. We hope that this review will serve as a general guide for new transplant program leadership with respect to the concerns of balancing high quality with concurrently lowering costs

Pediatric Hematopoietic Stem Cell Transplantation

The introduction and evolution of hematopoietic stem cell transplantation (HSCT) could be traced back to 1950s, to the studies on interactions among irradiation, covering spleen and bone marrow from it and injection of bone marrow cells. Today, HSCT is considered a well-established, effective and promising means of therapy for various malignant and non-malignant medical conditions, both in children and adult patients and it is no longer restricted by limited sources of HSCs, donor pools or explicit need for matched family members. Annual number of pediatric HSCTs has been increasing over past two decades and while its growth has become steadier since 2002. Household size and consanguineous marriages in the Middle East means that many pediatric candidates of HSCT can suitable donors among their siblings; however, both of these contributing factors are gradually declining in the region. Iran has been experiencing slower population growth and smaller household sizes since twenty years ago. Hence, according to statements on EMBMT website, Iranian Stem Cell Donor Program (ISCDP) has started its activity in 2010 and has joined Bone Marrow Donors Worldwide (BMDW), in an effort to maximize chances of finding HLA-matched donors in countries in the Eastern Mediterranean Regional Office (EMRO) of World Health Organization (WHO) and beyond. Total body irradiation (TBI) has been used in conditioning from the beginnings of HSCT; however various experiments with non-TBI conditioning regimens have shown an alternative path. Although numerous studies on pediatric HSCT have been published, most patients have had a component of irradiation in their regimens. Long-term detrimental consequences of HSCT, particularly those attributed to TBI, have been continuously studied; endocrine and metabolic abnormalities, growth retardation and short stature and neurocognitive sequel are but a few of these sequel , especially among pediatric recipients. Compared to other studies, non-malignant indications for HSCT constitute a greater proportion of performed HSCTs in Iran; inherited abnormalities of RBCs and thalassemia in particular are responsible for this disparity in part. Keyword:  Hematopoietic Stem Cell, Transplantation

Effect of Anti-CD3/CD28 Dynabeads and Allogeneic PBMCs on Expansion of Anti-MUC1 Chimeric Receptor T Cells

Background and purpose: In recent years, immunotherapy using chimeric antigen receptor T cells (CAR T cells) has been considered as a novel and promising treatment for some diseases, especially cancer. The CAR T cell production is a multi-step, complex, time-consuming, and costly process. One of the most important steps in production of CAR T cells is expansion of these cells at appropriate numbers for injection. Therefore, the aim of this study was to investigate the methods of expansion for human CAR T cells in ex vivo. Materials and methods: In this study, specifically engineered CAR T cells against the MUC1 tumor antigen were prepared. The cells were then treated with rIL-2, anti-CD3/C28 Dynadeads, and allogeneic PBMC (Rapid expansion protocol (REP)) for 14 days. Results: The results showed that using anti-CD3/CD28 antibodies in effective ratios; 1: 1 and 1: 3 (bead: cell) along with (IU100) rIL-2 resulted in a 27.5-fold increase in the number of cells. However, the use of rIL-2 alone or allogeneic PBMC eventually resulted in 4.5-fold increase and 9-fold increase, respectively. Conclusion: Anti-CD3/CD28 in combination with rIL-2 can provide all three signals required for T cell activation and proliferation which can be a suitable alternative to costly and expensive cell proliferation techniques for animal or human CAR T cell studies