Allogeneic Hematopoietic Progenitor Cell Transplantation Research Articles

A Real-World Prevalence Study of Cytomegalovirus Infection and Disease in Allogeneic Hematopoietic Progenitor Cell Transplant Recipients in Prophylaxis With Letermovir

A Real-World Prevalence Study of Cytomegalovirus Infection and Disease in Allogeneic Hematopoietic Progenitor Cell Transplant Recipients in Prophylaxis With Letermovir

Developing an Allogeneic Hematopoietic Progenitor Cell Transplant Service in a Resource-Limited Country: Challenges and Outcomes.

Introduction Allogeneic stem cell transplant has curative potential for many hematological disorders. Building an allogeneic hematopoietic progenitor cell transplant (HPCT) unit requires huge investment, infrastructure, equipment, medical supplies, and training of health care professionals. The key objective of this study is to share our experience of developing an allogeneic HPCT service at our tertiary care cancer hospital in a low-middle-income country. In addition, this study presents the outcomes of the first 30 allogeneic HPCTs done at our center. Methods This retrospective observational study included adult patients 18 years old or older with hematological malignancies who underwent allogeneic HPCT between July 2019 and April 2023 at Shaukat Khanum Memorial Cancer Hospital and Research Centre. Result Of the 30 patients, 24 underwent matched sibling donor (MSD) transplants in which a myeloablative-conditioning regimen (MAC) was used in 19, and a reduced conditioning regimen (RIC) was used in one. Of the six haploidentical-related donor transplants, four received MAC, and two received RIC. The median recipient age at HPCT was 23 and 21 years for MSD and Haplo-related donor transplants, respectively. The median follow-up duration was 12 months (Range: 10 days - 33 months). The overall survival rate at one yearwas 71.3% among all allogeneic stem cell transplant patients, whereas the disease-free survival rate at one yearwas 63.7%. In the acute lymphoblastic leukemia group, the disease-free survival rate at one year post allograft was 51.5%, while in the acute myeloid leukemia group, it was 78.7%. Conclusion This study demonstrates the successful development of an allogeneic bone marrow transplant unit at our hospital despite significant financial constraints. This has allowed us to provide a potentially curative and life-saving treatment to a substantial number of cancer patients. The bone marrow transplant outcomes of this study are comparable to those reported by international bone marrow transplant registries.

Gut microbiome in allogeneic HCT survivors: The insults are gone but the damage lingers.

The gut microbiome is an important regulator of health and disease. The report by Hino et al. suggests that damage to the microbiome, inflicted before and soon after allogeneic haematopoietic progenitor cell transplantation, does not heal by itself, most likely with consequences for late transplantation outcomes. Commentary on: Hino et al. Prolonged gut microbial alterations in post-transplant survivors of allogeneic haematopoietic stem cell transplantation. Br J Haematol 2023;200:725-737.

Cytomegalovirus Reactivation in Patients With Acute Lymphoblastic Leukemia in Non-transplant Setting.

Acute lymphoblastic leukemia is predominately a childhood disease and around two third of cases are of B-cell phenotype. Cytomegalovirus is an important cause of morbidity and mortality in allogeneic hematopoietic progenitor cell transplant; however, it is rare in patients with B-cell acute lymphoblastic leukemia in non-transplant settings. In this study, we evaluated 72 patients of acute precursor (pre) B-cell acute lymphoblastic leukemia at Shaukat Khanum Memorial Cancer Hospital and Research Center, out of which three were positive for Cytomegalovirus.

Successful Desensitization of Severe Alloimmune Platelet Refractoriness and Provision of Permissive Platelet Transfusions with a Novel IgG-Targeted Enzyme Therapeutic

AK and JCS contributed equallyBACKGROUND Alloimmune platelet refractoriness (APR), inadequate response to platelet transfusion secondary to alloantibodies targeting Human Leukocyte Antigens (HLA), affects ~25% of acute myeloid leukemia (AML) patients. For profoundly sensitized thrombocytopenic patients, HLA- or crossmatch-compatible platelet units may be unavailable, increasing the risk of thrombocytopenic hemorrhage. Imlifidase cleaves systemic IgG precluding complement fixation/phagocytosis and has been used to desensitize renal allograft recipients.1 Here we show that desensitization with imlifidase can significantly improve compatible platelet availability in APR and post-hematopoietic stem cell transplant platelet nadir. PATIENT CASE A 43-year-old woman with AML treated with cytarabine and daunorubicin was referred for matched-unrelated donor allogeneic hematopoietic progenitor cell transplantation. Her induction, at an outside institution, was complicated by bilateral retinal and mucosal hemorrhage secondary to APR and profound thrombocytopenia (platelet count to 0/µL). On presentation, her panel reactive antibody (PRA) showed exquisite sensitization (99.9%, i.e. ~99.9% of all donor platelet units predicted incompatible), precluding identification of HLA-compatible platelet units to support the patient through her anticipated platelet nadir. Desensitization included rituximab 375 mg/m2 (transplant D-13 and -6), therapeutic plasma exchange (TPE, D-2 and -1) and FDA-emergency-use-authorized imlifidase 0.25 mg/kg IV (D-1 and D+1). Following imlifidase administration, the number of unacceptable antigens and PRA decreased significantly (Figure) allowing sufficient compatible platelets to be identified and procured. During admission, the patient received 7 total platelet transfusions and experienced no hemorrhage (Table). She was discharged stable, post-platelet engraftment on D+19. STUDY DESIGN With IRB approval, the number of predicted clinically significant alloantibodies (antibodies with ≥ 3000 mean fluorescence intensity, MFI) and PRA (LABScreen single antigen and PRA Class I, One Lambda/ThermoFisher, West Hills, California) were compared at baseline, after rituximab/TPE, and after imlifidase administration. Corrected count increment (CCI) to platelet transfusions administered following imlifidase desensitization was calculated. CCI > 5000 was judged a permissive transfusion. Categorical variables were compared with Chi-squared followed by Fisher's Exact. P < .05 was significant. RESULTS AND CONCLUSION Compared to the baseline, unacceptable antigens (antigens targeted by antibodies at clinically significant levels) decreased significantly after rituximab/TPE (N=53/55 to 44/55 antigens, P = .015) and imlifidase (N = 44/55 to 16/55, P < .0001). PRA did not decrease significantly with rituximab/TPE (99.9 to 99.5%, P = .22) but did following imlifidase (99.5 to 87.2%, P < .0001). Of 7 transfusions given post imlifidase, the median CCI was 6000 (interquartile range: 500-7500), N=5/7 were judged permissive. In summary, the imlifidase-mediated decrease in PRA significantly aided the identification of numerous compatible platelet units for this patient and prevented further thrombocytopenic hemorrhage. Our limited data suggest a potentially novel application of imlifidase for desensitization of highly platelet allo-refractory patients requiring multiple platelet transfusions over a short period. We will perform western blot analysis of antibodies from in vivo samples collected over the treatment course to compare antibody fragmentation over time, as partially cleaved immunoglobulin detected by our microbead-based assays may not be pathologic.2 Additionally, as the patient's initial antibody levels exceeded the range of linearity of the bead-based assay, serial dilution studies of patient serum over the treatment course will more precisely semi-quantitate the true peak antibody levels. REFERENCES 1. Jordan SC, Legendre C, Desai NM, et al. Imlifidase desensitization in crossmatch-positive, highly sensitized kidney transplant recipients: results of an international phase 2 trial (Highdes). Transplantation. 2021;105(8):1808-1817. 2. Bockermann R, Järnum S, Runström A, et al. Imlifidase-generated single-cleaved IgG: implications for transplantation. Transplantation. 2022;106(7):1485-1496. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Blood and Blood Products to Support Allogeneic Hematopoietic Progenitor Cell Transplant Recipients at King Abdulaziz Medical City-Riyadh – Transfusion Medicine Services

Hematopoietic progenitor cell transplant (HPCT) is found throughout the body. HPCT is a set of undifferentiated cells that are capable of indefinite self-renewal and generation of a functional progeny of highly specialized cells. Allogeneic HPCT presents a distinct set of challenges for blood banks and transfusion services. When considering transfusion for an HPCT recipient, one has to take into account not only the complexities associated with the patient's underlying condition, but also potential problems associated with recipient alloantibodies, donor passenger lymphocytes, and the conversion of blood group substance after successful allogeneic HPCT. For an allogeneic HPCT recipient, it is vital that the blood transfusion service keep a detailed record of the donor and recipient's that include donor blood group and antibody screening results and recipient's pre- and posttransplant blood group and antibody screening results. The management of nonidentical and incompatible HPCT requires a unique strategies when major, minor, and bidirectional differences exist which have the potentiality to improve patient outcomes and allow for effective management of the blood and blood products inventory.

Prospective Phase I/II Study of Eltrombopag for the Treatment of Bone Marrow Failure in Fanconi Anemia

Fanconi anemia (FA) is an inherited disorder associated with loss of function mutations in gene members of the FA-BRCA pathway involved in interstrand cross-link DNA damage repair during cell division. Progressive bone marrow failure (BMF) is a primary cause of morbidity and mortality in patients with FA. Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation is the only curative treatment for FA-associated BMF. However, donor availability, graft failure, and FA-specific transplant toxicities remain significant hurdles. Attempts at genetic correction of FA are underway but collection of sufficient numbers of autologous HSPCs is challenging in subjects with advanced BMF. Androgens have been successfully used but side effects often prevent prolonged therapy. The orally bioavailable small molecule mimetic of thrombopoietin, eltrombopag (EPAG), was recently shown to stimulate multipotent long-term repopulating HSPCs in patients with acquired BMF, resulting in persistent trilineage hematopoiesis. EPAG promotes DNA repair (Guenther, Exp Hematol 2019) and maintains HSPCs under inflammatory conditions (Alvarado, Blood 2019), indicating potential relevance in FA. In this study, we investigated whether EPAG may offer a novel therapeutic modality for FA-associated BMF.We have enrolled 10 patients (FANCA, n=9 and FANCC, n=1) to date in a prospective phase I/II study of EPAG in Fanconi anemia (NCT03204188). All subjects received EPAG at an oral daily dose adjusted for age and ethnicity. The primary efficacy endpoint was the proportion of subjects with at least 2-fold increase in marrow cellularity or CD34+ HSPC frequency (marrow response), or clinically significant improvement in peripheral blood (PB) counts at 6 months (blood response). The primary safety endpoint was the global toxicity profile assessed at 6 months using CTCAE criteria. Responders were invited to continue on the extension phase of the study for an additional 3 years.Four of 10 patients have reached the 6-month assessment endpoint, and a pre-specified 3-month interim analysis is available on two additional subjects. A marrow response was observed in all 4 subjects at 6 months. Mean marrow cellularity increased by a factor of 4 (Fig. A/B), and CD34+ HSPC frequency improved 2.5-fold at 6 months relative to pre-treatment values (Fig. C/D). Marrow response criteria were also met in the other two subjects at the 3-month interim assessment. Primary PB response was observed in 2 of 4 patients in one (hemoglobin) or two lineages (hemoglobin and platelets) at 6 months of treatment. Responders continue to receive EPAG at 10 or 25 months with sustained improvements in blood counts and transfusion independence. The subject treated for 25 months recently met response criteria in a third lineage (neutrophils) (Fig. E). Both patients who had a marrow but no PB response are clinically well; one subject (FANCA) underwent an unrelated allogeneic HSPC transplantation one year ago, and the other subject (FANCC) recently entered the extension phase of this study. Unilineage PB response criteria were also met in one of two subjects at the 3-month interim assessment.No drug-related serious adverse events have occurred during EPAG treatment. All patients tolerated the maximum dose of EPAG and no interruption or dose reduction was required for adverse events attributable to EPAG. Patients without transfusional iron overload at study entry developed progressive depletion of iron stores attributable to the known potent iron chelating and mobilizing properties of EPAG. At a median of 3 months after initiating EPAG (range, 1 to 6 months), affected patients initiated daily oral iron supplementation with gradual amelioration of iron store levels. To date, there has been no occurrence of marrow fibrosis, solid malignancies or clonal evolution, defined as abnormalities on standard metaphase analysis of bone marrow or overt clinical transformation to MDS/AML.In sum, treatment with EPAG was associated with increased marrow HSPCs in all subjects and PB responses in a subset of patients with Fanconi anemia. The overall safety profile was favorable. Further follow-up and expansion of the ongoing patient cohort will confirm EPAG's potential as a safe and efficient long-term therapeutic modality for FA-associated BMF. Alternatively, EPAG could also be used safely to boost marrow CD34+ cell numbers prior to autologous gene therapy applications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

For Better or for Worse: COVID-19 Vaccination during or Early after (Immuno-) Chemotherapy or Hematopoietic Progenitor Cell Transplantation

Background: Patients with hematologic conditions have a high mortality rate when infected with SARS-CoV-2 (Williamson, Nature 2020). Protection of this group from severe COVID-19 is therefore important. However, according to available vaccination guidelines, one should consider to postpone vaccination of patients on or early after chemotherapy, hematopoietic progenitor cell transplantation (HCT) or with graft versus host disease, because of anticipated poor efficacy. Based on previous (non-COVID-19) vaccination studies among hematology patients, we hypothesized that a significant group of patients may acquire sufficient protection following COVID-19 vaccination, despite disease and therapy related immunodeficiencies.Methods: We conducted a prospective cohort study with 17 cohorts of hematology patients of particular risk for severe COVID-19 who are considered to have no or limited benefit from vaccination. We evaluated humoral immune responses following 2 doses (28 days apart) of the mRNA-1273 vaccine (Moderna/Spikevax) in 722 patients, at baseline and 28 days after each vaccination as SARS-COV-2 S1- (spike)-specific serum IgG antibody concentrations by bead-based multiplex immune assay. The threshold for adequate antibody response is set at ≥300 binding antibody units (BAU)/ml according to the international WHO standard, and is associated with virus plaque reducing neutralization test titers of ≥40 PRNT 50. This study is registered as EudraCT 2021-001072-41, NL76768.029.21.Results: Patient cohorts and corresponding vaccine responses are depicted in Table 1. Vaccine efficacy, as measured by antibody concentration, 4 weeks after the 2 nd mRNA-1273 vaccination was available for 691 out of 722 participants. The majority of patients (389/691; 56%) obtained an S1 antibody titer that is considered adequate (≥300 BAU/ml). Twenty-nine percent of patients (198/691) did not seroconvert (S1 antibody titer <10 BAU/ml), while the remaining 15% (104/691) did seroconvert but not to sufficient levels (10-300 BAU/ml). Adequate responses were observed in the majority of patients with sickle cell disease using hydroxyurea, chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor therapy, acute myeloid leukemia (AML) on or early after high dose chemotherapy, patients with myeloproliferative disorders on ruxolitinib, patients with multiple myeloma (MM), including those on daratumumab and those early after high-dose melphalan and autologous HCT, patients with untreated chronic lymphocytic leukemia (CLL), and patients with chronic GvHD. Insufficient or absent antibody responses were observed in the majority of AML patients receiving hypomethylating agents, CLL patients on ibrutinib, patients with B-cell non-Hodgkin's Lymphoma (NHL) during or shortly after rituximab-chemotherapy or following BEAM chemotherapy and autologous HCT, allogeneic HCT recipients <6 months after transplantation, and CAR-T cell therapy recipients. However, even in these low-responder groups considerable numbers of patients did mount sufficient antibody titers. In others, titers increased after each of both vaccinations, suggesting that booster vaccination may enhance antibody titers to sufficient levels (Figure 1).Conclusion: Vaccination with mRNA-1273 had significant efficacy in severely immunocompromised hematology patients. Adequate humoral immune responses after two dose vaccination were reached in the majority of patients receiving therapy for sickle cell disease, MPD, MM, CML and AML, in patients early after HCT and in patients with GvHD. We are currently evaluating clinical and immunologic parameters that correlate with sufficient antibody responses, pseudovirus neutralization and SARS-COV-2-specific B and T cell numbers, phenotype and function. Per study design, all participants with absent or insufficient antibody responses (<300 BAU/ml) will receive a booster vaccination 5 months after initial vaccination, and antibody responses to booster vaccinations will be presented as well. Unlike currently available guidelines, COVID-19 vaccination should not be postponed. Moreover, as antibody titers increased after each of both vaccinations, booster vaccination of patients with absent or insufficient antibody responses seems warranted. [Display omitted] DisclosuresMutsaers: AstraZeneca: Research Funding; BMS: Consultancy. Van Meerten: Janssen: Consultancy; Kite, a Gilead Company: Honoraria. Kater: BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nijhof: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Clinical Outcomes of Unrelated Umbilical Cord Blood Graft vs. Haploidentical Donor Transplantation: Critical Issues for an Adequate Comparison.

Unrelated umbilical cord blood (UCB) and haploidentical grafts have been used for allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation in patients without a related or non-related human leukocyte antigen (HLA)-matched donor. The less stringent HLA-matching requirement in both sources raises an important possibility for patients in need of urgent transplantation to treat any hematological disease. Selection of the best alternative donor is a difficult task that will depend on donor criteria, center experience, patient disease conditions, and risk, among others. Most comparisons available in scientific publications between both graft sources are obtained from retrospective analysis in wide time windows and a heterogeneous number of patients, types of disease, disease stages, previous treatments, graft source, conditioning regimen, graft vs. host disease (GVHD) approach, and evaluable endpoints. There is also an evident impact of the economic traits since low-income countries must consider less expensive treatments to satisfy the needs of the patients in the most effective possible path. Therefore, haploidentical transplantation could be an appealing option, even though it has not been completely established if any chronic treatment derived from the procedure could become a higher cost. In Colombia, there is a huge experience in UCB transplantation especially in units of pediatric transplantation where benign indications are more common than in adults. Due to the availability of a public UCB bank and HLA high-resolution typing in Colombia, there is a wider inventory of cord blood donors. Unfortunately, we do not have an unrelated bone marrow donor registry, so UCB is an important source along with haploidentical transplantation to consider in decision-making. This minireview focuses on comparing the main issues associated with the use of both HSCP sources and provides tools for physicians who face the difficult decision between these alternative donor sources.

Safety and Efficacy Trial of Escalation of Plerixafor for Mobilization of CD34+ Hematopoietic Progenitor Cells (HPCs) for Globin Gene Transfer in Patients with Sickle Cell Disease

▪There is presently no curative therapy for SCD other than allogeneic hematopoietic progenitor cell (HPC) transplantation. Incoming trials of autologous gene therapy approaches in patients with sickle cell disease (SCD) include the need of HPCs for gene transduction. However, the use of G-CSF for mobilization of HPCs is contraindicated in this patient population, having resulted in sickle crises and death in some patients.Plerixafor is an inhibitor of the CXCR4 chemokine receptor on HPCs and blocks binding of its ligand, stromal cell-derived factor-1α (SDF-1α). It is FDA-approved at doses of 240 μg/kg subcutaneously in combination with G-CSF for autologous HPC mobilization in non- Hodgkin lymphoma and multiple myeloma patients.We designed a multi center 3+3, phase 1 study of dose escalation of plerixafor for mobilization of HPC in patients with SCD. The primary goal of this trial is to evaluate the safety of, and the optimal dose for the mobilization of HPCs with plerixafor alone. The desired optimal peripheral blood CD34 concentration was set at > 30 cells/μl. Plerixafor was supplied by Sanofi following their approval of the protocol. Because of the ethical considerations, and the risks associated with the mobilization of patients with SCD, the protocol was submitted to, and approved by the FDA; IND 122657. It was registered with ClinicalTrials.gov; identifier: NCT02193191.Fourteen patients with SCD were entered on the study to date, and 13 patients were evaluable. Patients' age was 21-41 years (median 30 years). Patients had a history of SCD complications including vaso-occlusive crises, acute chest syndrome, osteomyelitis, cerebral aneurysm, retinal ischemia, and skin ulcers. Nine patients were on, and 4 patients were off hydroxyurea at the time of accrual on study.Six patients were treated at the first dose level of 80 μg/Kg, three patients at the second dose level of 160 μg/Kg, and to date, four patients at the third dose level of 240 μg/Kg. Two patients developed adverse events of vaso-occlusive crisis, 2 and 4 days following completion of plerixafor at the first and third dose level respectively, requiring increasing the first and third dose cohorts to 6 patients.White blood cell counts (WBC), absolute neutrophil counts (ANC), absolute lymphocyte counts (ALC) (x 10^9/L), CD34+ and CD34+CD38- cell counts were measured at the following time points: 0, 6-12 and 20-24 hours post-treatment with Plerixafor, which allowed to identify the optimal CD34 peak time in SCD patients.The results of peak WBC, ANC and ALC, and fold increase for these counts, as well as CD34+ concentrations (cells/μl), and number of patients achieving a CD34+count > 30 cells/μl are shown in Table 1 for patients at the 3 dose levels. There was a 1.8-2.8 fold increase in WBC and 1.0-2.2 fold increase in ANC at the 3 dose levels, and CD34 concentrations were: 7-132 cells/μl, 27-251 cells/μl and 19-95 cells/μl for the 3 respective dose levels. There were no significant variations in the levels of hemoglobin and platelets.In summary, this is the first trial on the use of plerixafor for HPC mobilization in patients with SCD. Our data in 13 patients support the safety of plerixafor administration at doses of 80, 160 μg/Kg, and 240 μg/Kg, which is especially significant, in view of the prior toxicity associated with G-CSF in this patient population. Plerixafor increased WBC, ANC and ALC to acceptable levels (1.8-2.8 fold), and allowed the mobilization of high numbers of CD34+ cells for 8 of 13 patients treated at the 3 dose levels. This study will allow us to define the optimal conditions for effective globin gene transfer after optimization of lentivirus-mediated globin gene transfer with the TNS9.3.55 vector in an upcoming trial. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinically relevant gene editing in hematopoietic stem cells for the treatment of pyruvate kinase deficiency

Pyruvate kinase deficiency (PKD), an autosomal-recessive disorder, is the main cause of chronic non-spherocytic hemolytic anemia. PKD is caused by mutations in the pyruvate kinase, liver and red blood cell (PKLR) gene, which encodes for the erythroid pyruvate kinase protein (RPK). RPK is implicated in the last step of anaerobic glycolysis in red blood cells (RBCs), responsible for the maintenance of normal erythrocyte ATP levels. The only curative treatment for PKD is allogeneic hematopoietic stem and progenitor cell (HSPC) transplant, associated with a significant morbidity and mortality, especially relevant in PKD patients. Here, we address the correction of PKD through precise gene editing at the PKLR endogenous locus to keep the tight regulation of RPK enzyme during erythropoiesis. We combined CRISPR-Cas9 system and donor recombinant adeno-associated vector (rAAV) delivery to build an efficient, safe, and clinically applicable system to knock in therapeutic sequences at the translation start site of the RPK isoform in human hematopoietic progenitors. Edited human hematopoietic progenitors efficiently reconstituted human hematopoiesis in primary and secondary immunodeficient mice. Erythroid cells derived from edited PKD-HSPCs recovered normal ATP levels, demonstrating the restoration of RPK function in PKD erythropoiesis after gene editing. Our gene-editing strategy may represent a lifelong therapy to correct RPK functionality in RBCs for PKD patients.

RETRACTED ARTICLE: Immunoinformatic mapping of conserved regions of the human adenovirus hexon protein

Human Adenoviruses (HAdVs) are important infectious agents associated with high incidence and morbidity and mortality in immunocompromised patients, such as those undergoing allogeneic hematopoietic progenitor cell transplantation (allo-TCPH). HAdVs belong to the family Adenoviridae, genus Mastadenovirus, and are further classified into seven species (A–G) and 103 genotypes, characterized so far. The HAdV capsid consists mainly of the hexon protein, which has four highly conserved regions (CR1—4) and known for their immunogenic potential, being one of the main targets of the T and B cell-mediated anti-HAdV immune response of the present study was to perform the mapping of potentially immunogenic epitopes, located in the HAdV hexon CRs and to evaluate the HAdV infection in patients undergoing allo-TCPH. To this end, predictions of T and B cell epitopes and IFN-γ induction were performed, considering 101 HAdV genotypes with sequences available in databases. The most conserved and best-classified epitopes were then selected by the prediction programs to perform the molecular docking analysis with HLA alleles of the study population, consisting of nine adult patients undergoing allo-TCPH. It was also carried out the HAdV research by TaqMan real-time polymerase chain reaction (qPCR) in the patient's serum samples. As a result, regions containing overlapping T and B cell epitopes were obtained and, based on immunoinformatics analysis (prediction and molecular docking), two peptides with high conservation and immunogenic potential were designed. Nine patients were positive for HAdV by qPCR TaqMan, with the average viral load found in the serum samples of the study population being 6.71 × 1011 CG / mL. The genomic sequencing of the positive samples returned sequences that showed 100% similarity with sequences of the hexad protein of HAdV C, deposited in a database. The present study allowed the mapping of the main immunogenic regions located in the HAdV hexon CRs, as well as the construction of two peptides that will be used in future studies to assess the immune response of patients undergoing allo-TCPH, participants in the present study.

Perspectives on establishing a public cord blood inventory in South Africa

The South African population is highly diverse, both ethnically and genetically. This diversity is particularly true for the African ancestry and various mixed ancestry population groups. These groups are under-represented in national and international bone marrow and peripheral blood donor registries, making it challenging to identify HLA-matched and mismatched unrelated donors when patients from these groups require allogeneic hematopoietic stem and progenitor cell transplantation. In most high-income countries, banked cord blood (CB) units provide an attractive source of hematopoietic progenitor cells for genetically diverse populations. SA does not have a public CB inventory, leaving many patients without access to this important treatment modality. Haploidentical transplantation provides an alternative. In recent years, the use of post-transplant cyclophosphamide has significantly reduced the incidence of graft-versus-host disease after haploidentical transplantation and has improved transplantation outcomes. However, it is difficult to identify suitable haploidentical donors in SA because of family disruption and a high prevalence of HIV. Here the authors provide a brief historical overview of the ethnic and genetic diversity of the country and region. The authors provide a southern African perspective on HLA diversity, consider the allogeneic hematopoietic stem and progenitor cell transplantation landscape and explore the need to establish a public CB bank (CBB) in SA. The health policy and regulatory frameworks that will impact on a CBB in the country SA are also explored. Finally, the authors discuss several matters we believe require attention when considering the establishment of a sustainable public CBB in the South African context.

460 - Health Related and Functional Outcomes for Infants Diagnosed with High Risk Acute Lymphoblastic Leukemia (ALL) Prior to Six Months of Age Who Undergo a Single Allogeneic Hematopoietic Progenitor Cell Transplant (HPCT) with a Total Body Irradiation (TBI) Conditioning Regimen Prior to Two Years of Age

460 - Health Related and Functional Outcomes for Infants Diagnosed with High Risk Acute Lymphoblastic Leukemia (ALL) Prior to Six Months of Age Who Undergo a Single Allogeneic Hematopoietic Progenitor Cell Transplant (HPCT) with a Total Body Irradiation (TBI) Conditioning Regimen Prior to Two Years of Age

Síndromes linfoproliferativos

Lymphoproliferative syndromes are hematologic neoplasms that have the common trait of clonal proliferation of lymphoid cells. They can be of B-cell or T-cell origin. All have proto-oncogenic and/or suppressor gene abnormalities that give tumor clone cells an advantage in terms of proliferation. Each lymphoproliferative syndrome has specific immunophenotypic and morphological characteristics. Therefore, to establish a certain diagnosis, it is necessary to perform a morphological, immunological, and molecular study in peripheral blood and/or the affected tissue. There are various therapeutic options that depend on the patient's comorbidity, the stage of the disease, and molecular alterations. Options include immunotherapy, a combination of immunochemotherapy, or even an allogeneic hematopoietic progenitor cell transplantation.

MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.

Bone marrow failure (BMF) in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGF-β pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow.

Nutrition support during allogeneic stem cell transplantation: evidence versus practice.

Enteral (EN) or parenteral nutrition (PN) is frequently required during allogeneic haematopoietic progenitor cell transplantation (HPCT), however there is limited consensus on the appropriate mode and timing of nutrition support commencement. This study aimed to investigate current nutrition support practices in Australian allogeneic transplant units and explore barriers and enablers to the use of EN and PN. All Australian adult allogeneic HPCT units were eligible to participate. A survey tool was developed, and phone interview with each unit dietitian was completed to explore current nutrition support and perceived barriers and enablers to provision of nutrition care. A total of 12 (100%) units agreed to participate. Six (50%) units reported using PN as standard care and six use EN routinely for one or more conditioning regimens. All units using EN place feeding tubes proactively with tolerance of EN reported at 50-95%. The most frequently reported barriers to the use of EN include perception of poor EN tolerance, medical team preference for PN, gastrointestinal symptoms and thrombocytopenia. Reported barriers to the use of PN include fluid overload, elevated liver enzymes, patient apprehension about PN commencement, medical team uncertainty if PN is required and patients approaching engraftment. There is wide variation in the mode and timing of nutrition support provided to patients undergoing allogeneic HPCT. Clinical guidelines should be updated to reflect recent findings on EN use and incorporate strategies to optimise EN tolerance. This will assist in standardising practice and facilitate evidence-based nutrition care.

Tolerability of proactive enteral nutrition post allogeneic haematopoietic progenitor cell transplant: A randomised comparison to standard care

Nutrition support is an important component of care to prevent malnutrition during allogeneic haematopoietic progenitor cell transplantation (HPCT) however there is no consensus on the optimal method of nutrition support. It is currently unclear whether enteral nutrition (EN) via nasogastric (NG) feeding is tolerated and improves clinical outcomes in comparison with parenteral nutrition (PN). This randomised study aimed to determine the tolerability and outcomes of proactive EN in comparison to PN (standard care). Patients aged ≥18 years undergoing allogeneic transplantation with reduced intensity (fludarabine/melphalan) or myeloablative (cyclophosphamide/TBI) conditioning at a tertiary Australian hospital were eligible to participate. Patients were recruited pre-transplant and randomised to proactive enteral nutrition (EN) or standard care. The EN group underwent NG tube insertion the day after stem cell infusion with feeding commenced at 30ml/h. Rate of feeding was increased to goal as oral intake declined. If patients were intolerant to NG feeding they were changed to PN if required. The standard care group commenced PN when oral intake was ≤60% of requirements for three days and was unlikely to improve for at least another week as per standard unit protocol. The primary endpoint was tolerance of EN. Forty-four patients, (median age [Q1-Q3]: 52 [38-59], 25 male, 19 female) were recruited and randomised to EN (n=22) or standard care (n=22). In the EN group eleven tolerated EN (55%), nine changed to PN and two withdrew from study. The median (Q1-Q3) duration of NG feeding was nine days (4-13) and this provided 86% of goal nutrition. In the standard care group 68% required PN, the median duration was nine days (0-17) and patients met 97% of goal nutrition. There were no statistically significant differences between groups for any clinical outcomes or grade 3-4 (CTCAE version 4) complications. Half of patients receiving allogeneic transplantation tolerate EN when commenced early post-conditioning. As the use of proactive EN will reduce the use of PN (and associated costs and risks), it should be considered first line nutritional support. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) trial number ACTRN12615000284561.

Hematopoietic stem progenitor cells prevent chronic stress-induced Tregs expansion in an IL12-dependent manner

Abstract Physical or psychological chronic stress induces the expansion of regulatory T cells (Tregs) to contribute to immunosuppression. However, the mechanisms remain to be defined. Recent studies from us and others have shown that hematopoietic stem progenitor cells (HSPCs) significantly modulate the immune system. Since allogeneic hematopoietic stem progenitor cell transplantation contributes to chronic graft-versus-host disease (cGVHD), but attenuation of cGvHD is associated with increased frequency of Treg. We hypothesized that HSPCs prevented the over-expansion of Tregs induced by chronic restraint stress to alleviate immunosuppression. Here we demonstrate that administration of HSPCs prevent Tregs expansion and alleviate the suppressive activity of Tregs following chronic stress. Moreover, we found this protective effect is dependent on IL-12. IL-12/STAT4 signal provides a critical role against the expansion of Tregs in chronic stress. When neutralizing antibody against IL-12 or treatment with selective STAT4 inhibitor was co-administered with HSPCs in chronic stressed mice, the protective effect of HSPCs was abrogated. Additionally, HSPCs treatment promotes IL-12 production by splenocytes in chronic stressed mice. These results suggest that HSPCs can prevent chronic stress-induced Tregs expansion in an IL-12-dependent manner, which might offer a novel strategy against immunosuppression.

The Role of Stem Cells on the Ovarian Failure Induced by Busulfan in Female Albino Rat

AbstractBackground: Many researches about stem cell therapy in premature ovarian failure treatment have been carried out. The adipose tissue has recently been identified as one of the alternative sources of multipotent resident stem cells in humans. One of the most devastating effects of chemotherapy is the damage of the reproductive system, which in young girls and women younger than 40 years of age is frequently associated with premature ovarian failure. Busulfan has a wide range of using as in a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myeloid leukemia and in patients undergoing bone marrow transplantation.Aim of the Study: The aim of the study was to evaluate the effect of administration of adipose tissue derived stem cells on the ovarian failure induced by the busulfan in female albino rats.Material and Methods: 70 female 8 weeks old albino rats were divided into 5 groups. Group I (control Group): They consisted of 20 female albino rats. They were received no treatment and served as untreated control. Group II (adipose tissue derived stem cells treated group): They consisted of 20 female albino rats. They were received adipose tissue derived stem cells (AT-ASCs). They received million and half of million units of AT-ASCs/single dose for each animal I.V. Group III (busulfan treated Group): They consisted of 10 female albino rats. In this group the ovarian failure was induced using busulfan therapy by a dose 2mg for successive 4 days. Group IV (busulfan treated, followed by AT-ASCs treated group): They consisted of 10 female albino rats. In this group the ovarian failure was induced by the same regimen as in group III. After one week of chemotherapeutic treatment, the animals received million and half of million units of AT-ASCs/single dose for each animal I.V. Group V (busulfan treated, followed by AT-AS Cs treated group): They consisted of 10 female albino rats. The rats in this group received the same regimen as group IV but they were sacrificed 4 weeks after the AT-ASCs injection. Biochemical study: Blood samples were taken from all rats from retro-orbital venous plexus and the serum samples were measured for FSH, LH and serum estrogen level using ELISA technique. Paraffin sections for female albino rat ovaries were prepared to be stained with H&E and Masson’s Trichrome stain for Light microscopic study. Specimens of the ovary were also prepared for electron microscopic study.Results: The AT-ASCs induced definite improvement in the histopathological changes associated with busulfan induced ovarian failure. This improvement was marked one week after AT-ASCs treated but after 4 weeks, there was some regression in this improvement.Conclusion: AT-ASCs transplantation can improve the ovarian damage induced by the busulfan. The need for second dose of AT-ASCs is suggested.