Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction. METHODS: ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested. RESULTS: The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity. CONCLUSION: Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.

Improving Unrelated Donor Equity: Assessing Mismatched Donor Opportunities with Real-World Data in a Minority-Predominant Cohort.

Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.

Graft-versus-host disease: teaching old drugs new tricks at less cost.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Currently, more patients can receive SCT. This is attributed to the use of reduced intensity regimens and the use of different GVHD prophylaxis that breaks the barrier of human leukocyte antigen, allowing an increase in the donor pool. Once an area with relatively few clinical trial options, there has been an increase in interest in GVHD prophylaxis and treatment, which has led to many US Food and Drug Administration (FDA) approvals. Although there is considerable excitement over novel therapies, many patients may not have access to them due to geographical or other resource constraints. In this review article, we summarize the latest evidence on how we can continue to repurpose drugs for GVHD prophylaxis and treatment. Drugs covered by our review include those that have been FDA approved for other uses for at least 15 years (since 2008); thus, they are likely to have generic equivalents available now or in the near future.

Decision analysis of allogeneic bone marrow transplantation versus immunosuppressive therapy for young adult patients with aplastic anemia.

BACKGROUND: Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor is recommended as an initial treatment for young patients. However, immunosuppressive therapy (IST) with cyclosporine and anti-thymocyte globulin may be a viable option even when an HLA-identical sibling donor is available. METHODS: We constructed a Markov model to simulate the 10-year clinical course of patients aged 21-40 years with newly diagnosed severe aplastic anemia. Immediate BMT and IST were compared as an initial treatment assuming the availability of an HLA-identical sibling donor. Transition probabilities after treatment were determined based on a registry data analysis for BMT and a long-term prospective study for IST. RESULTS: Quality-adjusted life years (QALYs) after treatment selection were 6.77 for BMT and 6.74 for IST. One-way sensitivity analysis revealed that the utility for being alive without GVHD after BMT, that for being alive with partial response after IST, and the response rate after initial IST strongly affected the results. CONCLUSIONS: BMT and IST produced similar QALY for young patients with severe aplastic anemia. An estimation of the response rate to the initial IST may enable an individualized comparison between BMT and IST.

Optimized therapeutic strategy for patients with refractory or relapsed acute myeloid leukemia: long-term clinical outcomes and health-related quality of life assessment.

BACKGROUND: Patients with refractory or relapsed acute myeloid leukemia (AML) have poor survival, necessitating the exploration of optimized therapeutic strategy. Here, we aimed to investigate clinical outcomes and health-related quality of life (HR-QoL) after total therapy, which included allogeneic hematopoietic stem cell transplantation (allo-HSCT), and prophylactic donor lymphocyte infusion (DLI) in the early phase after transplantation, followed by multiple measurable residual disease (MRD) and graft-versus-host disease (GvHD)-guided DLIs. METHODS: Consecutive patients who had refractory or relapsed AML and had received non-T-cell-depleted allo-HSCT at Peking University Institute of Hematology were included in the study. If the patients achieved complete remission at 30 days after transplantation and had no evidence of relapse, severe infection, organ failure, and active GvHD at the time of planned DLI, prophylactic DLI was administered at 30 days after transplantation for human leukocyte antigen (HLA)-matched related HSCT or at 45-60 days after transplantation for haploidentical or unrelated HSCT. Subsequently, multiple DLIs were administered based on MRD results and whether they developed GvHD after transplantation. RESULTS: A total of 105 patients were eligible. Eighty-seven patients received prophylactic DLI (group B), while 18 did not receive prophylactic DLI (group A). Among 105 patients, the cumulative incidence of grade 2-4 acute GvHD and chronic GvHD was 40.6% (95% confidence interval [CI] = 30.6%-50.6%) and 73.3% (95% CI = 67.4%-79.2%), respectively. The cumulative incidence of relapse (CIR), transplant-related mortality (TRM), and leukemia-free survival (LFS) at 5 years after transplantation were 31.5% (95% CI = 21.9%-41.1%), 22.1% (95% CI = 11.3%-32.9%), and 46.4% (95% CI = 36.8%-56.0%), respectively. In group B, the CIR, TRM, and LFS at 5 years after transplantation were 27.6% (95% CI = 17.6%-37.6%), 21.6% (95% CI = 11.2%-32.0%), and 50.8% (95% CI = 40.0%-61.6%), respectively. At the end of follow-up, 48 patients survived, and more than 90% of survivors had satisfactory recoveries of HR-QoL. CONCLUSIONS: Our study indicated that total therapy is not only associated with decreased CIR, comparable TRM, and better long-term LFS, but also with satisfactory HR-QoL for refractory or relapsed AML, compared with those of standard of care therapy reported previously. Therefore, total therapy may be an optimized therapeutic strategy for refractory or relapsed AML.

Costs of matched-sibling, unrelated, and haploidentical hematopoietic cell transplantation and risk factors for greater financial burden - a Brazilian FACT-accredited single-center analysis.

The complexity and costs of hematopoietic cell transplantation (HCT) have increased over the last decades with the popularization of unrelated donor (URD) transplantation and the introduction of haploidentical transplantation with posttransplant cyclophosphamide. Few studies have addressed this issue. The objective of this study was to analyze HCT costs in a single FACT-accredited private non-profit hospital. We included 79 patients who underwent HCT between 2018 and 2020. We have included all costs from admission day until D + 180. We used a lognormal regression. Median age was 53 y/o and most donors were unrelated (51%). Costs were higher with haploidentical donor (42%, p = 0.017, compared with URD), higher HCT-CI (15% for each point, p = 0.0056), and in patients with liver or gastrointestinal GVHD (45%, p = 0.033), and lower in patients who received CD34 > 2.5 × 10E6/kg (42%, p = 0.0038). We built a score based on the following risk factors: HCT-CI > 3, CD34 ≤ 2.5 × 10E6/kg, haploidentical donor, and donor age > 30 y/o. Patients with 2 + risk factors (N = 53) had a median cost of USD 226,156.00, compared with USD 93,048.00 in patients with zero or 1 point (N = 26, p < 0.0001). In summary, we have shown that HCT costs are higher with lower doses of CD34 cells, haploidentical HCT (provided that the costs of stem cell procurement and ATG are not included), and in patients with higher HCT-CI. Prospective and refined cost analyses comparing haploidentical and URD transplants, as well as effective strategies for patients with higher HCT-CI scores, are warranted. We found no difference in costs between URD and MSD transplantation.

Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplant.

Importance: Patient-specific human leukocyte antigen (HLA) genomic loss (HLA loss) is one of the reputed mechanisms of leukemia immune escape and relapse after haploidentical hematopoietic stem cell transplant (HSCT). However, clinical characteristics and prognosis of this distinct relapse type in the setting of haploidentical HSCT based on antithymocyte globulin (ATG) T-cell-replete conditioning are still unknown, especially for patients with lymphoid leukemia. Objective: To identify the incidence of and patient characteristics associated with HLA loss at hematologic cancer relapse after ATG-based haploidentical HSCT and to assess overall survival after HLA loss at relapse. Design, Setting, and Participants: This retrospective and multicenter case series study used data from medical records to identify patients who experienced relapse of hematologic cancer after receipt of ATG-based haploidentical HSCT. The study included 788 consecutive patients aged 8 to 70 years with lymphoid or myeloid leukemia who received ATG T-cell-replete haploidentical HSCT at the Zhejiang Cooperative Group for Blood and Marrow Transplantation between May 1, 2012, and May 31, 2021. Exposures: Relapse after ATG-based haploidentical HSCT. Main Outcomes and Measures: Incidence, risk factors, and postrelapse overall survival among patients with HLA loss at hematologic cancer relapse after receipt of haploidentical HSCT. Logistic regression analysis was used to identify characteristics associated with the likelihood of HLA loss, and Kaplan-Meier and Cox regression analyses were performed to evaluate postrelapse survival. Results: A total of 788 patients who received haploidentical HSCT for hematologic cancer were identified, 180 of whom experienced relapse after HSCT. Of those, 106 evaluable patients (median age, 30.9 years [range, 8.3-64.6 years]; 54 female [50.9%] and 52 male [49.1%]) were screened for HLA loss, which was detected in 54 patients (50.9%). Patients with HLA loss experienced relapse later than those without HLA loss (lymphoid group: median, 323 days [range, 98-2056 days] vs 151 days [range, 57-2544 days]; P = .01; myeloid group: median, 321 days [range, 55-1574 days] vs 223 days [range, 68-546 days]; P = .03). Among patients with lymphoid leukemia, those with minimal residual disease positivity before hematologic relapse (odds ratio [OR], 28.47; 95% CI, 1.99-407.98; P = .01), those with chronic graft-vs-host disease (OR, 27.68; 95% CI, 1.40-546.88; P = .03), and those with more than 180 days between HSCT and relapse (OR, 6.91; 95% CI, 1.32-36.22; P = .02) were more likely to lose unshared HLA at relapse, whereas male patients (OR, 0.03; 95% CI, 0.003-0.32; P = .04) were more likely to preserve their HLA genome at relapse. Patients with myeloid leukemia had different factors associated with HLA loss, including underweight status (OR, 0.10; 95% CI, 0.02-0.60; P = .01) and acute graft-vs-host disease (OR, 4.84; 95% CI, 1.14-20.53; P = .03). The receipt of preemptive donor lymphocyte infusion among patients with minimal residual disease recurrence did not postpone hematologic cancer relapse in those with HLA loss (median, 322 days [range, 204-1030 days]) compared with no receipt of donor lymphocyte infusion (median, 340 days [range, 215 days to not available]; P > .99). Conclusions and Relevance: In this study, HLA loss at leukemia relapse occurred frequently after receipt of ATG-based haploidentical HSCT. The identification of risk factors associated with HLA loss would help to prompt screening, avoid potentially harmful infusions of donor T cells, and develop alternative therapeutic strategies.

Tools for optimizing risk assessment in hematopoietic cell transplant - What can we get away with?

Unrelated allogeneic hematopoietic cell transplant (HCT) is a critical modality to treat hematologic malignancies. The current objective of donor selection is to match donor and recipient at the HLA (human leukocyte antigen) peptide-binding region which should lower the risk of graft-versus-host disease. However, depending on the patient's ethnicity/race, finding a matched donor is challenging, especially for HLA-DPB1 which is due to the weak linkage disequilibrium between HLA-DPB1 and the other HLA class II loci. Recent evidence, on the molecular level, has shown that certain HLA mismatches carry lower clinical risk. More specifically, there is an increasing understanding of polymorphisms of the innate and adaptive immune systems and their impact on transplant outcomes, allowing us to expand our "toolkit" for optimization of donor selection in HCT. Therefore, in this review we discuss matching strategies based on comparing donor and recipient polymorphisms that may influence innate and adaptive immune response genes in allorecognition and the role of single nucleotide polymorphisms in non-HLA genes that have the potential for providing additional tools to refine risk stratification.

Fixed-dose administration and pharmacokinetically guided adjustment of busulfan dose for patients undergoing hematopoietic stem cell transplantation: a meta-analysis and cost-effectiveness analysis.

This study aims to evaluate the efficacy, safety, and long-term cost-effectiveness of fixed-dose busulfan (Bu) administration and pharmacokinetically (PK) guided adjustment of Bu dose for patients who underwent hematopoietic stem cell transplantation. The efficacy and safety of both dosing strategies were compared using a systematic review and meta-analysis. A Markov model was used in estimating relevant cost and health outcomes from the perspective of the health system. The primary outcomes of interest were lifetime cost, quality adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratio (ICER) in dollar per QALY gained. Results showed that progression-free survival and overall survival in the PK-guided group were higher than that in the fixed-dose group, and the PK-guided group was associated with low non-relapse mortality and relapse rate. In contrast to safety, the incidence of acute graft-versus-host disease (GVHD) was the same in the two groups (P > 0.05). Cost-effectiveness analysis showed that the QALY of the PK-guided group (12.8135 QALYs and $582,475.07) increased by 2.0609 relative to that in the fixed-dose group (10.7526 QALYs and $562,833.20), and the ICER was $9530.72/QALY. One-way and probability sensitivity analyses confirmed the reliability of the results. In conclusion, the PK-guided approach has higher efficacy and is safer.

The impact of donor type on resource utilisation and costs in allogeneic haematopoietic stem cell transplantation in the Netherlands.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is increasingly used, but this treatment is complex and costly. As clinical outcomes of HSCT with matched unrelated donor (MUD) and haploidentical donors are similar, costs could influence donor choice. METHOD: We retrospectively compared resource utilisation and costs of HSCT using the three different donor types (matched related donor (MRD) (n = 32), haploidentical related (n = 30) and MUD (n = 60)) within the first year after transplantation. Costs were analysed through a bottom-up method. Non-parametric bootstrapping was applied to test for statistical differences in costs. Subgroup analyses were performed to identify predictors for costs. RESULTS: Cost pre-transplant for search and acquisition of the graft were significantly higher in MUD HSCT (€35 222) versus MRD and haploidentical HSCT (€15 356 and €16 097 respectively). The costs of haploidentical HSCT were the highest in the transplant phase. Main cost factors were inpatient days and medication. Overall, the costs for haploidentical and MUD HSCT were similar (€115 724 for MUD, €113 312 for haploidentical). CONCLUSION: Our study suggests no difference in total transplantation costs between allogeneic HSCT using a MUD or a haploidentical donor. Since clinical outcomes seem similar as well, the choice of donor type might be based on availability, speed and logistics.

Assessment of HLA-B genetic variation with an HLA-B leader tool and implications in clinical transplantation.

Sequence variation in the HLA-B gene is critically linked to differential immune responses. A dimorphism at -21 of HLA-B exon 1 gives rise to leader peptides that are markers for risk of acute graft-versus-host disease, relapse, and mortality after unrelated donor and cord blood transplantation. To optimize the selection of stem cell transplant sources based on the HLA-B leader, an HLA-BLeader Assessment Tool (BLEAT) was developed to automate the assignment of leader genotypes, define HLA-B leader match statuses, and rank order candidate stem cell sources according to clinical risk. The base cohort consisted of 9 417 614 registered donors from the Be The Match Registry with HLA-B typing. Among these donors, the performance of BLEAT was assessed in 1 098 358 donors with sequence data for HLA-B exon 1 (2 196 716 haplotypes). The accuracy of leader assignment was then assessed in a second cohort of 1259 patients and their unrelated transplant donors. We furthermore established the frequencies of HLA-B leader genotype (MM, MT, TT) representations in broad racial categories in the 9.42 million donors. BLEAT has direct applications for the selection of optimal stem cell sources for transplantation and broad utility in basic and clinical research in pharmacogenomics, vaccine development, and cancer and infectious disease studies of human populations.

Impact of a Bayesian Individualization of Cyclosporine Dosage Regimen for Children Undergoing Allogeneic Hematopoietic Cell Transplantation: A Cost-Effectiveness Analysis.

BACKGROUND: Cyclosporine A (CsA) is the main drug used to prevent graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). CsA therapeutic drug monitoring (TDM) has been performed for ages, with studies revealing clinical benefits, but failing to examine its economic impact. In this article, the main objective was to evaluate the economic impact of the CsA TDM strategy, based on a Bayesian approach, by assessing costs related to its clinical impact. Furthermore, TDM effectiveness was analyzed for pharmacokinetics and clinical outcomes. METHODS: A cost-effective, nonrandomized, retrospective, single-center study compared 2 CsA monitoring and dose adaptation strategies in pediatric patients undergoing HSCT. From 2014 to 2016, CsA TDM was performed using a population pharmacokinetics model-coupled Bayesian approach by a pharmacist ["pharmacist-assisted individualization" (PAI)]. From 2017 to 2018, CsA TDM was performed by the clinician without a Bayesian approach (non-PAI group). HSCT costs were evaluated from the French National Insurance perspective. Economic and clinical outcomes were assessed by measuring incremental cost-effectiveness ratios. RESULTS: The study included 144 patients: 90 and 54 patients in PAI and non-PAI groups, respectively. Both groups were comparable for sociodemographic and clinical characteristics. The mean total cost per patient was significantly lower (P < 0.01) in the PAI group (€85,947) than in the non-PAI group (€100,435). Multivariate analysis revealed that TDM based on the Bayesian approach was a protective factor (odds ratio = 0.86) for severe acute graft-versus-host disease. We noted that pharmacist-based TDM was the dominant strategy. Bayesian method-based TDM allowed an increase in the percentage of target attainment at any period post-HSCT. CONCLUSIONS: CsA TDM with a Bayesian approach is a cost-effective procedure, and highlighted clinical benefits encourage the development of new TDM strategies for HSCT.

Impact of the COVID-19 pandemic on liver donation and transplantation: A review of the literature.

The coronavirus disease 2019 (COVID-19) pandemic has upended healthcare systems worldwide and led to an inevitable decrease in liver transplantation (LT) activity. During the first pandemic wave, administrators and clinicians were obliged to make the difficult decision of whether to suspend or continue a life-saving procedure based on the scarce available evidence regarding the risk of transmission and mortality in immunosuppressed patients. Those centers where the activity continued or was heavily restricted were obliged to screen donors and recipients, design COVID-safe clinical pathways, and promote telehealth to prevent nosocomial transmission. Despite the ever-growing literature on COVID-19, the amount of high-quality literature on LT remains limited. This review will provide an updated view of the impact of the pandemic on LT programs worldwide. Donor and recipient screening, strategies for waitlist prioritization, and posttransplant risk of infection and mortality are discussed. Moreover, a particular focus is given to the possibility of donor-to-recipient transmission and immunosuppression management in COVID-positive recipients.

Chronic graft-versus-host disease in children and adolescents with thalassemia after hematopoietic stem cell transplantation.

Data on chronic graft-versus-host disease (cGVHD) in patients with thalassemia after hematopoietic stem cell transplantation (HSCT) have not been specifically explored. The present study aimed to determine the incidence and clinical manifestations of cGVHD in children and adolescents with thalassemia who underwent HSCT and to compare healthcare utilization and medical cost between patients with and without cGVHD. We retrospectively analyzed the presentations, treatments, and outcomes of historical cGVHD (Seattle criteria), post-transplant admissions and direct medical cost for HSCT patients (n = 66). We used the 2014 NIH consensus criteria to reclassify the diagnosis of cGVHD (NIH cGVHD). Among 28 historical cGVHD patients, 13 (46.4%) fulfilled the NIH criteria. Reasons why the NIH criteria were unmet were reclassification as late acute GVHD and presence of distinctive signs without confirmatory tests. At 2 years after HSCT, the cumulative incidence of NIH cGVHD was 21.67% (95% CI, 12.31-32.74%). Lung cGVHD was associated with inferior survival with a hazard ratio of 13.6 (95% CI, 1.42-131.48). Patients with historical cGVHD had significantly increased frequency of inpatient admissions and medical cost. In conclusion, cGVHD was common in children with thalassemia receiving HSCT. Patients with cGVHD required prolonged immunosuppressive treatment and incurred high medical expenses.

Evidence-based surgical hypothesis: Partial heart transplantation can deliver growing valve implants for congenital cardiac surgery.

Children undergoing congenital cardiac surgery often outgrow the valve implants. These children are thus committed to morbid reoperations for successive exchanges of the vavular implants that they have outgrown. Therefore the holy grail of congenital cardiac surgery is a valve implant that grows with the recipient child. Preserved homografts routinely are used as valve implants, but they do not grow as the child grows because they lose viability during preservation. In contrast, pulmonary autografts and pediatric heart transplants grow with the recipient children. Similarly, partial heart transplantation can deliver growing valve implants for congenital cardiac surgery. Temporary immune suppression would only be needed until the partial heart transplant can be exchanged for an adult-sized prosthetic valve in the grown child.

Cytomegalovirus in Allogeneic Hematopoietic Transplantation: Impact on Costs and Clinical Outcomes Using a Preemptive Strategy.

Cytomegalovirus (CMV) results in significant morbidity and mortality following hematopoietic cell transplantation (HCT). Establishing the cost and clinical impact is imperative to the selection of appropriate CMV preventative strategies. This is a retrospective cohort study of consecutive patients undergoing their first allogeneic HCT between January 1, 2009, and December 31, 2013. Detailed clinical and institutional cost data were obtained from the start of conditioning through 1-year post-transplantation. Baseline characteristics, resource utilization, costs, and outcomes were compared between patients with and without clinically significant CMV infection (csCMVi). One hundred seventy out of 388 patients (44%) developed csCMVi within 1 year after HCT. Within the first year post-HCT, patients with csCMVi had a significantly longer transplantation-related length of stay (mean, 91.7 days versus 78.3 days; P < .0001) and more frequent and prolonged hospitalizations (mean, 2.4 versus 1.7 admissions [P < .0001]; mean, 39.1 versus 31.5 inpatient days [P = .001]) without significantly more admissions to the intensive care unit (28.2% versus 21.6%; P = .408). The use of granulocyte colony-stimulating factor was greater in patients with csCMVi (73.5% versus 54.1%; P = .0001), although no significant differences were demonstrated in mean platelet or red blood cell (RBC) transfusions. Total costs were also higher in patients with csCMVi (mean cost difference, $45,811; 95% CI, $26,385 to $67,544). However, the incidence of graft-versus-host disease (GVHD) and selected infectious complications was not significantly different between the 2 groups. There were no significant differences in 1-year and 5-year post-transplantation overall survival (OS) or nonrelapse mortality (NRM) between those with and those without csCMVi, although relapse of underlying disease was significantly lower in the csCMVi group. Overall, our data show that allogeneic HCT recipients with csCMVi had significantly greater medical resource utilization and costs than those without csCMVi. However, clinical outcomes, including GVHD, infections, and mortality, were similar in the 2 groups. Further study is needed to determine the cost-effectiveness of CMV preventive modalities.

Feasibility and cost analysis of day 4 granulocyte colony-stimulating factor mobilized peripheral blood progenitor cell collection from HLA-matched sibling donors.

BACKGROUND: Guidelines recommend treatment with 4-5 days of granulocyte colony-stimulating factor (G-CSF) for optimal donor peripheral blood progenitor cell (PBPC) mobilization followed by day 5 collection. Given that some autologous transplant recipients achieve adequate collection by day 4 and the possibility that some allogeneic donors may maximally mobilize PBPC before day 5, a feasibility study was performed evaluating day 4 allogeneic PBPC collection. METHODS: HLA-matched sibling donors underwent collection on day 4 of G-CSF for peripheral blood (PB) CD34+ counts ≥0.04 × 106/mL, otherwise they underwent collection on day 5. Those with inadequate collected CD34+ cells/kg recipient weight underwent repeat collection over 2 days. Transplant and PBPC characteristics and cost analysis were compared with a historical cohort collected on day 5 per our prior institutional algorithm. RESULTS: Of the 101 patient/donor pairs, 50 (49.5%) had adequate PBPC collection on day 4, with a median PB CD34+ cell count of 0.06 × 106/mL. Day 4 donors were more likely to develop bone pain and require analgesics. Median collected CD34+ count was significantly greater, whereas total nucleated, mononuclear and CD3+ cell counts were significantly lower, at time of transplant infusion for day 4 versus other collection cohorts. There were no significant differences in engraftment or graft-versus-host disease. Cost analysis revealed 6.7% direct cost savings for day 4 versus historical day 5 collection. DISCUSSION: Day 4 PB CD34+ threshold of ≥0.04 × 106/mL identified donors with high likelihood of adequate PBPC collection. Day 4 may be the optimal day of collection for healthy donors, without adverse effect on recipient transplant outcomes and with expected cost savings.

Proposal for the International Society for Cell & Gene Therapy position statement on assays for the quality control and potency assessment of adoptive cellular immunotherapies.

Translation of cell and gene therapies from pre-clinical experiments to clinical trials and final drug licensing brings requires the development, verification and even validation of the assays essential for the definition of the drug product. The technical and scientific challenges in doing this are far greater than they seem at first and are compounded by a lack of approved standards for assays used to support (c)GMP manufacture. This paper highlights some of those challenges and proposes solutions based on the experience of our colleagues using similar assay platforms in regulated pathology laboratories.

Hematopoietic stem cell transplantation for sickle cell disease: Progress and challenges.

Sickle cell disease (SCD) presents challenges to hematopoietic stem cell transplantation (HSCT), including donor availability and morbidity with age/disease severity. However, severe SCD causes irreversible organ damage that HSCT can mitigate. This benefit must be balanced against preparative regimen toxicity, graft-versus-host disease, and mortality risk. We review efforts to balance HSCT complications with the promise of cure, and knowledge gaps that warrant further investigation. We highlight the burden of SCD, HSCT risks and benefits, and SCD families' approach to this balance. We emphasize the necessity for information exchange to ensure a joint decision-making process between providers and patients.

Comparative assessment of prophylactic transfusions of platelet concentrates obtained by the PRP or buffy-coat methods, in patients undergoing allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: Whole blood-derived platelet concentrates can be obtained by the platelet-rich plasma (PRP-PCs) or the buffy-coat (BC-PCs) method. Few studies have shown that BC-PCs display lower in vitro platelet activation, but scarce information exists regarding transfusion efficacy. We have performed a retrospective study assessing platelet transfusion in patients undergoing allogeneic hematopoietic cell transplantation (AHCT) in our clinic, before and after the implementation of BC-PCs. METHODS: We reviewed clinical records corresponding to 70 PRP-PCs and 86 BC-PCs prophylactic transfusions, which were performed to 55 AHCT patients. Transfusion efficacy was assessed by the 24-h post-transfusion corrected count increment (24-h CCI) and bleeding events. Clinical factors affecting transfusion outcome were also investigated. RESULTS: Clinical characteristics and the total number of platelet transfusions were similar among groups. Mean donor exposure was 5.8 and 5.0 in each single PRP-PCs and BC-PCs transfusion, respectively (p < 0.01). The 24-h CCI was significantly higher in patients transfused with BC-PCs than in those receiving PRP-PCs (8.3[2.7-13.4] vs. 4.7[1.3-8.1]; p < 0.01). Independent predictors of poor platelet transfusion response included diagnosis other than acute leukemia (HR 8.30; 95% CI 1.96-35.22; p = 0.004), splenomegaly (HR 8.75; 95% CI 2.77-27.60; p < 0.001), graft versus host disease prophylaxis different from cyclosporine A and methotrexate (HR 3.96; 95% CI 1.55-10.14; p = 0.004) and PRP-PCs transfusion (HR 4.54; 95% CI 1.72-12.01; p = 0.002). There were no differences between both groups regarding the bleeding events. CONCLUSION: In the AHCT setting, we hypothesize that BC-PCs transfusion, when compared to PRP-PCs, results in higher CCI and reduced donor exposure, but provides no significant benefit regarding bleeding outcome.