Stem cell homing: From physiology to therapeutics.

Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.

Results of the First Clinical Study in Humans That Combines Hyperbaric Oxygen Pretreatment with Autologous Peripheral Blood Stem Cell Transplantation.

Patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are at risk for multiple morbidities, including mucosal inflammation and neutropenic fever, both related to neutropenia. Evidence from our preclinical work in an umbilical cord blood (UCB) transplantation murine model suggests that treatment with hyperbaric oxygen (HBO) before UCB infusion improves UCB CD34+ cell engraftment by reducing erythropoietin levels. A pilot clinical trial using HBO in patients undergoing UCB transplantation showed improvement in kinetics of blood count recovery. In this study, we evaluated HBO in combination with auto-HCT. Our primary aim was to determine the safety of HBO in this setting and secondarily to determine its efficacy in reducing time to neutrophil and platelet engraftment compared with matched historic controls. Patients with multiple myeloma, non-Hodgkin lymphoma, and Hodgkin disease eligible for auto-HCT were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 90 minutes, in a monoplace hyperbaric chamber, breathing 100% oxygen. Six hours after the start of HBO, peripherally mobilized stem/progenitor cells were infused and patients were followed daily for toxicity and blood count recovery. All patients received daily granulocyte colony-stimulating factor starting on day +5 and until absolute neutrophil count (ANC) of ≥1500 or ANC of 500 for 3 consecutive days. A matched historic cohort of 225 patients who received auto-HCT between January 2008 and December 2012 was chosen for comparison and matched on sex, age, conditioning regimen, and disease type. We screened 26 patients for this study; 20 were treated and included in the primary analysis, and 19 completed the HBO therapy and were included in the secondary analysis. Although the median time to neutrophil count recovery was 11 days in both the HBO and control cohorts, the Kaplan-Meier estimates of the full distributions indicate that the time to neutrophil recovery was generally about 1 day sooner for HBO versus historical controls (log-rank P = .005; range, 9 to 13 for HBO patients and 7 to 18 for controls). The median time to platelet count recovery was 16 days (range, 14 to 21) for HBO versus 18 days (range, 11 to 86) for controls (log-rank P < .0001). In the secondary analysis comparing the HBO cohort who completed HBO therapy (n = 19) with our historical cohort, we evaluated neutropenic fever, growth factor use, mucositis, day +100 disease responses, and blood product use. HBO was associated with less growth factor use (median 6 days in HBO cohort versus median 8 days in controls, P < .0001). Packed RBC and platelet transfusion requirements were not statistically different between the 2 cohorts. Mucositis incidence was significantly lower in the HBO cohort (26.3% in HBO cohort versus 64.2% in controls, P = .002). HBO therapy appears to be well tolerated in the setting of high-dose therapy and auto-HCT. Prospective studies are needed to confirm potential benefits of HBO with respect to earlier blood count recovery, reduced mucositis, and growth factor use, and a cost-benefit analysis is warranted. © 2019 American Society for Blood and Marrow Transplantation.

Long-term results of a pilot study evaluating hyperbaric oxygen therapy to improve umbilical cord blood engraftment.

Umbilical cord blood (UCB) transplantation is a promising option for hematopoietic stem cell transplantation in patients with hematologic malignancies who lack an HLA-matched sibling or well-matched unrelated donor; however, it has a higher incidence of delayed or failed engraftment because cell doses are low and bone marrow homing is inefficient. We have demonstrated that pre-treating irradiated immune-deficient mice with hyperbaric oxygen (HBO) prior to UCB CD34+ cell transplantation lowered host systemic erythropoietin (EPO) and improved UCB CD34+ cell homing and engraftment. These findings suggested that EPO-EPO-R signaling plays a role in UCB CD34+ homing and engraftment. In a pilot clinical trial, we showed that recipients of HBO therapy prior to UCB cell infusion had reduced systemic EPO, which was associated with improved kinetics of blood count recovery. Although early clinical outcomes at day 100 were encouraging, with improved overall survival, the long-term effects of HBO therapy on UCB-transplanted patients were not evaluated. In this study, we examined the long-term outcome of patients in our pilot study, compared with a historic control group, and correlated their clinical outcomes to serum EPO response to HBO. While 50% of HBO-treated patients received single UCB units, ~ 90% of the control patients received double UCB units. Although HBO patients had much better rates of survival at 6 months, their 1-year survival did not significantly differ from the control group. HBO-treated patients had on average lower relapse and non-relapse mortality rates, and less chronic graft versus host disease (GVHD), but had increased acute GVHD. However, these differences were not statistically significant, probably because of the small sample size. In the HBO-treated cohort, immune reconstitution analysis showed significant improvement in early B cell recovery, with a trend toward improvement in early NK cell recovery. When we evaluated the ratio of 8 h to baseline EPO levels, we found a non-significant trend toward lower EPO values in those who neither relapsed nor died by 1 year, compared to those who died or relapsed. This result suggests that EPO response to HBO may be associated with better outcomes. Disease progression-free survival was also improved in those who had more than 80% reduction in EPO levels in response to HBO. Our study highlights the long-term safety of HBO therapy when used prior to UCB transplantation. Future UCB transplant patients who receive HBO should have their serum EPO response measured, as it may be a marker of relapse/mortality.

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation.

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).

Hyperbaric oxygen treatment effects on in vitro cultured umbilical cord blood CD34+ cells.

BACKGROUND AIMS: Umbilical cord blood (UCB) provides an alternative source for hematopoietic stem/progenitor cells (HSPCs) in the treatment of hematological malignancies. However, clinical usage is limited due to the low quantity of HSPCs in each unit of cord blood and defects in bone marrow homing. Hyperbaric oxygen (HBO) is among the more recently explored methods used to improve UCB homing and engraftment. HBO works by lowering the host erythropoietin before UCB infusion to facilitate UCB HSPC homing, because such UCB cells are not directly exposed to HBO. In this study, we examined how direct treatment of UCB-CD34+ cells with HBO influences their differentiation, proliferation and in vitro transmigration. METHODS: Using a locally designed HBO chamber, freshly enriched UCB-CD34+ cells were exposed to 100% oxygen at 2.5 atmospheres absolute pressure for 2 h before evaluation of proliferative capacity, migration toward a stromal cell-derived factor 1 gradient and lineage differentiation. RESULTS: Our results showed that HBO treatment diminishes proliferation and in vitro transmigration of UCB-CD34+ cells. Treatment was also shown to limit the ultimate differentiation of these cells toward an erythrocyte lineage. As a potential mechanism for these findings, we also investigated HBO effects on the relative concentration of cytoplasmic and nucleic reactive oxygen species (ROS) and on erythropoietin receptor (Epo-R) and CXCR4 expression. HBO-treated cells showed a relative increase in nucleic ROS but no detectable differences in the level of Epo-R nor CXCR4 expression were established compared with non-treated cells. DISCUSSION: In summary, HBO amplifies the formation of ROS in DNA of UCB-CD34+ cells, potentially explaining their reduced proliferation, migration and erythrocytic differentiation.

Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia.

We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation.

Potential mechanisms underlying ectodermal differentiation of Wharton's jelly mesenchymal stem cells.

Wharton's jelly mesenchymal stem cells (WJMSCs) are being increasingly recognized for their ectodermal differentiation potential. Previously, we demonstrated that when WJMSC were seeded onto an acellular matrix material derived from Wharton's jelly and cultured in osteogenic induction media, generated CK19 positive cells and hair-like structures indicative of ectodermal differentiation of WJMSCs. In this manuscript, we examine the underlying mechanism behind this observation using a variety of microscopy and molecular biology techniques such as western blotting and qPCR. We demonstrate that these hair-like structures are associated with live cells that are positive for epithelial and mesenchymal markers such as cytokeratin-19 and α-smooth muscle actin, respectively. We also show that up-regulation of ß-catenin and noggin, along with the expression of TGF-ß and SMAD and inhibition of BMP4 could be the mechanism behind this ectodermal differentiation and hair-like structure formation.

Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation.

Extracorporeal photopheresis (ECP) is a commonly used treatment for severe graft-versus-host-disease (GVHD). We sought to evaluate the effects of ECP over a prolonged period on forced expiratory volume in 1 s (FEV1) in patients with pulmonary GVHD. We identified eight patients who developed new airflow obstruction following allogeneic stem cell transplantation and a substantial decline in FEV1 despite receiving corticosteroids and standard therapy for pulmonary GVHD. Those eight patients were treated with ECP for a period of 1 year, with a primary endpoint of FEV1 change during this treatment period. Over the first 3 months of ECP, there was no further decline in FEV1 in seven of the eight patients. However, over the 1 year period, only two of the eight patients had stability in FEV1. The rate of FEV1 decline was substantially less once ECP was initiated, though the median FEV1 continued to decline over 1 year of therapy. All patients survived through the first year of ECP therapy. There was a significant decrease in the median dose of prednisone per patient throughout the 12 months of ECP treatment. ECP shows promise in slowing rate of decline of FEV1 in pulmonary GVHD, though the effects may not be long lived. J. Clin. Apheresis 31:347-352, 2016. © 2015 Wiley Periodicals, Inc.

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation.

Autologous stem cell transplantation (ASCT) after high-dose melphalan conditioning is considered a standard of care procedure for patients with multiple myeloma (MM). Current formulations of melphalan (eg, Alkeran for Injection [melphalan hydrochloride]; GlaxoSmithKline, Research Triangle Park, NC, USA) have marginal solubility and limited chemical stability upon reconstitution. Alkeran requires the use of propylene glycol as a co-solvent, which itself has been reported to cause such complications as metabolic/renal dysfunction and arrhythmias. EVOMELA (propylene glycol-free melphalan HCl; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) is a new i.v. melphalan formulation that incorporates Captisol (Ligand Pharmaceuticals, Inc., La Jolla, CA, USA), a specially modified cyclodextrin that improves the solubility and stability of melphalan and eliminates the need for propylene glycol. This new formulation has been shown to be bioequivalent to Alkeran. EVOMELA (200 mg/m(2)) was administered as 2 doses of 100 mg/m(2) each in a phase IIb, open-label, multicenter study to confirm its safety and efficacy as a high-dose conditioning regimen for patients with MM undergoing ASCT. At 5 centers, 61 patients (26 women) with a median age of 62 years (range, 32-73) were enrolled. All patients achieved myeloablation with a median time of 5 days post-ASCT, and all successfully achieved neutrophil and platelet engraftment with median times of 12 days post-ASCT and 13 days post-ASCT, respectively; treatment-related mortality on day 100 was 0%. Overall response rate (according to independent, blinded review) was high (100%), with an overall complete response rate of 21% (13% stringent complete response; 8% complete response) and overall partial response rate of 79% (61% very good partial response; 18% partial response). The incidence of grade 3 mucositis and stomatitis was low (10% and 5%, respectively) with no grade 4 mucositis or stomatitis reported (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events). Based on investigators' assessment of mucositis using the World Health Organization (WHO) oral toxicity scale, 75% of patients had a shift in mucositis score from WHO grade 0 at baseline to a higher grade on study, of which 13% of patients reported WHO grade 3 as the worst post-treatment mucositis over the course of the study; there were no reports of WHO grade 4 mucositis during the study. This study confirms the efficacy and acceptable safety profile of EVOMELA, a new propylene glycol-free melphalan formulation, as a high-dose conditioning regimen for ASCT in patients with MM.

Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34⁺ cells in a murine model of umbilical cord blood transplantation.

Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six- to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34⁺ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received 2 hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34⁺ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood, and spleen retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34⁺ cell infusion significantly improves engraftment.

Pulmonary manifestations of the pre-engraftment syndrome after umbilical cord blood transplantation.

Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment. We sought to determine the incidence and characterize the pulmonary manifestations of PES. A retrospective review of patients who underwent UCBT at the University of Kansas Medical Center over a 5-year period was performed. Data collected included patient baseline characteristics, presence of PES, pulmonary findings, treatments, and survival. Forty-four patients underwent UCBT with 22 of those patients developing PES. Full-intensity myeloablative conditioning regimen was found to be a risk factor for development of PES. Of those 22 patients, 13 had resting hypoxemia. The most common radiographic findings included diffuse ground glass opacities with pleural effusions. Fifteen patients with PES received corticosteroids, of which 12 had improvement in fevers and rash. These patients had a trend toward worse mortality than those not receiving corticosteroids. There was a nonsignificant trend toward worse survival in patients with PES and hypoxemia compared to those without hypoxemia. PES is a common complication following cord blood transplantation, with hypoxemia being present in over half of patients with PES. Hypoxemia with PES and treatment with corticosteroids may portend a worse prognosis.

Combined use of multiday palonosetron with aprepitant and low-dose dexamethasone in prevention of nausea and emesis among patients with multiple myeloma and lymphoma undergoing autologous hematopoietic stem cell transplant: A pilot study.

BACKGROUND: The current standard for prevention of chemotherapy-induced nausea/vomiting in autologous stem cell transplant only achieves 4-20% emetic control. OBJECTIVES: To assess emetic responses to multiday palonosetron, aprepitant, and low-dose dexamethasone among patients with myeloma and lymphoma undergoing autologous hematopoietic stem cell transplant. METHODS: Oral aprepitant 125/80/80 mg was administered with intravenous dexamethasone 4 mg and palonosetron 0.25 mg on days -3, -2, -1 for multiple myeloma and days -7 through -3 for lymphoma. Palonosetron was repeated day +3 in both groups. RESULTS: A total of 20 patients were enrolled and 18 analyzed. None experienced emetic failure with complete control achieved in 78, 33, and 17% in the acute, delayed, and extended phases, respectively. Nausea occurred in 78% although not significant in 61%, with median Nausea Visual Score of 4.5. Quality of life correlated with emetic and nausea control. Eight patients developed grade 2-3 nonhematologic toxicities with only one event attributed to the study medications. CONCLUSIONS: This triplet regimen was feasible with acceptable safety profile in the autologous hematopoietic stem cell transplant setting. Emetic control was best achieved in the acute phase. Lesser degree of emetic and nausea control in the delayed and extended phases impacted quality of life. Our results warrant further evaluation in a larger autologous hematopoietic stem cell transplant population.

Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts.

The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Referral to and receipt of allogeneic hematopoietic stem cell transplantation in older adults with acute myeloid leukemia.

INTRODUCTION: Recent data have shown improved outcomes in selected older adults with acute myeloid leukemia (AML) following allogeneic hematopoietic stem cell transplantation (HSCT). Nonetheless, practice patterns for referring and performing HSCT vary. We aimed to evaluate referral, utilization, and reasons for not referring/proceeding to HSCT in older adults with AML. MATERIALS AND METHODS: This is a single center retrospective analysis of patients aged ≥60 years diagnosed with AML evaluating rates of HSCT referral and utilization. Fisher's exact test was used to compare rates of referral and utilization across age groups and years of diagnosis. RESULTS: Median age of the 97 patients was 70 years (range 61-95); 30% (29/97) were referred for HSCT and of these, 69% (20/29) received HSCT. Common documented reasons (can be multiple) for not referring were performance status (n = 21), advanced age (n = 16), patient refusal (n = 15), refractory disease (n = 14), and prohibitive comorbidity (n = 6). Among patients who were referred but did not receive HSCT (n = 9/29), documented reasons for not proceeding with HSCT were refractory disease (n = 5), advanced age (n = 2), and prohibitive comorbidity (n = 2). HSCT referral and utilization rates significantly decreased with age (p < 0.01) but were generally stable over time from 2014 to 2017 (p = 0.40 for referral and p = 0.56 for utilization). DISCUSSION: Despite improvements in supportive care and HSCT techniques, HSCT referral and utilization rates remained low among older adults with AML but stable over time.

Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.

Osteopenia and osteoporosis are well-known consequences of allogeneic stem cell transplantation (allo-SCT). The role of prophylactic zoledronic acid on bone turnover following allo-SCT has not been well characterized. We prospectively studied the role of prophylactic use of zoledronic acid on bone metabolism in 17 patients with acute myeloid leukemia (AML) undergoing allo-SCT over a period of three yr (2006-2009). We measured bone mineral density using dual energy X-ray absorptiometry (DXA) scanning and the markers of bone turnover by urinary N-terminal telopeptide (uNTX) and serum osteocalcin levels prior to and serially following transplantation. All patients received 4 mg of zoledronic acid (Zometa, Novartis Pharmaceuticals Corp., Basel, Switzerland) intravenously prior to starting conditioning regimen and at six months after SCT. DXA scores did not change significantly in any patient over time (p > 0.05). uNTX progressively decreased over time (p < 0.001) and serum osteocalcin stabilized after six months. No patient developed osteonecrosis of the jaw. In conclusion, in this prospective pilot study, prophylactic use of zoledronic acid to prevent early bone loss was found to be safe and feasible in patients with AML undergoing allo-SCT during the immediate post-transplantation period.

The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells.

The complexity of the bone marrow (BM) microenvironment makes studying hematological malignancies in vitro a challenging task. Three-dimensional cell cultures are being actively studied, particularly due to their ability to serve as a bridge of the gap between 2D cultures and animal models. The role of 3D in vitro models in studying the mechanisms of chemotherapeutic resistance and leukemia stem cells (LSCs) in acute myeloid leukemia (AML) is not well-reviewed. We present an overview of 3D cell models used for studying AML, emphasizing the recent advancements in microenvironment modeling, chemotherapy testing, and resistance.

Portable medical orders and end-of-life measures in acute myeloid leukemia and myelodysplastic syndromes.

Patients with acute myeloid leukemia (AML) or a myelodysplastic syndrome (MDS) experience high rates of hospitalization, intensive care unit (ICU) admission, and in-hospital death at the end of life. Early goals-of-care (GOC) discussions may reduce the intensity of end-of-life (EOL) care. Portable Medical Order forms, known as Medical Orders for Life-Sustaining Treatment (MOLST) forms in New York state, assist patients in translating GOC discussions into specific medical orders that communicate their wishes during a medical emergency. To determine whether the timing of completion of a MOLST form is associated with EOL care in patients with AML or MDS, we conducted a retrospective study of 358 adult patients with AML or MDS treated at a single academic center and its affiliated sites, who died during a 5-year period. One-third of patients completed at least 1 MOLST form >30 days before death. Compared with patients who completed a MOLST form within 30 days of death or never, those who completed a MOLST form >30 days before death were less likely to receive transfusion (adjusted odds ratio [AOR], 0.39; P < .01), chemotherapy (AOR, 0.24; P < .01), or life-sustaining treatments (AOR, 0.21; P < .01) or to be admitted to the ICU (AOR, 0.21; P < .01) at EOL. They were also more likely to use hospice services (AOR, 2.72; P < .01). Earlier MOLST form completion was associated with lower intensity of care near EOL in patients with MDS or AML.

Autologous Stem Cell Rescue recipient with neutrophil tissue delivery detected prior to blood engraftment: a case report.

Neutrophil recovery after autologous hematopoietic cell transplantation (auto-HCT) is affirmed with achievement of an Absolute Neutrophil Count (ANC) of ≥500/uL. There is growing evidence that neutrophils may be observed despite undetectable peripheral ANC counts following autologous hematopoietic cell transplant and are preferentially delivered to sites of inflammation. We report an interesting case that confirms neutrophil tissue delivery to the skin two days prior to evidence of blood engraftment after an auto-HCT.

Decellularized Wharton jelly matrix: a biomimetic scaffold for ex vivo hematopoietic stem cell culture.

Hematopoietic stem progenitor cells (HSPCs) reside in the bone marrow (BM) hematopoietic "niche," a special 3-dimensional (3D) microenvironment that regulates HSPC self-renewal and multipotency. In this study, we evaluated a novel 3D in vitro culture system that uses components of the BM hematopoietic niche to expand umbilical cord blood (UCB) CD34+ cells. We developed this model using decellularized Wharton jelly matrix (DWJM) as an extracellular matrix (ECM) scaffold and human BM mesenchymal stromal cells (MSCs) as supporting niche cells. To assess the efficacy of this model in expanding CD34+ cells, we analyzed UCB CD34+ cells, following culture in DWJM, for proliferation, viability, self-renewal, multilineage differentiation, and transmigration capability. We found that DWJM significantly expanded UCB HSPC subset. It promoted UCB CD34+ cell quiescence, while maintaining their viability, differentiation potential with megakaryocytic differentiation bias, and clonogenic capacity. DWJM induced an increase in the frequency of c-kit+ cells, a population with enhanced self-renewal ability, and in CXCR4 expression in CD34+ cells, which enhanced their transmigration capability. The presence of BM MSCs in DWJM, however, impaired UCB CD34+ cell transmigration and suppressed CXCR4 expression. Transcriptome analysis indicated that DWJM upregulates a set of genes that are specifically involved in megakaryocytic differentiation, cell mobility, and BM homing. Collectively, our results indicate that the DWJM-based 3D culture system is a novel in vitro model that supports the proliferation of UCB CD34+ cells with enhanced transmigration potential, while maintaining their differentiation potential. Our findings shed light on the interplay between DWJM and BM MSCs in supporting the ex vivo culture of human UCB CD34+ cells for use in clinical transplantation.