Biology of Blood and Marrow Transplantation最新文献

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation. Early diagnosis and, subsequently, earlier intervention have been shown to be beneficial to clinical outcomes. Diagnostic criteria from the European Society for Blood and Marrow Transplantation include recommendations on the use of imaging for diagnosis. This review discusses evidence on the use of imaging in the management of VOD/SOS and how imaging biomarkers can contribute to earlier diagnosis/treatment.

The internet can be a valuable tool in delivering survivorship care to hematopoietic cell transplantation (HCT) cancer survivors. We describe the reach of INSPIRE, an Internet and social media-based randomized controlled trial, to address healthcare and psychosocial needs of HCT survivors. All survivors 2-10 years after HCT for hematologic malignancy or myelodysplasia from 6 transplantation centers in the US were approached by mail and follow-up calls. Eligible participants had access to the Internet, an email address, and did not have active disease in the past 2 years. We used logistic regression to determine characteristics of eligible survivors who were more or less likely to enroll. Of 2578 eligible HCT survivors, 1065 (41%) enrolled in the study. The mean age of enrollees was 56.3 ± 12.6 years (range, 19 to 89 years), 52% were male, and 94% were white. Survivors less likely to enroll included those who were male, age <40 years, and who received an autologous transplant (all P < .001). Compared with white survivors, African Americans were less likely to enroll (P < .001), whereas Native Americans/Alaska Natives were more likely to join the study (P = .03). The reach of the INSPIRE program was broad, including to survivors who traditionally have less access to resources, such as Native Americans/Alaskan Natives and rural residents. Strategies are still needed to improve the enrollment of online studies of survivorship resources for males, young adults, African American, and autologous HCT survivors because their use may improve outcomes.

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCC^low) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCC^low (± TBI) conditioned transplantation in children with SAA.

Cytomegalovirus (CMV) viremia occurs in 40% to 80% of CMV-seropositive (R+) recipients of allogeneic hematopoietic cell transplantation (HCT). The preemptive therapy (PET) strategy has reduced the risk of CMV end-organ disease (EOD) and associated mortality but may lead to substantial healthcare resource utilization (HCRU) and costs. Real-world data on the economic impact of PET is relevant for the evaluation of alternative strategies for CMV management. We examined the impact of clinically significant CMV treated with PET on inpatient length of stay (LOS), number of readmissions, and associated costs from day 0 through day 180 post-HCT.

This was a retrospective study of R+ adults who underwent peripheral blood or marrow allogeneic HCT at Memorial Sloan Kettering Cancer Center between March 2013 and December 2017. Patients were routinely screened for CMV by qPCR and received PET according to institutional standards of care. Data were extracted from electronic medical records and hospital databases. Itemized cost data per patient were obtained from the Vizient database, adjusted to 2017 dollars using inflation indices. Study outcomes included HCRU evaluated by inpatient LOS and inpatient cost in patients who received PET for clinically significant CMV (PET group) compared with those who did not receive PET (no PET group) and the frequency and cost of CMV-related readmissions compared with non CMV-related readmissions. We used generalized linear models to examine the incremental HCRU and costs associated with PET controlling for other potential factors. Of 357 patients, PET was initiated in 208 (58.3%), at a median of 35 days after HCT. By day 180, 23 patients (6.4%) had developed CMV EOD and 3 (.8%) had died of CMV. Compared with the no PET group, the PET group had a longer LOS for HCT admission (P = .0276), longer total LOS by day 180 (P = .0001), a higher number of readmissions (P = .0001), a higher mean inpatient cost for HCT admission ($189,389 versus $151,646; P = .0133), and a higher total inpatient cost ($297,563 versus $205,815; P < .0001). Among PET recipients, CMV-related readmissions were associated with higher mean cost per episode compared with non CMV-related readmissions ($165,455 versus $89,419; P = .005). CMV-related readmissions comprised 40.6% of total all-cause readmissions and incurred 55.9% of total all-cause readmission costs in PET recipients. Our data show that patients treated with currently available PET had greater inpatient HCRU and cost, by day 180 compared with patients who did not receive PET. The cost of CMV-related readmissions accounted for 56% of total readmission cost among PET recipients. Future studies are needed to examine the cost-effectiveness of alternative strategies for CMV management.

Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients.

Chronic graft-versus-host disease (cGVHD) remains a significant late effect issue for allogeneic hematopoietic cell transplantation (allo-HCT) survivors, contributing to morbidity and mortality. The etiology of cGVHD is not well elucidated. Owing to a lack of early diagnostic tests and pathophysiology ambiguity, targeted treatments remain limited. Biomarkers for prediction, control response, or prognostication have not yet been identified. Metabolomics, the quantification of metabolites, is a potential biomarker of cGVHD but has not been evaluated in this population. In this study, we examined global metabolites of stored plasma to identify differentially expressed metabolites of individuals discordant for cGVHD following allo-HCT. A descriptive, comparative, cross-sectional study design was used to examine differentially expressed metabolites of plasma samples obtained from 40 adult allo-HCT recipients (20 with cGVHD and 20 without cGVHD) from 2 parent studies. Metabolomics profiling was conducted at the University of Florida's Southeast Center for Integrative Metabolomics. Full experimental methods followed a previously published method. All statistical analyses were performed by a PhD-prepared, trained bioinformatics statistician. There were 10 differentially expressed metabolites between participants with cGVHD and those without cGVHD. Differential metabolites included those related to energy metabolism (n = 3), amino acid metabolism (n = 3), lipid metabolism (n = 2), caffeine metabolism (n = 1), and neurotransmission (n = 1). Serotonin had the greatest fold change (21.01). This study suggests that cGVHD may be associated with expanded cellular energy and potentially mitochondrial dysfunction. The differential metabolic profile between patients with and without cGVHD indicates metabolic perturbations that merit further exploration as potential biomarkers of cGVHD. These findings support the need for further examination using a larger, prospective study design to identify metabolomic risk factors that may signal the need for earlier preventive measures and earlier treatment to reduce cGVHD.

Severe thalassemia syndromes (ST) are highly curable by bone marrow transplant (BMT), but rejection may still occur. We retrospectively analyzed our fully matched related donor transplants to establish if isolated splenomegaly is an independent risk factor for rejection and if this risk can be reduced by modifying the conditioning protocol. In this study, we compared rejection rates between patients with and without splenomegaly in 189 consecutive low-risk ST transplants across 2 sequential conditioning regimens: regimen A (August 2013 to December 2016): busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg), and anti-thymocyte globulin (ATG) (Genzyme (Sanofi, Paris, France) 4 mg/kg or Fresenius (Grafalon, Neovii Biotech GmbH, Gräfelfing Germany) 16 mg/kg on days –12 to –10), and regimen B: same backbone as regimen A except fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg/kg in case of splenomegaly and/or sex-mismatched transplants (January 2017 to September 2018). Compared with regimen A, in regimen B, both overall rejection rates (RRs) (16% versus 6.5%, P = .023) and treatment-related mortality (TRM) (9.9% versus 2.8%, P = .038) improved significantly. By Cox regression analysis, the improvement in RR between the 2 protocols was particularly significant in patients with splenomegaly (RR 54.5% versus 6.5%, P = .00015; TRM 18.2% versus 6.5%, P = .25) (hazard ratio, 4.13; confidence interval, 1.61 to 10.6; P = .003). The increased risk of rejection related to splenomegaly can be overcome by adding fludarabine to the standard ATG-Busulfan- Cyclophosphamide (ATG-Bu-Cy) protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.

Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19⁺ B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms.

Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors.