Biology of Blood and Marrow Transplantation最新文献

Long driving distances to transplantation centers may impede access to care for hematopoietic cell transplantation (HCT) survivors. As a secondary analysis from the multicenter INSPIRE study (NCT01602211), we examined baseline data from relapse-free HCT adult survivors (2 to 10 years after allogeneic or autologous HCT) to investigate the association between driving distances and patient-reported outcome (PRO) measures of distress and physical function. We analyzed predictors of elevated distress and impaired physical function using logistic regression models that operationalized driving distance first as a continuous variable and separately as a dichotomous variable (<100 versus 100+ miles). Of 1136 patients available for analysis from 6 US centers, median driving distance was 82 miles and 44% resided 100+ miles away from their HCT centers. Elevated distress was reported by 32% of patients, impaired physical function by 19%, and both by 12%. Driving distance, whether operationalized as a continuous or dichotomous variable, had no impact on distress or physical function in linear regression modeling (95% confidence interval, 1.00 to 1.00, for both PROs with driving distance as a continuous variable). In contrast, chronic graft-versus-host-disease, lower income, and lack of Internet access independently predicted both elevated distress and impaired physical function. In summary, we found no impact of driving distance on distress and physical function among HCT survivors. Our results have implications for how long-term follow-up care is delivered after HCT, with regard to the negligible impact of driving distances on PROs and also the risk of a “digital divide” worsening outcomes among HCT survivors without Internet access.

The intestinal microbiota plays a fundamental role in the development of host innate immune cells, such as monocytes, dendritic cells (DCs), and natural killer (NK) cells. We examined the association between intestinal microbiota and subsequent immune reconstitution of circulating monocyte, DC, and NK cell subsets in 38 adult patients undergoing single-unit cord blood transplantation (CBT). A higher diversity of intestinal microbiota at 1 month was significantly associated with higher counts of plasmacytoid DCs at 7 months after CBT, as measured by the Chao1 index. Principal coordinate analysis of unweighted UniFrac distances showed significant differences between higher and lower classical monocyte reconstitution at 7 months post-CBT. The families Neisseriaceae, Burkholderiaceae, Propionibacteriaceae, and Coriobacteriaceae were increased in higher classical monocyte reconstitution at 7 months post-CBT, whereas the family Bacteroidaceae was increased in lower classical monocyte reconstitution at 7 months post-CBT. These data show that intestinal microbiota composition affects immune reconstitution of classical monocyte and plasmacytoid DCs following single-unit CBT.

Total body irradiation (TBI)/cyclophosphamide (CY) is a standard-of-care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or complete remission status between the 2 groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant-related mortality at 1 (11% versus 11%), 5 (13% versus 16%), or 10 years (16% versus 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% versus 26%), 5 (24% versus 36%), 10 (26% versus 37%), and 15 years (26% versus 37%) (P= .02) but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease-free survival (DFS) at 5 (59% versus 47%), 10 (56% versus 46%), and 15 years (49% versus 40%) (P = .05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% versus 53%), 10 (57% versus 50%), and 15 years (50% versus 44%) demonstrated no statistical difference between the 2 groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant-related mortality for pediatric ALL HSCT but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.

Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative treatment for children with nonmalignant diseases, such as bone marrow failure syndromes and primary immunodeficiencies. Because graft-versus-host-disease (GVHD) is a major factor affecting survival probability and quality of life after HSCT, the availability of HLA-matched donors restricts the application of HSCT. Recently, HSCT with post-transplantation cyclophosphamide (PTCy) has emerged as a potent method to prevent GVHD after HSCT from HLA-haploidentical donors, and some studies have suggested the safety of PTCy-HSCT for nonmalignant diseases. We conducted a prospective clinical trial aiming to help confirm the safety of HSCT and further reduction of GVHD using a combination of PTCy and low-dose antithymocyte globulin (ATG) from HLA-mismatched related donors for children with nonmalignant diseases. Six patients underwent HSCT and achieved engraftment at a median of 14.5 days, and no patient developed severe acute GVHD. All patients had sustained donor chimerism without developing chronic GVHD at the last follow-up. In conclusion, HSCT with PTCy and low-dose ATG from an HLA-mismatched related donor were feasible to control GVHD for nonmalignant diseases in the children involved in our study.

© 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Angiotensin II type 1 receptor activating autoantibodies (AT1R-AAs) have gained attention in solid organ transplant as non-HLA antibodies associated with rejection, vasculopathy, and graft dysfunction. These antibodies have also been reported in the context of pre-eclampsia, scleroderma, and isolated hypertension. Here, we present 3 post-hematopoietic stem cell transplant (HSCT) cases with patients demonstrating elevated levels of AT1R-AAs detected within the first year post-HSCT. All patients had hypertension, and 2 patients exhibited profound diarrhea and hypokalemia. The hypertension, in all cases, was refractory to multiple classes of antihypertensives. Upon autoantibody identification, an angiotensin receptor blocker, losartan, was promptly initiated, and all patients showed blood pressure improvement. The 2 patients with electrolyte disturbances had rapid normalization of these levels and resolution of the diarrhea. These cases demonstrate a previously unreported association of elevated AT1R-AA levels in post-HSCT patients with a rapid response to angiotensin receptor blockade initiation.

Autologous hematopoietic cell transplantation (autoHCT) is a standard initial treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient hematopoietic progenitor cells (HPCs) for 2 autoHCTs in all eligible patients. Despite a lack of published data on the utilization of HPCs stored for future use, it is common practice across transplantation programs to collect enough HPCs for 2 autoHCTs in MM patients. In this single-center retrospective study, we analyzed the utilization of HPCs collected and stored at the time of first autoHCT in patients with MM, along with the cost implications of HPC collection targets sufficient for 2 transplantations. In a cohort of 400 patients (median age, 63 years; range, 22 to 79 years), after a median follow-up of 50.4 months, 197 patients had relapsed and 36 had received HPC infusion as salvage autoHCT (n = 29) and/or HPC boost (n = 8). In this cohort, a median CD34⁺ cell dose of 4.3 × 10⁶/kg (range, 1.1 to 12.94.3 × 10⁶/kg) was used for first autoHCT, and a median of 4.4 × 10⁶/kg (range, 1.0 to 20.2× 10⁶/kg) CD34⁺ cells were stored for future use. At 6 years after the first autoHCT, the estimated cumulative incidence of salvage autoHCT was 12.0% without HPC boost and 13.9% with HPC boost. HPC utilization was significantly higher in the 60- to 64-year age group, whereas no patients who were age ≥70 years at the time of first autoHCT received salvage autoHCT. Using the CD34⁺ cell dose infused during the first autoHCT as the cutoff for individual patients, the estimated mean additional cost of HPC collection intended for subsequent use (over and above the HPCs used for first autoHCT) was $10,795 ($4.32 million for the entire cohort), an estimated 14% of which (ie, $583,600) was actually used up in salvage autoHCT by 6 years from first autoHCT. In conclusion, our results suggest the need for reappraisal of HPC collection targets for salvage autoHCT and argue against HPC collection and storage for salvage autoHCT in patients age ≥70 years at the time of first autoHCT.

Infection is a major cause of morbidity and mortality after hematopoietic cell transplantation (HCT). Gut microbiota (GM) composition and metabolites provide colonization resistance against dominance of potential pathogens, and GM dysbiosis following HCT can be deleterious to immune reconstitution. Little is known about the composition, diversity, and evolution of GM communities in HCT patients and their association with subsequent febrile neutropenia (FN) and infection. Identification of markers before HCT that predict subsequent infection could be useful in developing individualized antimicrobial strategies. Fecal samples were collected prospectively from 33 HCT recipients at serial time points: baseline, post-conditioning regimen, neutropenia onset, FN onset (if present), and hematologic recovery. GM was assessed by 16S rRNA sequencing. FN and major infections (ie, bloodstream infection, typhlitis, invasive fungal infection, pneumonia, and Clostridium difficile enterocolitis) were identified. Significant shifts in GM composition and diversity were observed during HCT, with the largest alterations occurring after initiation of antibiotics. Loss of diversity persisted without a return to baseline at hematologic recovery. GM in patients with FN was enriched in Mogibacterium, Bacteroides fragilis, and Parabacteroides distasonis, whereas increased abundance of Prevotella, Ruminococcus, Dorea, Blautia, and Collinsella was observed in patients without fever. A baseline protective GM profile (BPGMP) was predictive of protection from major infection. The BPGMP was associated with subsequent major infections with 77% accuracy and an area under the curve of 79%, with sensitivity, specificity, and positive and negative predictive values of 0.71, 0.91, 0.77, and 0.87, respectively. Our data show that large shifts in GM composition occur early after HCT, and differences in baseline GM composition are associated with the development of subsequent major infections.

Previous studies have reported a beneficial effect from cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (alloHCT) on immune reconstitution. We determined the CMV antigenemia level associated with increased CMV antigen-specific T cells (CASTs) at day +100 and decreased CMV reactivation after day +100. CMV reactivation and CASTs were measured with CMV antigenemia and CMV-specific major histocompatibility complex multimers. The analysis consisted of 775 CAST measurements obtained before and 30, 100, and 365 days post-alloHCT from 327 consecutive patients treated between 2008 and 2016. Detectable CASTs correlated with recipient (P < .0001) and donor (P < .0001) CMV seropositivity pre-alloHCT. CMV reactivation before day +100 was associated with a higher proportion of patients who achieved ≥3 CASTs/µL by day +100 (61% with versus 39% without reactivation, P < .001). In alloHCT recipients at high risk for CMV reactivation (R⁺D^±) with a maximum of grade II acute graft-versus-host-disease, reactivating CMV before day +100 and achieving ≥3 versus <3 CASTs/µL at day +100 was associated with reduced CMV reactivation from day +100 to +365 (27% versus 62%, P = .04). This protective effect was observed with low-level but not high-level CMV reactivation (<5 versus ≥5/50,000 polymorphonuclear leukocytes + pp65, respectively). These findings suggest low-level CMV reactivation may be beneficial and that treatment may be delayed until progression. These findings will need validation in prospective clinical trials using CMV PCR and antigenemia assays.

The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high nonrelapse mortality (NRM) in patients aged >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced-intensity conditioning (RIC) and higher graft-versus-leukemia effect associated with greater HLA disparities would expand its use for patients (aged 40 to 60 years) without compromising efficacy and compared outcomes between RIC and MAC regimens. In total, 288 patients aged 40 to 60 years, with de novo acute myeloid leukemia, receiving UCBT with at least 2 HLA mismatches with RIC (n = 166) or MAC (n = 122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts and more in vivo T cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral, and fungal), and grade II to IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (hazard ratio [HR], 0.98; P = .9), NRM (HR, 0.68; P = .2), and relapse (HR, 1.24; P = .5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients aged 40 to 60 years having ≥2 HLA mismatches are comparable after the RIC or MAC regimen.

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD.