Pre Hematopoietic Stem Cell Transplantation Research Articles

Abstract 4125252: Pre-Hematopoietic Stem Cell Transplantation Echocardiographic Indices and Post-Transplant Cardiovascular Outcomes

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with adverse cardiovascular (CV) events including the development of heart failure (HF) and arrythmias. While transthoracic echocardiogram (TTE) is routinely obtained prior to HSCT, its role in predicting the incidence of HSCT related CV events is poorly understood. Methods: We used data from the Cardiovascular Registry in Bone Marrow Transplantation (CARE-BMT) study, a multicenter observational study of adult patients (aged ≥18 years) who underwent autologous/allogeneic HSCT for malignant or nonmalignant bone marrow disorders at the University of Michigan Health System (UMHS) and Rush University Medical Center from 2008-2019. In this analysis, we included patients from UMHS with a baseline TTE. Data on pre-HSCT TTE parameters and post-HSCT CV outcomes were collected through manual chart review. Left ventricular (LV) function and dimensions were categorized into normal, mildly abnormal, and moderately/severely abnormal based on American Society of Echocardiography guidelines. The primary outcomes were new-onset HF and atrial fibrillation/flutter post-HSCT. Analyses were conducted using a Fine-Gray model adjusted for the pre-HSCT CARE-BMT CV risk score. Results: Of the 2071 patients (mean age at HSCT 55.5 + 12.9 years; 59.5% male) with a pre-HSCT TTE (median 25 days pre-HSCT), 116 (5.6%) and 128 (6.2%) patients experienced HF and atrial fibrillation/flutter, respectively, over a median period of 2.2 years. Greater abnormalities in left ventricular internal diameter at end-diastole (LVIDd) and end-systole (LVIDs) were linearly associated with a higher risk of HF (P-trend 0.018 and 0.004, respectively) (Table). Similarly, moderately/severely abnormal LVIDd was associated with a 2.41-fold (95% CI: 1.07, 5.43) increase in risk of atrial fibrillation/flutter (Table). Pre-HSCT ejection fraction (EF) was not associated with either endpoint. Conclusion: LV dilation, even when mild, was notably associated with increased risk of developing new HF or atrial arrythmias post-HSCT, regardless of EF. Whether evidence of LV dilation should prompt the initiation of guideline directed medical therapy to minimize the risk of incident HF warrants further study.

Risk factors for positive post-transplantation measurable residual disease in patients with acute lymphoblastic leukemia.

The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P<0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P=0.027; P=0.003; P=0.035; P=0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively (P<0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

Extracellular release of damaged mitochondria induced by prehematopoietic stem cell transplant conditioning exacerbates GVHD

AbstractDespite therapeutic advancements, graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing pathogen-associated molecular patterns, result in activation of host antigen-presenting cells (APCs) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APCs. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of major histocompatibility complex II (MHC-II), costimulatory CD86, and proinflammatory cytokines, resulting in increased donor T-cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC-mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggest that pre-HSCT conditioning results in extracellular release of damaged mitochondria, which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria after conditioning could serve as a novel strategy for GVHD prevention.

Full Body Screening Computed Tomography Prior to Allogeneic Hematopoietic Stem Cell Transplantation: A Single Institution Experience from an Academic Center

Background: The extent of pretransplant workup for allogeneic hematopoietic stem cell transplant (HSCT) differs considerably among transplant centers. Current practice at the University of Wisconsin is for all recipients to undergo screening CT (computed tomography) of the sinuses, chest, abdomen, and pelvis prior to HSCT which can reveal several incidental radiographic findings. Here, we examined the impact of this procedure on discovery of clinically meaningful incidental findings, on time to transplant, on detecting post-COVID-19 infection related complications and on overall clinical outcomes post-HSCT in the current era of novel treatments for malignant hematologic disorders. Methods: After IRB approval, all consecutive patients &amp;gt; age 18 years at the University of Wisconsin who underwent full body screening CT prior to HSCT, from January 2019 to August 2022 were studied. Imaging abnormalities were defined as any finding reported by the radiologist apart from isolated mucosal thickening on sinus CT scans. Post-transplant pulmonary complications were defined as abnormal chest CT scans within 6 months post-transplant. Patient and disease characteristics were tabulated, and descriptive statistics are reported. Progression free survival (PFS) is defined as the time from transplant to first identification of relapsed disease. Results: Table 1 shows clinical characteristics of the study cohort. Median follow up is 22.55 months (95% CI 12.04-34.78). A total of 205 patients underwent 577 screening CT scans prior to HSCT, of which 82% (n=169) had at least one abnormal finding and 52% (n=107) had an incidental finding. Of the patients with incidental findings, 53% (n=57) received no additional workup or intervention while 47% (n=50) underwent further workup, yet only 18% (n=19) had a change in management as depicted in figure 2. Therapeutic interventions included treatment with antifungals (n=11), antibiotics (n=5), thoracentesis (n=1), thoracotomy (n=1) and anticoagulation (n=1). Although 50% of all chest CT scans identified an abnormality, only 5% revealed an incidental finding that influenced management including pulmonary nodules (n=7), bronchiolitis (n=1) and pulmonary emboli (n=1), compared to just 3% for both sinus and abdominal CT scans including sinusitis (n=4), periapical abscesses (n=3) and abdominopelvic masses of the bladder (n=1), iliac fossa (n=1), pancreas (n=1) and ovary (n=1). Post-HSCT complications were identified in 23% (n=21) vs 16% (n=15) in those with abnormal and normal pre-HSCT chest CT, respectively. In the subset of patients who underwent therapeutic interventions resulting from abnormal screening chest CT, 28% (n=5) still experienced post-transplant complications. Finally, the incidence of post-transplant pulmonary complications was similar, 27% (n=4), in patients with and without documented COVID infection prior to transplant. Median time to HSCT after scan completion was similar in patients with normal vs abnormal imaging without additional workup at 23 days (range 11-47), compared to 24 days (range 8-62), respectively. In contrast, median time to HSCT was longer at 30 days (range 11-173) and 48 days (range 13-208) for those who received additional work up and a therapeutic intervention, respectively (p=0.0001). One year post HSCT non-relapse mortality was 9% and 12 % among patients with normal screening CT, and those with at least one abnormal finding, respectively. 2-year PFS was similar in patients with abnormal vs normal screening chest CT scans at 60% vs 58% respectively (p=0.98). Conclusions: We observed high rates of incidental findings leading to additional work up in over 40% of patients, though less than half of them led to changes in management. As expected, we noted a substantial risk of delay to HSCT in most recipients needing intervention. Chest CT scans had the highest prevalence of clinically significant incidental findings and meaningful impact on management, whereas routine sinus and abdomen-pelvic CT showed lower clinical benefit. No additional advantage of CT chest was found in asymptomatic patients who had a COVID-19 infection pre-HSCT. Our findings provide basis to re-evaluate current practice of pre HSCT screening, and identify at-risk patients who would benefit from screening. Additional analyses are needed to minimize risks of unnecessary interventions, delays and burden on patients and healthcare utilization.

Hematopoietic Stem Cell Transplantation (HCT) Conditioning Leads to NK Cell Cytotoxicity Limiting Endogenous Thymus Regeneration

The thymus is highly sensitive to acute injury such as the cytoreductive conditioning given pre-hematopoietic stem cell transplant (HCT). The thymus is capable of regeneration, however its reparative capacity and T cell productivity decline with age. This leaves HCT recipients vulnerable to relapse of malignancy and opportunistic infection - the leading causes of post-HCT mortality - during a prolonged period of lymphopenia. Better understanding the endogenous mechanisms by which thymus regeneration is regulated may inform therapeutic interventions to improve T cell reconstitution in these patients. Here, we report that HCT conditioning leads to rises in stimulatory cytokine IL-18, subsequent activation of NK cells and increased cytotoxicity, which aberrantly suppresses organ recovery. Our group has reported that HCT-conditioning by ionizing radiation leads to increased Caspase-1 mediated immunogenic cell death within the thymus (Kinsella 2023 BioRxiv). Consistent with the cleavage of Caspase-1, we found an increase in release of the inflammatory cytokines IL-1b and IL-18. Although mice deficient for IL-1b signaling receptor ( Il1r -/-) did not show any modulation in their ability to regenerate after TBI, we found that mice deficient for IL-18 signaling (Il18 -/-) exhibited increased thymic cellularity one week following acute damage by sublethal irradiation (SL-TBI) (Fig. 1A left). This led us to conclude that post-damage activation and release of IL-18 suppresses thymus regeneration. We found that IL-18R was not expressed on most developing thymocytes and although a minority of thymic epithelial cells expressed the receptor, mice with a deficiency in IL-18R restricted to TECs ( Il18r1fl/fl:Foxn1-Cre +) showed no difference in regenerative capacity following conditioning. To rule out an effect on hematopoietic progenitors, for which IL-18R expression has been reported ( Silberstein 2016 Cell Stem Cell 6;19), we performed a competitive transplantation of Il18r1 -/- and WT bone marrow and measured T cell production, which showed no competitive advantage of Il18r1 -/- donor cells; this demonstrated that IL-18 does not directly regulate progenitor cells themselves, but rather, more likely acts via a bystander thymus-resident population. Within the thymus, IL-18R was expressed by highly radioresistant NK1.1 + NKT and NK cells. Depletion of both populations with anti-NK1.1 monoclonal antibody improved thymus cellularity in WT mice (Fig. 1A middle). Notably, NKT deficient CD1d -/- mice showed no defective repair which suggested that the depletion upon NK1.1 + cell depletion is largely mediated by NK cells. Depletion of NK1.1 + cells in Il18 -/- mice did not improve regeneration further, suggesting that NK-mediated suppression is IL-18 dependent. Given the known role of IL-18 in NK cell activation, we hypothesized that the HCT-conditioning resultant rise in IL-18 stimulates NK cells leading to “accidental” targeting of regeneration promoting cells. NK cell production of cytotoxic factors including IFNg, GzmB and Perforin increases following radiation conditioning, although only mice deficient for Perforin and not IFNg -exhibited improved thymus cellularity 7 days post HCT-conditioning (Fig 1A right). Further supporting this hypothesis, IL-18R +CD49b + NK cells isolated from the thymus 2-days post-irradiation induced more target cell death in head-to-head cytotoxicity assays compared to NK cells isolated pre-radiation (Fig 1B). Finally, we observe TEC downregulation of NK cytotoxicity inhibitory ligand MHC-I following radiation conditioning, suggesting that critical regeneration promoting stroma may be the targets of these activated NK cells. These findings suggest that, while necessary for successful transplantation, conditioning regimens may induce cytotoxicity of bystander NK cells which suppresses thymus recovery. Furthermore, we implicate conditioning induced immunogenic cell death and increased IL-18 in the stimulation of these suppressive cytotoxic cells and suggest that therapeutically targeting IL-18 and NK cell cytotoxicity may improve T cell reconstitution post-HCT.

Gut Microbiome Faecalibacterium Abundance in Patients with Plasma Cell Disorders Undergoing Autologous Hematopoietic Stem Cell Transplant Is Associated with Progression Free Survival

Background: Different aspects of the gut microbiota (GM), including diversity, abundance, and functionality, have been linked to the development, progression, response, and adverse events to therapy in plasma cell neoplasms (PCN). The primary goal of this study was to further investigate the relationship between the composition of the GM, focusing on the genus Faecalibacterium that contains the most common anaerobic commensal bacterium in the GM ( Faecalibacterium prausnitzii), and clinical outcomes of patients with PCN undergoing autologous hematopoietic stem cell transplant (HSCT). Methods: GM samples were collected prospectively between 2017 and 2021 at our institution as part of a phase III, randomized clinical trial including patients with malignant hematologic diseases undergoing either chemotherapy or transplant. Fecal samples were obtained at pre (baseline), mid (defined as at 1 week from baseline), and end (defined as at engraftment, absolute neutrophil count &amp;gt; 500 cells/mm 3) autologous HSCT and processed by 16S rDNA sequencing (V1-V3) using Illumina MiSeq to determine Faecalibacterium abundance at each prespecified time point. Progression free survival (PFS) and overall survival (OS) were computed via Kaplan-Meier estimate. Results: 83 evaluable patients underwent autologous HSCT for PCN, 54 (65%) as part of frontline therapy. 79 (95%) of the transplant recipients carried a diagnosis of Multiple Myeloma. Melphalan was used as the conditioning regimen, with 54 (65%) of the patients receiving a dose of 200 mg/m 2 (versus 140 mg/m 2). The median age of the patients was 64 (range, 31-79) years and 50 (60%) were men. With median time to follow up for survivors (n= 82, alive &amp;gt; 1 month post HSCT) of 32 (range, 0.7-61) months, the median PFS was 40 months and median OS was not reached. Faecalibacterium relative abundance was 3.5%, 1.7%, and 2% of the GM at pre, mid, and end transplant, respectively. Higher baseline Faecalibacterium abundance was significantly associated with superior PFS (n= 79) (HR= 0.92, p= 0.01) and OS (HR= 0.88, p= 0.008). Patients were partitioned into 2 groups, those with pre-transplant Faecalibacterium abundance above median and below median, to generate representative Kaplan-Meier curves for PFS (Figure 1). Greater reduction in Faecalibacterium abundance during transplant, and especially from pre to mid transplant, were significantly associated with worse PFS (n= 75) (HR= 1.08, p= 0.007; HR= 1.10, p= 0.004, respectively) and OS (HR= 1.09, p= 0.021; HR= 1.09, p= 0.04, respectively). There was no significant relationship between Faecalibacterium abundance and PFS at mid (n= 83) (HR= 1, p= 1), end (n= 83) (HR= 1.01, p= 0.7), or notably mid to end transplant (n= 75) (HR= 1, p= 0.9). Levels of the bacteria also did not associate with OS from mid to end transplant (n= 75) (HR 1.01, p= 0.8). Conclusions: Our study indicated that Faecalibacterium abundance in the GM changed rapidly early after autologous HSCT in patients with PCN likely due to melphalan administration. Higher baseline levels and smaller reduction in Faecalibacterium abundance predicted superior PFS. Further follow up with more mature data is needed to confirm OS associations. These findings support the need for further investigation into the role of GM and possible interventions to modify GM to improve outcomes to autologous transplant in patients with PCN.

Torque Teno Virus Monitoring in Pediatric Hematopoietic Stem Cell Transplantation

Background Immune reconstitution (IR) after allogeneic hematopoietic stem cell transplantation (HSCT) is crucial to avoid infection, relapse, and graft versus host disease (GvHD). Torque Teno Virus (TTV) is a highly prevalent and ubiquitous small DNA virus which constitutes the main component of human virome. In the transplant setting, TTV viral load (VL) seems to correlate with immunodeficiency status, but most studies have focused on solid organ transplant recipients. Aims To study the kinetics of TTV VL in blood (log10 copies/ml), and its presence in nasopharyngeal aspirate (NPA) by qualitative PCR in children undergoing HSCT, and to study their correlation with HSCT outcomes and other markers of IR in the first year after the procedure. Methods Prospective single center study including patients &amp;lt;18 years old who underwent HSCT in 2020-2022, excluding those with lung disease. Blood and NPA samples were collected pre-HSCT and at days 0, +15, +30, +90, +180, +270 and +360 post-HSCT. Immune cell typing including T/B/NK, and NK phenotyping and cytotoxicity (%CD107a+) were performed in blood, and T/NK cells by flow cytometry and respiratory viruses by multiplex PCR were tested in NPA. TTV in blood was analyzed with TTV R GENE® kits (Biomérieux, France), whereas for NPA an in house PCR developed at the National Centre for Microbiology was used. Results We included 30 patients, whose main characteristics are summarized in Table 1. The most frequent indication for HSCT was malignant disease (76.7%). Donor was mainly HLA mismatch (67%). All patients had engraftment (median 10 days, IQR 10-13.5), but one experienced secondary graft failure. Acute GvHD occurred in 73% of patients (63% grades II-IV), and chronic in 37% (10% severe). Almost all patients (93%) presented at least one episode of infection (median 3, IQR 1-6). Endothelial injury complications occurred in 17%. During the first year post-HSCT, 2/21 patients relapsed. Overall survival was 67% (median follow up 601 days, IQR 424.25-880). No significant differences were found in pre HSCT TTV VL regarding patient age, sex, underlying disease, nor CMV status. TTV VL (Graphic 1) decreased after conditioning to minimum at +15 (mean log10 3.149, SD 1.8), increased from +30 being highest at +270 (mean log10 6.778, SD 1.7), and at +360 was still higher than pre-HSCT (mean log10 6.358, SD 1.9). At day +15, each increase in log10 TTV VL increased the risk of dying 39% (p=0.027). At day +30, TTV VL was higher when total lymphoid irradiation (TLI) was used vs serotherapy (p=0.01). No differences were found regarding GvHD development or infections episodes. TTV could be detected in NPA, although its prevalence seems lower than in blood: 14/44 NPA samples resulted positive (32%), most at day +15 (36%); while 50/182 (27.5%) were positive for respiratory virus, the majority at +270 (28%), without identifying any association with TTV positivity. We found several associations between TTV VL and some parameters of IR: there was an inverse correlation with leukocytes, total, and B lymphocytes at +90 (p=0.001, 0.013, and 0.035 respectively), and with leukocytes at +270 (p=0.042). There was also an inverse correlation at +90 with %CD4+CD45RA+ (p=0.043), and direct with %CD4+CD45RO+ (p=0.038). Finally, TTV VL was direclty associated at pre-HSCT with %CD3+HLADR+ (p=0.035). In our series, associations between TTV VL and NK were positive, the stronger with %CD16+ at +270 (p=0.023). Nevertheless, an inverse correlation was found with %CD107a+ at baseline (p=0.04) and at +15 (p=0.013). There was a lack of a consistent pattern of expression of NK receptors along our study. Conclusions 1. TTV is usually detected in blood in children undergoing HSCT, whereas its detection in NPA is less frequent. 2. TTV could be a potential early biomarker of survival after pediatric HSCT. 3. TTV correlates with less NK citotoxicity before and early after HSCT. 4. TTV VL correlates with slower IR at day 90 after HSCT.

CNS Prophylaxis in Adult ALL Patients after Stem Cell Transplantation: An EBMT Survey on General Practice

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for acute lymphoblastic leukemia (ALL) resulting in long-term remission. Despite advances in therapy, disease progression remains the major cause of mortality following HSCT accounting for 20-50% of all deaths. The central nervous system (CNS) is the most common extra-medullary site of disease progression after transplant in ALL. The established practice of CNS prophylaxis for ALL has largely been modeled in the pediatric population, given the higher incidence of ALL in this age group compared with adults. Although the use of CNS prophylaxis as part of the upfront treatment for ALL has led to significant decreases in CNS relapse and improved outcomes overall, the routine use of post-HSCT prophylactic CNS therapy as a strategy to prevent CNS relapse after transplant in adult patients is still controversial. Studies that utilized post-HSCT CNS prophylaxis have reported disparate results and there is no generalized consensus regarding the use of post-transplant CNS prophylaxis to prevent relapse. Methods In order to assess the current practice of post-HSCT prophylactic CNS therapy in preventing CNS relapse in ALL patients, we carried out a survey among EBMT centres to describe intrathecal (i.t.) prophylaxis or irradiation in HSCT for ALL in both patients with or without CNS manifestations at any time of disease (first or second complete remission [CR1, CR2] and relapsed/refractory [R/R] ALL). EBMT centres were asked whether they usually give i.t. prophylaxis or cranial irradiation before and after HSCT, and which drugs they use. Results Of 410 invited centres, 55 (13%) replied to the survey. Tables 1 shows the number of centres which use i.t. prophylaxis or cranial irradiation. Most of the 55 centres used both pre-and post i.t. prophylaxis and triple prophylaxis (steroids, cytarabine [AraC] and methotrexate [MTX]) was the most frequently adopted. As expected in the pre-transplant phase, almost 70% of centres use i.t. chemotherapy irrespective of the phase of the disease or of the use of total body irradiation (TBI) as conditioning regimen. In the post-transplant phase, the rate of i.t prophylaxis varies according to disease phase, TBI use, and history of CNS involvement pre HSCT. In patients w/o history of CNS involvement in CR1, i.t. prophylaxis is given in 23.6% and 21.5% (with or w/o TBI use, respectively). Notably in CR2 pts, i.t. prophylaxis is given in 20% of cases if the conditioning regimen includes TBI, and in 74.5% of cases if TBI is not used; 32.7% and 46.9% R/R pts (with or without TBI use, respectively) are given i.t. prophylaxis. In the setting of patients with history of CNS involvement in CR1, i.t. prophylaxis is given in and 30.9% and 38.2% (with or without TBI use, respectively); in CR2 pts, i.t. prophylaxis is given in 38.9% of cases if the conditioning regimen does not include TBI, and in 29.1% of cases if TBI is used; 38.9% and 45.3% R/R pts (with or without TBI use, respectively) are given i.t. prophylaxis. Pre-transplant cranial irradiation is planned in less than 10% of centres in CR1 and CR2 patients without CNS involvement, irrespective of the use of TBI in the conditioning regimen, while it is used in 22.4% and 25% of patients with R/R disease with or without TBI use for transplant, respectively. In the setting of patients with CNS involvement, among those in CR1 and CR2, approximately 30% receive pre-transplant cranial irradiation irrespective of TBI use, while 32.7% and 34.6% of patients receive cranial irradiation (with or without TBI use, respectively). Its use after transplant is uncommon irrespective of disease status at treatment. Conclusions CR2 pts (without CNS involvement) seem to be at higher risk of CNS relapse if TBI is not included in the conditioning regimen. R/R pts are always considered at higher risk for CNS relapse if TBI is not included in the conditioning regimen. Cranial irradiation before treatment is used in almost 1 out of 3 pts with CNS involvement despite the use of TBI as the conditioning regimen, and 1 out 4 R/R pts without CNS involvement at transplant. The rate of cranial irradiation after transplant is extremely low, irrespective of diseases status, previous CNS involvement or TBI use. In conclusion, the use of i.t. prophylaxis after HSCT in patients with or without CNS involvement is variable among European transplant centres, also in the era of novel therapies for patients with ALL.

Interleukin 18 (IL-18) Suppresses Thymus Regeneration

Abstract The thymus is highly sensitive to acute injury, particularly to cytoreductive conditioning given pre-hematopoietic stem cell transplant (HCT). The thymus is capable of a remarkable degree of regeneration, however its reparative capacity and T cell productivity decline with age. This leaves HCT recipients vulnerable to relapse of malignancy and opportunistic infection – the leading causes of post-HCT mortality – during a prolonged period of lymphopenia. Better understanding the endogenous mechanisms by which thymus regeneration is regulated may inform therapeutic interventions to improve T cell reconstitution in these patients. Here, we identify the inflammatory cytokine interleukin 18 (IL-18) as a suppressant of thymic function and propose its targeting to improve immune reconstitution. We posit that distinct forms of acute injury (i.e., irradiation, chemotherapy, infection and stress) lead to caspase-1 activation within the thymus and subsequently increased active IL-18. Our preliminary data suggests that IL-18 receptor (IL-18R) expressing natural killer (NK) cells are activated following acute damage in an IL-18 dependent fashion. Importantly, depletion of this NK1.1 +IL-18R +population improves thymus regeneration, suggesting that IL-18 induces an inflammatory response in organ-resident NK cells capable of impairing thymus repair. Our findings implicate IL-18 as a novel regulator of thymic regeneration and identify NK cells as likely mediators in its pathway. Furthermore, we suggest that IL-18 can be therapeutically targeted to improve T cell reconstitution following cytoreductive therapy and HCT. Supported by grants from NIH (R01 HL145276, P01 AG052359)

Risk of Secondary Malignancies in Hematopoietic Stem Cell Transplantation Recipients: A Nationwide Population-Based Study in Taiwan

The improvement of survival after hematopoietic stem cell transplantation has brought about a need to evaluate long-term complications, for instance, secondary malignancies. The risk of subsequent malignancies after hematopoietic stem cell transplantation must be clarified in a large population. To estimate the risk of secondary malignancies in hematopoietic stem cell transplantation survivors and compare it with the risk in patients without hematopoietic stem cell transplantation history. We conducted a population-based retrospective cohort study of 3,059 hematopoietic stem cell transplantation recipients from the National Health Insurance Research Database of Taiwan, containing 1,378 autologous, 1,641 allogeneic, and 40 cord blood stem cell transplantation recipients between 2000 and 2013. A control group of 12,236 patients without an hematopoietic stem cell transplantation history was identified. The covariates included age, sex, comorbidities, stem cell source, facility level of care, and history of total body irradiation. Comorbidities were estimated by the revised Charlson comorbidity index, and a higher score suggested more severe comorbidity. Adjusted hazard ratios were determined by adjusting for age, sex, comorbidity, and facility level of care. Overall, hematopoietic stem cell transplantation recipients had a higher risk of secondary malignancies with an adjusted hazard ratios of 1.348 (p = 0.017). Being male and female (adjusted hazard ratios 1.395, p = 0.009 and adjusted hazard ratios 1.291, p = 0.042, respectively) and pre-hematopoietic stem cell transplantation total body irradiation (adjusted hazard ratios 1.591, p < 0.001) were correlated with a high risk of secondary malignancies. Among the subsequent neoplasms, bone cancer showed the highest risk (adjusted hazard ratios 27.899, p < 0.001), followed by laryngeal (adjusted hazard ratios 6.643, p < 0.001), kidney (adjusted hazard ratios 5.580, p < 0.001), esophageal, pancreatic, thyroid (adjusted hazard ratios 1.993, p < 0.001), and skin (adjusted hazard ratios 1.992, p < 0.001) cancers. The median follow-up duration was 2.16 years in the hematopoietic stem cell transplantation group and 2.57 years in the control group, and the overall median follow-up duration was 2.21 years. Medical practitioners should be aware of the high risk of secondary malignancies in hematopoietic stem cell transplantation recipients later in life. These recipients should be informed about the importance of regular follow-up and photoprotective measures. Lifelong surveillance is recommended.

Interleukin 18 Suppresses Regeneration of the Thymus

The thymus is highly sensitive to acute injury, particularly to cytoreductive conditioning given pre-hematopoietic stem cell transplant (HCT). The thymus is capable of a remarkable degree of regeneration, however its reparative capacity and T cell productivity decline with age. This leaves HCT recipients vulnerable to relapse of malignancy and opportunistic infection - the leading causes of post-HCT mortality - during a prolonged period of lymphopenia. Better understanding the endogenous mechanisms by which thymus regeneration is regulated may inform therapeutic interventions to improve T cell reconstitution in these patients. Here, we identify the inflammatory cytokine interleukin 18 (IL-18) as a novel suppressant of thymic function and propose its targeting to improve immune reconstitution. Recently, our group reported that attenuation of homeostatic detection of apoptotic thymocytes after damage regulates tissue regeneration by releasing the brakes on the production of the regenerative factors IL-23 and BMP4 (Kinsella 2021 Cell Rep 37:1). However, our preliminary data also shows that upon acute damage by ionizing radiation, there is a switch towards an immunogenic pyroptotic cell death with an increase in cleaved caspase 1 (pyroptotic caspase) and release of damage-associated molecular patterns. Among these was the release of the caspase 1 dependent inflammatory factors IL-1b and IL-18 within the thymus following damage. Although mice deficient for IL-1b receptor (Il1r-/-) did not show any modulation in their ability to regenerate after total body irradiation (TBI), we found that mice deficient for IL-18 (Il18-/-) exhibited increased thymic cellularity (Fig. 1A). Based on these findings, we hypothesized that immunogenic cell death-induced IL-18 suppresses thymic repair following acute insult and that IL-18 can be targeted to improve T cell reconstitution in settings of lymphopenia. Although IL-18R was expressed by a substantial fraction of medullary thymic epithelial cells (mTECs), and TECs serve as the master regulators of thymic function, mice with a deletion for IL-18R specifically in TECs (using Il18r1fl/flFoxn1Cre+ mice) did not show any altered regenerative capacity compared to control mice, suggesting that IL-18 does not act directly on TECs. Instead, we determined most IL-18Rexpression was restricted to NK1.1+ Innate Lymphoid Cells. Strikingly, in vivo depletion of this population prior to induction of damage significantly improved thymic regeneration (Fig. 1B), consistent with what we observed in IL-18 deficient mice. Importantly, we found that thymic NK cells were activated after damage, with increased expression of Perforin, Gzma, and Gzmb, as well as the activation markers Nkg7, Klrd1, and Klrk1 (NKG2D). Suggestive of a mechanism that could be mediating this, mice with a germline deletion for Perforin showed improved thymus repair following acute damage further supporting an NK cell mediated mechanism of thymic suppression. Finally, mice treated with an antibody against IL-18 demonstrated early signs of improved thymic regeneration and export of new naïve T cells in a mouse model of allogeneic HCT. Taken together, these findings implicate the inflammatory cytokine IL-18, signaling through NK cells, as suppressive to endogenous thymic regeneration. Furthermore, our data suggests that this pathway can be therapeutically targeted to improve T cell reconstitution following cytoreductive therapy and HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HSCT Chemotherapy Supports Peripheral Macrophage Engraftment of the Brain.

Pre-hematopoietic stem cell transplantation (HSCT) chemotherapy creates a permissive niche in the brain for peripheral macrophage engraftment.

Longitudinal Tear Protein Changes Correlate with Ocular Chronic GVHD Development in Allogeneic Hematopoietic Stem Cell Transplant Patients

Ocular graft-versus-host disease (oGVHD) is a manifestation of chronic GVHD, frequently occurring in patients after allogeneic hematopoietic stem cell transplant (HSCT). We analyzed tear protein changes before and after allogeneic HSCT, and correlated their levels with the oGVHD development. This retrospective study included 102 patients, and data were recorded before the conditioning treatment, and after 3 to 6 months postoperatively. Tear protein analysis was performed with the Agilent-2100 Bioanalyzer on individual tears sampled by aspiration. Total protein (TP), Lysozyme-C (LYS-C), Lactoferrin (LACTO), Lipocalin-1 (LIPOC-1), Transferrin (TRANSF), Albumin (ALB), and Zinc-alpha-2-glycoprotein (ZAG-2) levels were retrieved and statistically analyzed. Following HSCT forty-three patients developed oGVHD. TP, LACTO, LYS-C, and ZAG-2 levels significantly decreased post-HSCT as compared to pre HSCT levels. In univariate analysis, TP, LACTO, and ZAG-2 decrease was associated with an increased development of oGVHD (OR = 4.49; 95% CI, 1.9 to 10.5; p &lt; 0.001; OR = 3.08; 95% CI 1.3 to 7.6; p = 0.01; OR = 11.1; 95% CI 2.7 to 46.6; p &lt; 0.001, respectively). TRANSF post-HSCT levels significantly increased (OR 15.7; 95% CI, 4.1 to 52.2; p = 0.0001). No pre-post-HSCT changes were shown in ALB and LIPOC-1 levels. Data suggest that TP content, LACTO, TRANSF, and ZAG-2 pre-post changes might be significant predictors of oGVHD development.

Risk Factors and Outcomes According to Age at Transplant with an HLA Identical Sibling for Sickle Cell Disease

Background: Hematopoietic stem cell transplant (HSCT) from an HLA identical (HLAid) sibling donor is a well-established curative therapy for sickle cell disease (SCD). However, the ideal age to perform HSCT in SCD patients remains controversial. We report the outcomes after HLAid sibling HSCT for SCD according to patient's age at the time of HSCT as well as their pre-transplant characteristics.Methods: We retrospectively analyzed 727 HLAid sibling HSCTs performed between 1986 and 2015 in 98 EBMT centres. Patients were divided in three groups according to their age at the time of HSCT: <5 year-old (n=176): group 1, 6-15 year-old (n=431): group 2 and >15 years old (n=120): group 3. Primary endpoint was probability of 3-year overall survival (OS) according to age group.Results: Median follow-up was 46 (range: 0.5-346) months. Median age at HSCT was 4 (range: 0.9-5) years in patients <5 years, 10 (range: 6-14) years in patients 6-15 years and 17 (range: 15-39) years in patients >15 years. Gender distribution did not significantly differ among the three groups. The most common SCD genotype was homozygous (SS) in the three groups (95% vs 92% vs 84%, p=0.004). Positive cytomegalovirus (CMV) serology was less frequent in group 1 (63% vs 79% vs 83%, p<0.001. Also, patients in group 1 were less treated with hydroxyurea (37% vs 60% vs 77%, p<0.001), received less than 20 red blood cell units transfusions (32% vs 43% vs 58%, p=0.002) and presented less than 3 SCD complications before HSCT (11% vs 19% vs 39%, p<0.001). For all age groups, vaso occlusive crisis (VOC), acute chest syndrome (ACS) and cerebral vasculopathy were the most reported SCD complications, and the main indications for HSCT were VOC, cerebral vasculopathy, ACS and nephropathy.The proportion of patients with Karnofsky performance status (KPS) <80 did not differ between groups. Graft source distribution was bone marrow (BM) in 74%, cord blood (CB) in 23% and peripheral blood (PBSC) in 3% of cases in group 1; BM in 85%, CB in 11% and PBSC in 4% of cases in the group 2; BM in 79%, CB in 1% and PBSC in 20% of cases in group 3 (p<0.001). Conditioning regimen was myeloablative in 97% of cases in group 1, 96% in group 2 and 83% in group 3 (p<0.001), and included in vivo T cell depletion, mostly antithymocyte globulin (ATG), in 74%, 86% and 90% of the cases, respectively (p<0.001). In all groups, graft versus host disease (GvHD) prophylaxis was mainly cyclosporine- A with methotrexate±mycophenolate mofetil. ABO and gender match between donor and recipient did not significantly vary among groups.Neutrophil engraftment at day +60 was 96%+1 in the first group, 98%+1 in the second group and 95%+2 in the third group (p=0.009). Four patients in group 1, 10 patients in group 2 and 6 patients in group 3 had primary graft failure. The first group experienced less acute GvHD (aGvHD) within 100 days after HSCT (9%+2 vs 18%+2 vs 17%+4, p=0.022) and less chronic GvHD (cGvHD) within 3 years after HSCT (9%+2 vs 12%+2 vs 20%+4, p=0.006). Three-year OS was significantly better in group 1 (99%+1 vs 95%+1 vs 88%+3, p<0.001) as well as 3-year event free survival (EFS) (96%+2 vs 92%+1 vs 84%+4, p=0.001). In a subset of patients with available chimerism data (n=405), in group 1 and group 2 65% were full donor, 32% mixed chimeras and 3% autologous reconstitution whereas in group 3 46% were full donor, 49% mixed chimeras and 5% autologous reconstitution. A univariate risk factor survival analysis was performed for group 3 (only group with sufficient events for analysis), but no patient, donor or HSCT risk factors influencing OS were identified.Conclusion: Patients transplanted at a young age have a better 3-year OS and 3-year EFS, with lower incidence of aGvHD and cGvHD. These findings outline the importance of early referral to HSCT for SCD patients. Strategies to further evaluate pre HSCT, HSCT and donor factors that may influence survival and adverse outcomes could help improve HSCT results. Disclosuresde la Fuente:Jazz Pharmaceuticals: Honoraria; bluebird bio: Consultancy; HCA: Consultancy. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma Benefits Patients with Persistent Disease and Results in a High Rate of Residual Disease Clearance

Introduction: Residual disease (RD) after autologous transplantation as well as following induction therapy in multiple myeloma (MM) patients ineligible for transplant is associated with inferior survival. The significance of RD quantified by multiparameter flow cytometry (MFC) in the setting of allogeneic hematopoietic stem cell transplantation (HCT) for MM has not been reported. Using MFC we assessed the likelihood of RD clearance after HCT and assess whether RD status before HCT and at 1 and 3 months after HCT was associated with survival.Methods:We include 51 consecutive patients who underwent HCT for high-risk relapsed MM at our center between January 2014 and October 2016. All received CD34+ selected peripheral blood stem cell grafts. Donors included matched related (n=15), matched unrelated (n=20) and HLA 9/10 mismatched unrelated (n=16). The preparative regimen included busulfan (0.8mg/kg x 10 doses), melphalan (70mg/m2 x 2days), fludarabine (25mg/m2 x5days) and rabbit ATG (2.5mg/kg x 2 days).RD was assessed using MFC at 3 time points (TP) including TP0: median of 28 days (14-64) before transplantation (n=51), TP1: median of 28 days (range 26-55 days) after HSCT (n=48) and TP2: median 97 days (range 90-180days) after HSCT (n=43). MFC RD analysis was performed on marrow aspirate samples using 8-color flow analysis with sensitivity of 0.01% of white cells in 2013-till December 2015 and 10-color flow analysis with sensitivity of 0.0005% subsequently.Standard criteria were used to define categorical MM disease response. Overall survival (OS) was assessed using the Kaplan-Meier method and groups were compared using the log rank test. A landmark analysis was performed to assess the significance of MRD status at TP1 and TP2, with patients who relapsed or progressed within 30 days of the respective TP excluded from the landmark analysis.Results:Themedian age was 55 years (range 35-67). All patients had undergone prior autograft. Twelve experienced disease progression or relapse and 21 died, including 7 deaths due to relapsed MM and 14 due to transplant related mortality. The median follow-up amongst survivors (n=30) was 524 days (97-1089 days). Categorical disease status at HCT included: CR (n=9), VGPR (n=12), PR (n=21) and SD/PD (n=9) and this was associated with RD status. Detected RD was noted in 2/9 (22%), 8/12 (67%), 18/21 (86%) and 6/9 (67%) patients in CR, VGPR, PR and SD/PD, respectively (p=0.01).At TP0 34/51 had RD including all 13 with ≥5% marrow plasma cells. At TP1 31/48 were RD- (3 did not undergo RD assessment at TP1 due to TRM 49, 50 and 122 days after HCT). Of the 31 who were RD+ at TP0 and had assessment at TP1, 15 became RD- (48%). Sixteen of 17 who were RD- at TP0 remained RD- at TP1 and only 1 became RD+. Between TP1 and TP2 the concordance of MRD status among 43 patients who had assessment at both time points was 81% (RD+ at TP1 and TP2 n= 12, RD- at TP1 and TP2 n=23). Two became RD- at TP2 and 6 (14%) became MRD+, 4 of whom died due to MM.Categorical disease status before HCT was associated with RD status at TP1 and TP2. At TP1, 3/20 (15%) evaluable patients who were in CR or VGPR before HCT were RD+, compared to 14/28 (50%) who were in PR/SD or PD (p=0.016). At TP2, 3/19 (16%) evaluable patients who were in CR/VGPR prior to HCT were RD+ compared to 15/24 (63%) who were in PR/SD or PD (p=0.004). (Table 1)Conclusions: HCT resulted in the clearance of RD at TP1 in 48% of patients. Unlike autologous transplantation and pharmacologic therapy, HCT benefited MM patients irrespective of pre HCT RD status. Recurrence of RD by MFC was identified in 14% of patients between TP1 and TP2 suggesting this may be an optimal time to intervene with post transplant maintenance strategies. Improved RD sensitivity may be needed to better assess progression risk of MM post HCT. [Display omitted] DisclosuresKoehne:Atara: Consultancy, Patents & Royalties.

Determinants for Oral Mucositis in Allogeneic Hematopoietic Stem Cell Transplantation: Prospective Evaluation and Risk Analysis

Background: Oral mucositis (OM), secondary to mucosal barrier injury of pre-hematopoietic stem cell transplantation (HSCT) conditioning, is a common and painful toxicity of transplantation. Mucositis has been associated with increased risk for infections, hospitalization, analgesia and total parenteral nutrition use, and higher costs. However, prevalence and incidence data for mucositis are inconsistent and underreported. We set to prospectively identify risk factors for oral mucositis in patients undergoing allogeneic HSCT.Methods: OM was prospectively evaluated on a weekly basis in patients undergoing allogeneic HSCT. The grade of OM was determined based on the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) scale (v. 4.0). Severe OM was defined as grade 2 or higher. Conditioning regimens were evaluated individually and according to intensity; myeloablative (MAC), reduced intensity (RIC) or reduced toxicity (RTC). The latter category included only patients receiving Fludarabine and Treosulfan (Flu/Treo). Variables associated with severe OM (p<0.05) were initially identified by univariate analysis (Chi-square and Mann Whitney U tests) and then analyzed in a multivariate logistic regression model. Cox and Fine and Gray regression models were used to study the association between severe OM and overall survival or nonrelapse mortality, respectively.Results: A total of 95 patients who underwent an allogeneic HSCT from 2016 to 2017 were included. Median age was 61 (range 19-75). Leading indications for HSCT were acute myeloid leukemia (51%), followed by myelodysplastic syndrome (15%), and non-Hodgkin lymphoma (12%). The majority of patients had a comorbidity score ≥3 (51%), were exposed to systemic antibiotics preceding transplantation (53%), and had no history of recent smoking (86.%). Donors were primarily HLA matched unrelated (51.1%) or HLA matched siblings (40%). RIC, MAC, and RTC regimens were used in 41%, 34%, and 25% of the patients, respectively. Methotrexate (MTX) (72.6%) or Mycophenolate mofetil (MMF) (27.4%), in conjunction with Cyclosporine, were given for graft versus host disease (GVHD) prophylaxis. Median follow-up was 165 days (95% CI 130-200).Median OM grade was 2 (range 0-4), with 65% of the patients experiencing severe mucositis. Median time from HSCT to OM and duration of OM were 8 days (1-14) and 10 days (2-40), respectively. Patients receiving Flu/Busulfan (Bu)-4 days (Flu/Bu4) were more likely to develop severe OM (91% vs. 9%, p<0.01), while among those conditioned with Flu/Treo, 29% had severe OM vs. 71% who did not (p<0.01) (Figure). In a univariate analysis, considering a broad range of patient, disease, and transplant characteristics (Table), only a history of recent smoking (19% vs. 3%, p=0.028), exposure to antibiotics in the preceding month pre-HSCT (61% vs. 39%, p=0.049), and use of MTX for GVHD prophylaxis (85% vs. 49., p<0.001) were associated with severe mucositis. Patients receiving RTC (i.e. Flu/Treo conditioning) had lower rates of severe OM compared to both RIC and MAC (p<0.001). Pre-HSCT albumin levels, obesity, and a low estimated glomerular filtration rate (eGFR) were not associated with OM. In a multivariate logistic regression model use of MTX vs. MMF had an increased risk for severe OM (odds ratio [OR] 11.6 [95% CI 3.2-42.4], p<0.001); compared to MAC, the risk for severe OM was reduced with RTC (OR 0.1 [0.0-0.4], p=0.001. OR for recent smoking was 6.8 (0.7-64.5), with a trend toward statistical significance (p=0.09). Severe OM was not associated with a decrease in short term overall survival (HR 0.59 [95% CI 0.2-1.5] or increase in non-relapse morality (HR 0.51 [0.1-2]).Conclusion: Our findings suggest that administration of Fludarabine and Treosulfan is an appealing option for conditioning since the risk for oral toxicity is low while intensity is high. Though having a borderline statistical significance, peri-transplantation smoking emerges as an important risk factor for oral mucositis. Therefore, patient counseling about smoking could potentially lower rates of mucositis. In contrast to previous reports, obesity and pre-HSCT albumin and reduced eGFR were not associated with mucositis in our cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Does Mesenchymal Stromal Cell Count in Pre-autologous Hematopoietic Stem Cell Transplant Peripheral Blood and Apheresis Product Predict for Infectious Complications in the Post-transplant Period?

Mesenchymal stromal cells (MSC) have gained attention in the recent past considering their multipotentiality and organ-healing properties. Exogenous administration of MSC in the pre-hematopoietic stem cell transplant (HSCT) setting has been reported to enhance engraftment, heal graft-vs-host disease and increase infections in the post-HSCT period. In this study, we aimed to determine the effect of endogenous pre-HSCT MSC on the post-HSCT infectious complications in patients undergoing autologous-HSCT. The study included patients undergoing autologous-HSCT (n = 25; multiple myeloma-20, lymphoma-5). MSC were analyzed and quantified by flow cytometry in the peripheral blood (PB) at baseline, and in both PB and apheresis product (AP) following mobilization with growth factors. Pre-HSCT MSC (PB/AP) were correlated with the post-HSCT duration of febrile neutropenia and duration of antimicrobial drugs using Pearson's correlation co-efficient, and with the mucositis grade using Spearman's rank correlation. Pre-HSCT MSC (baseline and post-mobilization) correlated positively with the longer duration of febrile neutropenia and duration of antimicrobials used in the post-HSCT period (p < 0.05). Pre-HSCT MSC failed to correlate with post-HSCT engraftment and onset/severity/duration of oral and gastrointestinal mucositis. Endogenous pre-HSCT MSC counts might predict for increased infectious complications in the post autologous-HSCT setting.

Pre-transplantation cytoreduction does not benefit advanced myelodysplastic syndrome patients after myeloablative transplantation with grafts from family donors.

BackgroundThe role of pre‐hematopoietic stem cell transplantation (HSCT) cytoreduction with either induction chemotherapy (IC) or hypomethylating agents (HMAs) in treating advanced myelodysplastic syndrome (MDS) remains debatable. We aimed to evaluate pre‐HSCT strategies by comparing the endpoints related to disease control between advanced MDS patients with pre‐HSCT cytoreduction and those with best supportive care.MethodsWe described 228 consecutive advanced MDS patients who received HSCT from a haploidentical donor (HID, n = 162) or matched related donor (MSD, n = 66) with uniform myeloablative conditioning regimens between January 2015 and December 2018. Of these 228 patients, 131 (57.5%) were treated exclusively with pre‐HSCT best supportive care (BSC), 49 (22.5%) were given HMA, and 48 (21.1%) received both IC and HMA. Propensity score‐matching analysis, multivariate analyses, and subgroup analyses were performed to elucidate the impact of pre‐HSCT strategies on transplant outcomes.ResultsThe 3‐year relapse‐free survival (RFS) rates were 78.2% and 70.0% for the BSC and cytoreduction cohorts (P = 0.189) and were 78.2%, 66.7%, and 73.2% for the BSC, HMA, and HMA+IC groups, respectively (P = 0.269). A propensity score‐matching analysis confirmed that the 3‐year RFS rates were 81.9%, 87.5%, and 66.9% for BSC, cytoreduction complete remission (CR), and cytoreduction non‐CR groups, respectively (P = 0.051). Multivariate analyses demonstrated that pre‐HSCT cytoreduction, older patient age, monosomal karyotype, and interval between diagnosis and HSCT were poor prognostic factors for RFS. In the subgroup analyses, BSC was associated with longer RFS compared to cytoreduction among the younger patients, those with international prognostic scoring system intermediate‐2/high risk at diagnosis, and those with intermediate/poor cytogenetics.ConclusionsDifferent pre‐HSCT therapies did not yield discrepant post‐HSCT outcomes. No benefit in terms of post‐HSCT outcomes were correlated with pre‐HSCT cytoreduction in advanced MDS even for cytoreduction CR patients. Early referral to HSCT is essential for advanced MDS patients.

Vitamins and minerals intake adequacy in hematopoietic stem cell transplant: results of a randomized controlled trial.

Micronutrient intake among hematopoietic stem cell transplant (HSCT) recipients is poorly studied. This randomized control trial (RCT) assessed the effect of nutritional counseling on micronutrient intake post HSCT. Patients with hematological malignancies receiving HSCT were randomized at hospital discharge into an intervention group (IG) and a control group (CG) between 2016 and 2017. IG received individualized nutritional counseling in the first 3 months post HSCT while CG received general qualitative education without reinforcement. At assessment points (hospital admission, discharge, 30, 60, and 100 days post HSCT termed T4), 24-h recalls were analyzed, and micronutrient intake was compared to patients' individual needs. Results were reported as percentages of dietary reference intake. Groups (IG, n = 22 and CG, n = 24) had similar characteristics pre HSCT. Copper and α-tocopherol intake at T4 were significantly better in IG. Many B vitamins, vitamin C, Manganese, Potassium, Zinc, and vitamin K improved in IG only at T4 compared to baseline intake. Median vitamin D intake remained low in both groups with <20% of patients meeting their individual needs post HSCT. In conclusion, counseling was associated with a trend of improved micronutrient intake. Vitamin D levels remained low irrespective of counseling.

Stable Pulmonary Function after Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide: A Single Center Experience

Background: Pre- and post-transplant pulmonary function tests (PFT) have been previously analyzed in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). A deterioration in pulmonary function could be observed in this setting and accounts for higher morbidity and mortality. Haploidentical allogeneic stem cell transplantation (HAPLO) with post-transplant cyclophosphamide (PTCY) is increasingly used. Limited data exists on evaluation of PFT after HAPLO and the number of patients who underwent HAPLO in previously published studies is negligible. We report the evolution of PFT as well as pre-transplant characteristics and outcomes after HAPLO in the adult setting. Methods: We retrospectively analyzed 80 HAPLO performed in a single center between 2013 and 2019. All patients with available pre- and post-transplant PFT results were included in the study. The Friedman test was used for comparing PFT at baseline, 100 days and 1 year after HAPLO. Results: The median follow up was 32 (range: 12-74) months. CMV serology was positive in 45% and 65% of patients were male. The median age was 58 (range: 16-73) years. The proportion of surviving patients with available PFT at 3 months and 1 year were 86% and 68%, respectively. Diagnosis was acute myeloid leukemia in 51% and disease risk index was intermediate-low in 75% of the cases. Disease status before HAPLO was complete remission in 61%. Graft source was peripheral blood stem cells in 91% of the cases. Conditioning regimen was reduced intensity in 40% and the most frequent chemotherapy regimen was thiotepa, busulfan and fludarabine. Graft-versus- host disease (GvHD) prophylaxis consisted of Cyclosporine A (CsA) and mycophenolate mofetil in all but one patient who received methotrexate and CsA. All patients received PTCY, 64 (80%) at days 3 and 5 after HAPLO, 7 (9%) at days 3 and 4, and 9 (11%) at day 3 only. Seventy-three (91%) patients received anti-thymocyte globulin. In total, 24% of the patients had previously smoked, 8% had type 2 diabetes, and 23% suffered from hypertension. Three patients had a lung infection at baseline, of which one was bacterial and two were possibly aspergillosis. At screening for HAPLO, five (6%) patients had restrictive lung disease, nine (11%) met the criteria for obstructive lung disease, and diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin was impaired in 74% of the patients. The median forced expiratory volume in the first second (FEV1) was 100 (range: 58-146) before HAPLO, 93 (range: 42-10) at 100 days after HAPLO and 99 (range: 32-144) at 1 year. The median forced vital capacity (FVC) was 106 (range: 57-153), 98 (range: 44-148) and 106 (range: 31-153) at pre HSCT, 100 days and 1 year after HAPLO, respectively. FEV1 and FVC were significantly different over time during the 1 year follow up (p=0.01 and p=0.001, respectively). The median FEV1/FVC was 80 (range 51-105) before HAPLO, 77 (range: 54-103) after 3 months, and 75 (range: 43-100) after 1 year. FEV1/FVC, residual volume, and total lung capacity (TLC) remained stable from baseline to 1 year (p=0.27, p=0.84 and p=0.21, respectively). In contrast, DLCO remained impaired during the follow-up period (p&amp;lt;0.001). The median DLCO was 72 (range: 39-105), 64 (range: 16-105) and 66 (range: 26-104) at baseline, 3 months and 1 year after HAPLO. Twenty-nine patients had an infectious respiratory complication during the follow-up period. Of these, 19 were bacterial, three were viral, two were fungal and five had no microbial documentation. During the 1-year follow-up period, four patients met the criteria for bronchiolitis obliterans syndrome and two for interstitial lung disease. Of these, only one had died at last follow-up. The cumulative incidence of grade II-IV acute GvHD was 21% (95% CI 14-33%). At 1 year, the cumulative incidence of chronic GvHD was 26% (95% CI 18-39%). Non-relapse mortality was 9% (95% CI 4-18%) at 100 days and 14% (95% CI 8-24%) at 1 year. Relapse incidence was 3% (95% CI 1-10%) and 14% (95% CI 8-24%) at 100 days and 1 year, respectively. Overall survival was 73% (95% CI 62-82%). In all, 22 patients died. Cause of death was relapse of hematological disease in 7 (35%), infection in 7 (35%), GvHD in 2 (9%), multi organ failure in 4 (20%) and other causes in 2. Conclusion: We observed a significantly impaired DLCO at baseline, which remained impaired at 3 months and 1 year after HAPLO, but with a substantial stable pulmonary function at 1 year. Disclosures Malard: Theralos/Mallinckrodt: Honoraria; Sanofi: Honoraria; Keocyt: Honoraria; Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Biocodex: Honoraria; Janssen: Honoraria.