Hematopoietic Stem Cell Transplantation Cohort Research Articles

Letermovir for CMV Prophylaxis in Very High-Risk Pediatric Hematopoietic Stem Cell Transplantation Recipients for Inborn Errors of Immunity.

The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort.

Pre-Transplant Levels of Multiparametric Flow-Cytometry Measurable Residual Disease (MFC-MRD) Predict Outcomes in Children with Acute Myeloid Leukemia Given Allogeneic Hematopoietic Stem Cell Transplantation

Background: Measurable residual disease assessed by multiparametric flow-cytometry (MFC-MRD) is largely used in trials for childhood de novo acute myeloid leukemia (AML) in the early phase of treatment, to stratify patients into different risk groups and to tailor treatment. Despite this, unlike acute lymphoblastic leukemia, the impact of MFC-MRD before allogeneic hematopoietic stem cell transplantation (HSCT) on patients' outcomes has yet to be established. The aim of this study was to evaluate the prognostic role of MFC-MRD before HSCT in a cohort of children with AML treated in centers belonging to Associazione Italiana Ematologia/Oncologia Pediatrica (AIEOP) cooperative group. Patients and Methods: We analyzed MFC-MRD in 208 pediatric patients affected by de novo AML who underwent a first allo-HSCT after a myeloablative conditioning regimen in an AIEOP Centre between 12/2011 and 12/2021. Assessment of MFC-MRD was performed on BM sample within 60 days from the transplantation date. Analysis of 5-10 color-panel MFC-MRD was centrally performed at the Laboratory of Diagnosis and Research, University of Padova, according to standardized operating procedures previously described (Buldini et al., BJH 2017). We defined MFC-MRD positivity as the presence of at least 50 leukemic events of 500,000 acquired nucleated cells. Five-year overall (OS) and event-free survival (EFS) were estimated using Kaplan and Meier method and differences between groups were tested using the log-tank test; the cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated using the Fine&Gray method to take into account the respective competitive risks. Results: Median age at HSCT of these 208 patients was 7.8 years (range 0.4-23.3); 168 patients (80.8%) were transplanted in CR1, 30 (14.4%) in CR2 and 10 (4.8%) in CR3 or more advanced disease. Forty-eight patients (23.1%) were transplanted from a matched family donor, 85 (40.9%) from an unrelated donor (59 fully-matched and 26 mismatched), while 75 (36%) from a partially matched family donor. The source of stem cells was bone marrow in 117 patients (56.2%), peripheral blood in 81 (39%) and cord blood in 10 (4.8%). Median time from MRD evaluation and HSCT was 22 days (range, 6-57). Overall,168 out of 208 (78.9%) patients were MFC-MRD negative in the pre-HSCT BM, while 44/208 (21.1%) showed a positive MFC-MRD. Among those, MFC-MRD was < 0.1% in 12/44 (27%) patients, 0.1-<1% in 16 patients (36.5%) and ≥ 1% in 16 patients (36.5%). The 5-year OS and EFS of the whole cohort were 79.2% and 65.7%, respectively, while CIR and NRM were 24.7% and 8.6%. Notably, patients with negative MFC-MRD had a significantly better 5-yr OS and EFS (Fig.A) as compared to those with any MFC-MRD positivity (OS 86.3% vs 50.2%; EFS 71.6% vs 42.4%, p <0.0001 in both analysis). CIR significantly differed between patients with MFC-MRD negative and positive (21.1% vs 43.9%, p=0.001) (Fig.B). We also observed a higher NRM in patients with MFC-MRD positivity (13.6%) as compared to those with negative MFC-MRD (7.2%), although this was not statistically significant (p=0.1). Disease status (CR1 vs CR2 vs other CR) did also influence EFS (69.9% vs 55.6% vs 23.3%, p<0.001), OS (83.2% vs 66.6% vs 40.6%, p=0.02) and CIR (21.1% vs 37.7% vs 66.6%, p<0.001), while other variables (including year of HSCT, type of donor and stem cell source employed) did not. In a multivariable model for OS, EFS and CIR, including MFC-MRD, disease status and year of HSCT, MFC-MRD (pos vs neg) remained statistically significant (HR for OS 3.5, p=0.0004; HR for EFS 2.38, p=0.003; HR for CIR 2.14, p=0.02). In addition, advanced disease phase was an independent risk factor for CIR (HR 1.81, p=0.008). Conclusion: These data document the independent prognostic value of MFC-MRD before HSCT in a large cohort of pediatric AML patients, using a centralized evaluation by 5-10 color MFC. Patients with negative MFC-MRD before HSCT have a significantly lower risk of treatment failure. In light of these results, we recommend monitoring MFC-MRD before HSCT in pediatric AML patients as a critical tool for therapy-intervention decision before or after HSCT (e.g., additional treatment for improving leukemia control or less intensive/shorter GvHD prophylaxis) with the aim to improve patients' outcomes.

Optimizing diagnostic methods and stem cell transplantation outcomes in pediatric bone marrow failure: a 50-year single center experience

Peripheral blood cytopenia, a frequent presenting symptom in pediatric patients, can be caused by bone marrow failure (BMF). Timely identification of patients with non-reversible BMF is of crucial importance to reduce the risks of invasive infections and bleeding complications. Most pediatric patients with severe persistent cytopenia, independent of the underlying cause, are offered allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Here we report on our management guidelines and HSCT outcomes of pediatric BMF patients to pinpoint improvements and future challenges. We formulated recommendations based on this 50 years’ experience, which were implemented at our center in 2017. By analysis of the HSCT cohort of 2017–2023, the 5-year outcome data is presented and compared to historical outcome data. In addition, outcomes of patients transplanted for identified inherited bone marrow failure syndromes (IBMFS) are compared to severe aplastic anemia (SAA) outcomes to underline the often multiorgan disease in IBMFS with implications for long-term survival. Survival of pediatric patients with irreversible BMF has improved tremendously. SAA patients transplanted after 2017 had a superior 5-year overall (OS) and event-free survival (EFS) of 97% and 85% compared to 68% and 59% in the cohort transplanted before 2017 (p = 0.0011 and p = 0.017). A similar trend was seen for BMF, with an OS and EFS of 89% for those transplanted after 2017 compared to 62% and 59% (p > 0.05). This improvement is mainly related to better survival in the first months after HSCT. The long-term survival after HSCT is lower in IBMFS patients as compared to SAA patients due to secondary malignancies and multiorgan toxicity. Conclusion: Unbiased protocolized in-depth diagnostic strategies are crucial to increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. A comprehensive approach to identify the cause of BMF can prevent treatment delay and be useful to tailor treatment and follow-up protocols.What is Known:• Irreversible BMF in pediatric patients can be caused by a wide spectrum of underlying diseases including (pre)malignant disease, IBMFS and AA. Identifying the exact underlying cause of BMF is crucial for tailored therapy, however often challenging and time-consuming.• Frontline allogeneic HSCT is offered to most pediatric patients with severe BMF as curative treatment.What is New:• Protocolized unbiased diagnostics, short time to treatment (< 3 months) and maximal supportive care until curative treatment can prevent complications with a negative effect on survival such as infection and bleeding.• Personalized follow-up protocols for IBMFS patients are essential to prevent a second decline in survival due to long-term treatment toxicity and extra-hematological disease complications.

Pneumocystis Jirovecii Infection in Autologous Hematopoietic Stem Cell Transplant Recipients

BackgroundInfections remain a common cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT). Pneumocystis jiroveci pneumonia (PJP) is an opportunistic infection that can occur in HSCT patients, although the association is best demonstrated in allogeneic HSCT, occurring less commonly in autologous HSCT. However, reports on PJP incidence, timing of infection, and outcomes among autologous HSCT cohorts are limited. Furthermore, while current guidelines recommend 3-6 months of prophylaxis against PJP following autologous HSCT, the optimal duration and even necessity of prophylaxis is not well established.Patients and MethodsWe performed a retrospective analysis of all consecutive patients who had autologous HSCT at the University of Michigan Blood and Marrow Transplantation program over a 20-year period from 1/1/2000 through 12/31/2019. The cohort consisted of a total of 2082 patients, 1221 male (58.6%), with median age 56 (range 10 months - 77 years, 91.2% ≥ 18 years). Records were searched for use of PJP prophylaxis over 6-month and 2-year follow-up periods post-HCT to determine rates of prophylaxis and choice of agent. Cases of polymerase-chain reaction (PCR)-confirmed PJP occurring within two years of HSCT were identified. The timing, clinical and laboratory features at diagnosis, use of concurrent immunosuppression, treatment, and outcomes were determined.ResultsOf the 2082 patients undergoing autologous HCT, 704 patients (33.8%) received PJP prophylaxis in the first 6 months following transplant. Prophylaxis rates varied over time, ranging from 14.6% to 80.0% when calculated by year of transplant (Figure 1). Trimethoprim-sulfamethoxazole (TMP-SMX) was the most used prophylaxis agent (70.3%), followed by inhaled pentamidine (31.8%), with intravenous pentamidine (8.1%), dapsone (7.1%), and atovaquone (2.6%) being used less frequently.There were 9 cases of PJP identified in our cohort, with an incidence of 0.43%. There were 6 males, with median age of 50 (range 34 - 69). Cases occurred a median of 126 days following HSCT (range 65 - 496), with 4 cases occurring after 6 months. None of the patients were on PJP prophylaxis at the time of diagnosis, and only 2 patients had received prophylaxis at any point after transplant. In 8 of 9 cases, patients were receiving concurrent pharmacologic immunosuppression in the form of steroids or maintenance brentuximab (Table 1).All patients presented with symptoms compatible with PJP, most often with fevers, dyspnea, and cough. Diagnosis was made by PCR from bronchoalveolar lavage specimen in 8 cases, and from sputum sample in 1 case. All patients were lymphopenic at the time of diagnosis, with median absolute lymphocyte count of 400 cells/µL (range 200 - 1100). Patients were most often treated with TMP-SMX. Three patients required transfer to the intensive care unit and 2 were intubated. Ultimately, 2 patients died from PJP infection; the remaining 7 recovered (Table 2).ConclusionOur analysis reveals that among a large cohort, incidence of PJP following autologous HSCT is low. This was the case even with relatively modest rates of PJP prophylaxis in the first 6 months following transplant. Most cases of PJP occurred in patients receiving additional immunosuppression and often occurred late following transplant. [Display omitted] DisclosuresPianko: Karyopharm: Honoraria.

Equal Access to Hematopoietic Stem Cell Transplant in a Minority-Rich, Ethnically Diverse, Socioeconomically Disadvantaged Population with Peripheral T-Cell Lymphomas at the Montefiore Medical Center/Albert Einstein College of Medicine

Introduction:Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous with poor prognosis. There is a paucity of data on outcomes in minority populations. We studied relationships between socioeconomic status (SES), race, and ethnicity and access to hematopoietic stem cell transplant (HSCT) and survival. For analyses of SES we used a measure of neighborhood disadvantage called the Area Deprivation Index (ADI), a composite of 17 measures of education, employment, housing quality, and poverty validated across a range of diseases (Kind et al NEJM 2018).Methods:To identify subjects with PTCL, we used SQL to query our Enterprise Data Warehouse for ICD 10 codes C84 and C91.5. We used medical record numbers for chart review and recorded the following in Excel: WHO 2016 PTCL classification (Swerdlow et al 2016 Blood), sex, race, ethnicity, address, date of birth, date of death/last contact, stem cell source (autologous [auto] vs. allogeneic [allo]), donor sources for allo (matched related [MRD], matched unrelated [MUD], haploidentical [haplo], or syngeneic), conditioning regimen, and date of stem cell infusion (HSCT D0). ADIs were obtained by geocoding subjects' addresses using an online tool (https://geocoding.geo.census.gov/) and matching census block groups to ADI 2019 national percentiles. Conditioning intensity was determined by the Center for International Blood and Bone Marrow Transplant Research operational definition (Giralt et al 2009). For survival analyses, subjects with more than 1 histology were analyzed according to that at HSCT D0. For subjects who underwent auto with subsequent allo, analyses were carried out on the allo. When there was an interval between last date known alive and first date known to have died, death was assumed at the end of the interval. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Python, pandas, Matplotlib, and lifelines were used for data analysis and visualization.Results:We identified 407 patients with PTCL, of which 48 underwent HSCT between 9/19/2006 and 4/5/2021 - 22 autos and 26 allos. Data on access to HSCT are summarized in Figure 1 and Table 1. There was not a significant relationship between ADI or ethnicity and access to HSCT. The relationship between race and access to HSCT was significant (p = 0.024). Baseline characteristics of the HSCT cohort are summarized in Tables 2 and 3. Notably, 12/26 allos had adult T-cell leukemia/lymphoma (ATLL). Looking at survival by type of HSCT (Figure 2, Table 4), autos had median OS not reached. Autos' 2 and 4-year OS probabilities were both 81.57%, whereas these were both 40.49% for allos (p = 0.03 for 2 year and 4 year OS). No differences were observed in survival by ADI among autos or allos (Figure 3, Table 5). There was no statistically significant association between race and survival by the log rank test (Figure 4, Table 6). P-values could not be calculated for autos' 2 or 4-year OS. Among allos, p-values suggested a statistical difference in 2 and 4-year OS between white subjects (n = 1) and black/African American (AA) as well as other subjects.Finally, examining survival by ethnicity, no significant differences were seen between Hispanics and Non-Hispanics (Figure 5, Table 7).Conclusions:In our inner-city, minority-rich PTCL cohort, neighborhood disadvantage and ethnicity did not preclude access to HSCT. The autologous transplant survival curve with median OS not reached (longest survivor 14.71 years) indicates that our patients did have optimal, potentially curative outcomes. Although our sample size is small our population is predominantly inclusive of ethnic minorities and low SES. Analyzing larger datasets of ethnically and socioeconomically diverse individuals can provide further insight into HSCT access and outcomes. [Display omitted] DisclosuresGritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; GLC: Consultancy; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy. Verma: Acceleron: Consultancy; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company.

Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Immunogenicity and Reactogenicity.

The severe acute respiratory syndrome coronavirus 2 messenger RNA vaccine–induced humoral response and reactogenicity profile are described in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Findings showed that 75.0% (by Simoa assay) or 80.0% (by Roche assay) of the HSCT cohort had a positive antibody response on series completion, compared with 100% in the healthy cohort.

Normalization of Cerebral Hemodynamics after Hematopoietic Stem Cell Transplant in Children with Sickle Cell Anemia

▪BackgroundChildren with Sickle Cell Anemia (SCA) are at high risk for overt or silent strokes, and this risk may be mitigated by hematopoietic stem cell transplant (HSCT). Our research group has shown that when cerebral oxygen delivery is compromised due to anemia in SCA, the cerebral blood flow (CBF) and brain oxygen extraction fraction (OEF) increase to maintain brain tissue oxygen delivery. We used novel magnetic resonance imaging (MRI) sequences to measure OEF and CBF in children with SCA treated with HSCT, testing the hypothesis that after HSCT, OEF and CBF will be similar to control values.MethodsChildren with SCA were enrolled in a pilot prospective, observational study of MRI-measured OEF and CBF. Brain MRI exams were performed without sedation on a 3T Siemens scanner. The MRI protocol included fluid-attenuated inverse recovery (FLAIR) sequences in two planes to evaluate for strokes, asymmetric spin echo to measure tissue-level OEF, and pseudo-continuous arterial spin labeling perfusion-weighted imaging to measure CBF. HSCT recipients underwent paired brain MRI 1-2 months before and >1 year after HSCT. Controls, non-anemic siblings of SCA patients, had a single brain MRI. Pre- and post-HSCT CBF and OEF were compared within subjects and between the HSCT and control cohorts using non-parametric tests. Bivariate correlations between OEF or CBF and hemoglobin (Hb) or Hb S concentrations were tested with Spearman's rho. The level of significance was specified as p < 0.05 after adjustment by the Benjamini-Hochberg procedure.ResultsFour children (two male, median age 10 years, range 8-21 years) underwent HSCT: one had prior overt stroke, one had silent strokes, and two had no neuroimaging abnormalities. All received a reduced intensity preparative regimen of alemtuzumab, melphalan, and fludarabine. One subject received marrow from an HLA-matched unrelated donor without Hb S trait; two received marrow from HLA-identical siblings. One child who had rejected a HSCT from an HLA-identical sibling underwent re-conditioning with antithymocyte globulin and cyclophosphamide and received CD-34-selected peripheral stem cells from the same donor. All sibling donors had Hb S trait. Brain MRIs of 20 non-anemic sibling controls of median age 11 years (range 6-17 years) were included for comparison.Median OEF and CBF were significantly elevated pre-HSCT compared to controls (OEF median 0.355 vs 0.288, p = 0.012; CBF median 99.8 vs 65.1 ml/100 g/min, p = 0.018; Figure). Median post-HSCT OEF and CBF were lower than pre-HSCT values (OEF median 0.270 vs 0.355, CBF median 65.1 vs 99.8 ml/100 g/min, p = 0.13 for both), but these analyses had low power to detect significant differences due to the small sample size. Post-HSCT, recipients' OEF and CBF were similar to controls (OEF median 0.270 vs 0.288, p=0.18; CBF median CBF 65.1 vs 75.8 ml/100 g/min, p = 0.42). None of the HSCT recipients had new overt or silent strokes on FLAIR imaging or developed severe acute or chronic GVHD after HSCT.Pre-HSCT, recipients were anemic compared to controls (median Hb 9.8 vs 12.8 g/dl, p = 0.018). Pre-HSCT Hb S concentrations were lower than expected for SCA due to recent red blood cell transfusions (median 50.6%, range 39.7-77.6%). At the post-HSCT imaging timepoint, recipients' anemia had resolved (median Hb 12.4 g/dl, range 11.3-15.7 g/dl), and Hb S concentrations were consistent with their donors' levels. When all pre- and post-HSCT measurements were compared, OEF had a strong negative correlation with Hb (Spearman's rho = -0.905, p = 0.002) and a strong positive correlation with Hb S concentration (Spearman's rho = 0.970, p < 0.001). CBF had a weaker negative correlation with Hb (Spearman's rho = -0.714, p = 0.047) and positive correlation with Hb S concentration (Spearman's rho = 0.731, p = 0.040).ConclusionIn this cohort, children with SCA had normalization of OEF and CBF after successful HSCT. OEF elevation was strongly correlated with Hb S concentration and inversely correlated with Hb concentration in these HSCT recipients. Our data suggest that when curative HSCT corrects hemolytic anemia, OEF and CBF normalize. This physiologic change may provide protection against strokes following HSCT for SCA. [Display omitted] DisclosuresHulbert:Pfizer: Other: Spouse employment at Pfizer. Fields:Proclara Biosciences: Equity Ownership.

"Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation".

It is established that pediatric hematopoietic stem cell transplant (HSCT) recipients have a lower rate of chronic graft-versus-host disease (cGvHD) compared to adults. Our group has previously published immune profiles changes associated with cGvHD of clinically well-defined adult and pediatric HSCT cohorts. Since all analyses were performed by the same research group and analyzed using identical methodology, we first compared our previous immune profile analyses between adults and children. We then performed additional analyses comparing the T cell populations across age groups, and a sub-analysis of the impact of the estimated pubertal status at time of HSCT in our pediatric cohort. In all analyses, we corrected for clinical covariates including total body irradiation and time of onset of cGvHD. Three consistent findings were seen in both children and adults, including elevations of ST2 and naive helper T (Th) cells and depression of NKreg cells. However, significant differences exist between children and adults in certain cytokines, B cell, and Treg populations. In children, we saw a broad suppression of newly formed B (NF-B) cells, whereas adults exhibited an increase in T1-CD21lo B cells and a decrease in T1-CD24hiCD38hi B cells. Prepubertal children had elevations of aminopeptidase N (sCD13) and ICAM-1. Treg abnormalities in children appeared to be primarily in memory Treg cells, whereas in adults the abnormalities were in naïve Treg cells. In adults, the loss of PD1 expression in naïve Treg and naïve Th cells was associated with cGvHD. We discuss the possible mechanisms for these age-related differences, and how they might theoretically impact on different therapeutic approaches to cGvHD between children and adults.

Electronic Symptom Assessment in Children and Adolescents With Advanced Cancer Undergoing Hematopoietic Stem Cell Transplantation.

Background/Purpose: Effective symptom assessment and management for children with advanced cancer undergoing hematopoietic stem cell transplantation (HSCT) is critical to minimize suffering. The purpose of this subanalysis was to compare feasibility of electronic data collection data and symptom prevalence, frequency, severity, and distress from children with advanced cancer undergoing HSCT with a non-HSCT cohort. Method: An abbreviated Pediatric Quality of Life and Evaluation of Symptoms Technology Memorial Symptom Assessment Scale was electronically administered every 2 weeks to children with advanced cancer. A subanalysis was conducted for the cohort of children who received autologous or allogeneic HSCT. Results: Forty-six participants completed 563 symptom assessments during the study. However, 11 of these 46 children received HSCT and completed 201 symptom assessments. The median age in the HSCT cohort was 12.7 years, 73% were female, and most children had a hematologic (45%) or solid tumor (45%) malignancy. Pain (35%), nausea (30%), sleeping difficulty (29%), and fatigue (22%) were the most commonly reported symptoms in children receiving HSCT. Children in the HSCT cohort had similar total, subscale, and individual symptom scores compared with children who did not receive HSCT. Certain domains of gastrointestinal symptoms (nausea, lack of appetite, and diarrhea) were higher for children receiving HSCT compared with children with advanced cancer not receiving HSCT (p < .05). Conclusion: Elicitation of patient-reported symptom experiences using electronic methods improves nurses' understanding of the symptom experience for children with advanced cancer undergoing HSCT and may promote timely assessment and treatment of distressing symptoms.

PPM1D and DNMT3A Mutations in Myelodysplasia and Clonal Hematopoiesis

Introduction: Age-related clonal hematopoiesis (CH) has been implicated in an increased risk of myeloid neoplasms. While common driver genes mutated in CH largely overlap to those in myeloid neoplasms, a notable exception is protein phosphatase Mg2+/Mn2+dependent 1D gene (PPM1D), encoding a p53-targeting phosphatase. Although it is known to be involved in DNA damage response pathways and more frequently mutated in therapy-related myeloid neoplasms than in primary ones, its role in CH and myeloid neoplasms has not been fully understood. Aim: To identify genetic features associated with PPM1D mutations, we examined genetic profiles in the large cohorts of healthy elderly individuals and patients with myelodysplasia. Methods: We enrolled 10,826 healthy individuals (&gt;60y) and 1,213 cases with myelodysplasia, including myelodysplastic syndromes (MDSs), myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) (n=1,080), and secondary acute myeloid leukemia (sAML) (n=133), of which 567 cases were treated by hematopoietic stem cell transplantation (HSCT) through the Japan Marrow Donor Program just after sampling, and 332 of them underwent any therapy before sampling. Samples from healthy individuals were subjected to multiplex-amplicon sequencing for 22 genes, including PPM1D and other genes, related to CH or myeloid neoplasms. Myelodysplasia samples had previously been sequenced for major myeloid drivers, except for PPM1D, which was newly sequenced in this study. Results: Frequency of PPM1D mutations in myelodysplasia and healthy individuals was 3.1% and 0.42%, with a median variant allele frequency (VAF) of 0.043 and 0.056, respectively. PPM1D mutations were more frequent in cases with previous treatment (4.8%) than in those without known history of therapy (2.3%) (P=0.038). In MDS and MDS/MPN cases, 59.5% of PPM1D mutations had accompanying mutations, in which DNMT3A mutations were the most frequently identified (16.2%, n=6). These 6 cases were diagnosed with RCUD (n=1), RCMD (n=2), RAEB-2 (n=2), or CMML (n=1). The association between PPM1D and DNMT3A mutations was also seen in 7 of 45 healthy individuals with PPM1D mutations, of which one had a DNMT3A-R882 mutation. In the HSCT cohort, 192 cases harbored ≥2 mutations of the 22 CH-related genes, and the relative temporal order of these mutations was investigated using Bradley-Terry model relying on their tumor cell fractions. The estimate of PPM1D mutations tended to be smaller than that of DNMT3A mutations. To further confirm chronological order of these mutations, VAF values were compared between them in the individuals with concurrent PPM1D and DNMT3A mutations (n=13; 6 myeloid neoplasms and 7 healthy donors). In the combined cohort, the VAFs of PPM1D and DNMT3A mutations were correlated (Spearman; correlation coefficient=0.87, P=1.2x10e-5). In both neoplastic and healthy cohort, the VAFs of DNMT3A-R882 mutations were larger than those of accompanying PPM1D mutations. These findings suggest that these mutations should be acquired in the same cell populations and that DNMT3A mutations might occur prior to PPM1D mutations. With regard to copy number alterations associated with PPM1D-mutated myelodysplasia, del(5q) (16.7%) and complex(-like) karyotypes (13.9%) were among the most frequent chromosomal abnormalities. Approximately 65% of PPM1D-mutated tumor samples had normal karyotype, which was similar to PPM1D-unmutated cases. PPM1D mutations did not significantly influence overall survival, although PPM1D mutations tended to negatively affect clinical outcome among patients who were treated with HSCT (Hazard ratio, 1.61; 95% confidence interval, 0.95 to 2.70). Conclusion: PPM1D mutations were more enriched in myelodysplasia than in CH, and the median value of VAF in PPM1D mutations in CH was not significantly different from that in myelodysplasia. The size of PPM1D-mutated clones tended to be relatively smaller compared with that of clones with other mutations in myelodysplasia. PPM1D and DNMT3A mutations might be cooperatively associated in the pathogenesis of myelodysplasia and CH. Disclosures Baer: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Ogawa:Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Qiagen Corporation: Patents &amp; Royalties; Asahi Genomics: Equity Ownership; RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership.

Electronic Symptom Assessment in Children and Adolescents with Advanced Cancer Undergoing Hematopoietic Stem Cell Transplantation

Background Effective symptom assessment and management for children with advanced cancer undergoing hematopoietic stem cell transplantation (HSCT) is critical to minimize suffering. Most literature specific to children receiving HSCT is based upon medical record reviews and parent report, and to a lesser extent, patient self-report. Objectives The purpose of this study was to describe symptom frequency, severity and level of distress in children and adolescents undergoing HSCT using patient self-report via electronic data collection. Methods A modified Memorial Symptom Assessment Scale (MSAS) was electronically administered to children with advanced cancer every two weeks. Clinical data was collected at corresponding time points. A sub-analysis was conducted for the cohort of children with advanced cancer who received autologous or allogeneic HSCT. Results Forty-seven children with advanced cancer were enrolled and completed 563 surveys during the course of the study. Eleven of these 47 children received HSCT and completed 201/563 surveys. The median age of children in the HSCT cohort was 12.7 years, 73% were female, and most children had a hematologic (45%) or solid tumor (45%) malignancy. Ninety-six percent of surveys administered to children receiving HSCT were completed, and 64% of surveys were completed at home. Pain (35%), nausea (30%), sleeping difficulty (29%) and fatigue (22%) were the most commonly reported symptoms in children receiving HSCT. Children in the HSCT cohort had higher total and physical subscale mean MSAS scores, and higher pain, nausea, fatigue, and lack of appetite mean scores compared to children with advanced cancer not receiving HSCT (p Conclusion Children with advanced cancer receiving HSCT may have increased symptom burden with higher levels of distress as compared to those who do not receive HSCT. Increased understanding of the symptom experience for children with advanced cancer undergoing HSCT may promote timely assessment and treatment of distressing symptoms.

Outcomes and Healthcare Utilization of Children with Mucopolysaccharidosis with and without Hematopoietic Stem Cell Transplantation

Introduction: Mucopolysaccharidosis Type I (MPS-I) is a lysosomal storage disease resulting in progressive multisystem involvement and ultimately death at a young age. Since 1980, hematopoietic stem cell transplant (HSCT) has been used to treat MPS-I and stabilize cognitive impairment. However, little is known regarding overall outcomes and healthcare utilization of HSCT compared to enzyme replacement therapy (ERT) versus other supportive treatments.Method: We utilized the Pediatric Health Information System, a validated multi-institutional pediatric and adolescent database from 45 individual pediatric institutions, to identify and analyze patients diagnosed with MPS-I between 2005 and 2017. A retrospective analysis was performed to examine outcomes and healthcare utilization between three cohorts: patients who received HSCT at less than one year old, patients who received HSCT at greater than one year old, and patients who did not receive HSCT.Results: In the largest reported cohort of 1,053 patients identified with MPS-I, approximately 15% received HSCT while others received ERT alone or supportive treatments. Approximately 23% of patients received HSCT at less than one year of age with the remainder of patients received HSCT at greater than one year of age (Table 1). There was no difference in incidence of acute graft versus host disease (GHVD) (p=0.980) between the younger (25.0%) and older (25.2%) transplant cohorts. In our sample, 12.2% of patients who received HSCT after one year of age were diagnosed with chronic GVHD in comparison to 5.6% of the younger cohort (p=0.364). There was no difference in likelihood of ICU admission when comparing non-HSCT management (53.9%) to both the younger (52.8%) and older (61.0%) HSCT cohorts (p=0.899, p=0.138 respectively). In both transplant cohorts the greatest likelihood of ICU admissions occurred during the first year post-transplant, after which the rate plateaued (see Figure 1). Infection was the most common reason for hospital admission among all patients, with severe infection being more common in both the younger HSCT cohort (OR 2.58, CI 1.32-5.04) and older HSCT cohort (OR 2.38, CI 1.62-3.49) when compared to non-HSCT management. When analyzing mortality between all cohorts, non-HSCT patients had a lower rate of mortality compared to patients who received HSCT at an older age (OR 3.50, CI 2.00-6.14). However, we found no difference in mortality between non-HSCT patients and HSCT at less than one year old (p=0.426). Approximately 50% of HSCT patients received ERT; we found no difference in overall survival between patients who received ERT and those who did not (p=0.796). Figure 2 shows the trend of MPS-I patients' first presentation to the hospital plotted alongside the incidence of HSCT in our sample between 2005 and 2017. When looking at the incidence of HSCT in relation to new presentations of MPS-I, a higher proportion of patients received HSCT during 2012-2017 (18.9%) as compared to 2005-2011 (12.6%) (p=0.005).Conclusion: When considering HSCT as treatment for MPS-I, HSCT at a younger age is associated with increased overall survival. This study found that ERT in addition to HSCT had no effect on overall mortality. The lack of difference between transplant and non-transplant ICU admissions indicates that HSCT does not significantly contribute to overall ICU admissions. Likelihood of ICU admission plateaus after one year, regardless of age at transplant. Infection is the most common reason for hospital admission for all patients with MPS-I diagnosis, however severe infection is more common among HSCT patients when compared to non-HSCT patients. First presentations to hospitals have down trended over the past several years while the number of HSCT each year has remained relatively stable, resulting in an increased proportion of HSCT incidence to new MPS-I presentations in hospital settings. One possible explanation is the recent implementation of newborn screening, which provides earlier detection of the disease. This may allow outpatient management at a young age and potentially avoid MPS-I manifestations resulting in hospital admissions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase 1b Study of Intravenous Vedolizumab Plus Standard of Care for Graft-Versus-Host Disease Prophylaxis in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies: 6-Month Results

BackgroundSubjects with lower gastrointestinal (GI) acute graft-versus-host disease (aGvHD) generally respond poorly to therapy, and therefore have increased morbidity and mortality. Vedolizumab, a gut-selective antibody targeting α4β7 integrin, is approved for the treatment of inflammatory bowel diseases. Vedolizumab interferes with gut-trafficking of immunocompetent donor T-lymphocytes and may have a role in preventing GI aGvHD. Here we present the 6-month results of a phase 1b study of the safety, tolerability and clinical activity of vedolizumab combined with standard graft-versus-host disease (GvHD) prophylaxis.MethodsThis is an open-label, dose-finding study of the addition of vedolizumab to standard GvHD prophylaxis in adults undergoing hematopoietic stem cell transplantation (HCT). Cohort 1 comprised subjects aged 18-60 years with a hematologic malignancy undergoing human leukocyte antigen (HLA)-matched or 1 locus-mismatched, unrelated-donor myeloablative transplantation. These subjects received intravenous (IV) vedolizumab (75 mg, on days -1, +13 and +42 of HCT). If subjects in cohort 1 experienced no engraftment failures or dose-limiting toxicities (DLTs), then subsequent subjects were enrolled into a dose-expansion cohort of IV vedolizumab 300 mg (cohort 2), following the same schedule. Key inclusion criteria for cohort 2 were myeloablative regimens (subjects aged 18-60 years) or reduced-intensity conditioning regimens (subjects aged 18-75 years), donor-recipient pairs who were HLA-matched or 1-locus mismatched, and subjects receiving peripheral blood- or bone-marrow-derived stem cells. All subjects received standard GvHD prophylaxis (tacrolimus and methotrexate). The primary objective was to identify an efficacious vedolizumab dose with an acceptable safety profile for future studies, using the following primary safety endpoints: frequency of DLTs from day -1 to day 28, and the number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events from administration of the first dose of vedolizumab until 18 weeks after the final dose. Secondary endpoints included time to neutrophil engraftment, cumulative incidence of grade II-IV aGvHD and frequency by maximum severity of aGvHD by modified Glucksberg criteria. Exploratory endpoints included overall survival (OS) and aGvHD-free survival.ResultsIn total, 24 subjects were enrolled at 5 centers (3 in cohort 1, then 21 in cohort 2). The median age was 55 years (range 18-72 years). Most subjects underwent an unrelated donor HCT (83%), and all except 1 were HLA-matched (Table 1). At 6 months after HCT, no DLTs were observed in either cohort. All subjects engrafted within 28 days; the median time to neutrophil engraftment was 14 days in cohort 2. All subjects experienced at least 1 TEAE, which was serious in 13 subjects (2 in cohort 1, 11 in cohort 2). TEAEs were considered vedolizumab-related in 2 subjects in cohort 1 and 6 in cohort 2, including 1 subject in cohort 2 who experienced 2 serious TEAEs: hypotension and febrile neutropenia. The most frequent infections were cytomegalovirus (4 cases) and Clostridium difficile colitis (3 cases). No adverse events led to discontinuation of vedolizumab. There were no cases of grade II-IV aGvHD at 6 months after HCT in cohort 1. In cohort 2, 4 subjects (19%) developed grade II-IV aGvHD at 6 months after HCT; 3 (14%) grade II (1 skin only involvement, 2 skin and lower GI involvement) and 1 (5%) grade III (liver, skin and lower GI involvement). All cases of lower GI aGvHD were limited to stage 1 disease. At 6 months after HCT, 1 subject died from disease relapse in cohort 1, and 2 subjects died in cohort 2; 1 from disease relapse and 1 from aGvHD-related complications. Among subjects in cohort 2, 6-month OS and non-relapse mortality were 90% and 5%, respectively, and grade II-IV and grade III-IV aGvHD-free survival were 76% and 90%, respectively (Table 2).ConclusionsIn subjects receiving vedolizumab in addition to standard GvHD prophylaxis, there were no DLTs or engraftment failures at 6 months after HCT, and the TEAEs observed have been as expected in this population. The low cumulative incidences of grade II-IV and grade III-IV aGvHD are promising; there were no cases of lower GI aGvHD greater than stage 1. Intravenous vedolizumab 300 mg added to standard GvHD prophylaxis for the prevention of GI aGvHD merits further study. DisclosuresChen:Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy. Shah:Lentigen Technology: Research Funding; Oncosec: Equity Ownership; Exelexis: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Geron: Equity Ownership. Jansson:Takeda Pharmaceuticals: Employment. Akbari:Takeda Pharmaceuticals: Employment. Chen:Takeda Pharmaceuticals: Employment. Quadri:Takeda Pharmaceuticals: Employment. Parfionovas:Takeda Pharmaceuticals: Employment. Devine:Kiadis Pharma: Consultancy.

Outcomes in Children with Severe Vasculopathy from Sickle Cell Anemia after Treatment with Chronic Transfusion, Surgical Revascularization and/or Allogenic Hematopoetic Stem Cell Transplantation

Background: Cerebral vasculopathy is a frequent complication of sickle cell anemia (SCA) and is associated with a high risk for stroke. This vasculopathy seen in SCA can be progressive and severe. Sickle cell patients with severe vasculopathy, including Moyamoya syndrome are at increased risk for neurological disabilities and death. While chronic transfusions decrease the risk of stroke in SCA; unfortunately, progression of vasculopathy can occur despite treatment. Limited data exists regarding long term outcomes for this population. We evaluated effectiveness of three treatment approaches at our center, namely chronic transfusions, surgical revascularization plus chronic transfusions and allogenic hematopoietic stem cell transplant (HSCT).Methods: A retrospective chart review was preformed to identify patients with SCA (hemoglobin SS, Sβ0) and severe vasculopathy including Moyamoya syndrome between 1986 to 2017. Severe vasculopathy was defined as having at least one cerebral artery with > 70% stenosis and/or occlusion as seen on MR angiogram (MRA), CT angiogram (CTA) or conventional angiogram (DSA) as determined by a neuroradiologist at our institution. Patients were identified from an institutional stroke database. Patients were included for analysis if they received at least one of the following: chronic transfusions, surgical revascularization (i.e. encephalo-duro-arterio-synagiosis (EDAS) plus chronic transfusions or HSCT. For HSCT, all graft types (bone marrow, peripheral blood stem cells, umbilical cord blood), conditioning regimens and donor types (related, unrelated and haploidentical) were included. Time to event analyses were performed from the time of intervention (transfusion, HSCT, EDAS/chronic transfusions) using overt clinical stroke, new silent infarcts, progression of vasculopathy or new vasculopathy. Survival curves were analyzed using the log-rank (Mantel-Cox) test.Results: Of 35 patients identified, 54% (n =19) underwent chronic transfusions, 23% (n=8) of patients underwent HSCT after being on chronic transfusions, 23% (n=8) underwent EDAS with chronic transfusions and 1 patient underwent each of the above three modalities (Table 1). Median age at time of intervention was similar for all three cohorts (Table 1). Males were overrepresented in all treatment arms (62.5-79% of patients). Average hemoglobin level prior to intervention was also similar: 7.6 g/dL (IQR 7.1-8.3) for the chronic transfusion cohort, 7.3 gm/dL (IQR 6.3-8.2) for the HSCT cohort, and 7.5 gm/dL (IQR 7.2-8) for the EDAS/chronic transfusion cohort. Absolute reticulocyte count was 492.9 K/ul (IQR 358.4-550) for the chronic transfusion group, 389.4 (IQR 174.3-449) for HSCT, and 250.2 (IQR 107.3-393) for EDAS/chronic transfusions (p=0.08). One patient died of overt stroke in the chronic transfusion cohort. The median follow-up times for the transfusion, HSCT and EDAS plus transfusion groups were 4.4, 2.4 and 6 years respectively.Time from date of intervention (transfusion, HSCT, EDAS) to overt clinical or silent stroke was evaluated (Fig 1). Two of the nineteen patients in the chronic transfusion cohort suffered an overt stroke, while one of eight and two of eight had strokes in the post-HSCT and EDAS plus chronic transfusion cohorts respectively. Fourteen of nineteen (74%) in the chronic transfusion cohort had progression of severe vasculopathy after being on transfusions while two of eight (25%) in the HSCT and four of the eight (50%) patients in the EDAS plus chronic transfusion cohorts had progression. The one patient with all three different interventions did not have additional infarction (clinical or silent) or vasculopathy progression during 1.5 years of follow-up.Conclusions: The risk for cerebral infarction and/or vasculopathy progression after initiation of treatment with either chronic transfusion, HSCT or EDAS is still a major concern. Our data suggest HSCT and surgical revascularization with chronic transfusion provide the greatest benefit in reducing stroke risk and HSCT reduces risk for progression of a severe vasculopathy. Additional, large population studies are needed to clarify the risk. [Display omitted] DisclosuresMajumdar:NIMHD: Research Funding. Campbell:Functional Fluitics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Feasibility and Cost Analysis of Day 4 Granulocyte Colony-Stimulating Factor Mobilized Peripheral Blood Progenitor Cell Collection from HLA-Matched Sibling Donors

Introduction: Published guidelines recommend mobilization of allogeneic peripheral blood progenitor cells (PBPC) with 4-5 days of granulocyte colony-stimulating factor (G-CSF) followed by PBPC collection on day 5. Given that some autologous transplant patients are adequately mobilized by day 4, and concern that a subset of allogeneic donors may be maximally mobilized before day 5 of G-CSF administration, we performed a feasibility study evaluating day 4 allogeneic PBPC collection.Methods: This single-center prospective study included adult patients with malignant diseases who received a first allogeneic hematopoietic stem cell transplant (HCT) at our center between 7/1/2013 - 6/30/2017. HLA-matched sibling donors received 10 μg/kg of G-CSF subcutaneously prior to PBPC collection. Donors were collected on day 4 of G-CSF if peripheral blood (PB) CD34+ counts were ≥0.04x106/ml. Donors with day 4 PB CD34+ counts <0.04x106/ml were collected on day 5, and those with inadequate collected CD34+ cells/kg recipient weight underwent repeat collection over two days. Patient and donor characteristics, PBPC product composition, transplant outcomes, and cost analysis of the PBPC collection procedure were compared to a historical cohort of donors collected on day 5 according to our prior algorithm.Results: One hundred and one patients/donors were eligible for inclusion on study, and 75 were included in the historical cohort. Of the 101 donors on study, 50 (49.5%) had adequate PBPC collection on day 4 of G-CSF, 26 (25.7%) were collected on day 5, and 25 (24.8%) required two-day collections on days 4 and 5. The median day 4 donor PB CD34+ cell count was 0.06 (range 0.03-0.13) x 106/ml among donors collecting on day 4, 0.03 (range 0.007-0.09) x 106/ml for donors collecting on day 5, and 0.019 (range 0.004-0.04) x 106/ml for donors collecting over two-days (p<0.001).The most common reported donor symptoms were bone pain, myalgia/malaise, headache, and circumoral tingling/electrolyte abnormalities. Compared to the historical cohort, donors with PBPC collection on day 4 were significantly more likely to develop bone pain, require narcotics, and take over-the-counter (OTC) medications, day 5 donors were significantly more likely to develop bone pain and take OTC medications, and two-day donors were significantly more likely to develop bone pain and circumoral tingling/electrolyte abnormalities.The median collected PBPC CD34+ cell count (7.25 x 106/kg recipient weight) and infused PBPC product CD34+ cell count (5.67 x 106/kg recipient weight) were significantly greater in products collected on day 4, compared to products collected on other days. In comparison, the infused PBPC product total nucleated cell (TNC) count (7.13 x 108/kg recipient weight), mononuclear cell (MNC) count (5.84 x 108/kg recipient weight), and CD3+ cell count (2.14 x 108/kg recipient weight) were significantly lower in products collected on day 4 compared to other collection cohorts (p<0.001, p<0.001, and p=0.002, respectively for day 5, two-day, and historical cohort).There were no significant differences in time to neutrophil or platelet engraftment, or in the incidence of acute or chronic graft-versus-host-disease, based on day of collection. There was a non-significant trend towards improved 1-year survival among patients transplanted with PBPC collected on day 4 (p=0.077). Cost analysis revealed a 6.7% savings in direct costs per collection procedure for the day 4 collection method versus historical cohort.Conclusions: Using a day 4 PB CD34+ threshold of ≥0.04x106/ml identifies donors with a high likelihood of adequate PBPC collection. While differences in PBPC product composition and donor symptoms were seen based on day of collection, we found no evidence of adverse post-HCT outcomes associated with day 4 PBPC collection. Day 4 may be the optimal day of stem cell collection for a population of healthy donors without adverse effect on transplant outcomes, and with an anticipated cost savings. Ongoing analyses include resource utilization review, matched cohort analysis of day 4 versus 5 collection and correlation with transplant outcomes, more detailed PBPC production composition analysis among the collection cohorts, and longer post-HCT follow-up and association with outcomes based on day of PBPC collection. These findings merit further analysis in larger HCT cohorts. [Display omitted] DisclosuresCook:Syros Pharmaceuticals: Consultancy. Maziarz:Incyte: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Athersys, Inc.: Patents & Royalties; Juno Therapeutics: Consultancy, Honoraria.

Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.

Early Transplant Improves Outcomes in Patients with Chronic Granulomatous Disease: Results from United States Immunodeficiency Network (USIDNET)

Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency due to defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in failure of killing intracellular pathogens. Clinical presentation and management of these patients remains heterogeneous. Current management involves non-transplant therapy with interferon-gamma and supportive care, or hematopoietic stem cell transplant (HSCT) in severe cases. There has been limited data on morbidity and outcomes with different treatment options using patient registries. There has been no registry-based study of CGD patients from the United States comparing different treatment options.Methods: We performed a multi-institutional analysis of data from the United States Immunodeficiency Network (USIDNET) registry, comparing morbidity, mortality, and different treatment options. Retrospective review of data from its inception in 1992 through 2016 was performed. We analyzed demographic, co-morbidity and treatment information (HSCT versus non-transplant therapy). Logistic regression was used to compare overall survival (OS), transplant related survival (TRS) and frequency of serious infections and co-morbidities among the treatment groups. Multivariate logistic regression was used to evaluate factors affecting survival.Results: Within the database, 507 CGD patients were identified, with 84% male. X-linked inheritance was most common (73%) with about 78% of patients having gp91 mutation. Of 507 patients, about 10% underwent HSCT (n=50). Overall mortality was 15% with relatively lower incidence in HSCT group (12%). In HSCT cohort, median age at transplant was 13.5 years (0.6-37.3 years), with 74% receiving reduced intensity conditioning (RIC). The most common graft source was peripheral blood stem cells (60%) from a matched-unrelated donor (72%). No mortality was reported in patients who received stem cells from matched siblings and in those who received bone marrow graft with RIC, at median follow-up of 24 months (range 3-402 months). Survival analysis included 302 patients. OS was not significantly different between HSCT and non-transplant groups (p=0.50; Figure 1 a, b). Among patients who underwent HSCT, there was significantly improved TRS in those transplanted before 14 years of age (p= 0.035, HR: 4.51; Figure 1 c, d). The proportion of patients who had >3 infections prior to transplant was significantly reduced by 2-years post-transplant (p < 0.0001, Figure 2). The rate of serious infections prior to transplant was significantly lower in patients transplanted at <14 years old compared to those transplanted at an older age (p< 0.001, 95% CI 19.2- 62.8). Stem cell source, graft type, conditioning regimen, and prior gamma-interferon treatment did not differ significantly between these two groups. Ten of 13 patients who had gastrointestinal granulomatous inflammation prior to transplant did not have documentation of disease at 1-35 months post-HSCT, with an additional subject experiencing relief of esophageal stricture post-transplant. In univariate analysis, patients with gp91 mutation had significantly worse survival compared to other mutations (p=0.008). In multivariate analysis for OS, gp91 mutation showed a trend towards significance within the entire cohort (p = 0.08, Table 1). Figure 3 shows comparison of mean quality of life (QoL) indicator for non-transplant (n=40) and post-transplant patients (n=12). The mean performance score was significantly higher in post-HSCT (93.33) patients compared to their non-transplant counterparts (84.73) for subjects 15 years or older (p=0.0021).Conclusion: This is the largest reported American CGD cohort. HSCT at <14 years of age is associated with improved survival, decreased burden of serious infections, and granulomatous inflammation. Post transplant CGD patients have significantly better QoL as compared to non-transplant ones. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dyslipidemia and lipid-lowering treatment in a hematopoietic stem cell transplant cohort: 25 years of follow-up data

Dyslipidemia is common after hematopoietic stem cell transplantation (HSCT). Few data regarding the time course of lipid profiles after HSCT, the effect of multiple transplantations, and efficacy and safety of lipid-lowering treatments are available. The objective of the study was to determine the prevalence and treatment of dyslipidemia over a 25-year period in a large, single-center cohort. One thousand one hundred ninety-six adult patients (≥16years) who underwent HSCT during 1973 to 2013 and who survived ≥100days were studied retrospectively. The prevalence of dyslipidemia before transplantation was 36% and 28% in the autologous and allogeneic groups, respectively (P<.001). Three months after HSCT, the prevalence rose to 62% and 74% (P<.001), and at 25years, it was 67% and 89%. Lipid profiles were similar after first and subsequent transplants. Baseline dyslipidemia (odds ratio [OR]= 2.72), allogeneic transplant (OR= 2.44), and age≥35years (OR= 2.33) were independent risk factors for dyslipidemia at 1 year. Lipid-lowering treatment was given to 223 (19%) patients, primarily in the form of statins (86%) and was associated with a decrease in total cholesterol from 246 to 192mg/dL (P<.01) and from 244 to 195mg/dL (P<.001) in the autologous and allogeneic groups, respectively. There were 10 cases (4%) of muscle symptoms prompting cessation of lipid-lowering therapy, including 1 case of rhabdomyolysis. The OR for dyslipidemia among patients who suffered a cardiovascular event (conditional logistic regression) was 3.5 (95% confidence interval= 1.6-7.7, P=.002). This study confirms that dyslipidemia is a common and long-lasting phenomenon among both allogeneic and autologous HSCT patients. Statins are effective, generally well-tolerated and should be highly recommended for the management of post-HSCT dyslipidemia.

Children Receiving Hematopoietic Stem Cell Transplantation are at Increased Risk of Onychocryptosis Requiring Surgical Management

At our institution, a high proportion of children with onychocryptosis (ingrown toenail) requiring surgical intervention were noted to have a history of hematopoietic stem cell transplantation (HSCT). We analyzed the characteristics of patients who underwent surgical intervention for onychocryptosis and examined our institutional HSCT database to determine if an association exists between onychocryptosis and HSCT. Surgical cases for onychocryptosis performed from 2000 to 2012 were identified. Nine demographic, clinical, and perioperative variables for both patients with and without prior HSCT were assessed. In a separate analysis, the institutional HSCT database was then queried to identify the prevalence and clinical characteristics associated with onychocryptosis after HSCT. We identified 17 children who had undergone surgical management of onychocryptosis, of which 8 (47.1%) had previous HSCT. Children who had undergone HSCT had an aggressive form of onychocryptosis with 50.0% having bilateral great toe and nail edge involvement and 37.5% having a recurrence. In HSCT cohort analysis of 1069 children, 91 (8.5%) had onychocryptosis. Male sex, non-black race, acute graft versus host disease, and increasing age at transplantation were independently associated with onychocryptosis. HSCT is strongly associated with onychocryptosis requiring surgical intervention. Children with a history of HSCT may also have more aggressive toenail disease, with higher rates of surgical intervention, bilateral ingrown toenails, recurrence, and need for return to the operating room. Clinicians should perform careful screening and early treatment in these patients.

Pulmonary Clinicopathological Correlation after Allogeneic Hematopoietic Stem Cell Transplantation: An Autopsy Series

Pulmonary complications are a significant cause of morbidity, mortality, and resource utilization after hematopoietic stem cell transplantation (HSCT). The objective of this study was to compare antemortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. All patients who underwent allogeneic HSCT at our institution (n = 1854) between January 1, 2000 and June 30, 2010 were reviewed and patients who died of any cause greater than 1 year after HSCT and had an unrestricted autopsy available for analysis were included. Presence of pulmonary graft-versus-host disease (GVHD) was assessed by a pathologist blinded to the autopsy report, as previously described by Yousem (1995). A total of 35 (1.9%) patients had autopsies available for review. Airway disease, vascular disease, and interstitial disease were all clinically under-recognized compared with the pathological findings on autopsy. Varying degrees of pathological changes were detected, including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-occlusive disease (PVOD). Pulmonary manifestations of chronic GVHD, particularly BO and PVOD, were clinically under-recognized in our cohort. Our results suggest that PVOD, which has traditionally been considered a rare complication, may be clinically and histologically under-recognized.