Post Bone Marrow Transplantation Research Articles

Using Targeted Transcriptome and Machine Learning of Pre- and Post-Transplant Bone Marrow Samples to Predict Acute Gvhd (aGVHD) and Overall Survival after Allogeneic HSC Transplantation

Using Targeted Transcriptome and Machine Learning of Pre- and Post-Transplant Bone Marrow Samples to Predict Acute Gvhd (aGVHD) and Overall Survival after Allogeneic HSC Transplantation

Atypical perigraft seroma masquerading as a forearm tumor in a dialysis patient.

An extremely rare manifestation of perigraft seroma (PGS), in which a dense, semisolid jelly-like mass had formed around the shunt instead of the standard fluid-like form of the usual seroma, leading to misdiagnosis with other entities, such as tumors around the synthetic arterio-venous shunt (AVS) was presented. A 64-year-old male with multiple myeloma post autologous bone marrow transplant with a renal impairment, presented with a rare form of PGS, which was noticed 2 months after placing a synthetic AVS vascular graft. The mass increased in size, and multiple attempts for excision failed due to recurrence, which led to tumor misdiagnosis. The mass reoccurrence stopped completely only after the radical shunt removal. This case report revealed a rare form of PGS, in which the seroma was represented as a firm, semisolid jelly-like mass rather than the typical fluid type transudate seroma. Despite its rarity, it was associated with a high recurrence rate because unlike the standard perishunt seroma, this semisolid jelly-like material could neither be aspirated, nor could it be resected en-bloc, leading to shunting dysfunction. Its management included advanced imaging and a high probability of shunt removal or replacement.

Donor natural killer cells trigger production of β-2-microglobulin to enhance post–bone marrow transplant immunity

AbstractAllogeneic hematopoietic transplantation is a powerful treatment for hematologic malignancies. Posttransplant immune incompetence exposes patients to disease relapse and infections. We previously demonstrated that donor alloreactive natural killer (NK) cells ablate recipient hematopoietic targets, including leukemia. Here, in murine models, we show that infusion of donor alloreactive NK cells triggers recipient dendritic cells (DCs) to synthesize β-2-microglobulin (B2M) that elicits the release of c-KIT ligand and interleukin-7 that greatly accelerate posttransplant immune reconstitution. An identical chain of events was reproduced by infusing supernatants of alloreactive NK/DC cocultures. Similarly, human alloreactive NK cells triggered human DCs to synthesize B2M that induced interleukin-7 production by thymic epithelial cells and thereby supported thymocyte cellularity in vitro. Chromatography fractionation of murine and human alloreactive NK/DC coculture supernatants identified a protein with molecular weight and isoelectric point of B2M, and mass spectrometry identified amino acid sequences specific of B2M. Anti-B2M antibody depletion of NK/DC coculture supernatants abrogated their immune-rebuilding effect. B2M knock-out mice were unable to undergo accelerated immune reconstitution, but infusion of (wild-type) NK/DC coculture supernatants restored their ability to undergo accelerated immune reconstitution. Similarly, silencing the B2M gene in human DCs, before coculture with alloreactive NK cells, prevented the increase in thymocyte cellularity in vitro. Finally, human recombinant B2M increased thymocyte cellularity in a thymic epithelial cells/thymocyte culture system. Our studies uncover a novel therapeutic principle for treating posttransplant immune incompetence and suggest that, upon its translation to the clinic, patients may benefit from adoptive transfer of large numbers of cytokine-activated, ex vivo–expanded donor alloreactive NK cells.

Association of Tracheomalacia and Bronchiectasis in Children

Source: Thomas R, Chang A, Masters IA, et al. Association of childhood tracheomalacia with bronchiectasis: a case-control study. Arch Dis Child. 2022 Jun;107(6):565-569. doi: 10.1136/archdischild-2021-322578.Investigators from Queensland’s Children’s Hospital, South Brisbane, Australia, and Griffith University, Gold Coast, Australia, conducted a case-control study to assess the association between childhood tracheomalacia and bronchiectasis. Cases were children ≤18 years old with radiographically confirmed bronchiectasis, unrelated to cystic fibrosis (CF), who were seen at a single pediatric center in Australia, enrolled in the Australian Bronchiectasis Registry, and chosen at random from the registry. Only patients who had a chest CT obtained between 2012 and 2018 and who underwent flexible bronchoscopy (FB) within 4 weeks of the CT were eligible as cases. Bronchiectasis was defined using specific radiographic findings and consistent clinical characteristics. Controls were children who had a recent bone marrow transplant and/or cancer and who had a chest CT and FB performed during the same time period for evaluation of febrile neutropenia. Two controls were chosen for each case study participant. For cases, the cause of bronchiectasis was recorded, and for controls, the underlying disorder was noted. The videos from FB in study children were reviewed by an experienced respiratory pediatrician, blinded to the patient’s case/control status, who noted the presence of any tracheomalacia (any-TM), defined as tracheal shape abnormality during expiration, or tracheomalacia, defined by the European Respiratory Society as >50% expiratory reduction in cross-sectional area (ERS-TM). Logistic regression was used to assess the relationship of any-TM and ERS-TM with bronchiectasis. Multivariable analyses adjusting for age, sex, and ethnicity also were conducted.A total of 45 cases and 90 controls were enrolled in the study. Cases were younger than controls (median ages 2.6 years and 7.8 years, respectively). Among cases, the etiology of bronchiectasis was post-infectious in 17 (38%), idiopathic in 15 (33%), aspiration in 7 (16%), primary ciliary dyskinesia in 3 (7%), and other causes in 3 (7%). For control children, 69 (77%) had a hematologic malignancy, and 9 (10%) were post-bone marrow transplant. On FB, 14 (31.3%) cases had any-TM compared to 3 (3.3%) controls (OR, 13.1; 95% CI, 3.5, 48). There were 9 cases and 0 controls with ERS-TM (OR, 30.1; 95% CI, 4.6, ∞). Multivariable analyses demonstrated both age and tracheomalacia were associated with bronchiectasis. After adjusting for age, tracheomalacia remained significantly associated with bronchiectasis using the any-TM definition (OR, 13.2; 95% CI, 3.2, 55).The authors conclude that tracheomalacia is associated with childhood bronchiectasis.Dr Lesser has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Bronchiectasis is commonly defined as airway dilatation on chest CT and occurs as a consequence of chronic bronchial inflammation and infection, leading to lung injury that can be irreversible.1 While bronchiectasis most commonly occurs with CF, other diseases such as primary ciliary dyskinesia, immunodeficiency, severe pulmonary infection, or chronic aspiration can cause bronchiectasis.1 Tracheomalacia, defined as an abnormal reduction in the tracheal lumen with expiration, has been hypothesized to sometimes cause bronchiectasis, related to ineffective cough and mucus impaction leading to chronic airway damage.2 The authors of the current study used a retrospective case-control design to ask if tracheomalacia is associated with bronchiectasis.A key strength of this study relates to all participants having had a chest CT and bronchoscopy, the gold standards for diagnosing bronchiectasis and tracheomalacia, respectively. Diagnosis of tracheomalacia may vary based on anesthesia conditions and bronchoscopy type, but the study employed a standardized approach to bronchoscopy, lending credence to the diagnosis. Establishing controls for a study involving bronchoscopy is challenging because it is invasive and not indicated for healthy children. The control population used in this study was composed of children affected by cancer and was significantly different from cases consisting of children with chronic respiratory disease. While the study was not designed to assess causality, whether tracheomalacia causes bronchiectasis exists as a key question. Even though tracheomalacia was seen more commonly in children with bronchiectasis, the bronchiectasis already was ascribed to a known cause other than tracheomalacia in 2/3 of cases. Thirty-three percent of children had idiopathic bronchiectasis, but the authors did not report the frequency of tracheomalacia in this group. Further study also is needed to ask if tracheomalacia is a marker of bronchiectasis severity or if its presence worsens existing bronchiectasis caused by another disease.Care for children affected by non-CF bronchiectasis continues to improve and gain an evidence base.3 Early identification and aggressive treatment will positively impact lung function and health throughout the lifespan. The authors should be commended for their carefully designed study of this under-researched disease.Bronchiectasis needs to be considered in children with tracheomalacia.Long considered an orphan disease,1 non-CF related bronchiectasis, with studies such as the 1 reviewed above, may yet reverse years of neglect and yield its etiologic and therapeutic secrets.

Prevalence and Characteristics of Cytomegalovirus Ocular Disease in Children: A Multi-Center Study.

PurposeThe objective of this study was to identify the prevalence of CMV ocular disease in children and to identify associated risk factors for ocular involvement.DesignRetrospective multicenter, cross-sectional study.MethodsSetting: Hospitalized patients screened for CMV viremia by PCR between 2005 and 2018 at four pediatric referral centers. Participants: Seven-hundred and ninety-three children showed CMV viremia (>135 copies/mL by polymerase chain reaction; PCR). Main Outcomes and Measures: (1) Occurrence of ophthalmologic examination. (2) Presence of CMV ocular disease, defined as retinitis, vasculitis, hemorrhage, optic nerve atrophy, or anterior uveitis in the setting of CMV viremia without other identifiable causes.ResultsA total of 296/793 (37%) underwent ophthalmologic examination following CMV viremia. A total of23/296 patients (8%) had ocular symptoms prompting evaluation while the rest had eye exams for baseline screening unrelated to CMV viremia. Of these, 13 cases (4% of those with an eye exam) with ocular disease were identified (three congenital CMV, five severe combined immunodeficiency disorder (SCID) status post-stem cell transplantation, three hematologic malignancy status post-stem cell transplantation for two of them, one Evans syndrome status post-stem cell transplantation, and one medulloblastoma status post-bone marrow transplantation). No patients with solid organ transplantation developed CMV ocular disease in our cohort.ConclusionCMV ocular disease was a rare occurrence in this cohort without an identifiable pattern across sub-groups. Excluding the three congenital CMV cases, nine out of ten patients with CMV ocular disease were status post-stem cell transplantation. We provide integrated screening guidelines based on the best available evidence for this rare condition.

Phosphoproteomic analysis of FAC overload-triggered human hepatic cells reveals G2/M phase arrest

Hepatic iron overload is a universal phenomenon in patients with myelodysplastic syndromes (MDS) who undergo bone marrow transplantation and may experience the toxicity of peri- and post-bone marrow transplantation. To clarify the mechanisms of iron overload-triggered liver injury, we determined the effects of iron overload on changes in protein phosphorylation in human hepatocyte cell line HH4 in vitro by using a phosphoproteomics approach. The hepatocytes were exposed to high concentrations of ferric ammonium citrate (FAC) to build up an iron overload model in vitro. Changes in protein phosphorylation initiated by iron overloading were studied by 2D-LC/MS. We identified 335 differentially expressed phosphorylated proteins under the condition of excess hepatocyte iron, 11% of which were related to cell cycle progression. The results of phosphoproteomics showed that iron overload induced 10.9 times increase in Thr 14/Tyr 15-phosphorylated Cdk1 in HH4 cells. Flow cytometry analysis revealed that FAC-treated HH4 cells showed significant G2/M phase arrest. Our subsequent RT-PCR and Western blot experiments indicated that FAC-induced G2/M phase arrest was related to the activation of p53-p21-Cdk1, p53-14-3-3 sigma-Cdk1, and 14-3-3 gamma pathway. Our findings demonstrate the first evidence that iron overload causes G2/M arrest in HH4 hepatocytes.

Further evidence supporting the role of DUT gene in diabetes with bone marrow failure syndrome.

In 2017, a homozygous DUT mutation was reported to cause a syndrome of diabetes and bone marrow failure. However, no further patient with this combination has been reported and the phenotype of heterozygous DUT mutation is unknown. We describe the genotype, phenotype, and post bone marrow transplantation (BMT) data of two unrelated families with this rare syndrome. Whole-exome and/or direct sequencing of the DUT gene were performed in all family members. Each family has two children presented within the first 10 years of life with thrombocytopenia, macrocytosis, with or without anemia, followed by non-autoimmune diabetes. The same homozygous missense DUT mutation, reported in 2017 (c.425A>G p.(Tyr142Cys), was detected in all affected children. The heterozygous carriers have no BM failure, one developed type 2 diabetes, and the rest have normal fasting glucose, insulin, HbA1c, and c-peptide. Multiple nevi were detected in homozygous and heterozygous mutation carriers. Allogenic BMT normalized BM aplasia without impact on diabetes. Post BMT follow-up revealed normal puberty and school performance; but three have height <2.5 SDS. We add two families with this syndrome supporting a role of DUT in bone marrow and β-cell function. The heterozygous carriers of this DUT mutation appear to be healthy.

Different Clinicoradiological Characteristics of Posterior Reversible Encephalopathy Syndrome in Pediatric Oncology and Post-Bone Marrow Transplantation Cases: A Retrospective Study.

Posterior reversible encephalopathy syndrome (PRES) is receiving increasing recognition in pediatrics. However, comparisons between PRES in pediatric oncology and post-bone marrow transplantation (BMT) are lacking. Therefore, we aimed to describe the risk factors and clinical and radiological features of PRES and investigate the differences between PRES in pediatric oncology and post-BMT. The PRES data of 13 patients from our center were combined with those of 217 cases from the PubMed, Scopus, and Web of Science databases. The patients were divided into either an oncology or a post-BMT group. We included 230 patients in the analysis, 26.1% of whom belonged to the post-BMT group. Oncology patients developed PRES at a younger age (p = 0.010) and were more likely to develop encephalopathy (p = 0.004). Systemic hypertension (S-HTN) preceding PRES occurred in 43.5% (66/154) of patients. Post-BMT patients were more likely to have S-HTN (p = 0.003). Cyclosporine levels were detected in 37 patients; 40.5% had supra-therapeutic levels. The radiological findings were atypical in 74.3% of patients, and delayed repeated imaging increased the occurrence of resolution (p = 0.004). Sixteen (7%) patients developed PRES recurrence after a median of 8 weeks, with the between-group difference being non-significant. Oncology patients were more likely to develop chronic epilepsy, while BMT patients were more likely to develop rare neurologic abnormalities (p < 0.001). In conclusion, atypical clinical presentation and imaging findings should not hinder the diagnosis of PRES. S-HTN is a risk factor, particularly in post-BMT patients. Supra-therapeutic levels of cyclosporine and previous exposure to immunosuppression did not increase the risk of recurrence.

Using mTOR Inhibitor Nanoimmunotherapy to Induce Cardiac Allograft Tolerance in Non-Human Primates

<h3>Purpose</h3> Though tolerance to kidney allografts has been consistently achieved using a mixed chimerism model, cardiac allografts remain resistant to tolerance induction. Lipoprotein-based nanobiologics loaded with a mammalian target of rapamycin inhibiting prodrug (mTOR inhibiting nanobiologics, mTORi-NBs) inhibit trained immunity and promote graft infiltrating M2-macrophages that provide a favorable local immunologic milieu for tolerance induction. In this study, we evaluate the ability of mTORi-NBs to induce tolerance in a cardiac allograft model in NHPs. <h3>Methods</h3> Six NHPs underwent simultaneous heterotopic heart and bone marrow transplantation for mixed chimerism induction. Group A (n=3) was conditioned with 3 Gy total body irradiation (TBI), 7 Gy thymic irradiation (TI), ATGAM, anti-CD40L monoclonal antibody on days 0, 2, 5,7, 9, and 12 post-bone marrow transplant (pBMTx), and cyclosporine until day 28 pBMTx. Group B recipients (n=3) underwent the same conditioning regimen with the addition of mTORi-NBs at a dose of 0.15 mg/kg on days 2, 5, 12, 19, and 26 pBMTx. Group B donors were also treated with a single dose of mTORi-NBs two days before transplant. <h3>Results</h3> In group A, all allografts had end stage rejection by day 175 pBMTx with a mean duration of lymphocyte chimerism of 74 days. The first recipient in group B developed durable full chimerism and mild graft versus host disease (GVHD) which resolved after a course of steroids and cyclosporine. After resolution of his GVHD, his graft continued beating strongly with no evidence of rejection through day 239 pBMTx. The second and third recipients received half dose (1.5 Gy) TBI and both allografts are contracting strongly at days 271 and 26 pBMTx, though the second recipient had some evidence of rejection at day 212 pBMTx. Currently, the mean duration of lymphocyte chimerism in Group B is 149 days. <h3>Conclusion</h3> Preliminary studies suggest that adding mTORi-NB nanoimmunotherapy to a mixed chimerism protocol prolongs both donor lymphocyte chimerism and heart graft survival in NHPs even when reducing pre-operative TBI.

Romiplostim in Eltrombopag Refractory Thrombocytopenia Post Bone Marrow Transplant in a Child with MDS: A Case Report

Thrombocytopenia is a well-known complication post bone marrow transplant, whether primary or secondary. Refractory thrombocytopenia is not uncommon and over the past few years, thrombopoietin receptor agonists have emerged as new agents for the management of the above. Namely Eltrombopag and more recently Romiplostim. In children however, though Eltrombopag is being more frequently used, Romiplostim usage is still rarely reported for management of thrombocytopenia post bone marrow transplantation. Our experience with Romiplostim was successful in the management of refractory thrombocytopenia in a child with MDS post bone marrow transplantation.

Pre-Transplant M Protein Level Predicts Minimal Residual Disease Status after Autologous Stem Cell Transplantation in Multiple Myeloma

Introduction: Autologous stem cell transplantation has been a staple treatment modality in patients with multiple myeloma for more than 30 years. Multiple studies have shown increased survival among patients who undergo transplant when compared to those who receive chemotherapy alone, even amongst elderly patients. Despite the efficacy associated with transplant among populations as a whole, individual response to therapy is variable and difficult to predict. Recent studies however have demonstrated that achieving minimal residual disease (MRD) negativity is associated with increased survival in patients with multiple myeloma. In this study, we performed a retrospective analysis on patients with multiple myeloma who underwent autologous stem cell transplantation and investigated potential markers to predict post-transplant MRD status.Patients and Methods: Patients with a diagnosis of multiple myeloma that underwent treatment with high-dose melphalan followed by autologous stem cell transplantation at the Indiana University Simon Cancer Center between 2019-2020 were included in the analysis. Patient demographics, disease characteristics, pre-transplant and post-transplant laboratory values, and approximately day +100 post-transplant bone marrow sample results were collected. MRD analysis on post-transplant bone marrow aspirations was performed using 8 color flow cytometry panel with a total of 10 markers. The limits of quantification and detection were calculated at 5X10 -6 and 2X10 -6, respectively. Post-transplant data was analyzed to determine MRD status. MRD negativity was defined as having no identifiable M protein via serum protein electrophoresis (SPEP) or immunofixation electrophoresis (IFE) and having negative MRD on post-transplant bone marrow biopsy testing. Patients with insufficient data to determine post-transplant MRD status were excluded from the analysis. Univariate logistic regression was performed to assess the association of pre-transplant variables with post-transplant MRD status. Multivariate logistic regression model was utilized to analyze markers with a p-value <0.25 in univariate analysis.Results: 133 Patients were included in the analysis with average age at transplant being 60.84 years (range 32.18 years-78.13 years). 83/133 (62.41%) patients were male and 118/133 (88.72%) patients were white. 84/133 (63.16%) patients had achieved a VGPR or less according to the International Myeloma Working Group (IMWG) response criteria prior to transplant. Among all patients, age at transplant, gender, race, body mass index, glomerular filtration rate on day -1, serum albumin on day -1, kappa/lambda ratio on day -1, melphalan dose received, and multiple myeloma immunoglobulin subtype were not associated with response to therapy. Pre-transplant M protein positivity was associated with a higher likelihood of post-transplant MRD positive status with an odds ratio of 24.318 (p<0.0001). VGPR status or less on day -1 was associated with an increased post-transplant MRD positive status with an odds ratio of 6.223 (p<0.0001) however was not found to be statistically significant following multivariate analysis (p=0.0664). When restricting analysis to include only patients at VGPR status or less prior to transplant, pre-transplant M protein positivity and increased age at transplant were associated with increased likelihood of MRD positive status with odd ratios of 9.000 (p=0.0121) and 1.066 (p=0.0366) respectively. Both variables were shown to be statistically significant following multivariate analysis.Conclusions: Detectable levels of pre-transplant M protein via serum protein electrophoresis is associated with an increased likelihood of having positive minimal residual disease following autologous stem cell transplantation in multiple myeloma. Age at transplant does not predict minimal residual disease status among all patients undergoing transplant, however increased age at transplant may be associated with inferior outcomes in patients achieving a VGPR or less prior to transplantation. [Display omitted] DisclosuresSuvannasankha: The Veteran's Affair: Patents & Royalties; Karyopharm: Consultancy, Research Funding; Regeneron: Research Funding; Sutro: Research Funding; Glaxo Smith Kline: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Abonour: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding; Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding. Abu Zaid: Syndax: Consultancy, Research Funding; Pieris: Current equity holder in publicly-traded company; Incyte: Research Funding; Pharamcyclic: Research Funding.

Post-Transplant MRD Status and T Cell Chimerism Predict Outcomes in Patients Allografted for AML/MDS-a Prospective Analysis from the UK NCRI Figaro Trial

▪Allogeneic stem-cell transplantation is an important curative strategy in acute myeloid leukaemia (AML) consequent upon the development of a graft-versus-leukaemia (GVL) effect. Disease relapse is the major cause of transplant failure and novel therapeutic strategies are required in patients with measurable residual disease (MRD) post-transplant. Recognizing that full donor T cell chimerism serves as a biomarker of GVL and that mixed donor T cell chimerism reflects the presence of bi-directional tolerance, we report the first prospective correlation of the impact of post-transplant T cell chimerism and MRD in patients allografted for AML/MDS.Methods: 186 patients from FIGARO, a prospective randomized trial of reduced intensity conditioning regimens in AML/MDS, were alive and relapse free, at the first MRD timepoint and provided post-transplant bone marrow samples for flow cytometric MRD monitoring (day+42, month+3/+6/+9/+12) and peripheral blood samples for T cell chimerism analysis (3-monthly during the first year). Results were not available to clinicians. Flow cytometric MRD incorporating an unsupervised immunophenotypic analysis approach was used on 778 sequential samples. The prognostic significance of post-transplant MRD from each sampling timepoint was assessed by landmark analysis.Results: 29 (15.6%) patients were MRD+ at one or more timepoints in the first year after transplant. The presence of post-transplant MRD was associated with reduced OS (HR:2.19, p=0.0026) and RFS (HR:5.36, p<0.0001), when analyzed as a time varying Cox variable. We, and others, have shown that pre-transplant MRD status is an important determinant of post-transplant survival. We therefore performed a multivariate analysis of factors that may determine the prognoses of patients with pre-transplant MRD+ disease. This demonstrated that the presence of detectable post-transplant MRD was the only independent determinant of RFS in this group of patients (HR 9.05 (95%CI:1.70-48.2), p=0.0099), even when adjusted for cytogenetics, FLT3-ITD and GVHD. The highest frequency of post-transplant MRD positivity occurred at day+42/month+3. The 2yr OS of day+42 MRD+ patients (n=13/158) was 30.8% (95%CI 9.5-55.4) compared to 67.1% (95%CI 58.5-74.2) in MRD negative patients (p<0.001); and 2yr CIR in day+42 MRD+ patients was 92.3% (95% CI:35.8-99.4) versus 22.8%% (95%CI:16.3-29.9) when MRD negative (p<0.001). Day+42 MRD was associated with more rapid relapse kinetics (median RFS of 2 months) compared to when MRD was first detected at later timepoints.Next, we examined the impact of T-cell chimerism, and post-transplant MRD on outcomes. In patients with mixed-donor T-cell chimerism (MDTC) at month+3 or +6, the presence of post-transplant MRD (preceding or at time of first MDTC) was associated with decreased OS (p=0.001) and RFS. Specifically, 2yr RFS in MRD+ patients was 23.1% (95%CI:5.6-47.5), compared to 63.6% (95%CI:44.9-77.5) in patients who were MRD negative (p=0.004) (Figure). In contrast, in 48 patients with full donor T-cell chimerism (FDTC) at months 3 and 6, only 5 patients were MRD+ post-transplant and their outcomes were equivalent to patients who were MRD negative (FDTC/MRD negative 2yr RFS: 80.9% (95% CI:65.3-90.0)).Downregulation of HLA class II molecules on AML blasts after transplant may result in immune evasion from GVL: we examined whether this had an additional impact on outcome in post-transplant MRD+ patients. Both RFS and OS were significantly lower in MRD+ patients when MRD+ blasts had down-regulated HLA-DR expression. In MRD+ patients, 2yr OS was 20.0% (95%CI:3.1-47.5) in those with HLA-DR down-regulation, versus 57.9% (95%CI 33.2-76.3) in those without (p=0.001).Conclusion We demonstrate that dynamic assessment of post-transplant MRD is an important predictor of outcome in patients allografted for AML/MDS, with additional prognostic value to pre-transplant MRD assessment. Post-transplant MRD and T-cell chimerism results are most informative when combined, underlining the importance of a GVL effect in AML/MDS. This suggests post-transplant strategies which result in FDTC may improve outcomes in patients allografted for AML/MDS. Our data also supports the clinical relevance of monitoring for leukemic immune escape as HLA-DR down-regulation identifies a post-transplant MRD positive subgroup at risk of almost inevitable relapse. [Display omitted] DisclosuresLoke: Novartis: Other: Travel; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Daichi Sankyo: Other: Travel. Protheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Jazz: Other: Education events; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

CXCL1, CXCL10 and CXCL12 Chemokines are Variously Expressed in Acute Myeloid Leukemia Patients Prior and Post Bone Marrow Transplantation.

Aim:The chemokine-receptor axes play parts in development of leukemia, CXCL1, CXCL10 and CXCL12 are involved in immune responses. Thus, we have examined the serum levels of these chemokines in parallel with their related cognate receptors (CXCR1, CXCR3 and CXCR4) in AML (acute myeloid leukemia) patients prior and post BMT (bone marrow transplantation) therapy. Main methods: Clinical specimens were collected from 46 AML patients (23 M1 and 23 M3 subtypes) before/after BMT. CXCL1, CXCL10 and CXCL12 concentrations were determined by ELISA. The mRNA levels of the related receptors were detected by QRT_PCR. Data were analyzed by T-test, χ2 and ANOVA statistical methods in SPSS software version 18. A difference was regarded significant if P value < 0.05. Key findings:Our results indicated that the elevated levels of CXCL12 in AML patients were remained unchanged after transplantation. The CXCL10 concentration was decreased in patients. All studied chemokines were elevated in BMT patients with history of 9 times PLT transfusion. In patients who received BMT from siblings CXCL1 and CXCL10 have been elevated, whereby they were compared to patients who received BMT from parents while CXCL12 sustained unchanged in groups. Serum measures of CXCL1 and CXCL10 were induced in acute and chronic GVHD patients in compare to these without GVHD. Significance:According to the results, it can be concluded that these chemokines play fundamental parts in pathogenesis of both AML and BMT. It is worthy to note that chemokines could be used as diagnostic markers alongside with possible promising therapeutic targets.

The Association Between Serum Vitamin D Levels and Bone-Related Outcomes in Patients 100 Days Post-Bone Marrow Transplant

Describe the effect of various risk factors on vitamin D status and BMD in patients who have received a bone marrow transplant. Bone marrow transplants (BMT) can have adverse outcomes, including low bone mineral density (BMD). However, little research has investigated the association of vitamin D status and bone-related outcomes in patients after BMT. Therefore, this study aims to describe the association between vitamin D status and bone-related outcomes in patients +100 days post-BMT, along with treatment practices that may affect vitamin D status. This retrospective chart review examined 149 BMT patient records and determined the relationship between serum 25(OH)D concentration and DXA T-scores using linear regression, correlation coefficients, and Chi-square tests. Chi-square tests were used to determine the association of vitamin D status and various categorical risk factors. The mean 25(OH)D concentration for the study population was 36.46 ng/mL. Over 60% of subjects had DXA T-scores that corresponded to a normal BMD. There was no significant association between 25(OH)D concentration and DXA T-scores. Vitamin D status was significantly associated with age (p=0.01), diagnosis (p<0.01), transplant type (p<0.01), immunosuppressant use (p<0.01), vitamin D supplementation (p=0.01) and amount (p=0.04), calcium supplementation (p=0.02) and amount (p=0.05). Risk factors are present post-BMT that may affect vitamin D status. However, the role that vitamin D plays in maintaining adequate bone mineral density in this population is unclear. Cross-sectional studies with larger sample sizes, stratification by transplant type, and increased length of time post-BMT should be conducted to further assess this association.

The utility of strain imaging in the cardiac surveillance of bone marrow transplant patients

ObjectiveTo evaluate the utility of two-dimensional multiplanar speckle tracking strain to assess for cardiotoxicity post allogenic bone marrow transplantation (BMT) for haematological conditions.MethodsCross-sectional study of 120 consecutive patients post-BMT (80...

Long Term Followup of Sickle Cell Disease Post Hematopoietic Stem Cell Transplant from Uganda

Introduction: Sickle cell disease (SCD) remains associated with high risk of morbidity and early death. Many patients in sub-Saharan Africa continue to experience severe complications despite best supportive care. Hematopoietic stem cell transplant (HSCT) can be considered for a select group of patients. When successful, HSCT is economical and improves quality of life. We report the experience from our south-south partnership whereby Ugandan patients with SCD have undergone HSCT at the Bone Marrow Transplant Center in Gurgaon, IndiaMaterial and methods: 23 consecutive patients suffering from SCD who underwent HSCT between June 2014 and July 2017 were included in the study. Eleven underwent matched sibling donor bone marrow transplant (BMT) using busulfan 3.2 mg/kg/day for 4 days, cyclophosphamid 50mg/kg/day for 4 days, and hATG (PfizerATGAM) 30mg/kg/day for 3 days. Two adult patients underwent matched sibling donor HSCT using reduced intensity conditioning with busulfan 3.2 mg/kg/day for 4 days, cyclophosphamid 60mg/kg/day for 2 days, and ATG (PfizerATGAM) 30mg/kg/day x 3 days. Immune suppression for for HSCT patients was cyclosporine 3mg/kg/day in 2 divided doses starting D-4 and methotrexate 10mg/m2 on D+1 followed by 7mg/m2 on day 3, 6 and 11 post HSCT. Ten patients underwent haploidentical HSCT using hypertransfusion (target Hb 11-13gm/dl), hydroxyurea (20mg/kg/day) and azathioprine (2mg/kg/day) from day -45, conditioned with Thiotepa 10mg/kg in two divided doses (D-7), fludarabine 30mg/m2 (D-6 to D-2), cyclophosphamide 14.5 mg/kg (D-5, D-4), TBI 2Gy with thymic shielding (D-1), rATG (Genzyme Thymoglobulin) 1.5 mg/kg (D-9 to D-7). GVHD prophylaxis included PTCy 50 mg/kg/day on D3 and 4, tacrolimus (target level 5-15 ng/ml) or sirolimus (target levels 10-15ng/ml) (till 6 months post HSCT) and MMF (till D35) starting from D5.Results: The median patient age was 8 years (range 10 months-31 years). Before transplantation all patients had repeated episodes of SCD complications warranting a transplant. All were non-responsive to hydroxyurea. Of the 23 patients, 18 survived without sickle cell disease with Lansky/Karnofsky scores of 100. One had a primary graft failure another secondary graft failure with recurrence of disease. At median follow up of 479 days (range 51-1204) the probabilities of survival, SCD-free survival, and transplant-related mortality after transplant were 87%, 78%, and 13%, respectively. Three children who underwent haploidentical HSCT died. One died due to PRES with intracranial hemorrhage at day 86 post BMT, another one due to primary graft failure with Klebsiella sepsis with shock. The third child died due to complicated falciparum malaria and possible invasive fungal infection at day 24 post HSCT. He had full donor chimerism.Conclusion: Outcomes of HSCT in SCD have improved significantly. With better conditioning regimens and improved supportive care, alternative donor transplant and adult HSCT have become viable therapeutic options. HSCT should be strongly considered as a curative modality for selected patients suffering from SCD. DisclosuresNo relevant conflicts of interest to declare.

Aautoimmune Hemolytic Anemia: Pattern of Clinical Presentation and Management Outcome — a Nine Year Observation from a Tertiary Care Hospital in Saudi Arabia

Introduction: Autoimmune hemolytic anemia (AIHA) is characterized by production of auto-antibodies that bind to antigen on the erythrocyte surface that leads to its premature destruction and removal from the circulation by macrophages. Occurrence of AIHA in children and adolescents is rare, exact incidence unknown. Objective of this retrospective study was to assess clinical and laboratory characteristics, and management outcome of patients diagnosed with AIHA seen at Pediatric Hematology/Oncology department of King Faisal specialist Hospital and Research Center ,Riyadh from 2005 to 2014. Method: Retrospective chart review of patients (1-14 yrs.) diagnosed with AIHA was conducted. Children were excluded if they have congenital hemolytic anemia, such as hemoglobinopathies, congenital membranopathy and erythrocyte enzyme deficiencies. Result: Thirty-one patients identified, 19(61%) female and 12(39%) male with a median age at diagnosis of 6 years (0.1-12.4). The direct Coombs test was positive in 23 (74%) patients. Underlying diseases observed as cause of AIHA in 14 (45%) patients: majority secondary to viral infections followed by severe combined immunodeficiency syndrome post bone marrow transplant GVHD complication, while systemic lupus erythematosus, antiphospholipid antibody syndrome, autoimmune hepatitis, hypereosinophilic syndrome, Hyper IgE syndrome, post-liver transplant, diabetes was observed in individual cases. Remaining 17 (55%) patients diagnosed as primary AIHA .Corticosteroids and/or immunoglobulin was given as first line of treatment to 64.5% (20) patients while 35.5% (11) required Rituximab and/or splenectomy as second line of treatment, of which 73%(8) were diagnosed as primary AIHA. Five-year overall survival (Kaplan-Meir) rate of 89% was observed with twenty-seven alive patients showing partial or complete response ,while four patients died due to underlying diseases.Conclusion: Our results demonstrates patients responding to first line of treatment, however serious cases required management through second line of treatment. Further, a regional multicenter observational study will enable better understanding of differences in disease presentation and treatment outcomes. DisclosuresNo relevant conflicts of interest to declare.

Head-to-head Comparison of Qualitative Radiologist Assessment With Automated Quantitative Computed Tomography Analysis for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation.

Computed tomography (CT) findings of bronchiolitis obliterans syndrome (BOS) can be nonspecific and variable. This study aims to measure the incremental value of automated quantitative lung CT analysis to clinical CT interpretation. A head-to-head comparison of quantitative CT lung density analysis by parametric response mapping (PRM) with qualitative radiologist performance in BOS diagnosis was performed. Inspiratory and end-expiratory CTs of 65 patients referred to a post-bone marrow transplant lung graft-versus-host-disease clinic were reviewed by 3 thoracic radiologists for the presence of mosaic attenuation, centrilobular opacities, airways dilation, and bronchial wall thickening. Radiologists' majority consensus diagnosis of BOS was compared with automated PRM air trapping quantification and to the gold-standard diagnosis of BOS as per National Institutes of Health (NIH) consensus criteria. Using a previously established threshold of 28% air trapping on PRM, the diagnostic performance for BOS was as follows: sensitivity 56% and specificity 94% (area under the receiver operator curve [AUC]=0.75). Radiologist review of inspiratory CT images alone resulted in a sensitivity of 80% and a specificity of 69% (AUC=0.74). When radiologists assessed both inspiratory and end-expiratory CT images in combination, the sensitivity was 92% and the specificity was 59% (AUC=0.75). The highest performance was observed when the quantitative PRM report was reviewed alongside inspiratory and end-expiratory CT images, with a sensitivity of 92% and a specificity of 73% (AUC=0.83). In the CT diagnosis of BOS, qualitative expert radiologist interpretation was noninferior to quantitative PRM. The highest level of diagnostic performance was achieved by the combination of quantitative PRM measurements with qualitative image feature assessments.

Designing food and meals for bone marrow transplant patients with compromised immunity

Immunocompromised post-bone marrow transplant patients must follow a restrictive diet after discharge to avoid microbiological risks in food. Despite the apparent health considerations, these restrictions can sometimes create confusion and apprehension during home meal preparation which has a negative impact on patients’ social dining experiences with families and friends and ultimately leads to adverse health effects such as appetite and weight loss. A user-friendly meal guidebook, specifically designed to fit patient’s needs, was developed to ensure a smooth transition from controlled hospital food to home-cooked meals without compromises in food safety and pleasure. With this guidebook, the objective of this uncommon collaboration between chefs and health professionals was to provide clear instructions to the patients on their diet and adapted recipes (six starters, eight main dishes and eight desserts) easy to do and share with the whole family. This design project represents a unique approach to addressing the food and nutrition needs of these transplant patients. Thus, this article presents an example of a multi-actor collaboration between health and culinary professionals who combined their expertise to help the patients feel less marginalized after their hospitalization and to support their recovery by providing adapted recipes that they can share with their family.

76. Hematocolpos caused by Vulvovaginal Graft-Versus-Host Disease

<h3>Background</h3> One of the mainstays of treatment of Diamond-Blackfan anemia after failure of initial supportive care is allogeneic transplantation. Of the many sequelae of allogeneic hematopoetic stem cell transplantation in female survivors, graft-vs-host disease of the vulva and vagina remains one of the most common and destructive to quality of life. Labial fusion and adhesions, urethral obstruction, vaginal scarring and more uncommon - hematocolpos - are some of the presentations of severe disease. In this case report, we will discuss the treatment hematocolpos as a sequelae of GVHD following allogeneic transplantation. <h3>Case</h3> 16 year old with Diamond-Blackfan anemia status post HLA-matched unrelated donor bone marrow transplant presented 7 months post-transplant with 2 days of low abdominal pain. Pain was 8/10, intermittent, nonradiating, worse with movement and completion of urination and improved with heat packs and oral pain medication. Menarche was at age 15, and she experienced one period prior to transplant which lasted 4 days with moderate flow and no pain. Pretransplant, she had received Depot Lupron and then maintained on norethindrone acetate 5mg daily which was increased after she developed breakthrough bleeding following transplant and then stopped taking 4 months after transplant. Following transplant, she developed secondary amenorrhea consistent with hypothalamic suppression. On presentation, she had GVHD with skin, oral and ocular involvement, normal abdominal exam and a pelvic exam with Tanner stage IV development, labia majora without posterior fusion, rugation, or hyperpigmentation, and labia minora without adhesions or lesions. The distal vagina was present with patent hymen, and a Q-tip was unable to be passed beyond 2cm into the vagina. Transvaginal ultrasound was notable for a complex cystic lesion continuous with the uterine edometrium and upper vagina, demonstrating an air-fluid level measuring 5.9 × 5.9 × 5.4cm, consistent with moderate hematocolpos. Left and right ovaries unremarkable. MRI corroborated these findings. She has undergone 3 separate exams under anesthesia with lysis of adhesions but remains nonadherent to topical steroid or estrogen therapy. She takes continuous combined pills for menstrual suppression. <h3>Comments</h3> This patient highlights an uncommon instance of stenotic vaginal, without vulvar, GVHD. With an absence of external symptoms of GVHD on her genitals, diagnosis may have been delayed. The patient's discomfort with topical therapy necessitates the use of alternative treatment options, which are limited. Menstrual suppression addresses the hematocolpos, but does not address the adhesions, which may impair both future sexual intimacy and overall quality of life.