Undergoing Bone Marrow Transplantation Research Articles

HLA alleles, haplotypes frequencies, and their association with hematological disorders: a report from 1550 families whose patients underwent allogeneic bone marrow transplantation in Egypt.

HLA alleles are representative of ethnicities and may play important roles in predisposition to hematological disorders. We analyzed DNA samples for HLA-A, -B, -C, -DRB1, and -DQB1 loci, from 1550 patients and 4450 potential related donors by PCR-SSO (Polymerase chain reaction sequence-specific oligonucleotides) and estimated allele frequencies in donors and patients from 1550 families who underwent bone marrow transplantation (BMT) in Egypt. We also studied the association between HLA allele frequencies and incidence of acute myeloid leukemia, acute lymphoblastic leukemia, and severe aplastic anemia. The most frequently observed HLA class I alleles were HLA- A*01:01 (16.9%), A*02:01 (16.1%), B*41:01 (8.7%), B*49:01 (7.3%), C*06:02 (25.1%), and C*07:01 (25.1%), and the most frequently observed class II alleles were HLA-DRB1*11:01 (11.8%), DRB1*03:01 (11.6%), DQB1*03:01 (27.5%), and DQB1*05:01 (18.9%). The most frequently observed haplotypes were A*33:01~B*14:02 ~ DRB1*01:02 (2.35%) and A*01:01~B*52:01~DRB1*15:01 (2.11%). HLA-DRB1*07:01 was associated with higher AML odds (OR, 1.26; 95% CI, 1.02-1.55; p = 0.030). Only HLA-B38 antigen showed a trend towards increased odds of ALL (OR, 1.52; 95% CI, 1.00-2.30; p = 0.049) HLA-A*02:01, -B*14:02, and -DRB1*15:01 were associated with higher odds of SAA (A*02:01: OR, 1.35; 95% CI, 1.07-1.70; p = 0.010; B*14:02: OR, 1.43; 95% CI, 1.06-1.93; p = 0.020; DRB1*15:01: OR, 1.32; 95% CI, 1.07-1.64; p = 0.011). This study provides estimates of HLA allele and haplotype frequencies and their association with hematological disorders in an Egyptian population.

A Parametric Cox Proportional Hazard Model with Application

Survival analysis has become integral to clinical studies, especially in emerging diseases and terminal ailments. This study focused on improving the popular Cox PH model. The new method developed is a parametric type, incorporating the hazard rate of the exponential distribution. It was noted that though the functional form of the Cox PH model was altered, the assumptions were upheld. Additionally, the new model parameters were estimated using the same maximum partial likelihood as the Cox model. Data on the survival times of 137 patients who underwent bone marrow transplants were deployed, and the proposed parametric Cox PH model proved superior to the Cox PH model.

Experiences of Multiple Myeloma Patients With Treatment in the Palestinian Practice: A Multicenter Qualitative Study in a Resource-Limited Healthcare System.

Background Multiple myeloma is a crippling cancer that puts a significant strain on patients and their families alike. The long and exhausting treatment journey with the disease is challenging not only for patients but also for healthcare systems. This exploratory study was conducted to look into these patients' experiences with their treatment and explore their recommendations and views to improve the Palestinian healthcare system, which can be viewed as an evolving healthcare system within a resource-limited and developing country. Methods The consolidated criteria for reporting qualitative research (COREQ) checklist was used for conducting this multicenter exploratory qualitative study. A total number of eight patients with multiple myeloma who received treatment in the Palestinian healthcare system participated in semi-structured in-depth interviews. The semi-structured in-depth interviews followed a set interview schedule. Thematic analysis of the data was done using the qualitative interpretive description approach. Results A total of 5.48 h (329 min) of total interview time was analyzed. Among the patients, 6 (75%) were males, 5 (63.5%) lived in urban areas, 5 (62.5%) reported satisfaction with their household income, 6 (75%) underwent bone marrow transplantation, and all of them (100%) had governmental insurance. The qualitative data that emerged after analysis were classified into three major themes and multiple sub-themes. The three major themes were: (1) treatment side effects, (2) factors affecting treatment experience, and (3) recommendations to improve healthcare service. Conclusion The results of this qualitative study offer insight into how people with multiple myeloma view the healthcare system in Palestine and shed light on the variable and challenging experiences with their treatment, side effects, and communication with healthcare providers within the context of a resource-limited and developing country. Future research should involve hemato-oncology doctors and benefit from their expertise in the field.

End-stage ADPKD with a low-frequency PKD1 mosaic variant accelerated by chemoradiotherapy

Autosomal dominant polycystic kidney disease (ADPKD) is commonly caused by PKD1, and mosaic PKD1 variants result in milder phenotypes. We present the case of a 32 year-old male with chronic active Epstein–Barr virus who underwent bone marrow transplantation with chemoradiotherapy at age 9. Despite a low-frequency mosaic splicing PKD1 variant, he developed severe renal cysts and end-stage renal disease in his 30 s. This case highlights how environmental factors may contribute to the genetic predisposition to ADPKD.

Shwachman-Diamond syndrome associated with rod-cone dystrophy.

To report a patient with Shwachman-Diamond syndrome and concomitant rod-cone dystrophy who underwent bone marrow transplantation. Retrospective single case report. A female patient with Shwachman-Diamond syndrome was referred to a tertiary hospital to investigate possible pigmentary retinopathy at the age of 16. She described poor night vision and was found to have reduced visual acuity (6/20 right, 6/38 left). Over the ten-year follow-up period, her visual acuity remained relatively stable with no new visual symptoms. Optical coherence tomography revealed progressive, diffuse outer retinal thinning with disruption of the ellipsoid zone, which initially was relatively preserved subfoveally. Fundus autofluorescence images revealed generalised areas of hypoautofluorescence beyond the vascular arcades and a perimacular ring of increased autofluorescence. The flash electroretinogram was in keeping with a severe rod-cone dystrophy. The pattern visual evoked potential was abnormal but detectable indicating macular pathway dysfunction, suggesting encroachment into central macular regions but with some functional preservation. We report a patient with Shwachman-Diamond syndrome with severe early-onset rod-cone dystrophy noted at the age of 16. Slow anatomical progression has been observed over the subsequent ten years, with relative functional macular preservation to support a visual acuity of 6/36 in both eyes.

One Tube Does Not Fit All: Parent Experiences and Decision-Making for Choosing a Nasogastric Tube or Gastrostomy for Their Child During Allogeneic Bone Marrow Transplant

Background: Children undergoing bone marrow transplant (BMT) are at risk of developing malnutrition. A feeding tube becomes a requirement for most children to meet their nutritional and medication requirements. Two tubes are typically used: nasogastric tube (NGT) or gastrostomy. At the UK center where this study took place, parents are offered a choice between these tubes. Objective: This qualitative data collection in a mixed methods study explored why parents choose either tube and their experiences of using it. Methods: Parents participated in 2 semistructured interviews. First, on admission to explore why they chose either tube. Second, 1–2 months postdischarge to explore their experience of using the tube. Interviews took place over 18 months. Transcripts were thematically analyzed. Results: Sixteen parents whose child had an NGT, 17 a gastrostomy, were interviewed. Choice was experienced across a continuum of difficulty and freedom. Many parents deferred to the expertise of professionals; others felt they were the experts in their child. Influential factors in decision-making included expected duration of need, the child’s age and activity, cosmetic differences, balancing gastrostomy surgery against NGT dislodgement, lay advice, healthcare professionals’ recommendations and prior tube feeding experiences. Conclusions: Parents valued choice appreciating 1 feeding tube might not suit every child. Implications for Practice: Choice of a gastrostomy or NGT should be offered to children prior to BMT. What is Foundational: Parents navigate a complex decision-making process when choosing a feeding tube for their child. Healthcare professionals can facilitate informed decision-making through collaborative discussions, inclusion of peer support, and provision of balanced information.

Susceptibility to mycobacterial infection in VEXAS syndrome.

VEXAS is a recently described acquired auto-inflammatory and hematologic syndrome caused by somatic mutations in UBA1. To date, VEXAS is not a recognized cause of acquired immunodeficiency. Two of our 10 VEXAS patients developed a disseminated Mycobacterium avium infection. To shed light on this observation, we retrospectively studied all patients with disseminated non-tuberculous mycobacterial infections (NTMi) seen at our institution over 13 years. Inclusion criteria were a positive blood/bone marrow culture, or 2 positive cultures from distinct sites, or one positive culture with 2 involved sites. patient 1 presented with fever, rash, orbital cellulitis and lung infiltrates. Patient 2 presented with fever and purpura. In both cases, Mycobacterium avium was identified on bone marrow culture. Twenty cases of disseminated NTMi were reviewed. Among 11 HIV-negative patients, three had chronic immune-mediated disease; three had untreated myeloid neoplasm; two had VEXAS; one had undergone kidney transplantation; one had GATA-2 deficiency; and one had no identified aetiology. None had lymphoid neoplasia or had undergone bone marrow transplantation. HIV-negative cases had higher CD4 counts than HIV-positive patients (median CD4: 515/mm3 vs 38/mm3, p< 0.001). Monocytopenia was present in seven cases. At 2 years, six patients had died, including both VEXAS patients. VEXAS patients have an intrinsic susceptibility to disseminated NTMi, which may result from monocytic dysfunction. NTMi can mimic VEXAS flare. Clinicians should maintain a high suspicion for opportunistic infections before escalating immunosuppressive therapy. Further studies are needed to confirm and better decipher the herein reported observations.

Evaluation of 5-Year Survival Rate of Patients with Multiple Myeloma Undergoing Bone Marrow Transplantation: A Descriptive Study

Background: Multiple myeloma is a progressive and high mortality neoplasm, and the prevalence increases with aging. The main treatment for new cases aged less than 65 years is high-dose chemotherapy with autologous bone marrow transplantation. This study aims to determine the five-year survival rate of patients with multiple myeloma.&#x0D; Methods: In this descriptive-analytical study, 97 patients with multiple myeloma who underwent bone marrow transplantation between 2011 and 2016 were investigated. Then, information related to gender, age at the time of transplantation, the time interval between diagnosis and transplantation, cases of death and, date of death of the studied patients were collected, and the survival of the patients from the date of diagnosis to the end of the study period (five years) was calculated. Data were analyzed using Cox proportional and chi-square tests.&#x0D; Results: Five-year survival of patients was 59.8%. The median overall survival of patients was 54.22 months, which shows that age (p value = 0.003), gender (p value = 0.591), and the time delay between diagnosis and bone marrow transplantation (p value = 0.005) all affect patient survival. There was a significant relationship between the patient's age and the time interval between diagnosis and transplantation with the five-year survival of the patients.&#x0D; Conclusion: As a result, bone marrow transplantation provides a higher survival rate. Also, the effect of the patient‘s age and time interval between diagnosis and transplantation, early diagnosis of the disease and, earlier bone marrow transplantation can bring longer survival for patients.

P25 Two cases of multicentric dermatofibrosarcoma Protuberans (DFSP) and adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID) in a tertiary centre

Abstract Dermatofibrosarcoma Protuberans (DFSP) are uncommon soft tissue sarcomas that are rarely metastatic though usually high-risk for local aggression and recurrence. DFSP is associated with t(17;22)(q22;q13) chromosomal translocation resulting in COL1A1-platelet-derived growth factorβ(PDGFB) fusion gene(Kesserwan et al. 2009). We present two patients referred to Dermatology at very different ages (patient A 12 years; patient B 6 months) with atrophic plaques and atypical nodules respectively, later demonstrated to be rare cases of multicentric DFSPs. Both were known adenosine deaminase deficient-severe combined immunodeficiency patients (ADA-SCID), associated with multiple additional pathologies(Ochs et al. 2007). Patient A had been treated aged 6 months by undergoing bone marrow transplant (BMT) from an unrelated donor, but did not present with skin lesions until ∼11 years later, whereas Patient B was referred to our centre from another country for BMT and had lesions incidentally detected whilst temporarily in the UK. Histology for both patients demonstrated a paucicellular highly infiltrative spindle cell proliferation in the deep dermis and subcutis and CD34 positivity, consistent with DFSP. Patient A’s tissue was sent to the Northern Genetics Service and the COL1A1-PDGFB fusion gene was detected. Both patients were referred to plastic surgery for multiple excisions (A-3; B-10 lesions). Patient A has since had two further plastic surgery procedures for further or wider excisions. An association between DFSP and ADA-SCID has become more widely reported, though as is highlighted by our two very different cases little is known about timing of presentations, optimal treatment and prognosis.

Complete Mouth Rehabilitation in a Patient with Fanconi Anaemia: A Rare Genetic Disorder

Fanconi anaemia is a rare, progressive congenital bone marrow failure syndrome characterised by autosomal recessive inheritance and clinical manifestations, including growth retardation, bone marrow failure leading to pancytopenia, an elevated risk of malignancy, skin pigmentation, and skeletal malformations. Patients who have undergone bone marrow transplantation can be treated comprehensively in the dental clinic like other routine patients, provided their blood indices are within normal limits. Its complications include aplastic anaemia, malignancies like acute myeloid leukaemia, liver tumours, and squamous cell carcinoma, often developing post-bone marrow transplantation. Dental anomalies, altered salivary flow, and increased susceptibility to cancer necessitate early diagnosis and specialised dental care. Hereby, the authors present a case of 15-year-old male with Fanconi Anaemia who had undergone bone marrow transplantation and was treated comprehensively in a hospital setting. The present case report aimed to equip healthcare practitioners, especially dentists, with the knowledge needed for accurate diagnosis and effective management.

Plain language summary of RACE study results: addition of eltrombopag to standard treatment of severe aplastic anemia.

Severe aplastic anemia (SAA) and very severe aplastic anemia (vSAA) are blood diseases of the bone marrow. If a suitable donor for bone marrow transplant as initial treatment is unavailable, standard immunosuppression is used. Standard immunosuppression treatment includes horse antithymocyte globulin (hATG) and cyclosporin A (CsA). This summary investigated the results of standard immunosuppression treatment (Group A) versus standard immunosuppression treatment with a medication called eltrombopag (Group B) in participants with SAA and vSAA. Eltrombopag is a medicine that improves the blood platelet level and is taken by mouth (orally). Compared to Group A, more participants in Group B showed increased blood cell level to a normal range without SAA or vSAA and faster treatment response. Side effects were similar in both groups even with the addition of eltrombopag for Group B. Participants in both groups reported feeling well after 6, 12 and 24months. Differences in the participant-reported scores (overall health, physical, emotional, and social) between Group A and Group B were minimal. Immunosuppression treatment (hATG plus CsA) with eltrombopag benefited participants with SAA and vSAA and could be the new standard for SAA in persons who cannot undergo bone marrow transplant. At this time, eltrombopag is only approved in specific countries to treat the condition under study that is discussed in this summary. Clinical Trial Registration: NCT02099747 (RACE study).

Evaluation of the bone marrow transplantat recipient patients regarding fever onset, fever permanence, risk factors, and underlying causes, during the pre-engraftment phase

Background: Patients undergoing bone marrow transplantation (BMT) are at higher risk of immune system deficiency. The immunosuppression, followed by pre-transplant chemotherapy makes patients vulnerable to a variety of infections, and fever is one of the first symptoms, which could develop as a result of infectious or non-infectious diseases. In the present study, the features of the fever during the pre-engraftment stage in BMT-receiving patients have been investigated.&#x0D; Materials and Methods: Sixty-four patients receiving BMT were prospectively evaluated during the pre-engraftment phase to evaluate the evidence of the febrile reaction. Data concerning the cause of fever, microbiological tests, the treatments and fever onset pattern, and treatment outcomes were recorded and analyzed.&#x0D; Results: 73.4% of the patients had autologous transplants, and the others received allogeneic. After transplantation, 75% of patients encountered fever during the pre-engraftment period. Of the 48 patients, 47.9% of the patients suffered from fever of unknown origin (FUO). Age, gender, underlying malignancy, type of transplantation, and acute phase reactants levels before transplantation were not associated with fever development. Among febrile patients, patients with autologous transplantation were significantly more likely to develop FUO (p-value = 0.036) There was also no significant difference in the onset of fever between patients with infectious fever and who suffered FUO&#x0D; Conclusions: During BMT, half of the patients developed a fever of unknown origin; nevertheless, it seems that patients undergoing autologous transplantation are at higher risk of FUO compared to patients who received an allogeneic transplant.

Liquid Chromatography-Tandem Mass Spectrometry Method for the Quantification of Plasma Busulfan.

Busulfan is an alkylating agent and functions as a myeloablative and anti-leukemic chemotherapy drug. It is widely used with cyclophosphamide for conditioning patients undergoing bone marrow transplantation for myeloid leukemia. Studies have shown that the busulfan plasma concentration correlates better with clinical efficacy and toxicity than the patient's administered dosage. Low concentrations predispose to disease recurrence and even graft rejection, and higher concentrations can increase the risk of hepatic toxicity. As a result, dosing levels can vary significantly from patient to patient. Therapeutic drug monitoring (TDM) of busulfan plasma concentration guides the dosage adjustment to optimally achieve complete bone marrow ablation while minimizing the dosage-dependent toxicity. The quick and precise (precision <10%) UPLC-MS/MS method described here for monitoring plasma busulfan levels between 50ng/mL and 5000ng/mL involves the addition of an organic solvent and deuterated internal standard (busulfan d-8) followed by a liquid-liquid extraction, injection of the extract onto a C18 column, and analysis by multiple reaction monitoring (MRM) in ESI-positive mode.

Assessment of Risk Factors for Developing Iron Overload in Patients with Pediatric Cancer and Bone Marrow Transplant Survivors: A Single Center Retrospective Chart Review

Background: Pediatric cancer survivors and those with chronic hematologic disorders are at risk for iron overload secondary to frequent transfusion therapy. As this patient population increases in number due to improvement of therapies, it is essential to identify risk factors associated with the development of iron overload. Classifying these risk factors will help improve screening methods and assist in decreasing side effects from iron overload, such as iron deposition resulting in organ damage. Objective: Assessment of risk factors associated with the development of iron overload in pediatric cancer survivors and those who underwent bone marrow transplant. Methods: Retrospective chart review of patients who completed therapy for pediatric malignancy or underwent bone marrow transplant and were screened for iron overload utilizing magnetic resonance imaging (MRI). Iron overload was defined as T2* liver MRI with iron levels of &amp;gt;5mg/g dry weight. Individuals determined to screen positive for iron overload were evaluated for additional demographic and treatment variables, such as race, age at diagnosis, and total transfused blood volume, to assess for risk factors associated with the development of iron overload. Statistical analyses were performed via univariate and multivariate regression models of the variables collected. Results: We report a large cohort of patients with a mean age of 10.6 years who underwent screening T2* liver MRIs. Of 71 patients who underwent liver MRI screening, 89% met criteria for moderately severe iron overload. Blood volume administered (ml) and Non-White Race were found to be statistically significant in association with higher iron content. Mean iron content was 12.9 mg/g in the Non-White group versus 8.8 mg/g in the White group (p=0.0185). For every 100ml/kg increase in the cumulative blood volume transfused, the predicted iron content increased approximately 1 mg/g (p=0.0227); mean transfused blood volume was 340ml/kg among those who met criteria for iron overload versus 224ml/kg among those who did not (p=0.1858). We did not find any correlation between iron content and age at diagnosis, primary diagnosis, BMI at diagnosis, or gender. Conclusions: Iron overload continues to be a risk for pediatric cancer survivors and those who receive chronic transfusions. Our study revealed a statistically significant correlation between increased amount of blood transfusions and development of iron overload; however, no specific quantity of cumulative transfused blood volume was determined to be the threshold for risk. Our study also revealed a statistically significant correlation between Non-White race and the development of iron overload independent of cumulative transfused blood volume. It is possible there are race-based differences in iron metabolism that result in this increased risk. Further studies regarding specific quantities of blood transfusions, assessing physiologic characteristics of the Non-White patient population, and development of iron overload are needed. These findings indicate the importance of continuing to research the development of iron overload in the pediatric cancer and bone marrow transplant population, as well as provide guidance for understanding the risk each unique patient has for developing this complication.

Analysis of Hospitalization Outcomes in Bone Marrow Transplant Patients with Graft-Versus-Host Disease: A Nationwide Study

Background: Graft-versus-host disease (GVHD) is a well-known complication in patients with bone marrow transplantation. There is a need for additional data on the in-patient outcomes of GVHD in patients who have undergone bone marrow transplantation. Our analysis aims to evaluate the outcomes of GVHD in hospitalized patients with bone marrow transplantation. Method: In this retrospective study, we utilized data from the National Inpatient Sample (NIS) database from 2016 to 2019. Using ICD-10 codes, we identified hospitalizations involving bone marrow transplantation and categorized them into two groups: those with GVHD and those without GVHD. To account for potential confounding variables, we considered a comprehensive set of factors, including age, sex, race, zip code-based income quartile, hospital region, hospital teaching status, hospital division, hospital bed size, insurance status, and the Charlson comorbidity index score. We performed univariable logistic regression analysis to calculate unadjusted odds ratios. Subsequently, we conducted a multivariable logistic regression analysis to account for potential confounding effects and calculated adjusted odds ratios.(see Figure), where the model included only variables that were found to be associated with the outcome of interest in the univariable regression analysis at a significance level of P &amp;lt; 0.2. Proportions were compared using the Fisher exact test for categorical variables, and continuous variables were compared using the Student t-test. All P-values were two-sided, and the significance level was set at P &amp;lt; 0.05, indicating statistical significance. Results: From 2016 to 2019, data were collected from 13,999 hospitalizations involving bone marrow transplants. Among these cases, 836 hospitalizations were linked to GVHD patients. A comparison of patient characteristics showed that individuals with GVHD had a mean age of 51.61 years, while those without GVHD had a slightly higher mean age of 55.55 years. There were slight variations in gender and race distributions between the two groups, with a higher percentage of males and whites observed in the GVHD group compared to the group without GVHD. The analysis of outcomes between the two groups revealed significant differences. Patients with GVHD experienced notably longer mean lengths of stay (41.40 days vs. 21.31 days, P = 0.000) and incurred higher mean total hospital charges ($824,058 vs. $335,765, P = 0.000). Furthermore, after adjusting for confounding factors, GVHD posed a substantial risk to patients undergoing bone marrow transplantation. The adjusted odds ratio (aOR) for mortality in those with GVHD was 7.20 (95% CI: 5.54 to 9.36, P = 0.000) compared to those without GVHD, indicating a considerably higher risk of death. The coefficient for the length of stay was 19.36 days (95% CI: 17.29 to 21.42), and the coefficient for total hospital charges was $453,733 (95% CI: $396,577 to $510,889) in patients with GVHD compared to those without GVHD hospitalizations. Moreover, the presence of GVHD in patients was associated with elevated risks of various medical conditions. The adjusted odds ratios (aORs) for sepsis, pneumonia, acute respiratory failure, intubation and mechanical ventilation, Clostridium difficile infection, and acute kidney injury (AKI) in patients with GVHD were 2.79 (95% CI: 2.28 to 3.41, P = 0.000), 3.30 (95% CI: 2.57 to 4.24, P = 0.000), 5.10 (95% CI: 4.01 to 6.49, P = 0.000), 4.88 (95% CI: 3.75 to 6.34, P = 0.000), 1.45 (95% CI: 1.13 to 1.86, P = 0.003), and 3.57 (95% CI: 2.97 to 4.29, P = 0.000), respectively (see Figure). Conclusion: Patients with GVHD in patients with bone marrow transplantation experience higher mortality rates, extended hospital stays, and increased hospital charges. Additionally, they are at a significantly higher risk of developing severe medical conditions, including sepsis, pneumonia, acute respiratory failure, Clostridium difficile infection, and acute kidney injury (AKI). These findings highlight the importance of closely monitoring and effectively managing GVHD to enhance patient outcomes and alleviate the burden of complications associated with bone marrow transplantation. Nevertheless, further prospective studies are necessary to gain a deeper understanding and more comprehensive evaluation of the outcomes in these hospitalized patients.

Predictive Capacity of Plasma and Urinary Biomarkers for Persistent Albuminuria in Patients with Sickle Cell Disease

Introduction: Chronic kidney disease (CKD) is common in sickle cell disease (SCD) and is associated with increased mortality and morbidity. As albuminuria and changes in estimated glomerular filtration rate (eGFR) occur well after substantial structural and functional tissue damage have occurred, novel biomarkers are needed to predict CKD prior to its development. In this multicenter study, we investigated the association of multiple plasma and urine biomarkers with persistent albuminuria (PA) and their potential in predicting PA in patients with SCD. Methods: Adult subjects with HbSS or HbSb 0 thalassemia were enrolled in a prospective, longitudinal cohort study of CKD in SCD. We excluded patients with diabetic nephropathy, cancer, connective tissue disease, other glomerular diseases, end-stage kidney disease on dialysis, known infection with hepatitis (B or C) or HIV, and who had undergone bone marrow transplantation and solid organ transplantation. Participants were enrolled during routine clinical visits in the non-crisis, “steady states.” PA was defined as at least 2 of 3 spot urine albumin-creatinine ratio (ACR) values ≥30 mg/g or a single value ≥100 mg/g. At baseline evaluation, plasma was analyzed for biomarkers of coagulation activation (D-dimer, thrombin antithrombin complex [TAT], ratio of cleaved high molecular weight kininogen-to-intact high molecular weight kininogen [cHK/iHK]), endothelial dysfunction (endothelin-1 [ET1], vascular endothelial growth factor [VEGF], vascular cell adhesion molecule-1 [VCAM-1]), and urine was analyzed for kidney injury molecule 1 (KIM-1), nephrin and angiotensinogen (AGT) using commercially available ELISA. All urinary biomarkers were normalized to urine creatinine. For baseline values, a standard t-test was performed for continuous variables and a chi-square test was performed for categorical variables. Logistic regression analysis was performed to assess univariate predictors of research biomarkers for PA. Results: Of 278 evaluated subjects, 104 (37.4 %) had PA with a median ACR of 194.5 mg/g [IQR: 102.4, 487.1], and 174 subjects (62.6 %) did not have PA (non-PA) with a median ACR of 13.0 mg/g [IQR: 7.4, 22.4]. Subjects with PA were older, had lower hemoglobin and fetal hemoglobin, but higher systolic and diastolic blood pressures than those without PA (Table 1). Plasma VCAM-1, urinary KIM-1, and urinary AGT were significantly associated with PA with odds ratios of 1.001 (AUC: 0.636; 95% CI: 1.00, 1.002), 1.737 (AUC: 0.661; 95% CI: 1.226, 2.575), and 1.053 (AUC: 0.71; 95% CI: 1.029, 1.084), respectively (Table 2). Surprisingly, ET1 and urinary nephrin-creatinine ratio were not significantly associated with PA in this cohort. Conclusion: Urinary AGT exhibited the highest sensitivity for PA, while urinary KIM-1 was the most specific. The relatively modest sensitivity of KIM-1, a marker of renal tubular dysfunction, is likely because albuminuria in SCD results from both glomerular and tubular dysfunction. These results highlight the potential importance of urinary AGT as a key biomarker in identifying individuals at risk for PA. Our ongoing studies will evaluate the predictive capacity of these biomarkers for development of PA in SCD.

Vitamin D Deficiency and Avascular Necrosis in Patients with Sickle Cell Disease: A Retrospective Cohort Study

Introduction Sickle cell disease (SCD) is an inherited hemoglobinopathy with complex systemic involvement. Avascular necrosis (AVN) is a devastating complication among patients with SCD. Vitamin D deficiency (VDD) is commonly found in SCD patients, but there is limited research on the potential role of VDD as a risk factor for AVN in SCD patients. This study aimed to assess the association between VDD and AVN and determine the patterns, risk factors, diagnosis, and treatment of AVN in SCD patients. Methods We conducted a retrospective cohort study of consecutive SCD patients diagnosed with VDD from January 2020 to December 2022 at Prince Sultan Medical Military City (PSMMC) in Riyadh, Saudi Arabia. Patients meeting the following criteria were included: (1) adults and children with confirmed SCD through hemoglobin electrophoresis and (2) tested for VDD. Patients who underwent bone marrow transplant were excluded. The main outcome measured was the occurrence of AVN. VDD was diagnosed in patients with 25-hydroxyvitamin D levels below 30 nmol/L. Magnetic resonance imaging was used to stage and confirm AVN diagnosis. Associations were assessed using the chi-square test, and logistic regression was performed to control for confounding. Results The study included 711 eligible SCD patients, with 271 (38%) being children. VDD affected 301 out of 711 patients (42.3%). Among these, 212 (70.4%) were adults (&amp;gt;18 years old). VDD was observed in 32.2% of children and 48.1% of adults. Of the total cohort, 127 (17.9%) patients experienced AVN, including 18 children. Among patients with VDD, 89 developed AVN, while VDD affected 212 patients without AVN. The time between VDD diagnosis and AVN presentation ranged from 3 to 12 months. Male patients accounted for 52% of AVN cases. The average age at AVN diagnosis was 30.9 ± 11 years. The most common clinical presentation of AVN was chronic joint pain in over 95% of patients. Other presentations included limping in 3.9% of patients and limited joint movement in one patient. Affected joints included the hip (86%), shoulder (16.5%), knee (4.7%), and sacroiliac joint (0.7%). Bilateral joint involvement was present in 50.4% of AVN patients. The majority of patients (76.4%) were diagnosed with advanced stage AVN (III/IV). Treatment of patients with AVN included joint replacement in 44 (34.6%) patients, while the remaining 83 patients managed with conservative therapy such as pain control and physiotherapy. Patients with a history of VDD were significantly associated with a higher risk of AVN (p &amp;lt; 0.001), as seen in Table 1. Multivariate logistic regression showed SCD patients with VDD had 9.79 times the odds of AVN compared to SCD patients without VDD (OR 9.79; 95% CI: 5.25-18.26). Other statistically significant risk factors for AVN included frequent vaso-occlusive crises (three or more episodes per year), older age, history of acute chest syndrome, and low hemoglobin F levels. Conclusion AVN is a significant cause of morbidity in our SCD cohort, with most patients having advanced AVN disease. VDD is an independent risk factor for AVN in patients with SCD. Well-designed randomized trials are needed to determine the effect of vitamin D supplementation in reducing AVN in children and adults with SCD.

Effect of Sacubitril/Valsartan and enalapril on left ventricular function in patients with hematologic malignancies after bone marrow transplantation

Abstract Background and Aims Optimizing treatment for heart failure early after initiation of chemotherapy may prevent myocardial dysfunction. We hypothesized that early initiation of treatment with sacubitril/valsartan (sac/val) or enalapril (ena) may prevent cardiotoxicity. Patients and methods 90 patients (mean age 45.7 ± 14,1 years old, 52 male) with normal LV ejection fraction, who suffered from hematologic malignancies (lymphoma, leukemia) and underwent bone marrow transplantation, were randomized to receive sacubitril/valsartan 24/26 mg bid daily or enalapril 5 mg bid daily or placebo. We measured at baseline, before transplantation and after six months: i) Global Longitudinal Strain (GLS) of left ventricle (LV) by speckle tracking imaging, ii) myocardial global work index (GWI), global constructive work (GCW), global wasted work (GWW) and myocardial global work efficiency (GWE), by longitudinal strain-peripheral blood pressure loops, and iii) Left Ventricular Ejection Fraction (LVEF). Results The 3 treatment groups had similar age, sex, risk factors and cardiotoxic medication before and after bone marrow transplantation. Compared to baseline, patients treated with sacubitril/valsartan or enalapril for six months did not show a deterioration of LV GLS (-19.8±2.8 vs -19.3±4.1%, p=0.403 for sac/val, -20.3±2.8 vs -20.0±3.6%, p=0.634 for ena). Conversely, patients treated with placebo for six months, presented a significant impairment of LV GLS (-20.9±2.1% vs -18.5±2.2, p=0,001). No significant changes were found in LVEF after treatment with sacubitril/valsartan or enalapril for six months (57.5±4.9 vs 57.9±6.8%, p=0.826 for sac/val, 58.8±5.4 vs 60.7±7.1%, p=0.419, for ena), while a borderline deterioration was noticed after treatment with placebo (60.6±5.4 vs 57.7±6.7%, p=0.045). Moreover, in the sacubitril/valsartan group, we noticed a significant reduction of left ventricular end diastolic and end-systolic volume [(102.3±26.9 vs 93.9±21.5 ml, p=0.042 and 44.5±15.4 vs 38.6±9.6ml, p=0.012), respectively]. At 6 months, we did not observe any alteration in GWi, GCW, GWW, GWE in patients treated with enalapril (p&amp;gt;0.05). Conversely, in patients treated with sacubitril/valsartan GWE was improved (94.2±3.1 vs 95.8±1.8 %, p=0.030) and GWW was reduced (111.5±75.7 vs 86.4±43.1 mmHg%, p=0.045), while GWI and GCW did not show any significant alteration. Conversely, in the placebo group, GWI was reduced (1909.9±336.4 vs 1727.9±340.9 mmHg%, p=0.027), GWW was increased (80.7±60.6 vs 110.6±65.1 mmHg%, p=0.045), GWE was also reduced (94.2±3.1 vs 95.8±1.8 %, p=0.030) and GCW did not change at 6 months. Conclusions Treatment with sacubitril/valsartan or enalapril prevented deterioration of myocardial function six months after bone marrow transplantation in patients with hematologic malignancies and preserved LV ejection fraction. Moreover, sacubitril/valsartan showed a more favorable effect on myocardial work.

Characteristics, Outcomes, Tfr Rates in Young Adults with Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era: A French Observational Study

Introduction. Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years. Our study emphasizes the fact that CML can present at younger ages. These patients have significantly different life challenges compared with older patients. The 2020 update of the ELN recommendations mentioned that“ TFR may be the main goal for any patient, irrespective of age, but it is clear that the younger the patient the stronger the case for achieving TFR”. We report here the main characteristics and TFR data in CML young adults. Methods. The French CML group (FI-LMC) initiated an observational study (CCTIRS no. 14.745) to describe the characteristics of CML in young adult patients in terms of characteristics at diagnosis, treatment choices, tolerance, adherence, therapeutic response, evolution and survival. Patients ranging from 18 to &amp;lt; 30 years with newly diagnosed CML in chronic phase (CP) or accelerated phase (AP) treated with a tyrosine kinase inhibitor (TKI) in first line were eligible for enrolment. Results. The observatory included 253 unselected young adults from 22 centers with newly diagnosed CML in CP (n=246) or in AP (n=7) among which 51.6% were treated within a first line trial. At the time of CML diagnosis, the median patient age was 24 years (range, 18-29 years); 165 patients were males (63%). Median (range) values were: WBC 154.3 G/L (6.5; 841); platelets 374 G/L (51; 1799), hemoglobin 11.3 g/dL (4.1; 18.3), blast cells 1 % (0; 20), spleen below costal margin 4 cm (0; 30). In CP patients, Sokal score was low in 132 (53.6%) patients, intermediate in 46 (18.7%), high in 37 (15.1%) and unknown in 31 (12.6%) and ELTS score was low in 142 (57.7%) patients, intermediate in 48 (19.5%), high in 22 (9%) and unknown in 34 (13.8%). Initial TKI was imatinib alone (52.4%) or in combination with IFN (2.4%) or Ara-C (0.8%), nilotinib alone (24.6%) or in combination with IFN (4%), dasatinib alone (8.2%) or in combination with IFN (0.4%), bosutinib (1.2%), ponatinib (4.8%) or asciminib (1.2%). Median follow-up is 106.2 months (range: 0.03; 279.2). Ninety-nine (39.3%) patients remained under first-line TKI at latest follow-up and 21 pts (8.3%) underwent bone marrow transplantation (BMT) for resistance or transformation. Median overall survival at 9 years is 96.9% [95% CI: 94.5- 99.4]. Event free survival without death, transformation, or BMT at 9 years is 93.1% [95% CI: 89.7- 96.7]. Six patients died, 1 from sarcoma, 5 from CML including 1 before any therapy (brain hemorrhage). We investigated the TFR strategy. In 169 patients treated for at least 5 years, 56 (33.1%) attempted TKI discontinuation. TKI free survival at 24 months is 57.9% [95% CI: 45.8- 73.2] (Figure 1). Complete analysis comparing characteristics and outcome between the 2 groups of patients (TFR vs no TFR), will be available for ASH presentation. Conclusion. Despite aggressive features including prominent splenomegaly, high WBC counts and high blast cell percentage, TFR seems achievable in young adults with CML.

Dosimetric Advantages of VMAT TBI Plans: A Direct Comparison to Conventional TBI Plans.

Total body irradiation (TBI) continues to play an integral role in the conditioning of patients undergoing bone marrow transplantation. Historically, conventional TBI (C-TBI) has been delivered based on a clinical plan without CT simulation. However, volumetric modulated arc therapy TBI (V-TBI) is emerging as an alternative method to deliver TBI in a contemporary fashion. We aimed to compare these two methods of TBI delivery. Patients undergoing treatment with V-TBI were identified. C-TBI plans were created using their existing simulation CT images. Patient thickness was measured on the scan and compensators such as lead sheets to attenuate dose in areas with less separation and lung blocks drawn on digitally reconstructed radiographs (DRR) were added when necessary. A 3D dose distribution was then calculated allowing for the direct comparison between C-TBI and V-TBI on the same patient using the same CT image set. Dosimetric data from each plan including target volume coverage, dose homogeneity, absolute max dose, and dose to lungs were recorded. V-TBI and C-TBI plans for a total of four patients were preliminarily analyzed. Two patients were prescribed 200 cGy in a single fraction, while the other two were prescribed 1200 cGy in eight fractions. V-TBI resulted in a more favorable dosimetry for all four patients in most evaluated metrics including dose coverage, dose homogeneity, and lung dose (Table 1). V-TBI did result in an increased absolute maximum dose to all four patients compared to c-TBI, but still met the desired constraint of D0.03cc<125%. V-TBI resulted in more favorable dosimetry for all four patients compared to C-TBI. To our knowledge, this is the first direct dosimetric comparison between the two methods. Analysis of 8 more V-TBI cases is currently underway. In the future, we plan to design a prospective study to evaluate the clinical outcomes of patients undergoing V-TBI vs C-TBI.