Candidates For Hematopoietic Stem Cell Transplantation Research Articles

Pre-transplant Screening for MMP-9 in Allogeneic HSCT Candidates

Purpose: InflammaDry® (Quidel Eye Health, San Diego, California), an FDA-approved point-of-care commercial test, measures matrix metalloproteinase-9 (MMP-9) levels in the tear film. MMP-9 is an inflammatory biomarker that is elevated in response to ocular surface stress, particularly observed in ocular graft-versus-host disease (oGVHD). The purpose of this study is to assess the prevalence of MMP-9 positivity and a score >4 on the OSDI-6 questionnaire in patients before allogeneic hematopoietic stem cell transplant (HSCT). Methods: A prospective, observational, cross-sectional single center pilot study was conducted among 23 patients (46 eyes) undergoing planned allogenic HSCT. InflammaDry® results, OSDI-6 questionnaire results, and development of oGVHD were collected. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and chi-square test were calculated. Results: InflammaDry® demonstrated high sensitivity (1.0) but low specificity (0.1429) for oGVHD development. The PPV was 0.25, while the NPV was 1.0. No statistical significance was found between InflammaDry® result and development of oGVHD (p-value> 0.05). Conclusion: InflammaDry® is not an effective tool for detecting the onset or predicting the risk of developing oGVHD. A significant percentage of patients exhibited ocular inflammation before allogeneic HSCT, suggesting that initiating prophylactic treatment could be valuable in reducing oGVHD development.

Practical Approach to Longitudinal Neurologic Care of Adults With X-Linked Adrenoleukodystrophy and Adrenomyeloneuropathy.

Although X-linked adrenoleukodystrophy (ALD) has historically been considered a childhood disease managed by pediatric neurologists, it is one of the most common leukodystrophies diagnosed in adulthood. An increase in both male and female adults reaching diagnosis due to familial cases identified by state newborn screening panels and more widespread use of genetic testing results in a large cohort of presymptomatic or early symptomatic adults. This population is in urgent need of standardized assessments and follow-up care. Adults with ALD/adrenomyeloneuropathy (AMN) may be diagnosed in a variety of ways, including after another family member is identified via genetic testing or newborn screening, presenting for symptomatic evaluation, or following diagnosis with primary adrenal insufficiency. Significant provider, patient, and systems-based barriers prevent adult patients with ALD/AMN from receiving appropriate care, including lack of awareness of the importance of longitudinal neurologic management. Confirmation of and education about the diagnosis should be coordinated in conjunction with a genetic counselor. Routine surveillance for adrenal insufficiency and onset of cerebral ALD (CALD) in men should be performed systematically to avoid preventable morbidity and mortality. While women with ALD do not usually develop cerebral demyelination or adrenal insufficiency, they remain at risk for myeloneuropathy and are no longer considered "carriers." After diagnosis, patients should be connected to the robust support networks, foundations, and research organizations available for ALD/AMN. Core principles of neurologic symptom management parallel those for patients with other etiologies of progressive spastic paraplegia. Appropriate patient candidates for hematopoietic stem cell transplant (HSCT) and other investigational disease-modifying strategies require early identification to achieve optimal outcomes. All patients with ALD/AMN, regardless of sex, age, or symptom severity, benefit from a multidisciplinary approach to longitudinal care spearheaded by the neurologist. This review proposes key strategies for diagnostic confirmation, laboratory and imaging surveillance, approach to symptom management, and guidance for identification of appropriate candidates for HSCT and investigational treatments.

Association Between Serum Levels of Vitamin D and Biochemical Markers Among Hematopoietic Stem Cell Transplantation Candidates: A Cross-Sectional Study

Background: Although vitamin D has been known as an effective substance in bone homeostasis, recent studies indicated a number of other biological properties attributed to vitamin D. Patients, who are candidates for hematopoietic stem cell transplantation (HSCT), were shown to be at high risk of vitamin D deficiency. Objectives: This study aimed at exploring the association between serum levels of vitamin D and biochemical markers among HSCT candidates. Methods: Totally, 214 patients, aged 18 to 65 years, were recruited in the current cross-sectional study. Within 24 hours of admission to the Bone Marrow Transplant ward, baseline clinical and demographic characteristics of study participants, serum levels of vitamin D, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin, albumin, total protein, CRP-albumin ratio (CAR), and body mass index (BMI) were assessed. Participants were divided into 4 groups based on their serum vitamin D levels: subjects with deficient, insufficient, sufficient, and optimal levels of vitamin D. Results: Across the 4 defined categories of serum vitamin D levels, there was no significant difference in terms of BMI, laboratory parameters, inflammatory factors, and biochemical markers. This lack of significant variation remained in both unadjusted and adjusted models. Conclusions: These observations indicate a lack of significant association between serum vitamin D levels and BMI, inflammatory factors, and biochemical markers in individuals undergoing evaluation for HSTC.

Eligibility for hematopoietic stem cell transplantation in a cohort of children with sickle cell disease: a single-center report

BackgroundHematopoietic stem cell transplantation (HSCT), is the only currently available curative option for SCD. Yet, the eligibility of SCD patients for HSCT is always limited by the significant associated toxicity and lack of suitable donors. At Cairo University’s pediatric hematology outpatient clinic, we aimed to determine hematopoietic stem cell transplantation (HSCT) candidates among a sickle cell disease (SCD) cohort, estimate the number of possible donors, and analyze the differences between patients with and without an HSCT indication.MethodsThis study was a cross-sectional analytic study including 128 SCD children. Their demographic, clinical, and laboratory profiles, total number, and number of siblings with SCD were obtained from their medical records.ResultsSixty-nine (53.9%) had at least one HSCT indication. Recurrent severe pain episodes despite hydroxyurea were the most common indication. Hemoglobin was lower, while reticulocyte count, serum ferritin, and aspartate aminotransferase were higher in HSCT candidates (p value < 0.001). Additionally, the prevalence of splenomegaly, the dose of hydroxyurea, and the number of transfusions were noticeably higher in HSCT candidates (p value = 0.013, 0.005, and < 0.0001 respectively). Among those indicated for HSCT; 75.3% had at least one healthy sibling who might be a potential donor.ConclusionMore than half were eligible for HSCT which should always be considered to provide a possible cure for the disease. Of the transplantation-eligible cases, about two-thirds had at least one healthy sibling who might potentially serve as a donor. Those meeting the requirements for HSCT eligibility should routinely undergo human leukocyte antigen (HLA) testing of their unaffected siblings.

Association between nutritional status and biochemical markers among hematopoietic stem cell transplant candidates: a cross-sectional study

AimCandidates of Hematopoietic Stem Cell Transplantation (HSCT) may be at nutritional risk due to decreased oral intake, high nutritional requirements and nutrient malabsorption. The aim of this study was to evaluate the association between nutritional status and blood biomarkers in candidates of HSCT.MethodsA total of 278 patients aged 18–65 years old were recruited and their baseline demographic and clinical characteristics were recorded. All subjects underwent nutritional status analysis using Nutritional Risk Screening (NRS-2002). Blood biomarkers including C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), hemoglobin, albumin and total protein as well as CRP-albumin ratio (CAR) and Body Mass Index (BMI) were measured and compared between two groups based on Nutritional Risk Screening (NRS-2002) within 24 h of admission in Bone Marrow Transplant ward.ResultsThe results showed that undernourished patients (NRS ≥ 3) had significantly higher inflammatory markers including ESR, CRP and CAR as well as lower BMI and serum albumin and hemoglobin concentrations (P < 0.05); however, no significant association was observed in terms of total protein even after adjusting for confounders (P > 0.05).ConclusionsThis study revealed that BMI combined with biochemical markers are the appropriate parameters for assessment of nutritional status in HSCT candidates. Furthermore, the nutritional status was verified to be significantly associated with systematic inflammation.

Integration of Transcriptomic Features to Improve Prognosis Prediction of Pediatric Acute Myeloid Leukemia With KMT2A Rearrangement.

Lysine methyltransferase 2A-rearranged acute myeloid leukemia (KMT2A-r AML) is a special entity in the 2022 World Health Organization classification of myeloid neoplasms, characterized by high relapse rate and adverse outcomes. Current risk stratification was established on the treatment response and translocation partner of KMT2A. To study the transcriptomic feature and refine the current stratification of pediatric KMT2A-r AML, we analyzed clinical and RNA sequencing data of 351 patients. By implementing least absolute shrinkage and selection operator algorithm, we identified 7 genes (KIAA1522, SKAP2, EGFL7, GAB2, HEBP1, FAM174B, and STARD8) of which the expression levels were strongly associated with outcomes. We then developed a transcriptome-based score, dividing patients into 2 groups with distinct gene expression patterns and prognosis, which was further validated in an independent cohort and outperformed the LSC17 score. We also found cell cycle, oxidative phosphorylation, and metabolism pathways were upregulated in patients with inferior outcomes. By integrating clinical characteristics, we proposed a simple-to-use prognostic scoring system with excellent discriminability, which allowed us to distinguish allogeneic hematopoietic stem cell transplantation candidates more precisely. In conclusion, pediatric KMT2A-r AML is heterogenous on transcriptomic level and the newly proposed scoring system combining clinical characteristics and transcriptomic features can be instructive in clinical routines.

Using a Modified Delphi Panel to Estimate Health Service Utilization for Patients with Advanced and Non-Advanced Systemic Light Chain Amyloidosis.

Patients with diagnosed with systemic light chain (AL) amyloidosis at advanced Mayo stages have greater morbidity and mortality than those diagnosed at non-advanced stages. Estimating service use by severity is difficult because Mayo stage is not available in many secondary databases. We used an expert panel to estimate healthcare utilization among advanced and non-advanced AL amyloidosis patients. Using the RAND/UCLA modified Delphi method, expert panelists completed 180 healthcare utilization estimates, consisting of inpatient and outpatient visits, testing, chemotherapy, and procedures by disease severity and organ involvement during two treatment phases (the 1 year after starting first line [1L] therapy and 1 year following treatment [post-1L]). Estimates were also provided for post-1L by hematologic treatment response (complete or very good partial response [CR/VGPR], partial, no response or relapse [PR/NR/R]). Areas of disagreement were discussed during a meeting, after which ratings were completed a second time. During 1L therapy, 55% of advanced patients had ≥1 hospitalization and 38% had ≥2 admissions. Rates of hematopoietic stem cell transplant (HSCT) in advanced patients were 5%, while pacemaker or implantable cardioverter defibrillator (ICD) placement were 15%. During post-1L therapy, rates of hospitalization in advanced patients remained high (≥1 hospitalization: 20-43%, ≥2 hospitalizations: 10-20%), and up to 10% of advanced patients had a HSCT. Ten percent of these patients underwent pacemaker/ICD placement. Experts estimated advanced patients, who would not be good candidates for HSCT, would have high rates of hospitalization (traditionally the most expensive type of healthcare utilization) and other health service use. The development of new treatment options that can facilitate organ recovery and improve function may lead to decreased utilization.

Abstract 42: Hematopoietic Stem Cell Transplants and Treatment of Severe Blood Disorders: Role of Providers in Medical Tourism

Abstract Purpose: Medical tourism provides international patients with medical services, but little data is present on the role of medical tourism in regard to hematopoietic stem cell transplant (HSCT) services. Over the last 10 years, the University of Illinois at Chicago Blood &amp; Marrow Transplant program has established an international network (GlobalBMT) of LMIC centers, that includes hospitals in Nepal, India, Nigeria, Tanzania, Bolivia, Cuba, Argentina, Ukraine. This project involves each hospital of the GlobalBMT network to: 1. qualitatively assess the current role of medical providers in international care of HSCT patients and 2. quantitatively and qualitatively assess the current policies of medical institutions for sending and accepting international transplant candidates. Methods: This is a mixed-methods cross-sectional study with a quantitative component (questionnaire) and a qualitative component (interview). A questionnaire was disseminated to 12 medical providers in 8 countries, who either refer or accept international HSCT patients, to assess the demographics, volume, and frequency of international referrals. We also conducted semi-structured virtual interviews with willing healthcare providers to qualitatively assess the current infrastructure in medical tourism for international HSCT candidates, as well as elicit ways in which this structure can be improved. Results: Here we will report on the results of the mixed-methods cross-sectional study that was conducted within the GlobalBMT network. In the setting of this research project, we suggest a need for a formalized provider-to-provider framework in the sphere of medical tourism for HSCT patients to be sent outside of their home countries to receive a HSCT, diminishing the impact of third party brokers and misinformation. Our data have uncovered themes in the existing structure of third-party agents searching for a profit, difficulty connecting with home physicians to coordinate care, and limited information for patients on the procedure. Conclusion: The data collected in this project provide an example of existing structures in medical tourism for HSCT in some LMICs. Gaps in center-to-center patient information, role of middle-men directly contacting patient families, or lack of advanced medical care in LMIC, are some of the relevant findings that based on this initial study could be exploited in a large multicenter international registry study. Citation Format: Deepika Khanna, Damiano Rondelli. Hematopoietic Stem Cell Transplants and Treatment of Severe Blood Disorders: Role of Providers in Medical Tourism [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 42.

Prevalence of latent Mycobacterium tuberculosis infection in hematopoietic stem cell transplantation comparing tuberculin skin test and interferon-gamma release assay.

The aim of this study was to evaluate the prevalence of latent Mycobacterium tuberculosis infection in hematopoietic stem cell transplantation candidates, using tuberculin skin test and QuantiFERON-TB Gold-Plus, in a high-burden tuberculosis country. Adult candidates for hematopoietic stem cell transplantation performed both tests before and those submitted to transplantation were followed up for 12 months. The prevalence of latent Mycobacterium tuberculosis infection was 17.1% and a moderate agreement between QuantiFERON-TB Gold-Plus and tuberculin skin test was observed in this population. Previous tuberculosis exposure was a risk factor for latent Mycobacterium tuberculosis infection. No cases of tuberculosis were diagnosed during follow-up period.

Prevalence of hepatitis E antibodies in solid organ and hematopoietic stem cell transplant candidates

Prevalence of hepatitis E antibodies in solid organ and hematopoietic stem cell transplant candidates

Transplantation Referral Patterns for Patients with Newly Diagnosed Higher-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia at Academic and Community Sites in the Connect® Myeloid Disease Registry: Potential Barriers to Care

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT.

Molecular genetics and management of world health organization defined atypicalchronicmyeloidleukemia.

Atypical chronic myeloid leukemia (CML) is a rare BCR::ABL1-negative hematopoietic stem cell disease characterized by granulocytic proliferation and granulocytic dysplasia. Due to both the challenging diagnosis and the rarity of atypical CML, comprehensive molecular annotation-based analyses of this disease population have been scarce, and it is currently difficult to identify the optimal treatment for atypical CML. To explore atypical CML genomic landscape and treatment options, we performed a systematic retrospective of the clinical data and outcomes of 31 atypical CML patients. We observed that the molecular landscape of atypical CML was highly heterogeneous, with multiple molecular events driving its pathogenesis. Patients with atypical CML had a low response to current therapies, with an overall response rate (ORR) of 33.3% to hypomethylating agent (HMA)-based therapy. The current treatment strategies, including hematopoietic stem cell transplantation (HSCT), did not improve overall survival (OS) in atypical CML patients, with a median survival of 20months. Thus, the benefits from HSCT and candidates for HSCT remain to be further evaluated. Acute myeloid leukemia (AML)-like chemotherapy followed by bridging allogeneic HSCT may be an ideal regimen for suitable individuals. The large-scale and prospective clinical studies will help to address the dilemma.

Survival Outcomes for Patients in the QUAZAR AML-001 Trial Who Received Subsequent Therapy for Acute Myeloid Leukemia (AML) after Discontinuing Oral Azacitidine or Placebo

Introduction: While many older patients (pts) with AML attain complete remission (CR) after treatment (Tx) with intensive chemotherapy (IC), most will relapse and overall survival (OS) is poor, especially for pts who are not candidates for hematopoietic stem cell transplant (HSCT). In the randomized phase 3 QUAZAR AML-001 trial (NCT01757535), oral azacitidine (Oral-AZA), a hypomethylating agent (HMA), significantly prolonged OS (24.7 months [mo] vs 14.8 mo with placebo [PBO], P < 0.001) and relapse-free survival (10.2 vs 4.8 mo, respectively, P < 0.001) vs PBO in pts with AML in first remission after IC who were not candidates for HSCT (Wei AH, et al. N Engl J Med 2020;383:2526-2537). After discontinuing study drug, pts in QUAZAR AML-001 continued to be monitored for OS even if they received subsequent AML Tx. Given the high rate of relapse in older pts and the limited Tx options for relapsed/refractory AML, it is important to evaluate the impact of Oral-AZA maintenance Tx on the clinical outcomes for pts who received subsequent AML Tx after relapse. Methods: Eligible pts were aged ≥ 55 years, had AML with intermediate- or poor-risk cytogenetics at diagnosis, Eastern Cooperative Oncology Group performance status score ≤ 3, and had achieved a first CR or CR with incomplete blood count recovery (CRi) after IC ± consolidation Tx. Within 4 mo of achieving CR/CRi, pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO once daily for 14 days per 28-day cycle. Randomized Tx could continue until pts developed relapse with > 15% blasts, unacceptable toxicity, or HSCT. These post hoc analyses assessed Kaplan-Meier (KM)-estimated OS and 1- and 2-year survival rates for pts who received subsequent AML Tx after relapse, both from the time of study randomization and from the time of receipt of first subsequent Tx, until death by any cause. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models stratified by age, cytogenetic risk, and receipt of consolidation Tx. These analyses were not prospectively powered to detect statistically significant differences between Tx arms. Results: At data cutoff (September 2020), 137/238 pts (58%) in the Oral-AZA arm and 172/234 pts (74%) in the PBO arm received subsequent AML Tx after discontinuing study drug. Demographic and disease characteristics at baseline in this subgroup were similar between the Oral-AZA and PBO arms and comparable to those for all pts in the trial (Wei AH, et al. N Engl J Med 2020;383:2526-2537). Pts from both Tx arms received similar classes of first-line subsequent Tx; 43% of pts in the Oral-AZA arm vs 45% in the PBO arm received IC, 50% vs 46% received lower-intensity therapies (including 25% vs 31% injectable HMAs), and in both arms 6% received supportive care and 1% received other Tx. In the Oral-AZA arm, 13 pts (9%) went on to receive HSCT, compared with 31 (18%) in the PBO arm. At a median follow-up of 51.7 mo, OS from the time of randomization for pts who received subsequent Tx was nominally prolonged with Oral-AZA vs PBO (median, 17.9 vs 12.5 mo, respectively; HR, 0.79 [95% CI, 0.62-1.0]) (Figure A). KM-estimated 1-year survival rates were 67% for Oral-AZA, compared with 51% for PBO, and 2-year rates were 41% and 29%, respectively. Median OS from the time of first subsequent Tx was similar in the Oral-AZA and PBO arms: 5.3 and 5.8 mo, respectively (HR, 1.1 [95% CI, 0.85-1.4]) (Figure B). Estimated 1-year survival rates from first subsequent Tx were 25% in the Oral-AZA arm and 31% in the PBO arm, and at 2 years, survival rates were 17% and 18%, respectively. Conclusions: Pts who received Oral-AZA during first remission, followed by subsequent Tx, showed a trend for improved OS from the time of study randomization compared with pts who initially received PBO. Survival outcomes from the start of first subsequent Tx were not meaningfully different between Oral-AZA and PBO. This suggests that Oral-AZA maintenance Tx can extend the duration of remission without influencing the clinical benefit of subsequent AML Tx. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: A First-in-Human Phase 1/2 Study of Hematopoietic Stem Cell Transplantation (HCT) with VOR33 (CD33-Deleted Allograft) Followed By Treatment with Gemtuzumab Ozogamicin (GO) in Patients with CD33+ Acute Myeloid Leukemia (AML) Who Are at High-Risk of Post-HCT Relapse

Background: Allogeneic HCT is the standard of care for eligible patients with AML harboring high-risk features such as adverse-risk cytogenetics or minimal residual disease (MRD). However, the majority of such patients still relapse post-HCT and have very poor outcomes. The use of maintenance therapies intended to control post-HCT relapse is often limited by hematopoietic toxicity towards normal engrafted cells. Gemtuzumab ozogamicin (GO, tradename: Mylotarg) is an FDA-approved anti-CD33 antibody-drug conjugate targeting CD33+ AML, but its use is limited by on-target hematopoietic toxicity towards CD33+ myeloid and progenitor cells. VOR33 is a CRISPR/Cas9 gene-edited allogeneic hematopoietic stem and progenitor cell (HSPC) product lacking CD33 protein that was developed to protect normal hematopoietic cells while exclusively targeting leukemia with CD33-directed therapies. VOR33 is manufactured from CD34+ cells isolated from healthy human leukocyte antigen (HLA)-matched donors. Pre-clinical murine and primate transplant studies using CD33-deleted HSPCs demonstrated unaltered long-term engraftment, multi-lineage hematopoietic differentiation and function, as well as long-term persistence of CD33 gene-edited hematopoietic cells. Additionally, subsequent treatment with GO eradicated CD33+ leukemia cells while the normal hematopoietic cells that reconstituted from CD33-edited HSCs were preserved. The improved therapeutic index for GO in combination with VOR33 has the potential to allow effective targeting of residual leukemia in AML patients post-HCT without dose-limiting hematopoietic toxicity. Study Design and Methods: VBP101(NCT04849910) is a first-in-human Phase 1/2 open-label multicenter trial to establish the safety of using VOR33 as a donor allograft for CD33+ AML patients who are at high risk of relapse and undergoing myeloablative HCT followed by treatment with low-dose GO. Participants (18-70 y) must have a diagnosis of CD33+ AML, an HLA-matched related or unrelated (10/10) donor and be a candidate for myeloablative HCT. Additional key inclusion criteria include CR1/CRi/CR2 with intermediate/poor cytogenetics and the presence of MRD. Patients with 5-10% bone marrow-only blasts with any cytogenetic risk are also eligible. Key exclusion criteria include prior auto/allo-HCT or prior treatment with GO. Related and unrelated donors undergo mobilization with G-CSF and plerixafor prior to cell collection. Manufacturing of VOR33 and isolation of an unmanipulated backup graft are performed centrally and both are cryopreserved. Subjects undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with VOR33. After engraftment and recovery of a sufficient CD33-negative neutrophil count (~Day 60), patients begin maintenance therapy with GO. Part 1 of the study will enroll 9-18 evaluable patients to be treated in a 3+3 dose-escalation strategy with GO (0.5-2.0 mg/m2) in a 28-day cycle for up to 4 cycles. Part 1 will evaluate the safety of VOR33/GO and will determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GO. The Part 2 expansion phase will enroll an additional 12 patients to further evaluate the safety of VOR33 and the preliminary efficacy of VOR33 and GO at the RP2D. A separate cohort is included for early relapse with treatment per the investigator's choice and may include use of GO. The primary endpoint is to assess the safety of VOR33 as measured by successful neutrophil engraftment at 28 days post-HCT. Secondary endpoints include time to neutrophil and platelet engraftment, assessment of the overall safety of VOR33 and GO (GvHD, graft failure, transplant-related mortality, RP2D, and MTD), non-hematological GO-related toxicities, GO pharmacokinetics, the efficacy of VOR33 in conferring protection from GO-related hematological toxicities, percent CD33 negative myeloid cells over time and survival rates (RFS and OS). Exploratory endpoints include the persistence of VOR33 gene editing and immune reconstitution. Study follow-up is 2 y with up to 15 y long term follow-up in a rollover safety study, VBP201 (NCT05309733). A Dose Escalation Committee and Data Safety Monitoring Committee will review GO dosing levels and monitor overall trial safety, respectively. VBP101 is currently open for enrollment and recruiting patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Healthcare Utilization Among Patients with Advanced Systemic Light Chain Amyloidosis

Introduction Information on health service use in advanced systemic light chain (AL) amyloidosis, a rare hematologic disease, is outdated and non-specific, in part because there was no ICD-10 code for AL amyloidosis when prior studies were conducted. While there is now an ICD-10 code for AL amyloidosis, healthcare claims datasets do not include lab results and therefore lack Mayo stage (disease severity). Given the limitations of prior real-world studies, we used a validated consensus method to estimate healthcare utilization in patients with advanced AL amyloidosis during different phases of treatment. Methods We used a RAND/UCLA modified Delphi panel method to estimate healthcare utilization in patients with AL amyloidosis including those with advanced stage disease. We defined advanced patients in two ways: Mayo stage 3 or 4 during first-line therapy or those with signs of cardiac involvement (i.e., elevated troponin and/or NT-proBNP) after completing first-line therapy. We conducted the following steps: 1) expert panelists (9 hematologists, 2 cardiologists, 1 patient advocate) with a median 15 years' experience treating and/or managing AL amyloidosis were provided a systematic literature review on utilization in AL amyloidosis; 2) panelists independently estimated utilization (inpatient, outpatient, testing, chemotherapy, procedures) during two treatment phases (the 1-year period after starting first-line therapy and the 1-year period after completing first-line therapy) among advanced patients with varied hematologic treatment response (complete or very good partial response [CR/VGPR], partial or no response); 3) we discussed areas of disagreement during a moderated meeting; 4) panelists completed ratings independently a second time following this discussion. Results During the 1-year period after starting first-line therapy, 1-5% of patients with advanced AL amyloidosis were expected to be treated with a hematopoietic stem cell transplantation (HSCT). Half (45-55%) were expected to have ≥1 hospital admission and 28-38% were expected to have ≥2 hospital admissions, depending on the presence of non-cardiac symptomatic organ involvement. Patients were also expected to have high rates of other utilization in the year after starting first-line therapy: ~25% would receive a bone marrow biopsy, 12-15% would receive a cardiac pacemaker placed, and up to 7% would begin chronic dialysis. In the year after completing first-line therapy, 10% with a CR/VGPR and 15-20% with partial or no response were expected to have ≥2 hospital admissions. High rates of other utilization were expected to continue, especially for advanced patients with partial or no response (50% would receive a bone marrow biopsy and up to 10% would receive a cardiac pacemaker or begin chronic dialysis). Conclusions A diverse panel of experts, guided by a review of the literature and clinical experience, used the modified Delphi panel method to estimate healthcare utilization in patients with advanced AL amyloidosis at different points in the disease course. During the year after starting first-line therapy, advanced patients were expected to have high rates of hospitalization (traditionally the most expensive type of healthcare utilization), were not considered to be good candidates for HSCTs and had high rates of other utilization. Utilization remained high in advanced patients after completing first-line therapy especially for those with partial or no response. The development of new treatment options that can induce CR/VGPR and facilitate organ recovery or improve function may lead to decreased utilization.

The Effect of the Continuous Care on the Self-Care Behavior in Hematopoietic Stem Cell Transplantation (HSCT) Recipients: A Semi-Experimental Study.

Background: Hematopoietic stem cell transplantation strongly affects the care of patients suffering from malignant hematologic disorders and the implementation of interventions such as continuous care can affect the outcomes of treatment in a positive way. The aim of the current study was to determine the effect of implementing a continuous care model on self-care behavior in patients receiving HSCT between 2019 and 2020 in Shariati Hospital affiliated to Tehran University of Medical Sciences. Materials and Methods: This semi-experimental study was conducted on 48 patients who were considered as candidates for HSCT at the Hematology, Oncology and Stem Cell Transplant Research Center, Shariati Hospital. Participants for the present study were selected by the continuous care model based on the inclusion criteria. A 4-stage continuous care model (CCM) developed was used as an intervention in the study. A valid and reliable assessment questionnaire designed to measure the self-care behaviors of the patient (PHLP2) was used for the collection of demographic information. It was completed in the first and fourth stages of implementing the continuous care model. Data were analyzed using SPSS 22 software (Chicago, IL, USA). Moreover, the Chi-square test, pair t-test, and independent samples t-test were used in this study. Results: There was no statistically significant difference between the intervention and control group in terms of demographic variables (p>0.05). Prior to intervention, no statistically significant difference was observed in the mean self-care score among HSCT patients in the intervention and control group (p=0.590), while, after the intervention, a statistically significant difference was observed in the mean self-care score among HSCT patients in the intervention and control group (p<0.001). Conclusion: The study concluded that due to the increase in the number of patients undergoing HSCT across the country in recent years as well as the ease of implementation and low cost of this strategy to promote the self-care of HSCT recipients, relevant authorities ought to do it with the proper planning and policy nationwide. According to the results of the study, the use of a continuous care model on self-care behavior in patients receiving HSCT is recommended.

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity.

The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001).Conclusion: Prevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI. What is Known:• Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT).• Active viral infections at the time of HSCT lead to worse prognosis.What is New:• In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease.• In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00431-022-04614-5.

Donor specific HLA antibody in hematopoietic stem cell transplantation: Implications for donor selection.

Advances in hematopoietic stem cell transplant (HSCT) have led to changes in the approach to donor selection. Many of these new approaches result in greater HLA loci mismatching, either through the selection of haploidentical donors or permissive HLA mismatches. Although these approaches increase the potential of transplant for many patients by expanding the number of acceptable donor HLA genotypes, they add the potential barrier of donor-specific HLA antibodies (DSA). DSA presents a unique challenge in HSCT, as it can limit engraftment and lead to graft failure. However, transient reduction of HLA antibodies through desensitization treatments can limit the risk of graft failure and facilitate engraftment. Thus, the consideration of DSA in donor selection and the management of DSA prior to transplant are playing an increasingly important role in HSCT. In this review, we will discuss studies addressing the role of HLA antibodies in HSCT, the reported impact of desensitization on DSA levels, and the implications for selecting donors for patients with DSA. We found that there is a clear consensus that moderate strength DSA should be avoided, while desensitization strategies are reported to be effective in most cases at reducing DSA to amenable levels. There is limited information regarding the impact of specific characteristics of DSA, such as HLA loci or overall level of sensitization, which could further aid in donor selection for sensitized HSCT candidates.

CHARACTERIZATION OF MINOR HISTOCOMPATIBILITY ANTIGENS AND THEIR ROLE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: SINGLE CENTER EXPERIENCE IN TURKIYE

Objective: The minor histocompatibility antigens (mHAgs) are the epitopes composed of polymorphic essential peptides, and they create T cell response limited to a variety of class I and II HLA alleles. In recent years, there has been extensive research on the distribution of polymorphic regions in different populations. The incompatibility between recipient and donor, may initiate a strong cellular immune response despite HLA full-matched transplantation. We determined the frequency of minor antigens among hematopoietic stem cell transplantation (HSCT) recipients who underwent transplantation for various hematological diseases. Material and Methods: The study population included 200 healthy individuals, 150 HLA-typed patients who were candidates for allogeneic HSCT, and 20 recipients/donors with allogeneic transplants. Minor HAgs identified by using polymerase chain reaction (PCR) and sequence specific primer (SSP) methods. Results: When the allele frequencies and genotypes of the patients were compared with those of the healthy group, the difference was not significant regarding to immunogenic or non-immunogenic allele frequencies. The individuals with immunogenic homozygous H allele (HH genotype) were a few more in the healthy group, and this difference proved to be statistically significant. In fact, our study population Insufficient though the number was, based on the data received from 20 transplant patients and donors, GvHD was observed in 5 of 10 patients who had minor incompatibility. Conclusion: We assume that determining the mHAg frequencies in the healthy Turkish population and in patients with malignant hematological diseases will likely contribute to the understanding of the immune response.

Is Severity Score Associated With Indication for Hematopoietic Stem Cell Transplantation in Individuals With Sickle Cell Anemia?

Manifestations of sickle cell disease (SCD) begin early in childhood and cause morbidity and decreased life expectancy. Hematopoietic stem cell transplantation (HSCT) is curative but associated with risk of mortality attributable to the transplant. This risk should be counterbalanced with SCD morbidity and mortality. A severity score using a Bayesian network model was previously validated to predict the risk of death in adult individuals with SCD. The objective of this study is to calculate the severity scores of participants in a multicenter cohort of Brazilians with SCD, using a previously published Bayesian network-derived score, associated with risk of death and then compare the severity scores between participants with and without an indication for HSCT as defined by the Brazilian Ministry of Health (MoH) criteria. This is an observational, retrospective study. We analyzed 2063 individuals with sickle cell anemia from the Recipient Epidemiology and Donor Evaluation Study-III Brazil SCD cohort and applied a Bayesian network-derived score to compare candidates and non-candidates for HSCT according to the Brazilian MoH transplant criteria. Classical statistical methods were used to analyze data and make comparisons. We compared severity scores between cohort members with (n=431) and without (n=1632) HSCT indications according to Brazilian MoH. Scores were not different in adult participants with ≥1 HSCT indication when compared to those with no indication (mean 0.342 versus 0.292; median 0.194 versus 0.183, P=.354) and receiver operating characteristic curves did not demonstrate an obvious threshold to differentiate participants with or without HSCT indications. Severity score may predict risk of death but does not differentiate HSCT candidates. Current indications should be evaluated to ensure that patients with more severe disease who might benefit from HSCT are appropriately identified.