Myeloablative Hematopoietic Stem Cell Transplantation Research Articles

Incidence, risk factors and therapy response of acute graft-versus-host disease after myeloablative hematopoietic stem cell transplantation with posttransplant cyclophosphamide.

Posttransplant cyclophosphamide, sirolimus and mycophenolate mofetil (PTCy/siro/MMF) constitutes an innovative and well-tolerated acute graft-versus-host disease (aGVHD) prophylaxis after allogeneic stem cell transplantation (allo-HSCT), but risk factors for aGVHD incidence and therapy failure in this setting are scarce. This study prospectively registered all consecutive adult patients with hematologic malignancies who received a myeloablative allo-HSCT using PTCy/siro/MMF prophylaxis at our institution between 2017 and 2023. A total of 385 patients were included, of whom 44%, 34% and 22% were transplanted from matched sibiling, matched unrelated and haploidentical donors, respectively. The 180-day cumulative incidence of aGVHD was 21% (95% confidence interval [CI] 17-25%) for grade II-IV and 11% (95% CI 8-14%) grade III-IV aGVHD. The use of haploidentical donors was associated with an increased risk of severe aGVHD. Among 75 patients receiving first-line systemic corticosteroids, 49% achieved a sustained complete response, while 23% and 24% developed steroid-dependent (SD-aGVHD) and steroid-refractory aGVHD (SR-aGVHD), respectively. SR-aGVHD was associated with worse salvage treatment response and overall survival compared to SD-aGVHD. The 1-year cumulative incidence of aGVHD-related mortality was 5.4% (95% CI, 3.3-8.1). Risk factors for aGVHD-related mortality included haploidentical donors, older donors, diagnosis of myeldysplastic neoplasms, and grade IV aGVHD. This study confirms a low incidence aGVHD with PTCy/siro/MMF prophylaxis. SR-aGVHD showed poorer response to salvage therapies and worse survival, while haploidentical donors and older donor age were negative predictors for aGVHD-related deaths.

Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied.We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18–3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023).These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.

SVEGF-R1 in acute non-infectious toxicity syndromes after pediatric allogeneic hematopoietic stem cell transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute non-infectious toxicities, including sinusoidal obstruction syndrome (SOS), engraftment syndrome (ES) and capillary leak syndrome (CLS) among others. These complications are thought to be driven by a dysfunctional vascular endothelium, but the pathophysiological mechanisms remain incompletely understood, and the diagnoses are challenged by purely clinical diagnostic criteria that are partly overlapping, limiting the possibilities for progress in this field. There is, however, increasing evidence suggesting that these challenges may be met through the development of diagnostic biomarkers to improve diagnostic accuracy of pathogenetically homogenous entities, improved pre-transplant risk assessment and the early identification of patients with increased need for specific treatment. Soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) is emerging as an important biomarker of endothelial damage in patients with trauma and sepsis but has not been studied in HSCT. ObjectivesTo investigate sVEGF-R1 as a marker of endothelial damage in pediatric HSCT patients by exploring associations with SOS, CLS, ES, and acute graft-versus-host disease (aGvHD). MethodsWe prospectively included 113 children undergoing myeloablative HSCT and measured sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant. ResultsAll over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL, p = 0.0035), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1–18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL, p = 0.007). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile, p = 0.023). ConclusionVEGF-R1 levels are found to be increased in pediatric patients developing SOS, reflecting the severity of morbidity. sVEGF-R1 were unassociated with both CLS and ES. The potential of sVEGF-R1 as a clinically useful biomarker for SOS should be further explored to improve pre-transplant SOS-risk assessment, SOS-severity grading, and to guide treatment.

A phase 2 trial of CD24Fc for prevention of graft-versus-host disease

AbstractPatients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD–free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD–free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review

Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy-1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation

ObjectivesResults from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of...

Role of abatacept in the prevention of graft-versus-host disease: current perspectives.

Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. Equivalent results are being reported in recent studies using alternative donors, in reduced-intensity conditioning HSCT and nonmalignant disorders. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD. This review summarized all the limited reports of this novels approach in the HSCT setting.

Administration of ciprofloxacin through a nasogastric tube in pediatric oncology and stem cell transplantation patients.

Pediatric oncology and hematopoietic stem cell transplantation patients are facing many gastrointestinal side effects of chemotherapy, including nausea, vomiting, mucositis, and diarrhea. International guidelines advise early enteral tube feeding as the first option of nutritional support in children undergoing myeloablative hematopoietic stem cell transplantation. When using enteral feeding tubes for nutritional purposes as well as drug administration, some pharmaceutical, nursing, and technical issues have to be taken into account. Ciprofloxacin is a fluoroquinolone, widely used because of its broad spectrum antimicrobial activity and favorable pharmacokinetic properties. However, its co-administration with polyvalent cations (as present in enteral feeding) makes the absorption of ciprofloxacin more difficult and may alter the pharmacokinetic parameters. Literature data are conflicting on how long the enteral feeding should be discontinued for patients receiving ciprofloxacin via an enteral feeding tube, ranging from 2 h before to 6 h after the administration of ciprofloxacin. Our research question was guided by challenges and concerns of nurses about the delay time between ciprofloxacin administration and restart of the enteral feeding without compromising the nutritional intake of the children. Our guideline was adapted, nurses were instructed accordingly, and patient leaflets with correct information were created.

Optimizing Management of the Central Nervous System in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplantation

PurposeTo evaluate clinical outcomes and patterns of failure, specifically in regards to the central nervous system (CNS), in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using total body irradiation (TBI)-based conditioning regimens. Methods and MaterialsAll adult patients (aged ≥18 years) with ALL undergoing allogeneic HSCT using TBI-based conditioning regimens treated from 1995 to 2020 at Duke University Medical Center were evaluated. Various patient, disease, and treatment-related factors were collected, including CNS prophylaxis and treatment interventions. Clinical outcomes, including freedom from CNS relapse, were calculated using the Kaplan-Meier method for patients with and without CNS disease at presentation. ResultsOne hundred and fifteen patients with ALL were included the analysis (myeloablative, 110; nonmyeloablative, 5). Of the 110 patients undergoing a myeloablative regimen, most (n = 100) did not have CNS disease before transplant. For this subgroup, peritransplant intrathecal chemotherapy was administered in 76% (median of 4 cycles) and 10 received a radiation boost to the CNS (cranial irradiation, 5; craniospinal, 5). Only 4 failed in the CNS after transplant, none of whom received a CNS boost, with freedom from CNS relapse at 5 years of 95% (95% confidence interval (CI), 84-98%). Freedom from CNS relapse was not improved with a radiation therapy boost to the CNS (100% vs 94%, P = .59). Overall survival, leukemia-free survival, and nonrelapse mortality at 5 years were 50%, 42%, and 36%, respectively. Among the 10 patients with CNS disease before transplant, 10 of 10 received intrathecal chemotherapy and 7 received a radiation boost to the CNS (cranial irradiation, 1; craniospinal, 6) and none subsequently failed in the CNS. A nonmyeloablative HSCT was pursued for 5 patients because of advanced age or comorbidities. None of these patients had prior CNS disease or received a CNS or testicular boost, and none failed in the CNS after transplant. ConclusionsA CNS boost may not be necessary in patients with high-risk ALL without CNS disease undergoing a myeloablative HSCT using a TBI-based regimen. Favorable outcomes were observed with a low-dose craniospinal boost in patients with CNS disease.

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

Long-Term Outcome of Low Dose of Anti-t-Lymphocyte Globulin in the Prophylaxis of Graft-Versus-Host Disease in Unrelated Myeloablative Hematopoietic Stem Cell Transplantation

INTRODUCTION In vivo T-cell depletion with Anti-T-lymphocyte globulin (ATLG; Grafalon) is one of the strategies used in the graft-versus-host disease (GVHD) prevention in the setting of hematopoietic stem cell transplantation (HSCT). One open-label randomized trial in HLA-matched unrelated myeloablative HSCT have reported the reduction of cGVHD with the incorporation of ATLG (60mg/Kg), however progression-free survival (PFS) and overall survival (OS) were lower than in the placebo group1. Other randomized trial in related myeloablative HSCT, using an inferior dose of ATLG (30mg/Kg), have reported this reduction in GVHD results without increasing transplantation-related mortality (TRM) or disease relapse (DR)2. Based on this, the policy in our center is to use a lower dose of ATLG (21mg/Kg) in unrelated myeloablative HSCT. The aim of this study is to analyze the outcome of this strategy in terms of GVHD results, PFS, OS, TRM and DR. METHODS We conducted a retrospective study in all patients who underwent a HLA-matched unrelated myeloablative HSCT at our institution between 2013 and 2021. Patients received a total dose of 21mg/Kg of ATLG divided into three doses of 7mg/Kg on days -3, -2 and -1. The primary endpoints were cumulative incidence (CI) of aGVHD, CI of moderate-severe cGVHD, PFS and OS. Secondary endpoints were TRM, CI of DR and toxicity. RESULTS Sixty-one patients were included. The median age was 51 years. Thirty-seven (60,7%) were men. Twenty-three (37,7%) patients had an acute myeloid leukemia (AML). Eighteen (29,5%) patients had an HLA-mismatched donor. Forty-two (68,8%) receive a Bu-Flu conditioning. Cyclosporine combined with mycophenolate mofetil (MMF) or short course of methotrexate (MTX) as GCVH prophylaxis was used in 43 patients (70,5%). Clinical characteristics of patients are showed in table 1. The median follow-up of the alive patients was 36 months. A median value of 0.1 x 106/L lymphocytes was observed on the first day of infusion. In 35 patients (57,4%) a grade 1 to 2 infusion reaction was reported and in 3 (4,9%) a grade 3 to 4. Those three patients did not complete all infusions, the rest of patients did. Median time to neutrophil engraftment (3 consecutive days of >500/μL) was 15 days (IR, 13-18) and to platelet engraftment (3 consecutive days of self-supported platelets >20000/μL) was 17 days (IR, 15-23). CI of aGVHD grade 2 to 4 within 180 days after HSCT was 39,5% (95% CI, 27,1% to 51,6%) and CI of aGVHD grade 3 to 4 was 11,6% (95% CI, 5,0% to 21%), CI of moderate-severe cGVHD at two years was 20,9% (95% CI, 11,4% to 32,4%). PFS at two years was 59,6% (95% CI, 47% to 71%) and OS at two years was 71,8% (95% CI, 59% to 83%). The cGVHD relapse free survival (cGRFS) at two years was 36,2% (95 CI, 24% to 48%). The CI of RD at two years was 23,3% (95% CI, 13% to 35,3%) and the TRM at two years was 17,1% (95% CI, 8,7% to 27,9%). Median time to cyclosporine or tacrolimus withdrawal was 6,7 months (interquartile range, 5-8 months) and median of use of any type of immunosuppressors (i.e corticosteroids) from the day of HSCT was 6,9 months (interquartile range, 5-10 months). In 4 (6,6%) patients a primary graft failure was reported, and two patients developed post-transplantation lymphoproliferative disease. CONCLUSSIONS The use of ATLG at dose of 21 mg/Kg in HLA-matched unrelated myeloablative HSCT offers promising results of OS and PFS with a low TRM, despite being related to a higher incidence of aGVHD and cGVHD than previously trials were the ATLG dose was higher. It showed a better profile of tolerability and adverse effects. More investigation should be undertaken to determine the appropriate dose of ATLG in this type of HSCT. REFERENCES 1. Soiffer RJ, Kim HT, McGuirk J, Horwitz ME et al. Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation. J Clin Oncol. 2017 Dec 20;35(36):4003-4011. doi: 10.1200/JCO.2017.75.8177. Epub 2017 Oct 17. PMID: 29040031; PMCID: PMC8462523. 2. Kröger N, Solano C, Wolschke Cet al. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med. 2016 Jan 7;374(1):43-53. doi: 10.1056/NEJMoa1506002. PMID: 26735993. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Stem cell transplantation for systemic sclerosis.

Stem cell transplantation for systemic sclerosis.

P509: CLONAL HEMATOPOIESIS-ASSOCIATED MUTATIONS AS MEASURABLE RESIDUAL DISEASE MARKERS IN ACUTE MYELOID LEUKEMIA PATIENTS FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION

Background: Clonal hematopoiesis (CH)-associated mutations (mut) are frequent in acute myeloid leukemia (AML), appear early in leukemogenesis, and often persist in remission after chemotherapy. Following allogeneic hematopoietic stem cell transplantation (HSCT), which replaces the patients’ hematopoiesis, CH mut may present useful measurable residual disease (MRD) markers. Aims: To evaluate patient specific CH-associated mut as MRD markers in AML patients (pts) after allogeneic HSCT. Methods: We analyzed 31 AML pts with CH-associated mut present at diagnosis (DNMT3A: n=17; SRSF2: n=9; IDH2: n=7; ASXL1: n=4; TET2: n=2, and JAK2: n=1), 23 pts had 1, 7 had 2, and 1 patient had 3 CH mut. All received a myeloablative (36%), reduced-intensity (48%), or non-myeloablative (16%) HSCT (median age 58, range 32-72 years). 84% were transplanted in complete remission (CR) or CR with incomplete recovery (CRi). European Leukemia Net (ELN) risk was 23% favorable, 37% intermediate, and 40% adverse. Mut-specific digital droplet PCR assays were developed using a competitive probe-approach. MRDpos was defined as variant allele frequency (VAF) ≥2% for ASXL1 & ≥0.05% for all other analyzed mut. 209 samples with a median of 6 (range 1-13) blood or bone marrow samples per patient were available after HSCT with a median of 1.2 years follow-up time for pts alive. Results: Prior to HSCT, 89% of pts remained CH-associated mut positive in CR/CRi. 11 pts relapsed after HSCT (35%), all with the same CH-associated mut present at diagnosis (median VAF at relapse 15.6, range 0.2-41.2%). Of those, 6 pts had at least 1 MRD sample available prior to relapse. In 5 pts, impeding relapse was predicted by a CH-associated mut MRD conversion with a median VAF of 0.27 (range 0.06-1.0)% at a median of 103 (range 14-199) days prior to relapse. The lead time was longest for a DNMT3A mut patient (199 days) & shortest for a SRSF2 mut patient (14 days). For the patient relapsing without prior CH MRD positivity, the last available sample was taken 169 days before relapse & was CH MRDneg. 20 pts retained remission during follow-up. Of those, 17 pts remained CH MRDneg in all samples (median samples per analyzed mutation 6, range 1-13). 2 pts had 2 MRDpos samples directly after HSCT but became MRDneg in subsequent samples. 1 patient received Enasidenib maintenance after HSCT with fluctuating CH-MRD values after HSCT (SRSF2 & IDH2, VAFs <0.05-0.34% & <0.05-0.14%, respectively). Of the pts with MRD samples within the first year after HSCT available, pts with at least 1 MRDpos sample after HSCT had a significantly higher cumulative incidence of relapse (CIR, P=.008, Figure 1A) & shorter relapse-free survival (RFS, P=.02, Figure 1B). 8 pts had concurrent NPM1 mut (n=4) or RUNX1 mut (n=4), which showed concordant MRD results in 7 pts (4 remained MRDneg, 3 concurrently converted MRDpos). 1 patient suffered a NPM1 MRDneg relapse which was predicted by 2 re-detected CH-associated mut (DNMT3A mut & IDH2 mut, 112 & 199 days prior to relapse, respectively, Figure 1C). Image:Summary/Conclusion: Prior to HSCT most CH-associated mut remain detectable in pts in CR/CRi. However, pts with at least one CH MRDpos sample following allogeneic HSCT had higher CIR & shorter RFS. All relapsing pts were positive for the same CH-associated mut present at diagnosis. 5 of 6 showed increasing VAFs prior to hematologic relapse & the majority of pts retaining remission remained CH MRDneg. While CH-associated mut in chemotherapy treated AML pts have limited MRD value, these mut are feasible MRD markers after HSCT & may inform relapse preventing therapy decisions.

Assessment of safety and immunogenicity of MHC homozygous iPSC-derived CD34+ hematopoietic progenitors in an NHP model

AbstractAdministration of ex vivo expanded somatic myeloid progenitors has been explored as a way to facilitate a more rapid myeloid recovery and improve overall survival after myeloablation. Recent advances in induced pluripotent stem cell (iPSC) technologies have created alternative platforms for supplying off-the-shelf immunologically compatible myeloid progenitors, including cellular products derived from major histocompatibility complex (MHC) homozygous superdonors, potentially increasing the availability of MHC-matching cells and maximizing the utility of stem cell banking. However, the teratogenic and tumorigenic potential of iPSC-derived progenitor cells and whether they will induce alloreactive antibodies upon transfer remain unclear. We evaluated the safety and efficacy of using CD34+CD45+ hematopoietic progenitors derived from MHC homozygous iPSCs (iHPs) to treat cytopenia after myeloablative hematopoietic stem cell (HSC) transplantation in a Mauritian cynomolgus macaque (MCM) nonhuman primate (NHP) model. We demonstrated that infusion of iHPs was well tolerated and safe, observing no teratomas or tumors in the MCMs up to 1 year after HSC transplantation and iHP infusion. Importantly, the iHPs also did not induce significant levels of alloantibodies in MHC-matched or -mismatched immunocompetent MCMs, even after increasing MHC expression on iHPs with interferon-γ. These results support the feasibility of iHP use in the setting of myeloablation and suggest that iHP products pose a low risk of inducing alloreactive antibodies.

Haematopoietic Stem Cell Transplantation in Adolescents and Young Adults With Acute Lymphoblastic Leukaemia: Special Considerations and Challenges.

Adolescents and young adults (AYAs) represent a challenging group of acute lymphoblastic leukaemia (ALL) patients with specific needs. While there is growing evidence from comparative studies that this age group profits from intensified paediatric-based chemotherapy, the impact and optimal implementation of haematopoietic stem cell transplantation (HSCT) in the overall treatment strategy is less clear. Over recent years, improved survival rates after myeloablative allogeneic HSCT for ALL have been reported similarly for AYAs and children despite differences in transplantation practise. Still, AYAs appear to have inferior outcomes and an increased risk of treatment-related morbidity and mortality in comparison with children. To further improve HSCT outcomes and reduce toxicities in AYAs, accurate stratification and evaluation of additional or alternative targeted treatment options are crucial, based on specific molecular and immunological characterisation of ALL and minimal residual disease (MRD) assessment during therapy. Age-specific factors such as increased acute toxicities and poorer adherence to treatment as well as late sequelae might influence treatment decisions. In addition, educational, social, work, emotional, and sexual aspects during this very crucial period of life need to be considered. In this review, we summarise the key findings of recent studies on treatment approach and outcomes in this vulnerable patient group after HSCT, turning our attention to the different approaches applied in paediatric and adult centres. We focus on the specific needs of AYAs with ALL regarding social aspects and supportive care to handle complications as well as fertility issues. Finally, we comment on potential areas of future research and concisely debate the capacity of currently available immunotherapies to reduce toxicity and further improve survival in this challenging patient group.

Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report

Secondary malignancy of donor origin in the form of acute lymphoblastic leukemia (ALL), post-allogeneic hematopoietic stem cell transplant (HSCT) for beta thalassemia (BT) major, is exceedingly rare. A10 year old male child, the first and only product of non-consanguineous conception, was diagnosed with BT major at the age of 9 months when he had diarrhea and his parents (both of whom had thalassemia minor) noticed yellowing of the skin. Until the age of 10 years, he received regular blood transfusion and iron chelation, when the requirements got escalated and he consequently had to undergo myeloablative haploidentical HSCT from his mother. The post-transplant period was uneventful, and follow up with short tandem repeat chimerism analysis revealed complete donor chimerism on all occasions. Five years after the transplant, he developed fever with pancytopenia. Peripheral smear (PS) and bone marrow revealed blasts that were immunophenotypically precursor B-ALL. Cytogenetics revealed twenty diploid female metaphases with modal karyotype 46, XX[20], and again, complete donor chimerism was noted. Thus, a diagnosis of donor cell leukemia (DCL) was considered. Induction chemotherapy was initiated; however, the patient succumbed to systemic sepsis midway through induction therapy. No evidence of leukemia was noted in the patient's mother, who was followed up with PSs for 5 years. DCL has a poor prognosis. Greater understanding of the disease biology could allow for appropriate donor screening, notification and shielding the recipient from DCL and its grave consequences.

Oral Mucositis Association with Periodontal Status: A Retrospective Analysis of 496 Patients Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) can induce serious oral complications, including oral mucositis (OM). The presence of periodontal inflammation before HSCT is believed to be associated with OM. The aim of our study was to determine the prevalence and severity of OM in patients undergoing HSCT and its relation to periodontal status. Patients and methods: This is a retrospective study of patients who underwent HSCT and a detailed dental examination between 2007 and 2015. The dental and periodontal status of all patients was evaluated by clinical and radiographic examination prior to HSCT. Oral health was assessed with the gingival index, the the community periodontal index, presence of plaque-related gingivitis, and marginal periodontitis. During the HSCT period, patients were examined daily for the presence of OM, which was graded according to World Health Organization (WHO) classification if present. The patients were assigned to the groups according to type of transplantation: autologous HSCT, myeloablative allogeneic HSCT, and non-myeloablative allogeneic HSCT. Results: A total of 496 patients were included in the study. OM was present in 314 of 496 patients (63.3%): 184/251 (73.3%) in the autologous group, 100/151 (66.2%) in the myeloablative allogeneic group, and 30/94 (31.9%) in the nonmyeloablative allogeneic group. Significantly more patients suffered from OM in the autologous and myeloablative groups versus the nonmyeloablative conditioning group (p < 0.001). The presence of periodontal inflammation did not significantly differ among the groups. There was only a borderline trend for the higher prevalence of OM in the non-myeloablative allogeneic nonmyeloablative group when periodontal inflammation was present (0.073939). Conclusions: Oral mucositis prevalence and severity after stem cell transplantation is not widely affected by the oral hygiene and periodontal disease presence before HSCT. We confirmed the wide-known connection of the conditioning regimen intensity to the prevalence of OM.

927. Clinical Characteristics and Outcomes of Norovirus Infection in Patients with Hematologic Malignancies: A Retrospective, Single Center Study

BackgroundNorovirus (NV) gastroenteritis has been identified as a cause of significant morbidity among hematopoietic stem cell transplant (HSCT) recipients, often with associated complications. Current guidelines recommend symptomatic relief with antimotility agents, rehydration, and reduction in immune suppression. Nitazoxanide (NTZ) is an anti-parasitic agent but some literature suggests a benefit of nitazoxanide therapy for NV. MethodsWe conducted a single center, retrospective chart review study and evaluated adult patients (age >18 years) who had NV infection and either: 1) underwent stem cell transplantation; or 2) received myeloablative chemotherapy within 4 weeks of NV diagnosis by positive test on gastrointestinal pathogen panel during the time period from January 2015 through March 2020. Results26 patients were reviewed. 14 patients (54%) had a history of HCST prior to infection. Three patients (12%) received both myeloablative chemotherapy and HSCT within four weeks of NV infection. Six patients (46%) had autologous, six (46%) had matched unrelated donor, and one (8%) had haploidentical allogeneic transplants. Nine (69%), three (23%), and one (8%) underwent myeloablative, reduced intensity and non-myeloablative conditioning, respectively. Median duration of diarrhea was 4.5 days (IQR = 2.25-7 days). Three (12%) patients received NTZ or intravenous immune globulin. The 6 month mortality was 42% (11/26), however, none of the deaths were directly attributable to NV infection.ConclusionNV infection led to severe diarrheal disease in our cohort. Overall mortality was high, and a trend toward increased mortality was seen among patients receiving NV-directed therapy; these patients likely received NV-directed therapy due to the severity of their illness. Clinicians must have a high suspicion for this illness and obtain PCR testing for timely diagnosis and management.Table 1. Characteristics of patients with hematologic malignancies and norovirus infection Disclosures All Authors: No reported disclosures

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3: impact on early haematopoietic reconstitution following allogeneic haematopoietic stem cell transplantation.

The aim of the study was to investigate whether high endogenous levels of insulin-like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3) were related to a faster reconstitution of different blood cell populations in the early phase after allogeneic myeloablative haematopoietic stem cell transplantation (HSCT). We measured IGF-1 and IGFBP-3 by chemiluminescence during the first three weeks after transplantation in 35 adult patients undergoing myeloablative HSCT and calculated area under the curve divided by time (AUC/t) for each patient. Circulating levels of IGF-1 and IGFBP-3 correlated with counts of reticulocytes (rs =0.44, p=.011 and r=0.41, p=.017, respectively) and thrombocytes (rs =0.38, p=.030 and rs =0.56, p=.0008) three weeks post-transplant. Furthermore, high IGFBP-3levels correlated with absolute lymphocyte counts 3weeks post-HSCT (rs =0.54, p=.012) and were associated with shorter time to neutrophil engraftment (rs =-0.35, p=.043). Both IGF-1 and IGFBP-3levels were associated with the number of circulating natural killer cells one month after HSCT (rs =0.42, p=.032 and rs =0.57, p=.0026). These data indicate that high levels of IGF-1 and IGFBP-3 relate to a faster haematopoietic reconstitution after HSCT and suggest a biological influence of these mediators in haematopoietic homeostasis in these patients.