Successful Hematopoietic Stem Cell Transplantation Research Articles

Silencing endomucin in bone marrow sinusoids improves hematopoietic stem and progenitor cell homing during transplantation.

Efficient homing of infused hematopoietic stem and progenitor cells (HSPCs) into the bone marrow (BM) is the prerequisite for successful hematopoietic stem cell transplantation. However, only a small part of infused HSPCs find their way to the BM niche. A better understanding of the mechanisms that facilitate HSPC homing will help to develop strategies to improve the initial HSPC engraftment and subsequent hematopoietic regeneration. Here, we show that irradiation upregulates the endomucin expression of endothelial cells in vivo and in vitro. Furthermore, depletion of endomucin in irradiated endothelial cells with short interfering RNA (siRNA) increases the HSPC-endothelial cell adhesion in vitro. To abrogate the endomucin of BM sinusoidal endothelial cells (BM-SECs) in vivo, we develop a siRNA-loaded bovine serum albumin nanoparticle for targeted delivery. Nanoparticle-mediated siRNA delivery successfully silences endomucin expression in BM-SECs and improves HSPC homing during transplantation. These results reveal that endomucin plays a critical role in HSPC homing during transplantation and that gene-based manipulation of BM-SEC endomucin in vivo can be exploited to improve the efficacy of HSPC transplantation.

Treatment Patterns and Clinical Outcomes of Patients with Moderate to Severe Acute Graft-Versus-Host Disease: A Multicenter Chart Review Study.

Acute graft-versus-host disease (aGVHD) remains a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT) outcomes. Contemporary comprehensive analyses of real-world clinical outcomes among patients who develop aGVHD post-HSCT are needed to better understand the unmet needs of this patient population. This multicenter, retrospective chart review describes treatment patterns and clinical outcomes among patients (≥18 years old) from Finland, Sweden, and France who developed grades II-IV aGVHD after their first HSCT (January 2016-June 2017). From 13 participating centers, 151 patients were included. The median (Q1, Q3) age at HSCT was 56 (45, 62) years old. One line of aGVHD treatment was received by 47.7%, and the most common first-line treatment was methylprednisolone (alone or in a combination regimen, 74.2%; monotherapy, 25.8%). Among patients treated with methylprednisolone, 79.5% achieved a complete or partial response. The median (Q1, Q3) number of treatment lines was 2.0 (1.0, 3.0). The median (Q1, Q3) time to obtain an aGVHD diagnosis from transplant was 29.5 (21.0, 44.0) days, and 14.5 (7.0, 34.0) days to achieve the best response for 110 evaluable patients. At 6 and 12 months, 53.6% and 49.0%, respectively, achieved a complete response. Chronic GVHD occurred in 37.7% of patients, and aGVHD reoccurred in 26.5%. Following aGVHD diagnosis, mortality rates were 30.0% at 6 months and 37.3% at 12 months. Findings from this study demonstrate a continuing unmet need for new therapies that control aGVHD and improve mortality.

FLAG with Bortezomib Salvage Therapy in Relapsed/Refractory Childhood Leukemia—A Reliable Bridge to Transplantation with Limited Toxicity

Relapsed refractory leukemia represents a difficult-to-treat population of patients. The balance between perceived benefit and potential side effects along with the significant financial burden of managing multidrug-resistant sepsis are factors that determine the choice of salvage regimen. Here, we present our experience with the combination of fludarabine, cytarabine, granulocyte-colony stimulating factor with bortezomib. The morphological complete response rate was 58% with 50% of the patients achieving complete remission. With only three patients requiring intensive care unit admission during remission induction, 66.6% of the patients went on to undergo successful hematopoietic stem cell transplantation. Thus, it proved to be a possible, safer alternative to other salvage regimens, while enabling a significant percentage of patients to achieve remission and proceed to allogenic stem cell transplantation.

Stem Cells Collection and Mobilization in Adult Autologous/Allogeneic Transplantation: Critical Points and Future Challenges.

Achieving successful hematopoietic stem cell transplantation (HSCT) relies on two fundamental pillars: effective mobilization and efficient collection through apheresis to attain the optimal graft dose. These cornerstones pave the way for enhanced patient outcomes. The primary challenges encountered by the clinical unit and collection facility within a transplant program encompass augmenting mobilization efficiency to optimize the harvest of target cell populations, implementing robust monitoring and predictive strategies for mobilization, streamlining the apheresis procedure to minimize collection duration while ensuring adequate yield, prioritizing patient comfort by reducing the overall collection time, guaranteeing the quality and purity of stem cell products to optimize graft function and transplant success, and facilitating seamless coordination between diverse entities involved in the HSCT process. In this review, we aim to address key questions and provide insights into the critical aspects of mobilizing and collecting hematopoietic stem cells for transplantation purposes.

Successful Hematopoietic Stem Cell Transplantation in a Child with Thalassemia major and Moderate Haemophilia A.

Successful Hematopoietic Stem Cell Transplantation in a Child with Thalassemia major and Moderate Haemophilia A.

Persistent hypersplenism following successful hematopoietic stem cell transplantation: unraveling the cellular components of extramedullary residual disease and donor hematopoiesis—a case report

In this study, we report an unprecedented case of graft failure following hematopoietic stem cell transplantation (HSCT) in a patient with a myeloproliferative neoplasm (MPN) who had achieved bone marrow (BM) remission. We outline the intricate cellular components of splenic hematopoiesis, which are derived from both the recipient and the donor, underpinning the persistence of fibrosis. Our investigation characterizes the distinct cellular populations that play a pivotal role in graft exhaustion and introduces an unusual hypothesis regarding the perpetuation of a malignant niche in extramedullary sites within the context of HSCT.

Reduced human leukocyte antigen mismatching is associated with more favourable outcomes after unrelated donor haematopoietic stem cell transplantation.

The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p=.031; hazard ratio [HR] 1.935) and 6 months (p=.004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p=.006; HR 2.642) as well as at 6-month (p=.007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p=.034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1+DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.

Neurodevelopmental outcomes in two cases of artemis deficiency

Background: Severe Combined Immunodeficiency (SCID) is a category of inborn errors of immunity where there is impaired T and B cell development and/or function. Artemis SCID (Art-SCID) is characterized by dysfunctional Artemis protein, which is crucial for V(D)J recombination in T and B cell maturation. Art-SCID is fatal without management, and current definitive treatment involves hematopoietic stem cell transplantation (HSCT) or gene therapy. As the prognosis and survival of SCID patients improves, current research has begun unveiling long-term complications and morbidities. Previous literature has reported neurodevelopmental abnormalities in SCID patients, such as developmental delay and Autism Spectrum Disorder (ASD). However, it remains unknown whether these neurodevelopmental differences are linked to the SCID mutation, an adverse outcome of treatment and hospitalization, or comorbid social isolation and psychosocial challenges. Aims: In this case series, we discuss two cases of Art-SCID which presented with neurodevelopmental deficits following successful HSCT. Results: In both cases, SCID was detected on Newborn Screening (NBS), and Art-SCID was confirmed with genetic testing. Both patients were successfully treated with HSCT at 80 days of life, and followed up clinically well, with robust cell counts. Both patients later presented in toddlerhood with developmental, speech and language delay, however only one patient met diagnostic criteria for ASD. Conclusion: The definitive relationship between SCID, HSCT, and neurodevelopmental outcomes remain unclear, and warrants further study to allow for early intervention. We are currently working with colleagues across the country to further investigate and define this complex relationship. Statement of Novelty: We are investigating the complex relationship between SCID, HSCT, and potential neurodevelopmental outcomes. We present two cases of patients with Artemis SCID who were successfully treated with HSCT, and later presented in toddlerhood with developmental, speech, and language delay.

Treatment of Molecular Relapses in Pediatric AML Saves Toxicities Prior to Hematopoietic Stem Cell Transplantation (HSCT) - Results of AMoRe2017 Trial

Introduction The long-term survival for children with AML has increased to 70 % - but relapsed AML patients still have a poor prognosis (about 30 %). Recent data suggest that in AML residual leukemic cells below the 5 % limit required for a morphologic CR can adversely affect outcome and that increasing levels of Minimal Residual Disease (MRD) are almost always followed by clinical relapse. Early MRD detection provides an opportunity to implement pre-emptive therapies as a bridge-to-transplant approach, to potentially prevent hematological relapse and increase the probability of successful HSCT. A promising approach is the use of Azacitidine (Aza) for treatment of molecular relapse which we evaluated within the clinical trial “AMoRe2017”. Aza has been shown to reverse epigenetic changes in malignant cells, restoring the normal function of genes critical for differentiation and cell cycle control. The trials' primary objective was the evaluation of the effect of Aza treatment in AML subjects at molecular relapse after CR1 regarding molecular response prior to further treatment (reinduction/HSCT). Patients and Methods AMoRe2017 enrolled children with AML (N=20), >3 months < 21 yrs., of which n=1 dropped out due to laboratory measurement error. The median age was 10.9 yrs. (range 1.7-18.9 yrs.). N=10 (53 %) had a CBFB-AML, n=5 (27 %) KMT2A-rearrangement, n=1 (5 %) NUP98::NSD1, n=1 (5 %) FLT3-ITD, n=1(5 %) PICALM::MLLT10 and n=1 (5 %) NPM1. N=8 (42 %) were classified to subgroup M2, n=4 (21 %) to M5, n=3 (16 %) into M1 and n=4 (21 %) to M4/M4 Eo. At baseline, the white blood cell count averaged 3.8x10 9/l (range 0.1-6.6x10 9/l), without leukemic blasts in PB or BM. Each patient had at least one quantifiable genetic marker (rt-PCR), achieved CR with molecular remission, following initial therapy, and subsequently had a molecular relapse (defined as an increase of the MRD level by at least 1 log, less than 5 % BM myeloblasts and absence of proven extramedullary disease). Patients were treated for up to 6 cycles with 75 mg/m 2 i.v. Aza on days 1 to 7 in a 28-day cycle. Molecular response was categorized as molecular stabilization (< 1 log decrease or increase from baseline), molecular progression (≥ 1 log increase from baseline without hematological relapse), molecular improvement (≥ 1 log decrease from baseline), and hematological relapse (at least 5 % blasts in PB and/or BM and/or proven histological extramedullary relapse). Results During Aza treatment, 10 patients (53 %) had an open relapse, which occurred in n=9 after 1 st or 2 nd cycle. These patients were monitored for KMT2A::SEPTIN6 (n=1), KMT2A::MLLT3 (n=2), PICALM::MLLT10 (n=1), FLT3-ITD (n=1), NUP98::NSD1 (n=1), CBFB::MYH11 (n=1) and RUNX1::RUNX1T1 (n=3). 9 patients (47 %; RUNX1::RUNX1T1 n=5, CBFB::MYH11 n=1, NPM1 n=1, KMT2A::ELL n=2) showed a molecular response to Aza and proceeded to HSCT without receiving intensive re-induction treatment. 16 out of the 19 patients are alive (overall survival 84 %), 2 died from HSCT-associated side effects (VOD, infection), and 1 from disease progression. Considering genetics, 7 out of 11 patients with favorable genetics (core-binding leukemia n=10 or NPM1 n=1) responded to the Aza therapy ( RUNX1::RUNX1T1 n=5, CBFB::MYH11 n=1, NPM1 n=1). By contrast, in cases with KMT2A-rearrangements, NUP98::NSD1 or FLT3-ITD, 2 out of 8 patients showed improvement or stabilization. In total 152 adverse events (AEs) associated to Aza were reported, the majority classified as grade 1 or 2 (n= 114; 75 %). Mainly affected was the hematopoietic system (40 %), the gastrointestinal tract (15 %), kidney and liver (14 %). Cardiotoxicity was not reported. Discussion The use of Aza as pre-emptive “bridge-to-transplant” approach treating the molecular relapse showed efficacy in patients with RUNX1::RUNX1T1, CBFB::MYH11, NPM1, and KMT2A::ELL, who could be transplanted directly. This pilot provided proof of principle that molecular relapses could be treated, and MRD levels be reversed, at least in subgroups. In addition, avoiding intensive re-induction therapy prior to HSCT is feasible. Conversely, the relatively slow-acting mechanism of epigenetic therapy seems to be ineffective in highly proliferative subgroups of AML with KMT2A-rearrangements or FLT3-ITD. Further studies are mandatory to define treatment options for molecular relapses of non-favorable pediatric AML and to confirm potential improvement of outcome post-HSCT.

The Effect of Allogeneic Hematopoietic Stem Cell Transplantation on Sickle Cell Disease-Related Organ Damage: A Systematic Review and Meta-Analysis

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative treatment option for patients with sickle cell disease (SCD). One of the main indications for HSCT is SCD-related organ damage, which is a major cause of morbidity and early mortality. However, whether HSCT is effective in recovering SCD-related organ dysfunction has not been systematically reviewed. Methods This is a systematic review and meta-analysis investigating the effects of HSCT on organ function in patients with SCD. We performed a comprehensive search in MEDLINE/PubMed and EMBASE up to June 2023, focusing on studies reporting pulmonary, cardiac, renal, splenic, and/or cerebral function parameters, as well as retinopathy and/or avascular osteonecrosis (AVN) before and after HSCT. Continuous data were analyzed using the weighted inverse-variance random effects meta-analyses, reported as standardized mean difference (SMD) and 95% confidence intervals (95%-CI). Binomial data were analyzed using the Mantel-Haenszel random effects meta-analyses, reported as risk ratio (RR) and 95%-CI. A negative SMD indicates an improvement and a positive SMD indicates a worsening of the measured parameter post-HSCT. A RR <1 indicates a result in favor of the transplantation and a RR >1 indicates a worsening of the measured parameter after HSCT. The ‘Newcastle-Ottawa Quality Assessment Scale’ and the ‘Clinical Diversity in Meta-analysis’ (CDIM) tool were used to assess the quality and the clinical heterogeneity of the studies. Results Thirty-two of 476 studies met our inclusion criteria, of which 17 were used for the meta-analyses and 15 for the qualitative part of the review. Of the studies that were included in the meta-analyses, 4 comprised adult patients (n=184) and 13 pediatric and/or young adults <22 years old (n=591). The majority of donors were matched sibling donors (86.4%), and studies with both myeloablative and/or reduced intensity conditioning regimens were included. The CDIM score was low or moderate for all performed meta-analyses, suggesting fair clinical comparability among the studies. Summary plots of the meta-analyses are shown in Figure 1. Pulmonary function test parameters remained stable following HSCT (SMD -0.08, p=0.64 for forced expiratory volume in 1 second; SMD -0.13, p=0.35 for forced vital capacity; and SMD -0.95, p=0.30 for diffusing capacity). Mean tricuspid regurgitation velocity (TRV) did not change significantly in the meta-analysis (SMD -0.34, p=0.14). However, 3 studies used for the qualitative review reported normalization in patients with prior elevated TRV. Whole brain cerebral blood flow improved significantly after transplantation (SMD -1.39, p=<0.01). Several studies reported an absent or very low incidence of new (silent) cerebral infarcts and a decrease of transcranial Doppler velocities following successful HSCT. In pediatric patients, creatinine clearance decreased significantly after HSCT (SMD -0.80, p=0.01) and the presence of proteinuria increased (RR 2.00, p=<0.01). Furthermore, splenic uptake ( 99mTc) and phagocytic function of the spleen improved (RR 0.31, p=<0.01 and RR 0.23, p=<0.01, respectively). Retinopathy and AVN before and after HSCT were investigated in only 1 study in children with SCD, both showing no significant changes post-HSCT. Discussion and Conclusion Allogeneic HSCT has the potential to stabilize or recover pulmonary and cardiac function parameters in SCD patients. In pediatric patients, splenic function parameters showed impressive improvement following HSCT. On the other hand, creatinine clearance decreased significantly in children. This might be a reflection of either normalization of SCD-related hyperfiltration or transplantation-related toxicity, which may also have contributed to the increased prevalence of proteinuria after HSCT. With respect to cerebral damage, cerebral perfusion parameters improved and progression of silent cerebral infarctions was prevented following HSCT. Last, we demonstrate a paucity of evidence regarding the course of renal function, retinopathy, and AVN in adult SCD transplant recipients. More research is needed to define which patients with SCD-related organ damage might benefit most from HSCT and which organs are less likely to recover.

Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: A Report from the Children's Oncology Group

Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of infants and toddlers. Upfront therapies typically include high-dose cytarabine or azacitidine, but the only definitive treatment is hematopoietic stem cell transplantation (HSCT). While HSCT cures ~50% of patients, the prognosis is dismal for those who relapse. In the absence of a second HSCT, patients who relapse have a 2-year overall survival of ~10%. JMML is initiated by germline and somatic driver mutations in NF1, KRAS, NRAS, PTPN11, and CBL. These mutations converge on Ras signaling, leading to elevated levels of active Ras-GTP in specific cell lineages. Genetically engineered mouse (GEM) models accurately model key molecular, biologic, and biochemical features of JMML. Preclinical trials of the allosteric MEK inhibitors in Kras and Nf1 mutant mice demonstrated dramatic phenotypic responses with reduction in white blood cell counts, resolution of splenomegaly, and reversion to normal erythropoiesis. Based on the promising efficacy signal in GEM models, we evaluated trametinib, an orally bioavailable allosteric inhibitor of MEK1/2, in a prospective clinical trial in children with relapsed or refractory JMML to determine the overall response rate to trametinib. Results: Ten infants and children with JMML (median age 23.6 months) were enrolled and all were evaluable for safety and efficacy. Patients received age-adjusted dosing of trametinib for 28-day cycles and could remain on study for up to 12 cycles in the absence of disease progression or toxicity. A clonal Ras pathway mutation was confirmed in the blood and/or bone marrow of all patients. The objective response rate was 50% (two complete and three partial clinical responses). Four patients proceeded to HSCT after receiving protocol therapy and remain alive in complete remission with undetectable levels of the Ras pathway mutation identified at enrollment. Three additional patients completed 12 cycles of trametinib and continue to receive off-protocol therapy 6-24 months later with no change in the variant allele frequency of the underlying Ras pathway mutation. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Paired pre- and post-trametinib RNASeq and proteomic analyses confirmed on-target biochemical effects of trametinib with down-regulation of both Ras/MAPK pathway related gene expression and MEK1/2 kinase activity, respectively. To gain deeper insight into how trametinib might affect distinct populations of hematopoietic cells, we generated single cell RNASeq data before and after treatment. The most prominent finding was a reduction in the proportions of classical and non-classical monocytes and broad downregulation of immune-related pathways in all cell populations. However, the downregulation of MAPK signaling genes was confined to specific cell types including, macrophages, classical monocytes, and granulocyte-monocyte progenitors, which uniquely displayed downregulated KRAS-related signatures following treatment. High DNA methylation and the presence of >1 mutation at enrollment correlated with lack of response to trametinib. Conclusions: We conducted an open label, phase 2 trial of trametinib in children with relapsed or refractory JMML. This is the first completed study of a MEK inhibitor in any hematologic malignancy in children. The trial met its primary objective and demonstrated a 50% objective response rate with 70% of patients bridging to a successful HSCT or completing the maximum 12 cycles permitted on study. The three patients who completed 12 cycles continue to receive trametinib off study for as long as 2 years. Although limited by a small number of patients, the long-term survival, and correlative molecular analyses from this trial raise provocative questions about whether certain patients with JMML might be spared the long-term adverse health risks of genotoxic HSCT conditioning regimens based on favorable molecular characteristics at diagnosis. This hypothesis will now be tested in a national, risk-stratified therapeutic trial (NCT05849662) of trametinib in combination with azacitidine in newly diagnosed patients. The authors would like to acknowledge funding and support from: NCTN Operations Center Grant (U10CA180886), NCTN Statistics & Data Center Grant (U10CA180899), and the St. Baldrick's Foundation.

Reclassification of ETS Family Transcription Factor Fusions in Pediatric AML Based on Molecular Drivers

Pediatric Acute Myeloid Leukemia (pAML) patients with a fusion involving an E26 transformation-specific (ETS) transcription factor have traditionally been considered high-risk. The most common fusions include ETV6::MNX1 t(7;12)(q36;p13) and FUS::ERG t(16;21)(p11;q22), yet primary fusion alone has proven incapable of predicting response to treatment. Indeed, within the 60 pAML patients with ETS fusions from the Children's Oncology Group (COG) trials AAML0531 and AAML1031, there were 25 unique fusions and diverse outcomes between patients who did share a primary fusion. A molecular based reclassification of ETS fused pAML could prove beneficial in the development of novel therapeutic additions to standard induction. Here, using genetic and RNAseq data from over 1,400 pediatric patients from AAML0531 and AAML1031, we reclassified ETS patients based on oncogenic transcriptional profiles as well as access to hematopoietic stem cell transplant (HSCT) ( Figure 1A). (19/60) patients presented with an enhanced MYC transcriptional signature (p-val < 0.00) independent of fusion partners [EP300::ETV6, ETV6::CCND3, ETV6::FAM133B, ETV6::FOXO1, ETV6::INO80D, ETV6::LMBR1, ETV6::MNX1, EWSR1::FEV, FLI1::IFIT2, FUS::ERG, FUS::FEV, FUS::FLI1]. Median event-free survival (EFS) was 293.5 days; median overall survival (OS) was 620.5 days. Notably, 100% (19/19) of patients with a MYC-driven signature relapsed; of the six patients who received HCST, five died within 3 years of diagnosis. Preliminary in vitro data in ETS cell lines with an enhanced MYC transcriptional signature (YNH-1, TSU-1621) suggests that the BET bromodomain inhibitor JQ1 may dampen MYC and induce anti-proliferative effects. (7/60) patients were defined by an EZH2-driven “immune-cold” signature characterized by global loss of immune receptors. Patients presented at diagnosis with significantly elevated EZH2 and low levels of MHC I and II receptors typically observed at relapse; additionally, there was significant downregulation in T cell and natural killer cell ligands and a 100% failure rate for HSCT. Median EFS was 255 days and median OS was 339 days. We have previously discussed the mechanism of leukemogenesis as well as proposed therapeutic interventions for this subset (Buteyn, ASH 2021). (34/60) patients did not possess either a MYC-driven or EZH2-driven signature. These “other” ETS were instead defined by whether or not the patient underwent HCST. (21/34) patients did not receive HCST and had median EFS and OS of 429 and 1194 days, respectively. The relapsed or refractory rate in this population was still 75%; (8/14) of R/R patients were deceased within three years. The remaining (13/60) ETS patients did receive HSCT in first remission. (11/13) are still alive and at a rate higher than the general pAML population post-HSCT (62.6%). Despite a survival rate at approximately 85%, ‘Other ETS +HSCT’ patients were all still categorized as ‘High Risk’ at the end of AAML1031. Overall, reclassification based on molecular drivers appears to not only be more accurate in predicting relapse and final outcome, but also in proposing novel agents for pAML patients who overwhelmingly do not respond to standard regimens. Reinvigoration of immune recognition by inhibition of EZH2 and/or inhibition of MYC-driven proliferation via BET inhibitors may prove an essential step in setting the stage for successful HSCT for a significant portion of pAML ETS patients.

Case report: Successful autologous hematopoietic stem cell transplantation in a patient with GAD antibody-spectrum disorder with rapidly progressive dementia

The prevalence of neurological syndromes associated with antibodies to glutamic acid decarboxylase is increasing. While cognitive impairment is a common feature of this condition, it seldom emerges as the primary symptom. In this study, we discuss a case of refractory dementia associated with the glutamic acid decarboxylase spectrum disorder. Interestingly, this case showed a favorable outcome following autologous hematopoietic stem cell transplantation. We also provide an in-depth review of the current literature on the use of this therapeutic approach for the treatment of this disease.

A successful second allogeneic hematopoietic stem cell transplantation from an alternative donor in a patient with loss of HLA heterozygosity relapse of juvenile myelomonocytic leukemia: case series analysis

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive myeloproliferative/myelodysplastic neoplasm of early childhood characterized by activation of the Ras signaling pathway. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only proven curative treatment for JMML. However, the 5-year overall survival is about 52–64%. In this work, we analyzed 4 clinical cases of patients with relapses of JMML with loss of heterozygosity in HLA (LoH) after allo-HSCT. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications. Two patients received a second allo-HSCT from an alternative donor, two patients – from the same donor. A positive result in the form of a durable remission was observed in one patient who underwent a second allo-HSCT from an alternative donor and restored HLA genetic heterozygosity. At the same time, immunotherapy with infusions of donor lymphocytes led to the development of graft-versus-host disease without potentiating the antileukemic effect. Thus, a second allo-HSCT from an alternative donor for the treatment of relapsed JMML with HLA LoH is necessary to restore the “graft-versus-JMML” response. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation.

Neurologic Status of Patients with Purine Nucleoside Phosphorylase Deficiency Before and After Hematopoetic Stem Cell Transplantation.

Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency. We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort. Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor. In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients.

Forging international collaboration and alliances to establish the largest transplant center in the north of Vietnam

Through collaboration with international experts, our institution established a highly active and successful hematopoietic stem cell transplant program, providing access to this potentially curative treatment modality for patients with a variety of benign and malignant hematological diseases. The initial development of an autologous stem cell transplant program provided our institution with the infrastructure, equipment, and expertise needed for the subsequent development of an allogeneic stem cell transplant program. Key transplant staff received training from international transplant experts at the NHLBI/NIH, the Mayo Clinic, the Johns Hopkins Hospital, and Nagoya Japan, providing them with the expertise to conduct a variety of different transplant approaches, including PBSC transplants from HLA-matched relatives, unrelated cord blood transplants, haploidentical transplants, and CD34 selected stem cell transplants. Patient characteristics were varied among all groups. The number of allogeneic and autologous transplants performed at the NIHBT has increased steadily every year since the initiation of our transplant program. By 2022, 547 transplant procedures had been performed, including 268 autologous and 279 allogeneic transplants. Allogeneic transplants were performed for both malignant and nonmalignant hematological diseases, with acute leukemia (AL) being the most common indication for allogeneic HCT. The majority of recipients undergoing allogeneic transplantation received G-CSF mobilized PBSC allografts from either HLA identical or haplo-identical relatives, with a smaller percentage of patients receiving a UCB transplant or a PBSC allograft that had been CD34+ selected. Amongst the 279 recipients of an allogeneic transplant, mortality rates within day 100 and beyond day 100 were 12.6% and 26.2% respectively. Overall survival (OS) and event-free survival at 5 years in benign and malignant subgroups were 81% and 73% vs 52% and 48% respectively. Through collaboration with international transplant experts, the National Institute of Hematology and Blood Transfusion in Hanoi has stood up the most active transplant center in the northern region of Vietnam. Patients coming from low-income financial backgrounds are now able to receive a variety of different state-of-the-art transplant approaches that are affordable and have been associated with excellent long-term outcomes.

AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

POSTER: AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

POSTER: AML-521 The Randomized Phase III SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) Trial: Successful Allogeneic Hematopoietic Stem Cell Transplantation Using Treatment With Iomab-B-Led Regimen for Patients With Active, Relapsed or Refractory AML With Failed Targeted Therapies

Successful allogeneic hematopoietic stem cell transplantation in a patient with type I CD36 deficiency: a case study and literature review.

CD36-deficient individuals may produce anti-CD36 antibodies through antigenic exposure to CD36, in situations including blood transfusions. Therefore, allogeneic hematopoietic stem cell transplantation (HSCT) from CD36-positive donors to CD36-negative patients remains a challenge. A 64-year-old man with acute myeloid leukemia became refractory to platelet transfusions during chemotherapy. Anti-CD36 antibodies without anti-HLA antibodies were detected in serum, and the absence of CD36 expression on platelets and monocytes confirmed type I CD36 deficiency. The patient achieved complete remission, and received maintenance therapy with CD36-negative platelet transfusions. However, he relapsed soon afterward, and thus underwent peripheral blood stem cell transplantation (PBSCT) from a CD36-positive unrelated donor. The anti-CD36 antibody titer had decreased before the transplant, and the PBSCT-course was uneventful. The patient has been well without any complications associated with CD36 status mismatch. The few reports of allogeneic HSCT in patients with CD36 deficiency have suggested that anti-CD36 antibodies could be involved in several post-transplant complications, such as delayed platelet recovery, transfusion refractoriness, and transfusion-related acute lung injury. Our present case confirmed that stem cell transplantation from CD36-positive donors to negative patients is feasible, when it includes careful prior assessment of anti-CD36 antibody titers and interventions to attenuate them.

Successful Treatment of a Child with Hemoglobin Hammersmith with Hematopoietic Stem Cell Transplantation

Hemoglobin (Hb) Hammersmith, formed by serine substitution for phenylalanine at residue 42 in the beta-globin chain, is a very rare variant of unstable hemoglobin with low oxygen affinity. For patients with hemoglobinopathies, it is well-established that hematopoietic stem cell transplantation provides a complete cure, but the literature on its role for those with Hb Hammersmith is limited. A seven-month-old girl who was examined for anemia and splenomegaly was followed up for congenital hemolytic anemia. The patient with visible cyanosis of the lips and whose p50 was low in blood gas was diagnosed with Hb Hammersmith through the DNA sequence analysis. During the follow-up, frequent blood transfusions had to be given due to anemia aggravated by infections. Following a successful hematopoietic stem cell transplant from an HLA-matched sibling, the patient completely recovered from Hb Hammersmith. The case is presented because of its rarity.