Publications by authors named "Polina Stepensky"

117 Publications

Evaluation of gastrointestinal symptoms in pediatric patients post hematopoietic stem cell transplantation: Ileo-colonoscopy versus sigmoidoscopy. A single-center experience and review of literature.

Pediatr Blood Cancer 2021 Jul 15:e29235. Epub 2021 Jul 15.

Department of Bone Marrow Transplant and Cancer Immunotherapy, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.

Background: Hematopoietic stem cell transplantation (HSCT) is a curative therapy used to treat high-risk hematological malignant disorders and other life-threatening nonmalignant diseases. Gastrointestinal (GI) symptoms post-HSCT might be due to GI graft-versus-host disease (GVHD) or GI infections or both. GI endoscopy with biopsies is safe and beneficial in guiding the management of GI symptoms in children after HSCT, justifying the therapeutic management and contributing to improved outcomes.

Methods: A retrospective cohort study including 16 children with malignant and nonmalignant diseases that underwent allogeneic HSCT who had 24 ileo-colonoscopies performed for GI symptoms. To facilitate an evidence-based approach to the endoscopic evaluation of GI symptoms in pediatric patients post HSCT, we examined whether a full ileo-colonoscopy, which includes right colon and terminal ileum (TI), as opposed to a limited sigmoidoscopy, was more accurate in the evaluation of GI symptoms in pediatric patients post HSCT.

Results: Specific findings on the right colon/TI were found in nine out of 24 ileo-colonoscopies (38%, CI = 19%-59%). The macroscopic findings on ileo-colonoscopy were compared with the histopathologic findings. When macroscopic findings were present, there were matching histopathologic findings in 100% of cases. However, even in the absence of any macroscopic findings on ileo-colonoscopy, there were histopathological findings in 29% of the cases (p-value = .016).

Conclusions: This cohort favors ileo-colonoscopy over sigmoidoscopy, with systematic biopsy sampling, in evaluating GI symptoms in pediatric patients post HSCT.
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http://dx.doi.org/10.1002/pbc.29235DOI Listing
July 2021

Toxicity and efficacy of chimeric antigen receptor T-cell in patients with diffuse large B cell lymphoma above the age of 70 years compare to younger patients - a matched control multi-center cohort study.

Haematologica 2021 Jul 8. Epub 2021 Jul 8.

BMT Unit, Aviv (Sourasky) Medical Center, Aviv, Israel; Sackler Faculty of Medicine, Aviv University, Aviv.

Data regarding efficacy and toxicity of Chimeric antigen receptor T cells (CAR-T) therapy in older aged -geriatric population are insufficient. Since 2019, Tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory (R/R) DLBCL. From May 2019, 47 R/R DLBCL patients, ≥70 years underwent lymphopharesis in 3 Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG-PS and LDH levels. There were no differences in CD4/CD8 ratio (p=.94), %CD4naiive (p=.92), %CD8 naive (p=.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T products in both cohorts. Forty-one elderly patients (87%) received CAR-T infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (p=.29), grade≥3 neurotoxicity (p=.54), and duration of hospitalization (p=.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (p=.145). Response rates were similar between the 2 groups (CR-46% and PR-17% in the elderly group, p=.337). Non-relapse-mortality at 1 and 3 months was 0 in both groups. With a median follow up of 7 (range, 1.3-17.2) months, 6- and 12-months progression-free and overall survival in elderly were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly vs younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between older aged-geriatric and younger patients, indicating that age as per se should not preclude CAR-T administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.
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http://dx.doi.org/10.3324/haematol.2021.278288DOI Listing
July 2021

Characterization of a L136P mutation in Formin-like 2 (FMNL2) from a patient with chronic inflammatory bowel disease.

PLoS One 2021 27;16(5):e0252428. Epub 2021 May 27.

Institute of Pharmacology, University of Marburg, Marburg, Germany.

Diaphanous related formins are highly conserved proteins regulated by Rho-GTPases that act as actin nucleation and assembly factors. Here we report the functional characterization of a non-inherited heterozygous FMNL2 p.L136P mutation carried by a patient who presented with severe very early onset inflammatory bowel disease (IBD). We found that the FMNL2 L136P protein displayed subcellular mislocalization and deregulated protein autoinhibition indicating gain-of-function mechanism. Expression of FMNL2 L136P impaired cell spreading as well as filopodia formation. THP-1 macrophages expressing FMNL2 L136P revealed dysregulated podosome formation and a defect in matrix degradation. Our data indicate that the L136P mutation affects cellular actin dynamics in fibroblasts and immune cells such as macrophages.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252428PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158924PMC
May 2021

Eltrombopag for enhancement of platelet engraftment in patients undergoing allogeneic cord blood transplantation.

Leuk Lymphoma 2021 May 20:1-8. Epub 2021 May 20.

Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel.

Platelet recovery after allogeneic umbilical cord blood (UCB) transplantation is delayed compared to other graft sources. We conducted a multicenter phase 2a study to explore whether eltrombopag, a thrombopoietin-receptor agonist, would enhance platelet recovery after UCB transplantation. Between 02/2013 and 07/2016, 12 (10 adults, 2 children) individuals (median age 50; range 6-74 years) with hematological malignancies in complete remission were enrolled. Eltrombopag was given for a median of 76 (range 15-175) days and was safe even at doses of 300 mg/day. Median time to neutrophil engraftment was 23 (range 16-40) days. Median time to platelets >20,000/µl and >50,000/µl was 55 (range 25-199) and 66 (range 31-230) days, respectively. A historical cohort comparison did not reveal an advantage for eltrombopag. In conclusion, in the present study eltrombopag seems safe. Based on our limited data, it seems unlikely that eltrombopag could enhance platelet engraftment after UCB transplantation.
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http://dx.doi.org/10.1080/10428194.2021.1929957DOI Listing
May 2021

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders.

Bone Marrow Transplant 2021 May 9. Epub 2021 May 9.

Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

Graft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m, treosulfan 20-24 g/m and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7-95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15-61) and 39 days (15-191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.
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http://dx.doi.org/10.1038/s41409-021-01323-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106764PMC
May 2021

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

J Clin Immunol 2021 Apr 30. Epub 2021 Apr 30.

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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http://dx.doi.org/10.1007/s10875-021-01031-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086229PMC
April 2021

Improved transplant outcomes with myeloablative conditioning for hemophagocytic lymphohistiocytosis in HLA-matched and mismatched donors: a national multicenter retrospective study.

Bone Marrow Transplant 2021 Apr 12. Epub 2021 Apr 12.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

We report the results of national retrospective study of 45 children with hemophagocytic lymphohistiocytosis (HLH) who underwent allogeneic hematopoietic stem-cell transplantation (HSCT) in Israel between the years 2000-2018. Donors were either HLA-matched (n = 26), partially mismatched (n = 7), haploidentical (n = 8), or cord-blood (n = 4). Myeloablative conditioning (MAC) was used in 20 procedures, and reduced-intensity conditioning (RIC) in 25. Forty-two patients engrafted, two had primary graft failure (one successfully retransplanted), one died prior to engraftment, and two developed secondary graft failure. Of the eight patients who had mixed donor chimerism at day 30 (5-95%), five achieved stable mixed or full donor chimerism. The 5-year probabilities of overall survival and event-free survival (EFS) were 86% and 82%, respectively. Five-year EFS was lower for patients receiving RIC compared to MAC (72% vs. 100%, p = 0.018) and following alternative-donor transplant (68% vs. 92% for HLA-matched donors, p = 0.034), mostly due to increased transplant-related mortality (TRM). Thus, both HLA-matched and alternative donor transplant procedures may benefit form a myeloablative conditioning regimen.
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http://dx.doi.org/10.1038/s41409-021-01290-1DOI Listing
April 2021

Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions.

Cancer Immunol Res 2021 Mar 24. Epub 2021 Mar 24.

Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel.

SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6 had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6 expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0800DOI Listing
March 2021

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

Blood Adv 2021 01;5(1):262-273

Pediatric Hematology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805328PMC
January 2021

A human case of GIMAP6 deficiency: a novel primary immune deficiency.

Eur J Hum Genet 2021 Apr 16;29(4):657-662. Epub 2020 Dec 16.

Hadassah University Medical Center, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Jerusalem, Israel.

The GTPase of immunity-associated proteins (GIMAPs) are a family of genes believed to contribute to lymphocyte development, signaling, and apoptosis, thus playing an important role in immune system homeostasis. While models of gene derangement have been described in both mice and immortalized cell lines, human examples of these diseases remain exceptionally rare. In this manuscript we describe the first documented human cases of a homozygous deleterious GIMAP6 variant in the GIMAP6 gene and their subsequent clinical and immunological phenotype. In order to interrogate the patients' immune defect, we performed whole-exome sequencing, western blot, flow cytometry analysis, lymphocyte activation and proliferation studies, cytokine release assays, and apoptosis studies. We found two siblings with a predicted deleterious homozygous variant in the GIMAP6 gene with no expression of GIMAP6 protein on western blot. Patients demonstrated accelerated apoptosis, but largely normal lymphocyte subpopulations, activation and proliferation and cytokine release. There appears to be a spectrum of clinical features associated with deficiency of GIMAP6 protein, with one patient suffering lymphopenia and recurrent sinopulmonary infections, and the other clinically asymptomatic. Biallelic variants in the GIMAP6 gene have now been shown to demonstrate disease in humans. The absence of GIMAP6 protein is associated with a spectrum of clinical manifestations and much remains to be learnt about the pathogenic mechanisms underlying this disease. We suggest that biallelic variants in the gene for GIMAP6 should be considered in children with lymphopenia and recurrent sinopulmonary infections.
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http://dx.doi.org/10.1038/s41431-020-00773-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739214PMC
April 2021

How we approach malignant infantile osteopetrosis.

Pediatr Blood Cancer 2021 03 12;68(3):e28841. Epub 2020 Dec 12.

Faculty of Medicine, Hebrew University of Jerusalem, Israel, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel.

Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder characterized by excessive bone overgrowth due to a defect in bone marrow resorption by osteoclasts. In most cases, hematopoietic stem cell transplantation (HSCT) may correct bone metabolism but the rapidly progressing nature of this condition necessitates early diagnosis and prompt treatment to minimize irreversible cranial nerve damage. The management of patients with MIOP presents many unique challenges. In this review, the clinical management of patients with MIOP is discussed, including diagnosis, preparation for HSCT and special transplant considerations, management of unique HSCT complications, and long-term follow-up.
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http://dx.doi.org/10.1002/pbc.28841DOI Listing
March 2021

Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation.

J Clin Immunol 2021 Jan 27;41(1):147-162. Epub 2020 Oct 27.

Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients.

Methods: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019.

Results: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective.

Conclusion: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.
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http://dx.doi.org/10.1007/s10875-020-00892-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591244PMC
January 2021

Haploidentical stem cell transplantation with post-transplant cyclophosphamide for osteopetrosis and other nonmalignant diseases.

Bone Marrow Transplant 2021 02 27;56(2):434-441. Epub 2020 Aug 27.

Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for a variety of nonmalignant disorders including osteopetrosis, bone marrow failures, and immune deficiencies. Haploidentical HSCT is a readily available option in the absence of a matched donor, but engraftment failure and other post-transplant complications are a concern. Post-transplant cyclophosphamide (PT-Cy) regimens are gaining popularity and recent reports show promising results. We report our experience with nine pediatric patients with nonmalignant diseases who were transplanted from a haploidentical donor with PT-Cy. From 2015 to 2019, nine children with nonmalignant diseases underwent haploidentical HSCT with PT-Cy, two as a second transplant and seven as primary grafts after upfront serotherapy and busulfan-based myeloablative conditioning. Patient's diseases included osteopetrosis (n = 5), congenital amegakaryocytic thrombocytopenia (n = 2), hemophagocytic lymphohistiocytosis (n = 1), and Wiskott Aldrich syndrome (n = 1). Two patients failed to engraft following upfront PT-Cy transplants, one was salvaged with a second PT-Cy transplant, and the other with a CD34+ selected graft. None of the patients suffered from graft-versus-host disease. Three patients died from early posttransplant infectious complications and six patients are alive and well. In conclusion, haploidentical HSCT with PT-Cy is a feasible option for pediatric patients with nonmalignant diseases lacking a matched donor.
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http://dx.doi.org/10.1038/s41409-020-01040-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450679PMC
February 2021

A mutation in POLR3E impairs antiviral immune response and RNA polymerase III.

Proc Natl Acad Sci U S A 2020 09 25;117(36):22113-22121. Epub 2020 Aug 25.

Microbiology and Molecular Genetics, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel;

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.
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http://dx.doi.org/10.1073/pnas.2009947117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486780PMC
September 2020

Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults.

Blood 2020 09;136(10):1201-1211

División of Pediatric Hematology and Oncology, Department of Pediatrics, Erciyes University, Kayseri, Turkey.

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
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http://dx.doi.org/10.1182/blood.2020005590DOI Listing
September 2020

Skeletal Changes After Hematopoietic Stem Cell Transplantation in Osteopetrosis.

J Bone Miner Res 2020 09 12;35(9):1645-1651. Epub 2020 Jul 12.

Pediatric Orthopedics Unit, Assuta Ashdod Medical Center, Ashdod, Israel.

Osteopetrosis is a rare skeletal dysplasia resulting from an osteoclast defect leading to increased bone mass and density. Hematopoietic stem cell transplantation can rescue the disease phenotype and prevent complications. However, little is known about the skeletal changes hematopoietic stem cell transplantation induces in patients with this disease. The purpose of this study was to describe the skeletal changes after hematopoietic stem cell transplantation in a retrospective cohort of patients diagnosed with osteopetrosis in one medical center over 13 years. For this purpose, all available epidemiological, hematological, biochemical, and radiographic data were collected and quantitatively analyzed. We found a significant early change in bone metabolism markers coinciding with hematopoietic recovery after stem cell transplantation. Hematopoietic stem cell transplantation induced a later significant improvement in both skeletal mineral distribution and morphology but did not lead to complete radiological normalization. Presumably, changes in bone metabolism, skeletal mineral distribution, and morphology were the result of renewed osteoclast function enabling bone remodeling. We propose that biochemical bone metabolism markers and radiological indices be routinely used to evaluate response to hematopoietic stem cell transplantation in patients with osteopetrosis. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4037DOI Listing
September 2020

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

J Allergy Clin Immunol 2020 10 9;146(4):901-911. Epub 2020 Apr 9.

Primary Immunodeficiencies Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.

Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.

Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling.

Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.

Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
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http://dx.doi.org/10.1016/j.jaci.2019.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246418PMC
October 2020

Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice.

Bone 2020 07 8;136:115360. Epub 2020 Apr 8.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease.
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http://dx.doi.org/10.1016/j.bone.2020.115360DOI Listing
July 2020

Enterococcal Bacteremia in Children With Malignancies and Following Hematopoietic Stem Cell Transplantation: A 15-Year Single-Center Experience.

Pediatr Infect Dis J 2020 04;39(4):318-324

From the Pediatric Infectious Diseases.

Background: Data on enterococcal bacteremia (EB) in immunocompromised children are scarce. We aimed to describe EB in children with hematologic malignancies (HM), solid tumors and/or following allogeneic hematopoietic stem cell transplantation (HSCT) and analyze their ampicillin and vancomycin resistance.

Methods: We conducted an observational retrospective study in the tertiary-care Hadassah University Medical Center (2001-2015). We collected demographic, clinical and laboratory data on EB and compared ampicillin and vancomycin sensitive with resistant episodes.

Results: Fifty-six of 1123 children developed 74 episodes of EB; 62.1% Enterococcus faecium, 36.5% Enterococcus faecalis; and 1.4% Enterococcus gallinarum. EB developed in 12.1% of HSCT patients, 5.1% of HM, 6.3% of neuroblastoma and 1.0% of other solid tumors patients. Of these episodes, 85.1% were nosocomial, and 71.6% developed while on antibiotic therapy. Resistance rates were: to ampicillin, 57.6%; to vancomycin (vancomycin-resistant enterococci), 21.6%; and higher rates among E. faecium. Among vancomycin-resistant enterococci, 1 of 16 was linezolid and 2 of 10 daptomycin resistant. Overall 7- and 30-day mortality rates were 2.7% and 5.4%, respectively. Thirty-day mortality was 18.2% in recurrent episodes and 0% in the first-time EB episodes (P = 0.006). In multivariate analysis, high treatment intensity was associated with ampicillin resistance [odds ratio (OR) = 3.18, 95% confidence interval (CI): 1.31-9.12], prior penicillin exposure (OR = 7.50, 95% CI: 1.41-39.81) and breakthrough on vancomycin (OR = 18.83, 95% CI: 3.31-101.14) with vancomycin resistance.

Conclusions: EB occurs mainly as a nosocomial infection in children receiving high-intensity chemotherapy, especially in those with neuroblastoma, HM and following HSCT. Antibiotic resistance is common. Vancomycin resistance can occur regardless of previous vancomycin use. Prognosis in immunocompromised children with EB is better than previously reported. Recurrent EB is associated with increased mortality.
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http://dx.doi.org/10.1097/INF.0000000000002579DOI Listing
April 2020

Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis.

Haematologica 2021 01 1;106(1):74-86. Epub 2021 Jan 1.

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute.

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis.
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http://dx.doi.org/10.3324/haematol.2019.238261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776247PMC
January 2021

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

J Allergy Clin Immunol 2020 05 27;145(5):1452-1463. Epub 2019 Dec 27.

Department of Bone Marrow Transplantation, Hadassah, Hebrew University Medical Centre, Jerusalem, Israel.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.

Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.

Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.

Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.

Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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http://dx.doi.org/10.1016/j.jaci.2019.12.896DOI Listing
May 2020

Skin toxicity following treosulfan-thiotepa-fludarabine-based conditioning regimen in non-malignant pediatric patients undergoing hematopoietic stem cell transplantation.

Pediatr Transplant 2020 02 15;24(1):e13626. Epub 2019 Dec 15.

Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of treosulfan-thiotepa-fludarabine and ATG for pediatric non-malignant diseases. As we often observe acute skin toxicities following this conditioning regimen, we conducted a prospective observational study to describe and characterize these toxicities. Fifteen pediatric patients undergoing HSCT for non-malignant diseases who were treated at Hadassah-Hebrew University Medical Center during 2015 were enrolled. A thorough dermatological assessment was done on days 0, 1, 7, and 14 from treatment initiation and included description of cutaneous reactions, measurement of BSA of affected skin, and response to local treatment. All the fifteen enrolled patients developed some degree of acute skin reaction. Cutaneous manifestations were variable and included erythematous patches in inguinal area and genitalia (80%), in neck and axillae (40%), diffuse hyperpigmentation (73%), erosions in inguinal area and buttock (47%), and xerosis and desquamation (40%). Average affected BSA reached 71.8%. Erosions were more prevalent in children younger than 2 years of age. The eruptions resolved without sequela in all patients and did not necessitate treatment other than topical agents. Observed extracutaneous toxicities included oral mucositis (40%), diarrhea (47%), and elevated liver enzymes (47%). TBC combined with thiotepa is highly toxic to the skin with various cutaneous manifestations. The toxicity resolves with no long-term sequela.
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http://dx.doi.org/10.1111/petr.13626DOI Listing
February 2020

The Evidence for Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Neutrophil Disorders: A Comprehensive Review by the Inborn Errors Working Party Group of the EBMT.

Front Pediatr 2019 24;7:436. Epub 2019 Oct 24.

Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel.

Congenital disorders of the immune system affecting maturation and/or function of phagocytic leucocytes can result in severe infectious and inflammatory complications with high mortality and morbidity. Further complications include progression to MDS/AML in some cases. Allogeneic stem cell transplantation is the only curative treatment for most patients with these diseases. In this review, we provide a detailed update on indications and outcomes of alloHSCT for congenital neutrophil disorders, based on data from the available literature.
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http://dx.doi.org/10.3389/fped.2019.00436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821686PMC
October 2019

The Broad Clinical Spectrum and Transplant Results of PNP Deficiency.

J Clin Immunol 2020 01 9;40(1):123-130. Epub 2019 Nov 9.

Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose: Purine nucleoside phosphorylase (PNP) is a known yet rare cause of combined immunodeficiency with a heterogeneous clinical presentation. We aim to add to the expanding clinical spectrum of disease, and to summarize the available data on bone marrow transplant for this condition.

Methods: Data was collected from patient files retrospectively. A review of the literature of hematopoietic stem cell transplantation (HSCT) for PNP deficiency was conducted.

Results: Four patients were treated in two centers in Israel. One patient died of EBV-related lymphoma with CNS involvement prior to transplant. The other three patients underwent successful HSCT with good immune reconstitution post-transplant (follow-up 8-108 months) and excellent neurological outcomes.

Conclusion: PNP is a variable immunodeficiency and should be considered in various clinical contexts, with or without neurological manifestations. HSCT offers a good treatment option, with excellent clinical outcomes, when preformed in a timely manner.
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http://dx.doi.org/10.1007/s10875-019-00698-1DOI Listing
January 2020

Allogeneic stem-cell transplantation with sequential conditioning in adult patients with refractory or relapsed acute lymphoblastic leukemia: a report from the EBMT Acute Leukemia Working Party.

Bone Marrow Transplant 2020 03 27;55(3):595-602. Epub 2019 Sep 27.

EBMT Paris Office, CEREST-TC, Department of Hematology, Saint Antoine Hospital, Paris, France.

Treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) remains a clinical challenge with generally dismal prognosis. Allogeneic stem-cell transplantation using sequential conditioning ("FLAMSA"-like) has shown promising results in relapsed/refractory acute myeloid leukemia, but little is known about its efficacy in RR-ALL. We identified 115 patients (19-66 years) with relapsed (74%) or primary-refractory (26%) ALL allografted from matched related (31%), matched unrelated (58%), or haploidentical donor (11%). Median follow-up was 37 (13-111) months. At day 100, cumulative incidences of grade II-IV/III-IV acute graft-versus-host-disease (GVHD) were 30% and 17%, respectively. Two-year cumulative incidence of chronic GVHD was 25% with 11% extensive cases. Two-year relapse incidence (RI) was 45%, non-relapse mortality was 41%. Two-year leukemia free survival (LFS) was 14%, overall survival (OS) 17%, and GVHD relapse-free survival (GRFS) was 14%. In multivariable analysis, Karnofsky score <90 negatively affected RI, LFS, OS, and GRFS. Conditioning with chemotherapy alone, compared with total body irradiation (TBI) negatively affected RI (HR = 3.3; p = 0.008), LFS (HR = 1.94; p = 0.03), and OS (HR = 2.0; p = 0.03). These patients still face extremely poor outcomes, highlighting the importance of incorporating novel therapies (e.g., BITE antibodies, inotuzumab, CAR-T cells). Nevertheless, patients with RR-T-cell ALL remain with an unmet treatment need, for which TBI-based sequential conditioning could be one of few available options.
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http://dx.doi.org/10.1038/s41409-019-0702-2DOI Listing
March 2020

Successful treatment with daratumumab for post-HSCT refractory hemolytic anemia.

Pediatr Blood Cancer 2020 01 22;67(1):e28010. Epub 2019 Sep 22.

Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Autoimmune cytopenias (AIC) following allogeneic hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality and are often challenging to treat. We present a case of a pediatric patient with primary myelofibrosis of infancy caused by VPS45 protein deficiency, who developed severe refractory hemolytic anemia and immune-mediated thrombocytopenia 3.5 months following HSCT. After the failure of several treatments, he received daratumumab, an anti-CD38 specific antibody, and demonstrated fast and sustained response. The only side effect was delayed recovery of humoral immunity. Daratumumab, by targeting antibody-producing plasma cells, may be a valid treatment option for refractory post-HSCT AIC.
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http://dx.doi.org/10.1002/pbc.28010DOI Listing
January 2020

Gram-negative Bacteremia in Children With Hematologic Malignancies and Following Hematopoietic Stem Cell Transplantation: Epidemiology, Resistance, and Outcome.

J Pediatr Hematol Oncol 2019 Nov;41(8):e493-e498

Pediatric Infectious Diseases Unit.

Gram-negative rod (GNR) infections adversely affect the outcome of patients with malignancies and following hematopoietic stem cell transplantation (HSCT). This retrospective observational study aimed to describe the epidemiology, outcome, and resistance patterns of GNR bacteremia in children with hematologic malignancies (HM) and after HSCT during the period spanning from 2010 to 2014 in a tertiary children's hospital. A total of 270 children were included in the analysis; 65 (24%) developed 85 episodes of GNR bacteremia; the rate was 36/122 (29.5%) in post-HSCT and 29/178 (16.3%) in HM patients (P<0.05). Overall, 10% of the GNRs were carbapenem resistant. In multivariate analysis, prolonged neutropenia (≥7 d; odds ratio: 19.5, 95% confidence interval: 2.6-148.4) and total hospitalization for a duration of >30 days in the last 3 months (odds ratio: 17.5, 95% confidence interval: 1.4-224.4) were associated with carbapenem-resistant GNR bacteremia. Thirty-day mortality following GNR bacteremia was 0% in HM and 7/52 episodes (13.5%) in HSCT patients (P<0.05). Carbapenem-resistant versus carbapenem-sensitive bacteremia was associated with longer duration of bacteremia (mean: 3.8 vs. 1.7 d), higher risk for intensive care unit hospitalization (44.4% vs. 10.1%), and higher mortality rate (33% vs. 5.8%) (P<0.05). To summarize, GNR bacteremia was frequent, especially in post-HSCT children. Carbapenem resistance adversely affects patients' outcome, increasing morbidity and mortality. Empirical antibiotic therapy must be adjusted to the local resistance patterns.
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http://dx.doi.org/10.1097/MPH.0000000000001556DOI Listing
November 2019

Primary Cutaneous Clonal CD8+ T-Cell Lymphoproliferative Disorder Associated With Immunodeficiency due to RAG1 Mutation.

Am J Dermatopathol 2020 Jan;42(1):e11-e15

Department of Dermatology, Rambam Medical Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8 lymphocytic infiltrates and cutaneous CD8 granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8 T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8 T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.
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http://dx.doi.org/10.1097/DAD.0000000000001492DOI Listing
January 2020

Lymphocyte counts may predict a good response to mesenchymal stromal cells therapy in graft versus host disease patients.

PLoS One 2019 12;14(6):e0217572. Epub 2019 Jun 12.

Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Steroid-resistant GvHD is one of the most significant causes of mortality following allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Treatment with mesenchymal stromal cells (MSC) seems to be a promising solution, however the results from clinical studies are still equivocal. Better selection of candidate patients and improving monitoring of patients following MSC administration can increase treatment effectiveness. In order to determine which characteristics can be used to predict a good response and better monitoring of patients, blood samples were taken prior to therapy, one week and one month after therapy, from 26 allogeneic HSCT patients whom contracted GvHD and were treated with MSCs. Samples were examined for differential blood counts, bilirubin levels and cell surface markers. Serum cytokine levels were also measured. We found that the level of lymphocytes, in particular T and NK cells, may predict a good response to therapy. A better response was observed among patients who expressed low levels of IL-6 and IL-22, Th17 related cytokines, prior to therapy. Patients with high levels of bilirubin prior to therapy showed a poorer response. The results of this study may facilitate early prediction of success or failure of the treatment, and subsequently, will improve selection of patients for MSC therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217572PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561566PMC
February 2020

Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years.

Blood Adv 2019 03;3(6):862-868

Department of Pediatrics and Adolescent Medicine.

Osteopetrosis (OP) is a rare disease caused by defective osteoclast differentiation or function. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available in the infantile "malignant" form of OP. Improved clinical and genetic diagnosis of OP has seen the emergence of a cohort of patients with less severe and heterogeneous clinical presentations. This intermediate form of OP does not call for urgent intervention, but patients accumulate debilitating skeletal complications over years and decades, which are severe enough to require curative treatment and may also require intermittent transfusion of blood products. Here we present data from 7 patients with intermediate OP caused by mutations in (n = 2), (n = 2), (n = 1), (n = 1), and (n = 1), who were transplanted between the ages of 5 to 30 years (mean, 15; median, 12). Donors were matched siblings or family (n = 4), matched unrelated (n = 2), or HLA haploidentical family donors (n = 1). Conditioning was fludarabine and treosulfan based. All 6 patients transplanted from matched donors are currently alive with a follow-up period between 1 and 8 years at time of publication (median, 4 years) and have demonstrated a significant improvement in symptoms and quality of life. Patients with intermediate OP should be considered for HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2018025890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436016PMC
March 2019