Two decades of stem cell transplantation in patients with Fanconi anemia: Analysis of factors affecting transplant outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for the hematological complications of patients with Fanconi anemia (FA). Over the last two decades, HSCT outcomes have improved dramatically following the development of regimens tailored for FA patients. In this study, we analyzed genetic, clinical, and transplant data of 41 patients with FA who underwent HSCT at Hadassah Medical Center between November 1996 and September 2020. Overall survival (OS) was 82.9% with a median follow-up time of 2.11-years (95% CI, .48-16.56). Thirteen patients (31.7%) developed acute graft-versus-host disease (GVHD), three of them with grades 3-4. Nine patients developed chronic GVHD, five had extensive disease. Twelve patients (29.3%) developed stable mixed-chimerism with complete resolution of bone marrow failure (BMF); none of them had acute nor chronic GVHD. Significantly higher GVHD rates were observed in transplants from peripheral blood stem cell grafts as compared to other stem cell sources (p = .002 for acute and p = .004 for chronic GVHD). Outcome parameters were comparable between HSCT from matched-sibling (n = 20) to other donors (n = 21), including survival rates (p = .1), time to engraftment (p = .69 and p = .14 for neutrophil and platelet engraftment time, respectively), chimerism status (p = .36 and p = .83 for full-donor and mixed chimerism, respectively), and GVHD prevalence (p = 1). Our results demonstrate the vast improvements in HSCT outcomes of patients with FA, narrowing the gap between matched-sibling versus alternative donor transplantations. Our data identifies factors that may significantly affect transplant outcomes such as graft source and chimerism status.

High rate of adenovirus detection in gastrointestinal biopsies of symptomatic stem cell transplant recipients.

OBJECTIVES: The gastrointestinal (GI) tract is a major human adenovirus (HAdV) replication site in patients undergoing hematopoietic stem cell transplantation (HSCT), yet the prevalence and correlates of HAdV GI infection in this setting have remained poorly recognized, especially among adult HSCT recipients. DESIGN OR METHODS: We retrospectively studied the prevalence and risk factors of HAdV GI-tissue infection in HSCT recipients (73 adults and 15 children) with GI symptoms who underwent GI-tissue biopsy between January-2012 and December-2017. The presence of HAdV in the GI tissues was determined by real-time PCR. RESULTS: HAdV GI-tissue infection was detected in 21 (23.9%) patients, with similar infection rates identified in adults and children. GI-tissue detection was more common at late (>100 days) compared to early times post-transplantation (50% vs. 12.9%, p < .001). The presence of bloody diarrhea, Arab ethnicity (p = .014) and concurrent cytomegalovirus GI-tissue detection (p = .025) were significantly correlated with HAdV GI-tissue infection, while chronic graft versus host disease was of borderline association (p = .055). CONCLUSIONS: Our findings reveal a high rate and new clinical-demographic correlates of HAdV GI-tissue infection in adult and pediatric HSCT recipients with GI symptoms. The findings highlight the need for future prospective studies to assess the relatedness of HAdV infection to the GI symptoms, and the prevalence, impact, and treatment of HAdV GI infection in HSCT recipients.

Vedolizumab for pediatric patients with gastrointestinal acute graft-versus-host-disease.

Vedolizumab, an anti-α4ß7 integrin monoclonal antibody, impairs homing of T-cells to the gastrointestinal (GI) endothelium and acts as a gut-selective anti-inflammatory agent. Recent reports of the efficacy of vedolizumab in treating lower GI acute graft-versus-host disease (aGVHD) are promising, but experience in children is scarce. We present a cohort of 13 pediatric patients who were treated with vedolizumab for GI aGVHD. Ten of the patients were treated for steroid-refractory disease, out of which, six suffered from severe (stage 3 or 4) GI disease before the first dose of vedolizumab. In the other three patients, vedolizumab was introduced early in the disease course. Median time between GI GVHD onset to vedolizumab treatment was 23 days (range 7-59 days), with a median of 3 doses (range 1-5) per patient. GI GVHD staging was evaluated at various time points after the first vedolizumab dose, showing improvement in nine of the 13 patients. After a median follow-up time of 13 months (range 6-34 months), eight patients completely recovered, two had ongoing chronic colitis, and three patients died. During the vedolizumab treatment period, 38 infectious episodes were noted, most of them GI related. The unique activity profile of vedolizumab makes it an appealing treatment option for lower GI aGVHD, but caution for concurrent infections is warranted.

[STEM CELL TRANSPLANTATIONS FOR PATIENTS WITH FANCONI ANEMIA: AN ISRAELI TERTIARY CENTER EXPERIENCE].

INTRODUCTION: Fanconi anemia (FA) is a rare genetic syndrome characterized by increased chromosomal breakage, congenital anomalies, bone marrow failure and an increased tendency to develop malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure and the hematologic malignancies these patients develop. Given the sensitivity of FA patients to chemotherapy and radiation, as to the clinical symptoms of graft versus host disease (GvHD), HSCT in these patients is challenging. Since the mid-nineties, HSCT for FA patients is performed in our center by using the fludarabine based reduced-intensity protocol. AIMS: To summarize the results of HSCT for patients with FA using a fludarabine based reduced-intensity conditioning regimen at the Hadassah Medical Center. METHODS: This retrospective research is based on the collection and analysis of clinical and laboratory data from the medical records of patients. RESULTS: Since June 1996 up till February 2020, 39 patients with FA underwent 43 HSCTs with a fludarabine based protocol at the Hadassah Medical Center. Four patients required a second transplant due to primary engraftment failure. Nine patients (23%) suffered from acute GvHD, four of them severe. Eight patients (20%) developed chronic GvHD, two with an extensive and debilitating disease. Thirty-three (85%) of the patients survived and six died, five shortly after the transplant, and one twenty years later from malignancy. CONCLUSIONS: Our results show high survival rates with low rates of engraftment failure and reasonable rates of GvHD. DISCUSSION: As of today, there is an effective and safe treatment for patients with FA who require HSCT by using a fludarabine-based reduced-intensity conditioning regimen, with high survival rates and few complications.

[SURVIVAL OF PEDIATRIC PATIENTS WITH NON-MALIGNANT DISEASES REQUIRING HOSPITALIZATION IN THE INTENSIVE CARE UNIT FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION AND RISK FACTORS FOR MORTALITY].

INTRODUCTION: Although Hematopoietic Stem Cell Transplantation (HSCT) is the only curative option for children with certain non-malignant disorders, a proportion of these children are admitted to the Pediatric Intensive Care Unit (PICU) due to treatment related life-threatening complications. AIMS: To analyze risk factors for ICU hospitalizations, morbidity and mortality in children with genetic diseases who have undergone HSCT and were admitted to intensive care units. METHODS: This retrospective study is based on the collection and analysis of clinical and laboratory data from the medical records of patients from the departments of Bone Marrow Transplantations and Intensive Care, from 2 hospitals, Hadassah and Rambam Medical Centers. RESULTS: Over the course of 15 years (2005-2019), 463 HSCT were performed for pediatric patients with non-malignant diseases, 68 of them (15%) required hospitalization in Intensive Care Units (ICU), 41% of the patients survived. The PICU mortality rate has decreased over the last years. Factors found to have a significant negative impact on PICU survival were severe neutropenia at admission to ICU, mechanical ventilation, inotropic support, and Multi Organ Failure (MOF). CONCLUSIONS: Our results showed low incidence of ICU admissions and relatively high survival rate for pediatric patients with non-malignant disorders post HSCT, comparing with literature data.

Survival of pediatric patients requiring admission in the intensive care unit post hematopoietic stem cell transplantation: Prognostic factors associated with mortality.

BACKGROUND: Although hematopoietic stem cell transplantation (HSCT) is the only curative option for some children with malignant and nonmalignant disorders, the procedure itself carries a high risk of complications. A proportion of children undergoing HSCT develop severe transplant-related complications requiring hospitalization in the pediatric intensive care unit (PICU). METHODS: A retrospective cohort study included 793 children with malignant and nonmalignant diseases that underwent 963 HSCTs in two large pediatric hospitals over 15 years. Ninety-one patients needed 105 (11%) PICU admissions. The objective of the study was to analyze the risk factors associated with morbidity and mortality in children post HSCT who were admitted to the PICU. RESULTS: Survival rate of a single PICU hospitalization was 43%. Long-term survival rate (classified as 1 year and 3 years) was 29.1% and 14.9% among PICU hospitalized patients compared with 74.6% and 53.3% among patients who had undergone HSCT and did not require PICU hospitalization. Factors found to have a significant negative association with PICU survival were respiratory failure as indication for PICU admission, neutropenia, graft-versus-host disease, mechanical ventilation, inotropic support, need for dialysis, and multiple-organ failure (MOF) with more than one systemic intensive intervention. The strongest prognostic factors associated with mortality were MOF (p < .001) and the need for inotropic support (p = .004). CONCLUSIONS: Neutropenia was found to be negatively associated with survival, suggesting non-engraftment and late engraftment are important risk factors for HSCT patients hospitalized in PICU. MOF and inotropic support were found to be the main negatively associated predictive factors with survival.

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

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.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.

Hematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalopathy: A single-center experience underscoring the multiple factors involved in the prognosis.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE. PROCEDURE: HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. RESULTS: Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors. CONCLUSIONS: Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.

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

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.

The Broad Clinical Spectrum and Transplant Results of PNP Deficiency.

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.

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

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.

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

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.

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

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.

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αß/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.

Successful hematopoietic stem cell transplantation for osteopetrosis using reduced intensity conditioning.

BACKGROUND: Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients treated with a combination of fludarabine, treosulphan, thiotepa, and antithymocyte globulin. PROCEDURES: Thirty-one patients with IMO who underwent hematopoietic stem cell transplantation with fludarabine, treosulphan, thiotepa, and antithymocyte globulin at our center from 2012 to 2017 are retrospectively reviewed in this study. Twenty-six patients were transplanted from 10/10 matched donors (13 from siblings, 11 from unrelated, and two from extended family donors), four from 9/10 matched unrelated donors, and one from a 9/10 matched family donor. RESULTS: Overall survival was 100% with a median follow-up of 363 days (range 74-1891). There were 12 cases of acute graft versus host disease (GvHD) (38.7%), no cases of veno-occlusive disease, and eight cases of hypercalcemia (25.8%). Almost 80% of patients suffered viral reactivations with two cases of Epstein-Barr-virus-driven post-transplant lymphoproliferative disease. All cases of GvHD and viral reactivation were successfully treated. CONCLUSIONS: We conclude that transplantation in children with IMO using fludarabine, treosulphan, thiotepa, and antithymocyte globulin is safe and effective and should be performed as early as possible following diagnosis, prior to the development of severe disease sequelae.

Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients.

Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) protein deficiency is a rare syndrome of primary immune deficiency and immune dysregulation. In this study, we sought to summarize our experience with respiratory manifestations in LRBA-deficient patients. We conducted a retrospective analysis of the medical records of LRBA-deficient patients treated at Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Data retrieved included pulmonary workup, disease course, treatment, and outcome. Ten patients were included. Mean age at presentation of LRBA deficiency-related symptoms was 4.65 years (range 3 months-14 years). Respiratory symptoms were noted in six patients and consisted of chronic cough. Computed tomography revealed consolidation in five patients, atelectasis and bronchiectasis in two patients each, and diffuse interstitial lung disease in two additional patients. Respiratory tract cultures yielded a bacterial pathogen in five patients. Seven patients required active therapy: intravenous immunoglobulins (six patients), immunosuppressive drugs (five patients), and one was successfully treated with abatacept. Two patients underwent successful bone marrow transplantation. Mean follow-up period was 4.5 (range 0.4-14.4) years. On their latest examination, seven patients had no respiratory symptoms. CONCLUSION: Pulmonary manifestations are common in LRBA deficiency. Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from the time of diagnosis. What is Known: • Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a syndrome of primary immune deficiency and immune dysregulation. • Studies concerning the pulmonary characteristics of LRBA-deficient patients are lacking. What is New: • Respiratory manifestations include infections, bronchiectasis, interstitial lung disease, thoracic lymphadenopathy, and clubbing. • Awareness to pulmonary morbidity in LRBA-deficient patients and involvement of a pulmonologist in the workup and clinical decision-making is important. • Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from a young age.

Allogeneic Stem Cell Transplantation in Congenital Hemoglobinopathies Using a Tailored Busulfan-Based Conditioning Regimen: Single-Center Experience.

Hematopoietic stem cell transplantation (HSCT) is the only proven curative option for patients with hemoglobinopathies, both thalassemia and sickle cell anemia (SCA). A busulfan-based myeloablative conditioning regimen is the standard of care for HSCT in these patients, although increased treatment-related morbidity, including veno-occlusive disease (VOD), has been demonstrated. Thirty-eight pediatric patients, median age 8 years (range, 6 months to 22 years), suffering from hemoglobinopathy were treated at Rambam Medical Center in Haifa, Israel, between 1998 and 2011. Thirty-four patients had thalassemia major and 4 had SCA. The 38 patients underwent 40 HSCTs, 34 of which were first transplants and 6 second transplants. Most transplants (32/40) were from matched sibling donors. Sources of stem cells were peripheral blood in 30 transplants, bone marrow in 7 transplants, and cord blood in 3 transplants. All received different customized busulfan-based conditioning regimens tailored by pharmacokinetic analysis of busulfan levels. Primary engraftment occurred in 37 of 40 transplants. Neutrophil engraftment (>.5 × 10(9)/L) occurred at a median of 15.3 days post-transplantation (range, 10 to 45). Platelet transfusion independence (>20 × 10(9)/L) occurred at a median of 22.3 days (range, 11 to 60). The rate of 5-year overall survival for thalassemia patients after first transplantation was 90.5% ± 5.3%. The rate of 5-year thalassemia-free survival was 81.7% ± 6.8%. Cumulative incidence of acute graft-versus-host disease (GVHD) was 17.6%. Rate of grades III to IV GVHD was 8.8%. Cumulative incidence of chronic GVHD was 23.5%, with 11.8% incidence of extensive chronic GVHD. One patient developed VOD. Full donor chimerism occurred in 36.4% of patients with class 1 + 2 thalassemia, compared with 78.6% in class 3 thalassemia (P = .049). Overall survival above 90% in patients undergoing their first transplant was demonstrated using busulfan-based conditioning regimens. The low incidence of VOD was probably due to busulfan area under the curve measurements and dose adjustment.

Infections and neutrophils in the pathogenesis of bronchiolitis obliterans syndrome in children after allogeneic stem cell transplantation.

It is plausible that infections post-hematopoietic SCT play a role in the pathogenesis of BOS. A prospective study for children with history, questionnaire, examination, PFTs, and blood counts at one, three, six, nine, 12, 18, and 24 months post-SCT was conducted. Between September 2009 and September 2011 (n = 39), six developed BOS at 200 days (range 94-282), three patients had probable clinical respiratory infection, and all six had higher neutrophil count compared to non-BOS patients (4.7 vs. 2.4 at three months and 6.3 vs. 2.9 at six months ×10(9) /L, p = 0.03). Contribution of clinical and subclinical infection needs to be considered in the pathogenesis of BOS.

Safety and Role of Gastrointestinal Endoscopy in the Management of Gastrointestinal Acute GVHD in Children After Hematopoietic Stem Cell Transplantation.

Gastrointestinal (GI) endoscopy and biopsy is a common procedure to confirm the diagnosis of acute graft-versus-host disease (aGVHD) in children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Its safety and benefits in aGVHD management is unclear. We aimed to review the safety and benefits of GI endoscopy and biopsy for GI-aGVHD management. From January 2000 to December 2009, 450 Children received allo-HSCT at SickKids. Seventy-nine (17.5%) patients underwent GI endoscopy and biopsy for suspicion of GI-aGVHD. GI-aGVHD grading was I (n=5), II (n=39), III (n=23), and IV (n=12). GI biopsy confirmed aGVHD in 49 (62%) patients and results were negative in 30 (38%). Thirty-two (40%) patients started treatment based on clinical criteria before procedure. Twenty-four out of 79 patients had a change in therapy because of biopsy results. Treatment change was significantly more common in patients who had a positive biopsy results compared with those with negative results (24/49 vs. 4/30, P=0.02). Comparing patients who started therapy before the biopsy results (n=32) and the remaining patients (n=47) who were not started on therapy, the biopsy results had more impact in altering/starting therapy in these patients (24/47 vs. 0/32, P<0.00001). For the 32 patients who started therapy before the procedure, the biopsy confirmed aGVHD diagnosis in 20 of them (63%). Only 1 patient (1.25%) had duodenal hematoma and needed prolong GI rest and ultimately recovered. GI endoscopy and biopsy was safe and useful in guiding therapy for GI-aGVHD.