Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

BACKGROUND: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. OBJECTIVE: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. METHODS: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. RESULTS: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. CONCLUSIONS: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Assessing the diagnostic utility of the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system using real-world data.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive condition associated with clinical features such as splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone abnormalities. Three clinical forms of GD have been defined based on the absence (type 1, GD1) or presence (types 2 and 3) of neurological signs. Early diagnosis can reduce the likelihood of severe, often irreversible complications. The aim of this study was to validate the ability of factors from the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system to discriminate between patients with GD1 and controls using real-world data from electronic patient medical records from Maccabi Healthcare Services, Israel's second-largest state-mandated healthcare provider. METHODS: We applied the GED-C scoring system to 265 confirmed cases of GD and 3445 non-GD controls matched for year of birth, sex, and socioeconomic status identified from 1998 to 2022. The analyses were based on two databases: (1) all available data and (2) all data except free-text notes. Features from the GED-C scoring system applicable to GD1 were extracted for each individual. Patients and controls were compared for the proportion of the specific features and overall GED-C scores. Decision tree and random forest models were trained to identify the main features distinguishing GD from non-GD controls. RESULTS: The GED-C scoring distinguished individuals with GD from controls using both databases. Decision tree models for the databases showed good accuracy (0.96 [95% CI 0.95-0.97] for Database 1; 0.95 [95% CI 0.94-0.96] for Database 2), high specificity (0.99 [95% CI 0.99-1]) for Database 1; 1.0 [95% CI 0.99-1] for Database 2), but relatively low sensitivity (0.53 [95% CI 0.46-0.59] for Database 1; 0.32 [95% CI 0.25-0.38]) for Database 2). The clinical features of splenomegaly, thrombocytopenia (< 50 × 109/L), and hyperferritinemia (300-1000 ng/mL) were found to be the three most accurate classifiers of GD in both databases. CONCLUSION: In this analysis of real-world patient data, certain individual features of the GED-C score discriminate more successfully between patients with GD and controls than the overall score. An enhanced diagnostic model may lead to earlier, reliable diagnoses of Gaucher disease, aiming to minimize the severe complications associated with this disease.

Cancer Risk in Patients with Gaucher Disease Using Real-World Data.

The association between GD and cancer has been uncertain due to ascertainment bias in previously published studies. We analyzed cancer incidence using the Maccabi Healthcare Service (MHS) electronic health records among 264 patients with GD compared to 3440 matched controls. We ascertained cancers diagnosed before and after the index date (i.e., the first documentation of GD in cases and the corresponding date for controls). Before the index date, cancers were diagnosed in 18 individuals, with 11 (4.2%) in the GD group and 7 (0.2%) in the control group. After the index date, cancers were diagnosed in 57 individuals, with 20 (7.9%) in the GD group and 37 (1.1%) in the control group, with a median follow-up of almost 13 years in both groups. The most common cancers diagnosed in GD were non-melanoma skin cancer (NMSC) and hematological malignancies, with a clustering of diagnoses around the time of GD diagnosis. The incidence of cancers (excluding MNSC) was 4.1 (95% CI 2.2-7.1) and 0.7 (95% CI 0.4-0.9) per 1000 patient-years in the GD and control groups, respectively, with an incidence rate ratio of 6.37 (95% CI 3-12.7). Patients with GD underwent more cancer screening tests than their counterparts in the control group. While our study revealed an increased occurrence of cancers in patients with GD, this finding might be partly attributed to the more rigorous surveillance procedures employed in this patient population.

Pediatric overweight and obesity increased in Israel during the COVID-19 period.

Reports from many settings suggest that pediatric overweight and obesity increased in 2020 and 2021, presumably due to lifestyle changes associated with the COVID-19 pandemic. Many of these previous reports have relied on convenience samples or subsets of the population. Here, we present results of a longitudinal study of the entire population of Israel, a nation of approximately 9 million people, with the proportion with underweight, normal weight, overweight, and obesity at age 7 and at age 14-15, across the years 2017-2021. Our results show that the prevalence of overweight and obesity, which had been steady or improving through 2019, increased relatively quickly in 2020 and 2021. For example, among 7-year-olds, the percentage of children with obesity in 2019 was 6.8% (99% CI: 6.69-7.05), and by 2021, it had increased to 7.7% (99% CI: 7.53-7.93). There were important disparities in overweight and obesity based on SES; for example, the rate ratio for obesity comparing the poorest with the wealthiest 14-15-year-olds in 2019 was 1.63 (99% CI: 1.55-1.72). However, these disparities did not change meaningfully in 2020 and 2021, implying that while obesity did become more prevalent, this increase in prevalence was not differential across socioeconomic status. Like many other nations, Israel too experienced considerable increases in pediatric overweight and obesity in 2020-2021, erasing the improvements of the previous years among younger children.

Insights into the Value of Lyso-Gb1 as a Predictive Biomarker in Treatment-Naïve Patients with Gaucher Disease Type 1 in the LYSO-PROOF Study.

Gaucher disease (GD) is a rare autosomal recessive disorder arising from bi-allelic variants in the GBA1 gene, encoding glucocerebrosidase. Deficiency of this enzyme leads to progressive accumulation of the sphingolipid glucosylsphingosine (lyso-Gb1). The international, multicenter, observational "Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease"-LYSO-PROOF study succeeded in enrolling a cohort of 160 treatment-naïve GD patients from diverse geographic regions and evaluated the potential of lyso-Gb1 as a specific biomarker for GD. Using genotypes based on established classifications for clinical presentation, patients were stratified into type 1 GD (n = 114) and further subdivided into mild (n = 66) and severe type 1 GD (n = 48). Due to having previously unreported genotypes, 46 patients could not be classified. Though lyso-Gb1 values at enrollment were widely distributed, they displayed a moderate and statistically highly significant correlation with disease severity measured by the GD-DS3 scoring system in all GD patients (r = 0.602, p < 0.0001). These findings support the utility of lyso-Gb1 as a sensitive biomarker for GD and indicate that it could help to predict the clinical course of patients with undescribed genotypes to improve personalized care in the future.

Real-World Experiences with Taliglucerase Alfa Home Infusions for Patients with Gaucher Disease: A Global Cohort Study.

Taliglucerase alfa is an enzyme replacement therapy approved for Gaucher disease. We assessed the duration/compliance/safety of such home infusions in commercial use in four countries where home infusion programs are available. The treatment duration/compliance study included 173 patients (Israel, 58; US, 61; Brazil, 48; Australia, 6) who received ≥1 taliglucerase alfa home infusion through 6/2021. The median age at home therapy initiation was 38 (range, 2-87) years; 58% were females. The median treatment duration (at home) was 2.7 (range, 0.04-9.0) years. The annual compliance rate was stable (≥95%) throughout the study period. A search of the Pfizer global safety database (through 6/2021), identified 19 adverse events (AEs) as related to "definite home use" and 14 to "possible home use" of taliglucerase alfa; 42.4% of these AEs were serious; none were fatal. Twelve serious AEs in five separate case reports were considered treatment related: one case of chest discomfort/pain and hypertension and one case of erythema associated with a toe blister, for which causality could not be excluded; pain in extremity; projectile vomiting and chills, alongside excessive eye blinking; and an infusion-related AE (pruritus). In conclusion, this real-life global study demonstrated that taliglucerase alfa home infusions are safe with high compliance rates.

A Deep-Learning Approach to Spleen Volume Estimation in Patients with Gaucher Disease.

The enlargement of the liver and spleen (hepatosplenomegaly) is a common manifestation of Gaucher disease (GD). An accurate estimation of the liver and spleen volumes in patients with GD, using imaging tools such as magnetic resonance imaging (MRI), is crucial for the baseline assessment and monitoring of the response to treatment. A commonly used method in clinical practice to estimate the spleen volume is the employment of a formula that uses the measurements of the craniocaudal length, diameter, and thickness of the spleen in MRI. However, the inaccuracy of this formula is significant, which, in turn, emphasizes the need for a more precise and reliable alternative. To this end, we employed deep-learning techniques, to achieve a more accurate spleen segmentation and, subsequently, calculate the resulting spleen volume with higher accuracy on a testing set cohort of 20 patients with GD. Our results indicate that the mean error obtained using the deep-learning approach to spleen volume estimation is 3.6 ± 2.7%, which is significantly lower than the common formula approach, which resulted in a mean error of 13.9 ± 9.6%. These findings suggest that the integration of deep-learning methods into the clinical routine practice for spleen volume calculation could lead to improved diagnostic and monitoring outcomes.

Anesthetic Approaches and Perioperative Complications of Total Hip Arthroplasty in Gaucher Disease: A Control-Matched Retrospective-Cohort Study.

OBJECTIVES: Gaucher disease's (GD) pathophysiology generates anesthetic concerns in total hip joint arthroplasty (THA), and due to its rareness, data on perioperative risks are scarce. This 22-year study at a large reference center addresses anesthetic management and perioperative outcomes in GD. METHODS: This retrospective-cohort study assessed anesthetic success and safety in 30 THA patients, comparing them with a control-matched group. Data on clinical characteristics, perioperative events, and outcomes were collected. The primary outcome was the success rate of anesthesia induction performance at first attempt. Secondary outcomes were difficult intraoperative course and hemodynamic management, and the development of postoperative complications. The age, sex, weight, body mass index, and primary-to-revision hip arthroplasty ratio were similar in both groups. RESULTS: There was no significant difference at all-type anesthesia first initiation attempt success. No particular preference by staff anesthetists for general anesthesia or neuraxial procedures was observed. The GD group showed a significantly higher mean of intraoperative packed Red Blood Cell units administered ((0.73 vs. 0.18); (p = 0.038)), higher intraoperative and postoperative platelet transfusion incidence ((5/30 [16.7%] vs. 0/56 [0.00%]; p = 0.004) and (3/30 [10%] vs. 0/56 [0%]; p = 0.040)), and longer mean recovery room length of stay (426 ± 412 vs. 175 ± 140; p = 0.004). Postoperative complications were not significantly different.

A global neuronopathic gaucher disease registry (GARDIAN): a patient-led initiative.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder. GD types 2 and 3 are known as neuronopathic Gaucher disease (nGD) because they have brain involvement that progresses over time. Implementing a systematic approach to the collection of real-world clinical and patient-relevant outcomes data in nGD presents an opportunity to fill critical knowledge gaps and ultimately help healthcare providers in the management of this patient population. This paper summarizes the development of a patient-initiated Gaucher Registry for Development Innovation and Analysis of Neuronopathic Disease (GARDIAN). METHODS: The International Gaucher Alliance led the GARDIAN planning, including governance, scope, stakeholder involvement, platform, and reporting. Registry element input was determined in a series of meetings with clinical experts, patients, and caregivers, who identified key clinical variables and the draft content of nGD patient-reported outcomes (PRO) and observer-reported outcomes (ObsRO) focusing on symptoms, patient physical and emotional functioning. These were then tested in cognitive interviews with patients with nGD (> 12 years of age) and caregivers. RESULTS: Core registry data elements (n = 138) were identified by seven global clinical experts from Egypt, Germany, Israel, Japan, United Kingdom (UK), and United State (US) and reviewed via online Delphi method by 14 additional clinicians with experience of nGD from six countries and three pharmaceutical representatives. The elements were consistent with those identified via interviews with 10 patients/caregivers with nGD from Japan, Sweden, UK, and US. Key domains identified were demographics, diagnostic information, health status, clinical symptomatology, laboratory testing, treatment, healthcare resource utilization, aids/home improvements, and patient/caregiver burden and quality of life, specifically physical functioning, self-care, daily and social activities, emotional impacts, support services, and caregiver-specific impacts. Nine caregivers and six patients from the US, UK, China, Mexico, Egypt, and Japan participated in the cognitive interviews that informed revisions to ensure that all items are understandable and interpreted as intended. CONCLUSIONS: The comprehensive set of clinical and patient relevant outcomes data, developed collaboratively among all stakeholders, to be reported using GARDIAN will bridge the many gaps in the understanding of nGD and align with regulatory frameworks on real-world data needs.

Rapid home therapy infusion of velaglucerase alfa in naïve patients with Gaucher disease.

BACKGROUND: Enzyme replacement therapy (ERT) has revolutionised the management of patients with Gaucher disease (GD). In 2018, we published the safety and efficacy of rapid 10-min infusion of velaglucerase alfa in previously treated patients, mostly on low-dose therapy. AIM: To improve quality of life (QoL) for patients needing lifelong bi-weekly infusions by introducing a 10-min infusion instead of 1 h per label in patients naive to ERT and on high-dose therapy. METHODS: Fifteen naive patients were enrolled; all received bi-weekly infusions of 60 units/kgBW velaglucerase alfa; the infusion rate was gradually reduced in the hospital, followed by home infusions. Each infusion was followed for safety. Efficacy parameters were assessed every 3 months. Patient-reported outcome questionnaires were collected at baseline and follow-up. RESULTS: Ten-minute rapid infusions were well tolerated without related severe adverse events (SAEs). Two patients experienced a non-related SAE and another a possibly related AE. In three patients, the infusion rate was increased to 30 or 60 min (two because of suboptimal response and one because of AE). Two patients dropped out because of an unwillingness to attend follow-up visits during the COVID-19 pandemic. All 13 remaining patients reached the 24-month end-point. The platelet counts increased by a median (range) of 68.38% (12.5-300%) and the lyso-Gb1 levels decreased by 62.6% (32.9-89.9%). CONCLUSION: Home therapy with rapid infusion of high-dose velaglucerase alfa was a safe, effective and preferable alternative for patients with GD naïve to treatment. We believe that shortening the infusion time improves the QoL of patients with GD who have a lifelong commitment to intravenous therapy.

Reply to Mistry et al. The Two Substrate Reduction Therapies for Type 1 Gaucher Disease Are Not Equivalent. Comment on "Hughes et al. Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS). J. Clin. Med. 2022, 11, 5158".

Thank you for allowing us the opportunity to respond to the commentary from Mistry and colleagues (Comment: The two substrate reduction therapies for type 1 Gaucher disease are not equivalent) [...].

Simultaneous Bilateral Femoral Osteonecrosis in Gaucher Disease.

Gaucher disease (GD) is one of the most common lysosomal storage disorders. Bone complications are the most critical irreversible consequence of GD. Osteonecrosis (ON) of the femoral head inevitably leads to osteoarthritis and may be managed by hip arthroplasty. The introduction and worldwide use of therapeutic agents (specifically enzyme replacement therapies (ERT)) lowered the prevalence of osteonecrosis events per patient. We present the cases of two female patients who sustained simultaneous bilateral femoral head osteonecrosis after receiving ERT for long periods while exposed to concomitant risk factors related to femoral head ON. Both patients suffered severe pain and deterioration of their daily activity capabilities, and thus, were offered bilateral hip arthroplasty. Surgery was performed in both hip joints during the same procedure. The current report highlights several key aspects of femoral head ON in young patients with GD.

High-Dose Ambroxol Therapy in Type 1 Gaucher Disease Focusing on Patients with Poor Response to Enzyme Replacement Therapy or Substrate Reduction Therapy.

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103/L, lumbar spine bone density T-score < -2.0, and/or LysoGb1 > 200 ng/mL, and for a group of naïve patients who had abnormal values in two of these three parameters. We enrolled 40 patients: 28 ERT- or SRT-treated, and 12 naïve. There were no severe adverse effects (AEs). There were 24 dropouts, mostly due to AEs (n = 12), all transient, and COVID-19 (n = 7). Among the 16 completers, 5 (31.2%) had a >20% increase in platelet count, 6 (37.5%) had a >0.2 increase in T-score, and 3 (18.7%) had a >20% decrease in Lyso-Gb1. This study expands the number of patients exposed to high-dose ABX, showing good safety and satisfactory efficacy, and provides an additional rationale for adding off-label ABX to the arsenal of therapies that could be offered to patients with GD1 and a suboptimal response or those unable to receive ERT or SRT.

The Bone Biomarker of Quantitative Chemical Shift Imaging in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long-Term Enzyme Replacement Therapy.

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5-26) years and 30 (30-60) U/kg/month, respectively. Low FF scores (<0.30) were observed for seven patients (23%; 95% confidence interval, 10-42%) and were more common in females (n = 6) versus males (n = 1; p < 0.025); one female was menopausal. These baseline data demonstrate that prolonged low-dose ERT with imiglucerase or velaglucerase alfa led to an adequate bone response, assessed by QCSI, in the majority of patients. A minority of such patients with suboptimal bone response require therapeutic change. The next phase of the study will address the effect of switching to taliglucerase alfa on bone status for patients with less than optimal QCSI scores (<0.30).

Contribution of Glucosylsphingosine (Lyso-Gb1) to Treatment Decisions in Patients with Gaucher Disease.

Glucosylsphingosine (lyso-Gb1), the deacylated form of glucocerebroside, was shown to be the most specific and sensitive biomarker for diagnosing Gaucher disease (GD). The aim of this study is to assess the contribution of lyso-Gb1 at the time of diagnosis for treatment decisions in naïve patients with GD. Newly diagnosed patients from July 2014 to November 2022 were included in this retrospective cohort study. The diagnosis was done by sending a dry blood spot (DBS) sample for GBA1 molecular sequencing and lyso-Gb1 quantification. Treatment decisions were based on symptoms, signs, and routine laboratory tests. We diagnosed 97 patients (41 males), both type 1 (n = 87), and neuronopathic (n = 10). The median (range) age at diagnosis was 22 (1-78), with 36 children. In 65 patients, GD-specific therapy was started with a median (range) lyso-Gb1, 337 (60-1340) ng/mL, significantly higher than in patients who did not go on to treatment, 153.5 (9-442) ng/mL. Using a receiver operating characteristic (ROC) analysis, a cutoff of lyso-Gb1 > 250 ng/mL was associated with treatment with a sensitivity of 71% and specificity of 87.5%. Predictors of treatment were thrombocytopenia, anemia, and elevated lyso-Gb1 (>250 ng/mL). In conclusion, lyso-Gb1 levels contribute to the medical decision related to the initiation of treatment, mainly among mildly affected newly diagnosed patients. For patients with a severe phenotype, as for all patients, the main value of lyso-Gb1 would be to monitor response to therapy. The variable methodology and differences in the units of lyso-Gb1 measurements between laboratories prevent the adaptation of the exact cut-off we found in general practice. However, the concept is that a significant elevation, i.e., a several-fold increase from the diagnostic lyso-Gb1 cutoff, is related to a more severe phenotype and, accordingly, to the decision regarding the initiation of GD-specific therapy.

[PERIOPERATIVE MANAGEMENT OF AN ADOLESCENT GIRL WITH SEVERE FACTOR XI DEFICIENCY AND INHIBITORS].

INTRODUCTION: Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by injury-related hemorrhage, mostly associated with surgical procedures at sites noted for high fibrinolytic activity. Severe FXI deficiency is defined when the FXI level is lower than 15-20 IU/dL. Perioperative prophylactic treatment for high-bleeding-risk surgery in patients with severe FXI deficiency is based on fresh frozen plasma (FFP) transfusions or FXI concentrate (where available). Exposure to FFP and to FXI concentrate may lead to the development of inhibitory antibodies against FXI. This phenomenon occurs mostly in patients with very severe FXI deficiency (baseline FXI <1IU/dL) and is associated with an increased risk of substantial perioperative bleeding, unresponsive to FXI replacement. Thus, in individuals with severe FXI deficiency, routine testing for the presence of inhibitory antibodies against FXI is recommended. We present a 17-year-old adolescent patient with very severe FXI deficiency, who developed an inhibitor to FXI following FFP exposure associated with neurosurgery for medulloblastoma. Prophylactic treatment for subsequent invasive procedures consisted of single low dose (10 mcg/kg) recombinant activated factor VII (rFVIIa) and tranexamic acid (Hexakapron). The procedures were performed uneventfully, with no hemorrhagic or thrombotic complications. In patients with very severe FXI deficiency, the development of inhibitory antibodies following plasma replacement therapy comprises a rare and challenging occurrence. The formulation of a safe and effective evidence-based protocol for hemostatic support in these patients requires multi-center collaboration.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Real-Life Experience with Oral Eliglustat in Patients with Gaucher Disease Previously Treated with Enzyme Replacement Therapy.

Three types of enzyme replacement therapies (ERTs) and two substrate reduction therapies (SRTs) are approved for symptomatic patients with type 1 Gaucher disease (GD1). Eliglustat is the second SRT approved, yet the first to be approved as first-line therapy for any adult patients with compatible CYP2D6 metabolizer genotype. Herein we report safety and efficacy data of the first 29 patients switched from ERT to eliglustat from the Gaucher Unit at Shaare Zedek Medical Center (SZMC) between 07/2017 and 06/2022; the median (range) time on ERT was 13 (0.66-30) years, and the median (range) time on eliglustat was 7 (1-52) months. Most patients switched due to oral preference or sub-optimal response to low-dose ERT. Twelve patients stopped eliglustat after a median (range) of 4 (1-18) months; 11 due to adverse events (AEs) and one due to personal request. There were no drug-related serious AEs and no drug-related cardiac events. Most AEs were mild and transient, mainly dyspepsia. Efficacy achievements were reflected by maintaining stability. We concluded that switching from ERT to eliglustat is safe if choosing the appropriate patients. Reassuring patients to tolerate early AEs may reduce discontinuation. Following the response and compliance to therapy is important to ensure long-term efficacy.