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Lubor Goláň,1 Ozlem Goker-Alpan,2 Myrl Holida,3 Ikka Kantola,4 Mariusz Klopotowski,5 Johanna Kuusisto,6 Aleš Linhart,1 Jacek Musial,7 Kathleen Nicholls,8 Derlis Gonzalez-Rodriguez,9 Reena Sharma,10 Bojan Vujkovac,11 Peter Chang,12 Anna Wijatyk12 1First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic; 2Lysosomal Research and Treatment Unit, Fairfax, VA, USA; 3Stead Family Department of Pediatrics, Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 4Division of Medicine, Turku University Hospital, Turku, Finland; 5Institute of Cardiology, Warsaw, Poland; 6Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; 7Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland; 8Department of Nephrology, Royal Melbourne Hospital and the University of Melbourne, VIC, Australia; 9Instituto Privado de Hematologia E Investigacion Clinica (IPHIC), Asuncion, Paraguay; 10Salford Royal NHS Foundation Trust, Salford, UK; 11General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia; 12Shire, Lexington, MA, USA Purpose: Efficacy and safety of agalsidase alfa at 0.2 mg/kg weekly were compared with 0.2 mg/kg every other week (EOW). Exploratory analyses were performed for 0.4 mg/kg weekly.Patients and methods: This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18 years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height >50 g/m2.7 for males and >47 g/m2.7 for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti–agalsidase alfa antibodies.Results: Twenty patients were randomized to 0.2 mg/kg EOW (mean age, 50.3 years; 70% male), 19 to 0.2 mg/kg weekly (51.8 years; 53% male), and 5 to 0.4 mg/kg weekly (49.4 years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2 g/m2.7 and 0.5 g/m2.7, with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classi­fication. No significant differences were found between 0.2 mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21 mL/min/1.73 m2 vs -3.32 mL/min/1.73 m2) or plasma globotriaosylceramide (-1.05 nmol/mL vs -2.13 nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti–agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status.Conclusion: No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4 mg/kg weekly showed similar results. Keywords: adverse events, exercise tolerance, left ventricular hypertrophy, lysosomal storage disorder, quality of life, renal function

The utility of bone marrow transplantation for childhood leukemia in patients unable to achieve a remission prior to transplant is controversial. To address this issue, we analyzed a subset of patients with advanced leukemia entered on prospective transplant trials at our hospital. Fifty-eight patients with ALL or AML (age 1–19) were identified. They had failed standard chemotherapy and were in relapse (22 in 1st, 27 in 2nd, three in 3rd, and three in 4th) or had never achieved an initial remission (three) at the time of transplant. Fifty-two patients received marrow from mismatched family members (haplo or DR-identical), while six received marrow from matched siblings. Most patients received myeloablative therapy consisting of total body irradiation, etoposide, cyclophosphamide, and cytosine arabinoside. Marrow from mismatched donors was T cell depleted. Only one of 52 patients transplanted with a mismatched donor survived long-term while three of six patients transplanted in relapse with a fully matched sibling donor are alive 6–10 years post BMT. The major causes of death were infection (39%) and relapse (28%). Acute GVHD grade III–IV was noted in 7% of patients. A comparable group of patients with leukemia transplanted at our center in remission using similarly mismatched family member donors (haplo or DR-identical) had an event-free survival of 28%. In conclusion, our data suggest that BMT utilizing mismatched family member donors is a poor option for patients in relapse at the time of transplant. New treatment strategies need to be developed to effectively manage these patients. Bone Marrow Transplantation (2000) 25, 943–948. [ABSTRACT FROM AUTHOR]

Aspergillus infections in pediatric bone marrow transplant (BMT) patients are usually fatal. We began the use of a prophylactic nasal spray of amphotericin in 1990. This nasal spray was provided in addition to low-dose intravenous amphotericin. During the time of this study, the number of fatal cases of aspergillus in the pediatric BMT population was reduced significantly from 13.8% to 1.8% (P < 0.0025) thereby suggesting that the use of nasal amphotericin in this population helps to prevent fatal aspergillus infections. the lack of significant side-effects and the ease of administration make this a very helpful preventive measure in the supportive care of pediatric bone marrow transplant patients. [ABSTRACT FROM AUTHOR]

Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m 2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m 2 /year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m 2 /year who had received agalsidase beta for ≥1 year., Methods: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms., Results: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m 2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m 2 /year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m 2 /year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths., Conclusions: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions., Trial Registration Number: NCT02795676., Competing Interests: Competing interests: ELW has consulting agreements and/or grants with Sanofi, Protalix, Chiesi, Idorsia, 4DMT, Amicus and Natera. OG-A has conducted contracted research, received consulting fees and/or served on advisory boards with Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, Takeda, 4DMT and Avrobio. WRW has been or is currently involved in clinical trials and/or registries with Alexion, Amicus, BioMarin, Chiesi, Freeline, Idorsia, Orphazyme, Pfizer, Protalix, Sanofi, Sangamo, Takeda and 4DMT. He has received honoraria from Alexion, Amicus, BioMarin, Sanofi, Spark and Takeda, and research funding from Amicus and Takeda. MH received speaker-related fees from Protalix and has been, or is currently, involved in clinical trials with Sanofi, Sangamo, Avrobio, Protalix and Idorsia (no direct funding received for these trials because they are institution directed). JB receives research support from Avrobio, BioMarin Pharmaceutical, Chiesi Farmaceutici, Idorsia Pharmaceuticals, Pfizer, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, Takeda, Travere Therapeutics; and has received a speaker honorarium from the Fabry Support and Information Group; and has participated in advisory boards for Chiesi USA, Sanofi and Takeda. NL receives research support from and has participated in advisory boards for Amicus, Astellas, Avrobio, BioMarin Pharmaceutical, Homology, Horizon, Moderna, Pfizer, Protalix Biotherapeutics, PTC Biotherapeutics, Reneo, Sanofi, Takeda and Ultragenyx (no direct funding is received because they are institution directed). DH has received honoraria for speaking and consulting fees for advisory boards from Protalix, Takeda, Sanofi, Freeline and Sangamo, administered through University College London consultants and used in part to support research in lysosomal storage diseases. PG has been involved in premarketing studies with Genzyme, Protalix and Idorsia, and has received grants from Sanofi-Genzyme and Takeda; monies received for these activities have been deposited into the Spanish Foundation for the Study and Treatment of Gaucher Disease (FEETEG) to contribute to the development of research in lysosomal storage disorders. MJM, DO, MM, BAB, JK, TG and KN have no disclosures. RJH has received consulting fees from Alexion, Amicus Therapeutics, Inc., Avrobio, Chiesi, Sangamo, Sanofi/Genzyme, and Takeda; advisory fees from Alexion, Amicus Therapeutics, Inc., and Sanofi/Genzyme; speakers' bureau fees from Alexion and Sanofi/Genzyme and grants/research funding from Alexion, Amicus Therapeutics, Inc., Idorsia, Protalix, Sangamo, Sanofi/Genzyme and Takeda. CT has received honoraria, travel support, and/or participated as an investigator in clinical studies supported by Protalix, Sanofi, Idorsia, Takeda, Amicus, Freeline and Acelink. All received honoraria went to her institution Haukeland University Hospital. AL has received consultancy and speaker's honoraria from Amicus Therapeutics, Sanofi, Takeda, 4DMT and Chiesi. PD has been a paid consultant with Sanofi; received speaker honoraria from Sanofi and Takeda and participated in an advisory board with Protalix. AJ has received a grant from Amicus and consultancy and speaker’s honoraria from Takeda, Sanofi and Amicus. VK is an advisory board member for the Sanofi-Genzyme North American Pompe Registry. She is the principal investigator for Sanofi-Genzyme Lysosomal Storage Disease registry at UC Irvine. She has received education grants, lecturing honoraria, and research support from Sanofi-Genzyme. She participates as an investigator in clinical studies supported by Protalix, Sanofi, Idorsia, Chiesi Farmaceutici and Sangamo. BV has received honoraria, travel and accommodation funding from Greenovation Biotech GmbH, Sanofi, Takeda, Amicus, Chiesi and Swixx, and is a member of the EU Advisory Board of Fabry Registry, sponsored by Sanofi. AN received lecturing honoraria and research support from Takeda, Amicus and Sanofi/Genzyme. AP received travel expenses and grants from Takeda, Sanofi, Amicus and Chiesi. DPG has received consulting honoraria from Chiesi, Idorsia Pharmaceuticals, Sanofi and Takeda, and speaker honoraria and travel support from Sanofi and Takeda. IK has received lecture, travel and consulting fees from Amicus, Chiesi, Bayer, Boehringer-Ingelheim, Sanofi-Genzyme and Takeda-Shire. AM has received non-financial support from Chiesi Pharmaceuticals, during the conduct of the study; personal fees from AstraZeneca, Bayer Pharmaceuticals and Janssen Pharmaceuticals, outside the submitted work. AK has received honoraria, travel support and/or participated as an investigator in clinical studies supported by Protalix, Sanofi and Idorsia and on advisory meetings for Protalix, Sanofi, Takeda, Amicus and Chiesi. SW has been a paid consultant to Protalix. ML is involved in premarketing studies with Sanofi-Genzyme, Protalix/Chiesi and Idorsia. Financial arrangements were made through AMC Research BV. No fees, travel support or grants were obtained from the pharmaceutical industry. EBA and RC were full-time employees of Protalix Biotherapeutics at the time of study conduct and analysis and are now consultants to Protalix Biotherapeutics. SA is a full-time employee of Protalix Biotherapeutics. RR is a full-time employee of Chiesi Farmaceutici S.p.A. AS was a paid consultant to Protalix at the time of study conduct and analysis and is currently a paid consultant to Chiesi USA, Inc. DGW is involved in clinical trials/registries/consulting with Amicus, Chiesi, Idorsia and Protalix., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD., Methods: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks., Results: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed., Conclusion: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD., Competing Interests: Conflict of Interest Derralynn Hughes has received speaker’s honoraria from Amicus Therapeutics, Takeda, Sanofi, Freeline, Protalix, and Idorsia. Derlis Gonzalez has been or is currently involved in clinical trials with Takeda, Protalix, and mAbxience. Gustavo Maegawa has received grants, personal and consultant fees from Sanofi; grants from Pfizer Inc.; personal fees from Sio Gene Therapies; grants from NIH/NINDS, and personal fees from NIH/CSR. John A. Bernat receives research support from Avrobio, BioMarin Pharmaceutical, Chiesi Farmaceutici, Idorsia Pharmaceuticals, Pfizer, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, Takeda, and Travere Therapeutics; has received a speaker honorarium from the Fabry Support and Information Group; and has participated in advisory boards for Chiesi USA, Sanofi, and Takeda. Myrl Holida has received speaker honoraria from Protalix and Chiesi and has participated in advisory boards for Amicus and Sanofi. Pilar Giraldo has been involved in premarketing studies with Genzyme, Protalix, and Idorsia and has received grants from Sanofi and Takeda; monies received for these activities have been deposited into the Spanish Foundation for the Study and Treatment of Gaucher Disease (FEETEG) to contribute to the development of research in lysosomal storage disorders. Mohamed G. Atta declares no conflicts of interest. Sari Alon is a full-time employee of Protalix. Raul Chertkoff and Einat Brill Almon were full-time employees of Protalix at the time of study conduct and are now consultants to Protalix. Rossana Rocco is a full-time employee of Chiesi. Ozlem Goker-Alpan has conducted contracted research with Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, Takeda, 4DMT, Avrobio; received consulting fees from Amicus, Sanofi, Takeda, Sangamo, 4DMT, Avrobio; served on advisory boards for Amicus, Sanofi, Takeda, Sangamo, 4DMT, Avrobio; and participated in speakers’ bureaus for Sanofi, Takeda., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: With the recent approval of COVID-19 vaccines, recovered COVID-19 subjects who are vaccinated may be ideal candidates to donate COVID-19 convalescent plasma (CCP)., Case Series: Eleven recovered COVID-19 patients were screened to donate CCP. All had molecularly confirmed COVID-19, and all but one were antibody positive by chemiluminescence immunoassay (DiaSorin) prior to vaccination. All were tested again for antibodies 11-21 days after they were vaccinated (Pfizer/Moderna). All showed dramatic increases (~50-fold) in spike-specific antibody levels and had at least a 20-fold increase in the IC50 neutralizing antibody titer based on plaque reduction neutralization testing (PRNT). The spike-specific antibody levels following vaccination were significantly higher than those seen in any non-vaccinated COVID-19 subjects tested to date at our facility., Conclusion: Spike-specific and neutralizing antibodies demonstrated dramatic increases following a single vaccination after COVID-19 infection, which significantly exceeded values seen with COVID-19 infection alone. Recovered COVID-19 subjects who are vaccinated may make ideal candidates for CCP donation., (© 2021 AABB.)

Purpose: A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management., Methods: Retrospective review of patients seen over a two-year period in the RGC., Results: One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified., Conclusion: An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.

Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m 2 at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

Unlabelled: Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified., Trial Registration: ClinicalTrials.gov NCT01196871.

Children who require a marrow transplant may receive such hematopoietic cells from one of many sources. This study reviews the experience of one center with 58 children who received marrow from unrelated donors over a 10-year period. These children had a variety of malignant and non-malignant diseases. During that time period, only three of these children had failed to meet engraftment criteria. All donor marrow specimens were T-lymphocyte-depleted using an antibody/complement methodology. No difference was demonstrated in outcome between donors who were perfectly HLA-DR DNA matched versus those who were only partially matched. The increased size of various marrow donor registries has increased the number of potential donors available for these patients. The lack of a requirement for perfect matching means that there is an ever-increasing number of donors available. No graft-versus-host disease (GvHD) or grade III-IV GvHD was associated with a poorer outcome. Stable, long-term engraftment with minimal morbidity has been demonstrated in these children as evidenced by stability of survival curves by two years after marrow transplant.

Reconstitution of the immune system following T-cell-depleted bone marrow transplantation (BMT) in children has yet to be fully elucidated. Thus, we prospectively studied the recovery of immune function in 64 children who underwent T-lymphocyte-depleted marrow transplants using either matched family member donors or matched unrelated donors. We measured in vitro posttransplantation proliferative responses to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, and Candida albicans antigen and assessed unidirectional allogeneic mixed-lymphocyte culture (MLC) responses at various times. A total of 129 healthy individuals served as normal controls for these assays. Responses to T-cell mitogens normalized within 12 months posttransplantation, while MLC responses normalized by 9 months. The presence of graft-versus-host disease (grade II or greater) and cytomegalovirus infection was associated with delays in immune function recovery. Importantly, immune function recovery correlated temporally with a rise in peripheral lymphocyte count. In contrast, the CD4/CD8 ratio was not predictive of immune recovery. Knowledge of immune function recovery may guide clinicians in devising strategies to minimize the risk of infection post-BMT.

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.

Severe hemorrhagic cystitis developed in 6 children after marrow transplantation, 3 of whom had a viral etiology. All 6 patients received instillations of prostaglandin E1 directly into the bladder and 5 of the 6 had complete resolution of hematuria. This finding contrasts with our previous experience with severe hemorrhagic cystitis, particularly the type due to a viral infection, persisting in the face of numerous bladder manipulations. We encourage the use of this nontoxic treatment to gain further information regarding its effect on the bladder epithelium. The mechanism of action remains completely unknown.

Two children developed lymphoproliferative processes following marrow transplantation. One of the two lymphoproliferative processes was documented to be Epstein-Barr virus (EBV)-associated. Both children received an extended course of alpha-interferon and gammaglobulin and responded with the disappearance of the lymphoproliferative process. Side effects from the alpha-interferon were minimal. Previous experience with EBV-associated lymphoproliferative processes following marrow transplantation have been usually fatal. This report further substantiates that alpha-interferon has a role in the treatment of EBV-associated lymphoproliferative processes following marrow transplantation.