A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation

Curelaru, S; Desai, Ankit K.; Fink, Daniel; Zehavi, Yoav; Kishnani, Priya S.; Spiegel, Ronen

doi:10.1016/j.ymgmr.2022.100893

Cited by 7 publications

(8 citation statements)

References 24 publications

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“…For the younger subjects (Subject B2-B5), ITI was initiated swiftly upon the detection of elevated ADA titers, thereby minimizing the duration of high ADA exposure and potentially mitigating its impact. Recent reports have also addressed the importance of regular monitoring of ADA titers across both IOPD and LOPD patients ( 24 , 30 ). Secondly, our study’s reliance on conventional clinical outcome measures, such as the 6MWT and FVC, may not be sensitive enough to discern subtle improvements within the six-month study duration.…”

Section: Discussionmentioning

confidence: 99%

“…Before ITI initiation, patients underwent screening for infections such as hepatitis B, hepatitis C, and TB. Our protocol, modified from Duke University’s “Immune Response Protocol” ( 24 ), involved a six-month immunomodulation cycle with rituximab, oral methotrexate administered before ERT sessions, monthly IVIg, and four doses of bortezomib post-first ERT session. Patients with inadequate ADA reduction after six months, defined as ADA ≥ 1:6,400, underwent a second round of ITI cycle.…”

Section: Methodsmentioning

confidence: 99%

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Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Chen,

Hsu,

Fang

et al. 2024

Front. Immunol.

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IntroductionPompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels.MethodIn a single-center, open-label prospective study, we assessed ITI therapy’s efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI.ResultsThis study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea.ConclusionITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Chen,

Hsu,

Fang

et al. 2024

Front. Immunol.

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“…In previous studies, we have demonstrated the safety and efficacy of ITI with bortezomib, rituximab, methotrexate, and IVIG in inducing immune tolerance in patients with HSAT (14, [16][17][18][19]. These include the first known cases where bortezomib was successful in inducing long-term immune tolerance in patients with Pompe disease who developed HSAT.…”

Section: Discussionmentioning

confidence: 99%

“…In our current approach, a patient with anti-rhGAA antibody titers of 12,800 at two or more time points with or without evidence of a clinical decline/plateau is initiated on a bortezomib-based ITI regimen (29). The first example of our updated approach was presented in a recent case report, in which we reported on a CRIMnegative IOPD patient (patient 7) who was treated with immunomodulation with rituximab, methotrexate, and IVIG with weekly ERT at 40 mg/kg at the age of 4.5 months (Table 1) (19). The patient had noticeable initial progress in clinical response to treatment, however, a gradual increase in antibody titers was noticed with antibody titers peaking at 12,800 (week 24).…”

Section: Discussionmentioning

confidence: 99%

“…In this article, we summarize the lessons learned from patients previously reported who received a bortezomib-based ITI regimen and report on two new CRIM-positive IOPD patients who developed high antibody titers (14, [16][17][18][19]. Both newly reported patients failed to achieve durable immune tolerance despite routine immune modulation with TLD-MTX in the ERT-naïve setting.…”

Section: Introductionmentioning

confidence: 99%

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An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation

Desai,

Shrivastava,

Grant

et al. 2024

Front. Immunol.

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IntroductionHigh sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT.MethodsHere, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment.ResultsIn total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week.DiscussionThese case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

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Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies

Rana

Munoz

Biswas

2022

Cellular Immunology

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A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation

Cited by 7 publications

References 24 publications

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation

Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies

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