Response of 33 UK patients with infantile‐onset Pompe disease to enzyme replacement therapy

Broomfield, Alexander; Fletcher, Joan; Davison, James; Finnegan, Niamh; Fenton, Matthew; Chikermane, Ashish; Beesley, Clare E.; Harvey, Katie; Cullen, Emmaline; Stewart, Catherine; Santra, Saikat; Vijay, Suresh; Champion, Michael; Abulhoul, Lara; Grünewald, Stéphanie; Chakrapani, Anupam; Cleary, M. A.; Jones, Simon A.; Vellodi, Ashok

doi:10.1007/s10545-015-9898-5

Cited by 61 publications

(90 citation statements)

References 34 publications

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“…CRIM-negative cases from across the globe have demonstrated their susceptibility to the development of high rhGAA IgG titers (2,7,32,33). However, unlike other prognostic factors, such as degree of existing damage at baseline, underlying genotype, differences in skeletal muscle fiber-type distribution, ACE and ACTN3 genotyping, and defective autophagy, immunogenicity is an avertable complication (34).…”

Section: Discussionmentioning

confidence: 99%

“…A role for omalizumab in preventing the development of an IgG response cannot be excluded in this case. Therefore, we believe that CRIM-negative ERT monotherapy cases who did not develop HSAT represent a smaller subset compared with CRIM-negative cases reported from across the globe with higher susceptibility to the development of high rhGAA IgG titers (2,7,32,33). Currently, there is no way to predict CRIM-negative cases who would not develop HSAT/SIT, and this can be a confounding factor while interpreting the efficacy of this ITI protocol.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

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Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

Kazi¹,

Desai²,

Kl³

et al. 2017

JCI Insight

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BACKGROUND.Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown. METHODS.Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy. RESULTS.ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of ≤6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of ≥51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m 2 at baseline to 76.8 g/m 2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of ≤6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy. CONCLUSION.Evidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT. TRIAL REGISTRATION. Clinicaltrials.gov NCT01665326. FUNDING.

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Section: Discussionmentioning

confidence: 99%

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

Kazi¹,

Desai²,

Kl³

et al. 2017

JCI Insight

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“…12 However, treatment of severe cardiac disease remains quite challenging. [13][14][15] CONCLUSION Typically, patients with infantile-onset Pompe disease and severe hypertrophic cardiomyopathy are not as responsive to enzyme replacement therapy as patients with mild or no hypertrophic cardiomyopathy. Our patient had severe hypertrophic cardiomyopathy, and despite her death, we believe that her heart had significantly improved, and her death was related to the sequelae of her respiratory infection and hypotonia rather than cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Improvement in Cardiac Function With Enzyme Replacement Therapy in a Patient With Infantile-Onset Pompe Disease

Niyazov

Lara

2018

TOJ

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“…The otherwise fatal course of IPD has been altered with improved survival since the availability of enzyme replacement therapy (ERT) using alglucosidase alfa (rhGAA) [6]. However, the response to ERT and thereby the clinical outcome is largely influenced by many factors including the cross-reactive immunologic material (CRIM) status and antibody response to rhGAA [7,8]. CRIM-negative patients and a subset of CRIM-positive patients develop high sustained antibody titers (HSAT) and sustained intermediate titers (SIT) neutralizing the efficacy of the therapeutic protein, thereby leading to a progressive course of illness in spite of ongoing ERT [8–10].…”

Section: Introductionmentioning

confidence: 99%

“…However, the response to ERT and thereby the clinical outcome is largely influenced by many factors including the cross-reactive immunologic material (CRIM) status and antibody response to rhGAA [7,8]. CRIM-negative patients and a subset of CRIM-positive patients develop high sustained antibody titers (HSAT) and sustained intermediate titers (SIT) neutralizing the efficacy of the therapeutic protein, thereby leading to a progressive course of illness in spite of ongoing ERT [8–10]. HSAT is defined as titers ≥1:51,200 on two or more separate occasions after ≥6 months on ERT [11], yet it needs to be recognized that titers ≥1:12, 800 over a period of time (SIT) also reduce enzyme efficacy.…”

Section: Introductionmentioning

confidence: 99%

High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient

Rairikar

Kazi

Desai

et al. 2017

Molecular Genetics and Metabolism

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Alglucosidase alfa (rhGAA) has altered the course of an otherwise fatal outcome in classic infantile Pompe disease (IPD), which presents with cardiomyopathy and severe musculoskeletal involvement. However, the response to therapy is determined by several factors including the development of high and sustained antibody titers (HSAT) to rhGAA. Cross-reactive immunologic material (CRIM) negative patients are at the highest risk for development of HSAT. Immune tolerance induction (ITI) with methotrexate, rituximab, and intravenous immunoglobulin (IVIG) has been largely successful in preventing the immune response and in achieving tolerance when done in conjunction with enzyme replacement therapy (ERT) initiation. Reducing antibody titers in cases with an entrenched immune response remains a challenge in the field despite the use of multiple immunomodulatory agents. Success has been shown with addition of bortezomib to the ITI regimen, yet the prolonged course and potential risks with the use of such agents’ demands caution. We present here a 7-year-old CRIM-negative IPD patient who was not successfully tolerized by an ITI regimen with rituximab, methotrexate, and IVIG due to intolerability to the regimen and recurrent infections. She went on to develop HSAT, with significant clinical decline, loss of all motor abilities, and a fragile medical state, which made it challenging to institute the bortezomib based regimen to reduce HSAT. She had severe developmental delay, respiratory failure with invasive ventilation and tracheostomy, persistent hypotonia, ptosis of eyelids, diffuse severe osteopenia, contractures, and was completely G-tube fed. As a rescue mechanism, we treated her with high dose and high frequency IVIG in an attempt to reduce rhGAA IgG antibody titers (antibody titers; titers). Her titers saw a steady decline on weekly IVIG doses at 1 g/kg for 20 weeks. Subsequently when the IVIG regimen was altered to 1 g/kg every month, rising titers were detected and therefore the regimen was changed to a biweekly regimen. High dose IVIG resulted in an eightfold decrease in antibody titers. Clinically, she showed improvement with partial recovery of previously lost motor abilities, especially hand movements and better head and neck control than before. The regimen was safely tolerated with no hospitalizations. The effectiveness of IVIG as a single agent, in this case with multiple comorbidities and fragile clinical status, was lifesaving and may represent an effective, perhaps lifesaving rescue approach to reduce antibody titers.

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Response of 33 UK patients with infantile‐onset Pompe disease to enzyme replacement therapy

Abstract: The outcome of treated patients remains heterogeneous despite attempts at immunomodulation. Failure to thrive at baseline and left ventricular dilation appear to be associated with poorer outcomes.

Cited by 61 publications

References 34 publications

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

Improvement in Cardiac Function With Enzyme Replacement Therapy in a Patient With Infantile-Onset Pompe Disease

High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient

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