CRIM-Negative Pompe Disease Patients with Satisfactory Clinical Outcomes on Enzyme Replacement Therapy

Khallaf, Hamoud H. Al; Propst, Jennifer; Geffrard, Serge; Botha, Eleanor G.; Pervaiz, Muhammad Khalid

doi:10.1007/8904_2012_192

Cited by 11 publications

(12 citation statements)

References 15 publications

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“…This is consistent with a previous study that compared the level of antibody titers between patients treated with 20 or 40 mg/kg eow (Banugaria et al 2011). In line with previous observations (Khallaf et al 2013; van Gelder et al 2014) the patient's peak antibody titer seemed to be related to the age at start of therapy.…”

Section: Discussionsupporting

confidence: 91%

Effects of a higher dose of alglucosidase alfa on ventilator‐free survival and motor outcome in classic infantile Pompe disease: an open‐label single‐center study

Gelder

Poelman

Plug

et al. 2016

J of Inher Metab Disea

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BackgroundThough enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome.MethodsEight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated.ResultsAll eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3–5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation.ConclusionsOur data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.

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Section: Discussionsupporting

confidence: 91%

Effects of a higher dose of alglucosidase alfa on ventilator‐free survival and motor outcome in classic infantile Pompe disease: an open‐label single‐center study

Gelder

Poelman

Plug

et al. 2016

J of Inher Metab Disea

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“…As previously suggested (van Gelder et al 2012 ; Al Khallaf et al 2013 ), our study indicates that the age at start of ERT might play a role in the immune response since none of the patients who started ERT before 2 months of age developed titers > 1:6250. There are at least two plausible explanations for this: First, the neonatal immune system is immature, and very early administration of ERT might induce tolerance (Brooks 1999 ; Dierenfeld et al 2010 ).…”

Section: Discussionsupporting

confidence: 85%

“…Analysis of the immune response in 34 treated infants showed a strong tendency toward higher and sustained antibody titers in CRIM-negative compared to CRIM-positive infants (Kishnani et al 2010 ). However, CRIM-positive patients can also develop high titers (Banugaria et al 2011 ), and CRIM-negative patients low titers (Abbott et al 2011 ; Al Khallaf et al 2013 ). Our study in 11 infants has led to similar findings.…”

Section: Discussionmentioning

confidence: 99%

Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease

Gelder

Hoogeveen‐Westerveld

Kroos

et al. 2014

J of Inher Metab Disea

125

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BackgroundEnzyme-replacement therapy (ERT) in Pompe disease—an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy—can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response.MethodsEleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years.ResultsERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients’ CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer.ConclusionAntibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9707-6) contains supplementary material, which is available to authorized users.

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“…Of the 4 patients who developed titers during the study period, only one patient developed HSAT. Although there are 3 cases previously reported describing CRIM-negative patients who did not develop HSAT without ITI, one patient received omalizumab, an IgG monoclonal antibody that binds to IgE, for a severe allergic reaction to alglucosidase alfa; the other sibling pair had a splice site mutation in heterozygosity (35,36). A role for omalizumab in preventing the development of an IgG response cannot be excluded in this case.…”

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

confidence: 86%

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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CRIM-Negative Pompe Disease Patients with Satisfactory Clinical Outcomes on Enzyme Replacement Therapy

Cited by 11 publications

References 15 publications

Effects of a higher dose of alglucosidase alfa on ventilator‐free survival and motor outcome in classic infantile Pompe disease: an open‐label single‐center study

Effects of a higher dose of alglucosidase alfa on ventilator‐free survival and motor outcome in classic infantile Pompe disease: an open‐label single‐center study

Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease

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

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