Table 1.
Study characteristics
| Source | Year | N | Country | Study cohort | Inclusion criteria | Severe % | Ethnicity % |
F8 genotype % |
ITI outcome definitions |
Quality | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Complete success | Partial success | Failure | ||||||||||
| Barnes [37] | 2006 | 32 | Canada | MC | † | 94 | 66 white, 9 African American, 16 Asian, 9 others | na | (A) ‡ (n = 12) (B) (i) Negative inhibitor; (ii) normal recovery (n = 4); (C) Negative inhibitor (n = 6); (D) No criteria (n = 1) |
na | na | +/- |
| Batorova[38] | 2016 | 19 | Slovakia | MC | Children (≤18 y) | 100 | na | 32 Int22Inv, 5 Int1Inv, 21 small deletion, 26 missense mutation, 16 nonsense mutation | ‡ | (i) Negative inhibitor; (ii) Inability to normalize FVIII recovery or half-life; (iii) Clinical response to FVIII therapy without an anamnestic increase | (A) Inability to eradicate inhibitor; (B) Inability to install an effective prophylaxis within 36 mo of ITI | +/- |
| Callaghan[39] | 2011 | 31 | US | SC | Children (≤18 y) | 100 | 26 white, 61 African American, 13 others | na | ‡ | na | (A) Inability to achieve CS in 22 mo; (B) ≤20% decrease inhibitor titer over a 6-mo period after 3 mo ITI | + |
| DiMichele[25] | 2002 | 164 | US, Canada | MC | † | 93 | 63 white, 13 Asian, 24 others | na | ‡ | na | (A) ineffectiveness ITI; (B) self desire to terminate ITI; (C) CVAD complications; (D) adverse reaction to therapy; (E) loss of medical insurance; (F) patient relocation; (G) death from unrelated causes; (H) poor patient compliance; (I) enrollment in a BPA study | +/- |
| Di Minno[40] | 2021 | 137 | Italy | MC | HR inhibitors | 100 | na | 53 Int1/22Inv, 7 small deletion, 8 small insertion, 9 large deletion, 3 missense, 8 nonsense, 3 splice site | ‡ | (A) Inhibitor <5 BU/mL; (B) Inability to normalize FVIII recovery or half-life | (A) Inability to achieve CS in 33 mo; (B) ≤20% decrease inhibitor titer over a 6-mo period after 3 mo ITI | +/- |
| Dou[41] | 2021 | 110 | China | MC | † | na | na | na | Negative inhibitor (<0.6 BU/mL) | na | na | - |
| El Alfy[42] | 2000 | 10 | Egypt | SC | Children (<18 y) | 100 | na | na | (i) Inhibitor <2 BU/mL; (ii) FVIII recovery ≥60%; (iii) absence of anamnestic response on subsequent FVIII exposure | na | No decrease inhibitor titer over a 6-mo period | +/- |
| Elafly[43] | 2021 | 20 | Egypt | MC | Children (2-18 y); HR inhibitors |
100 | other | na | (i) Negative inhibitor (<0.6 BU/mL); (ii) FVIII recovery >66% | (i) Inhibitor <5 BU/mL; (ii) FVIII recovery <66% | Inability to achieve CS/PS in 24 mo | +/- |
| Escobar[44] | 2020 | 13 | US | MC | † | 92 | 15 white, 46 African American, 8 Asian, 31 others |
31 Int22Inv, 15 small deletion | ‡ | (i) Inhibitor <5 BU/mL; (ii) Inability to normalize FVIII recovery or half-life; (iii) Clinical response to FVIII therapy without an anamnestic increase | Inability to achieve CS/PS | +/- |
| Greninger[45] | 2008 | 11 | US | SC | HR inhibitors; treatment (≥1) with Alphanate | 100 | 46 white, 9 African American, 9 Asian, 36 others | 36 Int22Inv, 9 small deletion, 9 missense, 18 nonsense, 9 splice site | ‡ | (i) Negative inhibitor (<0.6 BU/mL); (ii) Inability to normalize FVIII recovery or half-life | Inability to achieve CS/PS | +/- |
| Hay[21] | 2012 | 115 | na | MC | Children (<8 y); Peak inhibitor titer ≥5 - ≤200; Pre-ITI titer ≤10 BU/mL |
100 | 51 white, 8 African American, 20 Asian, 20 others | na | ‡ | (i) Negative inhibitor (<0.6 BU/mL); (ii) Inability to normalize FVIII recovery or half-life; (iii) Clinical response to FVIII therapy without an anamnestic increase | (A) Inability to achieve CS in 33 mo; (B) ≤20% decrease inhibitor titer over a 6-mo period after 3 mo ITI; (C) Withdrawal from study | + |
| Haya[46] | 2001 | 42 | Spain | MC | † | 83 | na | na | (i) Negative inhibitor; (ii) FVIII half-life ≥8 hours | (i) Immune response shifted from a high- to low responder (<10 BU/mL) | No decrease inhibitor titer | +/- |
| Kreuz[47] | 2016 | 48 | Croatia, Germany, Poland, Portugal, Russia, Slovakia, Slovenia, Spain | MC | † | 83 | 96 white | na | ‡ | (i) Negative inhibitor (<0.6 BU/mL); (ii) Inability to normalize FVIII recovery or half-life | (A) Inability to achieve CS/PS in 36 mo; (B) Withdrawal from study | + |
| Kurth[30] | 2011 | 33 | US | MC | HR inhibitors; Treatment with pdFVIII/VWF |
100 | 54 white, 24 African American, 6 Asian, 15 others | na | ‡ | (i) Inhibitor titer <5 BU/mL; (ii) Clinical response to FVIII therapy without an anamnestic increase | (A) Inability to achieve CS in 33 mo; (B) ≤20% decrease inhibitor titer over a 6-mo period after 3 mo ITI |
+/- |
| Lapalud[48] | 2015 | 15 | France | MC | Children (≤6 y); HR inhibitors; Follow-up ≥33 mo |
100 | na | na | ‡ | na | Inability to achieve CS/PS | +/- |
| Lenk[49] | 2000 | 140 | Germany | MC | † | 87 | na | na | (i) Therapy completed; (ii) Normal FVIII recovery; (iii) Normal FVIII half-life | (i) Inhibitor ≤2 BU/mL; and/or (ii) Inability to normalize FVIII recovery or half-life | Inability to achieve CS/PS (lack of compliance, additional diseases or death included) | - |
| Lin [50] | 2011 | 29 | Taiwan | SC | † | 93 | na | na | (i) Negative inhibitor (<0.6 BU/mL); (ii) Absence of anamnestic response on subsequent FVIII exposure | (i) >50% reduction of inhibitor titer; (ii) Clinical response to FVIII therapy; (iii) No need for bypass therapy | No decrease inhibitor titer | + |
| Mariani[51] | 2001 | 314 | Australia, Canada, Europe, Japan, US | MC | † | 100 | na | na | ‡ | Immune response shifted from a high- to low responder | No decrease inhibitor titer | +/- |
| Nakar[52] | 2015 | 58 | US | MC | † | 95 | 85 white, 2 African American, 2 Asian, 10 others | 48 Int22Inv, 2 Int1Inv, 10 small deletion, 2 small insertion, 16 missense, 3 nonsense, 3 frame shift | (i) Negative inhibitor; (ii) Ability to use FVIII concentrate for treatment of bleeding | (i) Inhibitor titer 1-5 BU/mL; (ii) Ability to use FVIII concentrate for treatment of bleeding | (A) Inability to achieve CS/PS in 36 mo; (B) Withdrawal from study | + |
| Nogami[31] | 2018 | 155 | Japan | MC | † | 90 | Asian | na | Negative inhibitor | na | No decrease inhibitor titer under threshold | +/- |
| Oldenburg[53] | 2014 | 60 | Germany, Italy, Spain | MC | Treatment with high-purity pdFVIII/VWF. | na | 88 white, 12 others | na | ‡ | (i) Negative inhibitor (<5 BU/mL); (ii) Inability to normalize FVIII recovery or half-life; (iii) Clinical response to FVIII therapy without an anamnestic increase | Inability to achieve CS/PS | +/- |
| Rivard[54] | 2013 | 32 | Canada, France, Greece, Italy, Spain | MC | Children (≤8 y); Treatment with rFVIII-FS; HR inhibitors; Treatment ≥9 mo |
100 | 78 white, 6 African American, 6 Asian, 9 others | na | (A) (i) Negative inhibitor; (ii) Normal FVIII recovery (n = 9); (B) Negative inhibitor (n = 8); (C) ‡ (n = 5) |
na | na | +/- |
| Rocino[55] | 2016 | 71 | France, Germany, Italy, Netherlands, Portugal, Spain, Sweden | MC | Follow-up ≥12 mo | 100 | na | 61 Int22Inv, 3 Int1Inv, 9 small deletion, 5 large deletion, 6 nonsense, 6 splice site | ‡ | (i) Negative inhibitor (<0.6 BU/mL); (ii) Inability to normalize FVIII recovery or half-life; (iii) Clinical response to FVIII therapy without an anamnestic increase | Inability to achieve CS/PS within 9 mo follow-up | +/- |
| Ryu[56] | 2015 | 17 | Korea | SC | Historical titer >5 BU/mL; Pre-ITI titer <10 BU/mL |
100 | Asian | 35 Int1Inv, 12 small deletion, 29 nonsense, 24 frame shift | ‡ | (i) Immune response shifted from a high- to low responder; (ii) Ability to use FVIII concentrate for treatment of bleeding | No decrease inhibitor titer for 10 wk | +/- |
| Salviato[24] | 2007 | 16 | Italy | MC | † | 100 | na | 31 Int22Inv, 19 small deletion, 13 large deletion, 31 nonsense, 6 splice site | na | na | na | - |
| Ter Avest[57] | 2010 | 21 | Netherlands | SC | Children (<6 y) Low dose ITI treatment |
100 | White | 52 Int22Inv, 14 small deletion, 29 large deletion | ‡ | (i) Negative inhibitor (<0.6 BU/mL); (ii) Inability to normalize FVIII recovery or half-life; (iii) Clinical response to FVIII therapy without an anamnestic increase | (A) No decrease inhibitor titer for ≥ 26 wk ITI treatment; (B) Switch to a high dose regimen | +/- |
| Unuvar[58] | 2008 | 21 | Turkey | MC | Children (≤20 y); HR inhibitors | 95 | na | na | ‡ | (i) Inhibitor titer <5 BU/mL; (ii) Clinical response to FVIII therapy without an anamnestic increase | (A) Inability to achieve CS/PS within 6-36 mo follow-up; (B) No decrease inhibitor titer <5 BU/mL | +/- |
Abbreviations: na = not available, N = number of participants, ITI = immune tolerance induction, SC = single center, MC = multicenter, HR inhibitors = High-responding inhibitor ≥5 BU/mL, Int22Inv = intron 22 inversion, Int1Inv = intron 1 inversion, Int1/22Inv = Intron 1 or Intron 22 inversion, y = year, CS = complete success, PS = partial success, BU = Bethesda Unit, rFVIII-FS = recombinant FVIII formulated with sucrose, pdFVIII/VWF = plasma-derived FVIII containing von Willebrand Factor.
Study quality scored according to the JBI checklist as follows: + high-quality, +/- intermediate- quality, - low quality.
†
inclusion criteria (i) hemophilia A; (ii) inhibitor; (iii) ITI treatment.
‡
ITI success defined according to the International ITI study: (i) Negative inhibitor (<0.6 BU/mL); (ii) FVIII recovery >66%; (iii) FVIII half-life >6 hours; ((iv) Absence of anamnestic response on subsequent FVIII exposure).[21]