PMID- 31985872
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7933 (Print)
IS  - 1538-7836 (Linking)
VI  - 18
IP  - 4
DP  - 2020 Apr
TI  - Combined anti-CD20 and mTOR inhibition with factor VIII for immune tolerance 
      induction in hemophilia A patients with refractory inhibitors.
PG  - 848-852
LID - 10.1111/jth.14740 [doi]
AB  - BACKGROUND: Hemophilia A (HA) inhibitor patients that fail traditional immune 
      tolerance induction (ITI) have increased morbidity and mortality. Preclinical 
      studies support factor VIII (FVIII) tolerance induction with a combined approach 
      of anti-CD20 mediated transient B cell depletion and rapamycin mediated 
      regulatory T cell (Treg) induction. METHODS: Two refractory HA inhibitor patients 
      were treated with rituximab, rapamycin, and FVIII ITI. Their clinical course, 
      anti-FVIII immunoglobulins, cytokines, and select lymphocytes were followed. 
      RESULTS: One patient achieved complete and the other partial FVIII tolerance; 
      both had marked annualized bleeding rate improvement. FVIII-specific 
      immunoglobulins, but not total Treg counts, correlated with tolerance induction. 
      IL-6 and IL-21 correlation with complete tolerance induction may support that 
      down-regulation of T effectors and IgG4 production, respectively, contribute to 
      the pathogenesis of tolerance induction. CONCLUSIONS: This regimen may be 
      considered to induce FVIII tolerance in HA patients with refractory inhibitors. 
      Further characterization of the FVIII-specific immune response is necessary to 
      clarify the mechanism of immune tolerance.
CI  - (c) 2020 International Society on Thrombosis and Haemostasis.
FAU - Doshi, Bhavya S
AU  - Doshi BS
AUID- ORCID: 0000-0001-7578-4231
AD  - Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, 
      PA, USA.
AD  - Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Raffini, Leslie J
AU  - Raffini LJ
AD  - Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, 
      PA, USA.
AD  - Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
FAU - George, Lindsey A
AU  - George LA
AUID- ORCID: 0000-0002-9763-1559
AD  - Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, 
      PA, USA.
AD  - Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
AD  - Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The 
      Children's Hospital of Philadelphia, Philadelphia, PA, USA.
LA  - eng
GR  - K08 HL146991/HL/NHLBI NIH HHS/United States
PT  - Case Reports
DEP - 20200302
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 9001-27-8 (Factor VIII)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - B-Lymphocytes
MH  - *Factor VIII
MH  - *Hemophilia A/drug therapy
MH  - Humans
MH  - Immune Tolerance
MH  - TOR Serine-Threonine Kinases
PMC - PMC7888210
MID - NIHMS1579718
OTO - NOTNLM
OT  - hemophilia A
OT  - immune tolerance
OT  - neutralizing antibody
OT  - rituximab
OT  - sirolimus
COIS- CONFLICTS OF INTEREST LAG has served as a consultant for Pfizer. BSD and LJR have 
      no conflicts of interest to declare.
EDAT- 2020/01/28 06:00
MHDA- 2021/05/15 06:00
PMCR- 2021/02/17
CRDT- 2020/01/28 06:00
PHST- 2019/10/14 00:00 [received]
PHST- 2019/12/31 00:00 [revised]
PHST- 2020/01/14 00:00 [accepted]
PHST- 2020/01/28 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2020/01/28 06:00 [entrez]
PHST- 2021/02/17 00:00 [pmc-release]
AID - S1538-7836(22)00286-0 [pii]
AID - 10.1111/jth.14740 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2020 Apr;18(4):848-852. doi: 10.1111/jth.14740. Epub 2020 Mar 
      2.