[CIS PIDD] VL: VL: [cis-pidd] treatment for IL12Rb1 deficiency

Wed May 21 01:27:20 EDT 2014

Dear Elena,

please see below Jacinta Bustamante's reply (me and Anne Puel forwarded Your request)

Mikko Seppänen, Finland
________________________________
Lähettäjä: Jacinta Bustamante [jacinta.bustamante at inserm.fr]
Lähetetty: 17. toukokuuta 2014 9:52
Vastaanottaja: Seppänen Mikko; Anne.puel at inserm.fr
Aihe: Re: VL: [cis-pidd] treatment for IL12Rb1 deficiency

Dear Mikko and Elena,

Thank you for your note and I apologize by my delayed response. I send my answers below:

Hi everybody,

We would like to ask your opinion for treatment approaches for BCGosis for a patient with IL12Rb1 chain deficiency.

This is a 3.5yr-old with a compound heterozygous IL-12 receptor beta1 chain deficiency complicated by BCGosis involving mainly pelvic and inguinal LN. His BCGosis has been treated with a combination of INH, rifampin, levofloxacin, clarithromycin for antimicrobial therapy. He also received interferon gamma 50 mcg/M2 3 times a week subcutaneously between February 2012 and April 2013. We saw him in July 2013 and performed antimicrobial serum drug levels sent to National Jewish, which were all somewhat low.  He also reinitiated IFN-gamma at that point at the above dose, and is currently still on it.  Recently, his MRI demonstrated slight increase in size of the R pelvic side LN, and his other para-aortic and mesenteric LNs are stable.  He’s clinically doing reasonably well, growing and developing appropriately. We plan to send blood to Wisconsin for flow cytometry analysis of any residual IL12R surface expression and function (STAT1, STAT4).

Here are our questions:

-        Has anyone been able to definitively treat BCGosis in the setting of Th1 immune defects using the combo of antimicrobials plus interferon-gamma?
Yes, the treatment should be antimycobacterial antibitics (three or four according to sensibility of antiogram) and interferon-gamma, during at least two-three years depend of resolution of acute infection. Please check if the concentration of ATB are in the range expected by assessment on blood.  The treatment with ATB is during long time, even after resolution of active infection.

-        If so, what dose and duration of IFN-gamma was used?
IFNg is used during acute period of infection. You can start the treatment at 50ug/m2 and you increase the dosis if it is well tolorated (without secondary effect)

-        Are there alternative approaches we might consider other than HCT or gene therapy?

Normally, BMT is not considered as treatment in this immunodeficiency. IL12RB1 deficiency confers big sites of infections, especially lymphadenophaties in abdomen. Surgery can resolve with the removal of active site of infection (in addition of ATB+ IFNg)

-        Paper from Dr. Cassonava’s group (Alangari et al., Clinical and Developmental Immunology, 2010) suggested that for IL12b1 deficiency patients, 200ug/M2 dose is effective and not at lower doses.  If anyone has used these higher doses, what are the toxicities we should monitor? (currently renal and liver function intact)

Yes, you can add the dosis of IFNg.
Finally, if you like I can check in our database if your two mutations have been found in our lab.

All the best,

Jacinta

We appreciate your input.

Thanks.

Elena Hsieh, MD

Allergy and Immunology Fellow

Stanford University

---Le 16/05/2014 12:06, Anne PUEL a écrit :
Dear Mikko,
Thank you so much for your email. I am forwarding it to Jacinta who is in charge of these kind of patients; she will soon reply to you and Elena.
All my best wishes,
Anne

--
Please note that our address has changed

Anne Puel, PhD
Génétique Humaine des Maladies Infectieuses
INSERM UMR 1163
Université Paris Descartes-Sorbonne Paris Cité
Institut Imagine
Pièce 421-B1
24 boulevard du Montparnasse
75015 PARIS
FRANCE

phone:  33 1 42 75 43 19
fax:    33 1 42 75 42 24
email: anne.puel at inserm.fr<mailto:anne.puel at inserm.fr>
web site: http://www.hgid.net

Le 16/05/2014 09:05, Seppänen Mikko a écrit :
Dear Anne,

this may be of interest to You and You might even be able to help Elena?

Mikko

dos Mikko Seppänen, LKT
Immuunipuutosv-o, HYKS

Mikko Seppänen, MD, PhD, Associate professor/Senior Lecturer
Specialist in Internal Medicine and Infectious Diseases
Senior Consultant, Physician in charge (PIDD)
Immunodeficiency Unit
Division of Infectious Diseases
Department of Medicine
Helsinki University Central Hospital
Hospital District of Helsinki and Uusimaa
Aurora Hospital, Ward 4-2 and Outpatient Clinic
P.O.Box 348
FI-00029 HUS, Helsinki
FINLAND
phone +358 9 47175923, fax +358 9 47175945

Lähettäjä: Elena Hsieh [mailto:whsieh at stanford.edu]
Lähetetty: 16. toukokuuta 2014 5:48
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] treatment for IL12Rb1 deficiency

Hi everybody,

We would like to ask your opinion for treatment approaches for BCGosis for a patient with IL12Rb1 chain deficiency.

This is a 3.5yr-old with a compound heterozygous IL-12 receptor beta1 chain deficiency complicated by BCGosis involving mainly pelvic and inguinal LN. His BCGosis has been treated with a combination of INH, rifampin, levofloxacin, clarithromycin for antimicrobial therapy. He also received interferon gamma 50 mcg/M2 3 times a week subcutaneously between February 2012 and April 2013. We saw him in July 2013 and performed antimicrobial serum drug levels sent to National Jewish, which were all somewhat low.  He also reinitiated IFN-gamma at that point at the above dose, and is currently still on it.  Recently, his MRI demonstrated slight increase in size of the R pelvic side LN, and his other para-aortic and mesenteric LNs are stable.  He’s clinically doing reasonably well, growing and developing appropriately. We plan to send blood to Wisconsin for flow cytometry analysis of any residual IL12R surface expression and function (STAT1, STAT4).

Here are our questions:

-        Has anyone been able to definitively treat BCGosis in the setting of Th1 immune defects using the combo of antimicrobials plus interferon-gamma?

-        If so, what dose and duration of IFN-gamma was used?

-        Are there alternative approaches we might consider other than HCT or gene therapy?

-        Paper from Dr. Cassonava’s group (Alangari et al., Clinical and Developmental Immunology, 2010) suggested that for IL12b1 deficiency patients, 200ug/M2 dose is effective and not at lower doses.  If anyone has used these higher doses, what are the toxicities we should monitor? (currently renal and liver function intact)

We appreciate your input.

Thanks.

Elena Hsieh, MD

Allergy and Immunology Fellow

Stanford University

---

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--
< PLEASE NOTE OUR NEW  ADDRESS>

Jacinta Cecilia Bustamante MD, PhD
Laboratoire de Génétique Humaine
des Maladies Infectieuses INSERM U1163 (ex U980)
Institut Imagine
24 Boulevard de Montparnasse
75015 Paris, FRANCE, UE

Téléphone 33 1 42 75 43 20
FAX 33 1 42 75 42 24
E-mail jacinta.bustamante at inserm.fr<mailto:jacinta.bustamante at inserm.fr>
web site http://www.hgid.net

Centre d'Etudes des Déficits Immunitaires (CEDI)
Tour Lavoisier - 2ème étage
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