[CIS PIDD] [cis-pidd] Transplanted boy with WAS

Thu Aug 7 15:29:00 EDT 2014

Dear All,
Thank you all for most helpful input. Re NK cell testing, mutation analysis and other functional tests we are relying on Yenan so we feel we have exhausted all possible diagnostic approaches for both the twin donors and the patiens.  So the point about Yenan by Paul is important - no worries about transportation of material to the USA.

Also, we will consider alemtuzumab to deplete both macros and possible faulty T cells and NK cells . Discussions with the parents will take place next week.

And will do another round of meticulous search for any infections. At his first HLH event, it is likely that a fungal infection was the trigger. He had in retrospect for a month at least very high beta-glycans not followed-up by the treating doctor. He is now on prophylactic Ambisome since months with normal beta-glycan.  Fungal cultures never revealed the specific agent.  

Once again thank you all for your advice
Best
Anders

Anders Fasth, MD, PhD
Professor of Pediatric Immunology, 
Dept of Pediatrics, University of Gothenburg
Address: The Queen Silvia Children’s Hospital,
SE-416 85 Göteborg, Sweden
Tel +46-31-343 5220 (343 4000 switchboard)
Mobile +46-76-050 6117 (work) +46-70-687 5970 (private)
Fax +46-31-707 0694

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Thank you

On 7 aug 2014, at 21:08, Szabolcs, Paul <paul.szabolcs at chp.edu> wrote:

> Could we avoid the myriads of short term and long term risks associated with a second transplant ( esp.  a MAC regimen) by giving Alemtuzumab ( 1mg/kg/dose x 1-2 days) + Steroids with the possibility of graded DLI from non-carrier sister if Anders is concerned of T cell recovery ( or a dangerous opportunistic infection)? Alemtuzumab at this higher dose would be expected to ablate most monocytes as well not to mention the lymphocytes.
> 
> If this "resetting" of his immune clock/dysregulated immunity failed,- he would still be eligible for a subsequent transplant intervention
> 
> Best regards, Paul
> 
> Paul Szabolcs, MD
> 
> Professor of Pediatrics and Immunology,
> University of Pittsburgh School of Medicine,
> Chief, Division of Blood and Marrow Transplantation and Cellular Therapies
> Children’s Hospital of Pittsburgh of UPMC
> http://www.chp.edu/CHP/bmt
> 
> One Children’s Hospital Drive
> 4401 Penn Avenue, Rangos, Room 5125
> Pittsburgh, PA 15224
> Phone:  412-692-6225
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> E-mail:  paul.szabolcs at chp.edu<mailto:paul.szabolcs at chp.edu>
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> 
> 
> From: "Notarangelo, Luigi" <Luigi.Notarangelo at childrens.harvard.edu<mailto:Luigi.Notarangelo at childrens.harvard.edu>>
> Reply-To: CIS CIS servlist <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Date: Thu, 7 Aug 2014 17:51:19 +0000
> To: CIS CIS servlist <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Subject: Re: [cis-pidd] Transplanted boy with WAS
> 
> Good question, Jack. It has been successfully used while preparing for HSCT in patients with HLH who had viral reactivation, but in those cases specific antivirals were used at the same time. Not knowing what the virus (if any), may be a problem.
> 
> Gigi
> 
> Luigi D. Notarangelo, MD
> Professor of Pediatrics and Pathology
> Harvard Medical School
> Jeffrey Modell Chair of Pediatric Immunology Research
> Division of Immunology, Children's Hospital Boston
> Karp Research Building, Room 10217
> 1, Blackfan Circle
> Boston, MA 02115
> 
> tel: (617)-919-2277
> FAX: (617)-730-0709
> 
> 
> 
> From: <Bleesing>, Jacob <Jack.Bleesing at cchmc.org<mailto:Jack.Bleesing at cchmc.org>>
> Reply-To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Date: Thursday, August 7, 2014 at 1:18 PM
> To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Subject: RE: [cis-pidd] Transplanted boy with WAS
> 
> Gigi:
> Would you use anti-IFN-g if there is a viral reactivation?
> 
> J
> 
> From: Notarangelo, Luigi [mailto:Luigi.Notarangelo at childrens.harvard.edu]
> Sent: Thursday, August 07, 2014 1:15 PM
> To: CIS-PIDD
> Subject: Re: [cis-pidd] Transplanted boy with WAS
> 
> Dear Anders,
> 
> I also think that primary HLH is extremely unlikely. I believe this is probably due to viral reactivation and therefore is a secondary HLH. I would consider using anti-IFN-g (you may inquire at Novimmune) which has worked very well in controlling HLH prior to HCT. I would also use HLH-2004 at the same time, then re-transplant with myeloablative regimen, and would definitely NOT use cord blood
> 
> 
> Gigi
> 
> 
> 
> Luigi D. Notarangelo, MD
> Professor of Pediatrics and Pathology
> Harvard Medical School
> Jeffrey Modell Chair of Pediatric Immunology Research
> Division of Immunology, Children's Hospital Boston
> Karp Research Building, Room 10217
> 1, Blackfan Circle
> Boston, MA 02115
> 
> tel: (617)-919-2277
> FAX: (617)-730-0709
> 
> 
> 
> From: Elie Haddad <elie.haddad at umontreal.ca<mailto:elie.haddad at umontreal.ca>>
> Reply-To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Date: Thursday, August 7, 2014 at 1:09 PM
> To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Subject: Re: [cis-pidd] Transplanted boy with WAS
> 
> Dear Anders,
> indeed the case is weird...
> If one considers primary HLH, then it would mean that the donor has primary HLH (weird...) and therefore, looking at NK cell degranulation in donors and in the patient would be necessary. Nevertheless, there is something that seems to me not logical with the hypothesis of primary HLH of the donor. Indeed, you said that you have a split chimerism, 1/3 male, 2/3 female. If the female has primary HLH, then 1/3 from a normal bone marrow should be enough  to control the HLH from the female, unless both donors have HLH...very weird...but why not, and this is the reason why I think you should test NK cell degranulation in both donors. Of course, if both donors have HLH, then you should retransplant with an unrelated donor. Really, when you think that these parents did HLA-PGD to cure their child with a WAS, and then both siblings have an HLH without any clinical signs but they transmitted HLH to their brother .....what a terrible story ...
> Now, if one considers secondary HLH, then you have to rule out malignancy, autoimmunty and infection and I suppose you already did this. Nevertheless, sometimes it is not easy to rule out completely. However, there is one cause of secondary HLH that is rare and that can come with a kind of skin eruption that is Histiocytosis X. I remember a case I was involved in when I used to work in Alain Fischer's group. The patient had relapsig HLH-like episodes and skin eruption that eventually was histiocytosis X. Did your pathologist perform CD1a staining ?
> I hope it helps...
> All the best
> Elie
> 
> 
> Elie Haddad MD, PhD,
> Professeur Titulaire, Département de Pédiatrie, Université de Montréal,
> Chef du Service d'Immunologie, Rhumatologie et Allergologie Pédiatriques
> CHU Sainte-Justine,
> 3175 Chemin de la Cote Sainte-Catherine
> Montreal, QC, H3T 1C5, Canada
> T: 514 345 4713
> Fax: 514 345 4897
> e-mail: elie.haddad at umontreal.ca<mailto:elie.haddad at umontreal.ca>
> 
> Le 2014-08-07 à 04:31, Anders Fasth a écrit :
> 
> 
> Dear All,
> This case below I have asked for advice earlier in July, but nobody replied. Too difficult case ???
> 
> I am still anxious for your advice. The update is even more troublesome: He was started on the HLH04 protocol again and after dexamethasone and two etopside his ferritin has gone from 2000 to 18 000. The pediatric oncologist are afraid of retransplantation, but does he has a chance without a new transplantation?.
> 
> The case as from my mail in late July.
> 
> I need your advice re a six year old boy with WAS transplanted with a double cord 14 months ago. Donors were his sibling twins (sister - non-carrier and brother) born after HLA-PGD. More or less eventful course for the first 3 months. Trombocytes returned to normal, full donors chimera, today about ⅔ female donor and ⅓ male donor. In late September last year he developed a rash that nobody could put a dx to: biopsy - no GvhD, possible eczema. In December, 8 months post SCT, he develops HLH with all typical findings and ferritin >100 000. New skin biopsy at time of HLH showed massive infiltrates of histeocytes. Nu mutation in FHL genes. Treated according to HLH-04 protocol and quickly clinically  better, but only slowly normalizing his ferritin over many months.
> Now for about a month normal ferritin, but as steroids was tapered down his skin rash is back since a couple of weeks. And last week ferritin was slowly raising and is today 1900 + fever = relapse of his HLH.
> 
> My concern is of course  - how to get a sustained response. Should we re-transplant him? He has his matched twin siblings that now are 1 ½ years of age so we can use bone marrow this time.
> 
> Anders
> 
> 
> Anders Fasth, MD, PhD
> Professor of Pediatric Immunology,
> Dept of Pediatrics, University of Gothenburg
> Address: The Queen Silvia Children’s Hospital,
> SE-416 85 Göteborg, Sweden
> Tel +46-31-343 5220 (343 4000 switchboard)
> Mobile +46-76-050 6117 (work) +46-70-687 5970 (private)
> Fax +46-31-707 0694
> 
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> 
> CONFIDENTIALITY NOTICE: This E-mail message, including any attachments, is for the sole use of intended recipient(s)and may contain confidential and privileged information. Any unauthorized review, use, disclosure or distribution is prohibited. If you are not the intended recipient, please contact the sender by reply E-mail and destroy all copies of the original message and its attachments without reading or saving in any manner.
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> Thank you
> 
> 
> 
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