[CIS PIDD] [cis-pidd] ADA SCID tx

Tue Jul 15 07:20:47 EDT 2014

The introduction of newborn screening for Krabbe disease in NY State a couple of years ago has created similar stress

The incidence may be lower but once there is low galactocerebrosidase ( GLC) level found on the Guthrie cards a slew of tests may/should follow. While infantile Krabbe is devastating by 3-4 months of age  parents may not be able to identify tell tell signs ~ 6-8 weeks after birth.

Nevertheless, some  may not even have disease onset till they are juvenile despite n  confirmed near zero GLC levels. MRI, nerve conduction, along with  CSF samples are tested by Maria Escolar while David Wenger has identified a few mutations amongst >100s that may have sufficient predictive  power nevertheless, this is still research in progress.

Paul

From: <Notarangelo>, "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: Monday, July 14, 2014 at 8:44 PM
To: CIS CIS servlist <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Subject: Fwd: [cis-pidd] ADA SCID tx

We also are facing similar issues. It is important to discuss this at the PIDTC meeting in Montreal. It has been suggested to look into similar issues with other newborn screening tests that have been in practice for years, but I do not think this works. The problem with SCID is that:

A) the baby looks healthy, yet the family is told that there is a severe immunodeficiency with susceptibility to life threatening infections. As already mentioned by Jack Bleesing on this listserv, families have a hard time believing this, and they often do not trust results of immunological tests

B) NBS for SCID is also unique in that we tell families that the baby needs transplant ASAP as a life saving treatment. There is no other similar example in other newborn screening tests where such a radical and risky therapeutic approach is proposed while the baby looks perfectly fine to the families

I think there is a need for a multiinstitutional survey/study of this problem, and interaction with patient advocacy groups would be important.

Gigi

Sent from my iPad

Luigi D. Notarangelo, MD
Jeffrey Modell Chair of Pediatric Immunology Research
Division of Immunology, Boston Children's Hospital
Professor of Pediatrics and Pathology, Harvard Medical School
Karp Research Building, Room 10217
1, Blackfan Circle
Boston, MA 02115
USA

Tel: 617-919-2277
FAX: 617-730-0709

Begin forwarded message:

From: "Cowan, Mort" <mcowan at peds.ucsf.edu<mailto:mcowan at peds.ucsf.edu>
Date: July 14, 2014 at 8:21:26 PM EDT
To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Subject: RE: [cis-pidd] ADA SCID tx
Reply-To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>

I think this is a very important topic and I'm sure that we can learn from the literature, but I suspect we will need to also chart new ground.  At UCSF we have seen the potentially devastating effects of notifying parents who have a perfectly healthy-appearing baby that their child has 1) a severe and life-threatening disease 2) needs a bone marrow transplant  3) needs to be in the hospital urgently, and 4) may need to stop breast-feeding depending on the CMV sero-status of the mother.  This is also around the time that maternal post-partum depression (without any of the above) may kick in. On top of all of this parents are generally being separated as the mother comes with the baby to the hospital leaving the father to work and also manage any other children.  It's really the perfect storm.  We are starting a study of this to try to develop better supportive approaches, but of course, the first thing is to recognize it as a real problem and start working with the parents as soon as you tell them about their child's diagnosis.

Mort

Morton J. Cowan, M.D.
Professor of Pediatrics
Chief, Allergy, Immunology, and Blood and Marrow Transplant Division UCSF Children's Hospital, Room M659
505 Parnassus Ave
San Francisco, CA 94143-1278

Phone: 415-476-2188
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-----Original Message-----
From: Infante, Anthony J [mailto:INFANTEA at uthscsa.edu]
Sent: Monday, July 14, 2014 10:45 AM
To: CIS-PIDD
Subject: RE: [cis-pidd] ADA SCID tx

Newborn screening has clearly changed the psychosocial impact of SCIDS in my experience. Previously, most patients were desperately ill at diagnosis, parents knew something was seriously wrong, and were relieved to get a diagnosis. Now, baby looks perfectly well and parents are devastated to hear their child has a fatal disorder. Perhaps there is literature on other conditions which have been screened in newborns for a long time.

Tony Infante

-----Original Message-----
From: Perez, Elena [mailto:e.perez13 at med.miami.edu]
Sent: Sunday, July 13, 2014 9:37 AM
To: CIS-PIDD
Subject: RE: [cis-pidd] ADA SCID tx

Thanks Gigi and Paul. Very helpful. We discussed on Friday and also decided to hold off a little longer on ADA. Will keep you posted.

It was tough at the very beginning with this NBS identified baby to decide ADA vs imminent tx...he had some respiratory distress at presentation but no infection (detectable) and I wondered whether ADA would have corrected that (having read mice studies about ada and lung issues)... But we decided to go to tx asap, and support him through it (only ever needed NC O2)  and he got better eventually on antibiotics (so maybe it was infection?). Now he is doing great except that he had pyloric stenosis on top of it, this was surgically corrected and now he's eating like crazy.

On the side, I wonder if anyone yet has looked into the effects of NBS on post partum depression...mom of baby is having a very tough time.

Thank you again for your support!
Elena

________________________________________
From: Notarangelo, Luigi [Luigi.Notarangelo at childrens.harvard.edu<mailto:Luigi.Notarangelo at childrens.harvard.edu>]
Sent: Sunday, July 13, 2014 10:02 AM
To: CIS-PIDD
Subject: Re: [cis-pidd] ADA SCID tx

Agree with Paul! Also, you may want to have lineage specific chimerism data.

Gigi

Luigi D. Notarangelo
Professor of Pediatrics and Pathology, Harvard Medical School Jeffrey Modell Chair of Pediatric Immunology Research Division of Immunology, Children¹s Hospital Boston Karp Research Building, Room 10217
1 Blackfan Circle
Boston, MA 02115

tel: +1-(617)-919-2277
FAX: +1-(617)-730-0709

On 7/13/14 8:58 AM, "Szabolcs, Paul" <paul.szabolcs at chp.edu<mailto:paul.szabolcs at chp.edu>> wrote:

Elena

The data is not that hopeless with these details. A second donor search
can be initiated but this graft is not lost yet. I would follow now Q2
weeks chimerism and holding ADA at least till next dataset is
worthwhile indeed.
Best, Paul

On 7/12/14, 9:09 AM, "Sokolic, Robert (NIH/NHGRI) [E]"
<sokolicr at mail.nih.gov<mailto:sokolicr at mail.nih.gov>> wrote:

Elena-
I agree with what the others have said in terms of withdrawal of
immunosuppression. Would then start PEG-ADA. Rather than going to
haplo or another cord, I would advise looking for a MUD, b/c the child
should be stable after a 3-4 months on PEG. This is assuming that a
MUD is less toxic than a haplo as done by your transplanters  You
could try withholding the PEG while immunosuppression is withdrawn to
give an added advantage to the donor cells.
Rob

From: Perez, Elena [e.perez13 at med.miami.edu<mailto:e.perez13 at med.miami.edu>]
Sent: Friday, July 11, 2014 12:26 PM
To: CIS-PIDD
Subject: RE: [cis-pidd] ADA SCID tx

Jack and Cary- I double checked, on stem cell processing lab sheet and
TNC/kg=1.69x10^8 is listed, so previous email was a typo taken from
EMR chart. Today chimerism is back: Unseparated 6.7%; T lymph 5.47%; B
lymph 8.82%; grans 2.72%, 40d post tx. Also match was 6/6 (there was a
mismatch at C locus so BMT coordinator called it a "7/8").
Summary of chimerism:
      unsep   T       B       gran
20d     2.75    0       2.6     1.6
30d     5.77    insuff  insuff  3.56
40d     6.7     5.47    8.82    2.72

Baby is stable, room air, feeding.
Looking into PEG-ADA; discussing with transplanters here the next
steps...
Appreciate all the comments/suggestions.

Thanks again!
Elena

Elena E. Perez, M.D.,Ph.D.
Associate Professor
Chief, Pediatric Allergy and Immunology Jeffrey Modell Diagnostic and
Research Center for Primary Immunodeficiencies Division of Immunology
and Infectious Diseases Batchelor Children's Research Institute, Suite
316 University of Miami Miller School of Medicine
1580 NW 10th Avenue
Miami, FL 33136

Office: 305-243-4863
Nurse (Maria Rodriguez) 305-243-9514
FAX: 305-243-7409
Email: e.perez13 at med.miami.edu<mailto:e.perez13 at med.miami.edu>

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-----Original Message-----
From: Bleesing, Jacob [mailto:Jack.Bleesing at cchmc.org]
Sent: Thursday, July 10, 2014 9:28 AM
To: CIS-PIDD
Subject: RE: [cis-pidd] ADA SCID tx

Elena:

Are you sure about the cell dose that you shared with us?

Jack

________________________________________
From: Perez, Elena [e.perez13 at med.miami.edu<mailto:e.perez13 at med.miami.edu>]
Sent: Thursday, July 10, 2014 9:10 AM
To: CIS-PIDD
Subject: RE: [cis-pidd] ADA SCID tx

Thanks for all the comments so far. I will pass them along. He has
been off of cyclosporine for a couple of weeks and results of next
chimerism (whole blood and lineage specific) are due today. I believe
that match was 8/8 but will double check. Will keep you posted & thanks again.
Elena

-----Original Message-----
From: Szabolcs, Paul [mailto:paul.szabolcs at chp.edu]
Sent: Thursday, July 10, 2014 8:32 AM
To: CIS-PIDD
Subject: Re: [cis-pidd] ADA SCID tx

Agree with Gigi that withdrawal of Imm Supp drugs is your last hope
but if the repeat chimerism is falling below 5% it is going to be hopeless.
I have never seen clinically significant GVHD in this setting ( n:
5-7) but the chances are very poor that it will work being so close to UCBT.
If You were at 100days or beyond with 5% donor cells  you may have a
bit more likely graft survival but even that would be against the odds

I doubt that ADA SCID could engraft with Bu doses <12

Best wishes, Paul

Paul Szabolcs, M.D.

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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On 7/9/14, 10:04 PM, "Notarangelo, Luigi"
<Luigi.Notarangelo at childrens.harvard.edu<mailto:Luigi.Notarangelo at childrens.harvard.edu>> wrote:

Dear Elena,

I assume chimerism is on total blood, correct? What is T cell count now?
Can you do lineage specific chimerism? What immunosuppression? (You
may consider reducing it to favor donor cells, although risk of GvHD
would still be there). I see no advantage in rushing toward haplo.
Lastly, did you adjust Bu exposure?

Gigi

Sent from my iPad

Luigi D. Notarangelo, MD
Jeffrey Modell Chair of Pediatric Immunology Research Division of
Immunology, Boston Children's Hospital Professor of Pediatrics and
Pathology, Harvard Medical School Karp Research Building, Room 10217
1, Blackfan Circle Boston, MA 02115 USA

Tel: 617-919-2277
FAX: 617-730-0709

On Jul 9, 2014, at 9:55 PM, "Perez, Elena"
<e.perez13 at med.miami.edu<mailto:e.perez13 at med.miami.edu>>
wrote:

Dear "transplant-for-Primary Immunodeficiency" community:

We have a 2mo boy with ADA deficiency picked up on NBS who received
an HLA matched umbilical cord transplant on DOL45 after being
conditioned with 50% dose reduced Busulphan, Fludarabine and ATG and
rituximab, which was well tolerated. Stem Cell Dose: 16.7 x 10e5
CD34 pos cells/kg;
1.69 x 10e7 TNC/kg.

Early evaluation of peripheral cell genotype unfortunately revealed
mixed chimerism of 3% donor suggestive of primary graft failure. His
most recent chimerism revealed 5% donor, and the transplanters are
planning to send another one this week before deciding about
retransplant. Today is +41d post transplant.

In anticipation of need for retransplant, I offered to post his
case on the list serve for feedback to our transplanters. They are
considering retransplant with umbilical cord blood but hesitant to
redose chemo vs maternal haplo but clinimacs cell purification IND
is not available here.

He is infection free but has developed seizures that are controlled
on Keppra. He is maintained on IVIG and all the usual prophylaxis
and so far has remained free of detectable infections, except on
presentation required oxygen which has improved to room air.

He is on medicaid with very limited family resources, which makes
it difficult to transfer care out of state.

Feedback from transplanters in the group appreciated, and will
share with transplanters here.

thank you,
Elena Perez
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