[CIS PIDD] BMT for newborn with CGD

[Cowan, Mort]

Jane,

Under the circumstances moving forward with a transplant may make sense. The only issue is conditioning and I think that as long as you reduce the fludarabine appropriately, you should be ok but my sense is that when folks have gotten into trouble with conditioning in these young babies, it's been the fludarabine that was likely the culprit although we don’t know for sure.  I think that if we were in the same position, we would use bu/flu (reduced dose) rather than bu/cy, but that is an alternative.

Mort

Morton J. Cowan, M.D.
Professor of Pediatrics
Chief, Allergy, Immunology, and Blood and Marrow Transplant Division
UCSF Children's Hospital, Room M659
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-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Jane Peake
Sent: Wednesday, August 29, 2012 3:41 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS PIDD] BMT for newborn with CGD


Thanks Hans
The brothers in the paper below had a splice defect with several splice products and decreased NADPH oxidative activity. Our patients' defect is a premature stop codon and in all 3 patients their oxidative burst (DHR-123) was 0%. This may suggest why the pateitns described in the paper had a mild phenotype with good outcome and late presentation whereas ours did very poorly suggesting a severe phenotype asnd I believe making this baby at high risk.
Cheers Jane
________________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] on behalf of Ochs, Hans [hans.ochs at seattlechildrens.org]
Sent: Wednesday, 29 August 2012 12:25 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS PIDD] BMT for newborn with CGD

Jack has a point not classifying this very young CGD infant that has been discussed in detail as "very high risk", in view of the report by J. Roesler from Dresden, below Are there mutations in P67-phox that are universally fetal during the first few weeks of life?
hans


PLoS One. 2012;7(4):e34296. Epub 2012 Apr 13.
P67-phox (NCF2) lacking exons 11 and 12 is functionally active and leads to an extremely late diagnosis of chronic granulomatous disease (CGD).
Roesler J, Segerer F, Morbach H, Kleinert S, Thieme S, Rösen-Wolff A, Liese JG.
Source
Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany. roeslerj at rcs.urz.tu-dresden.de Abstract Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000 + 2T → G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.
PMID:

Hans D. Ochs, MD, Dr. med
Professor of Pediatrics | Jeffrey Modell Chair of Pediatric Immunology Research Center for Immunity and Immunotherapies Seattle Children's Research Institute | University of Washington

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allgau at u.washington.edu, hans.ochs at seattlechildrens.org

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-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Bleesing, Jacob
Sent: Tuesday, August 28, 2012 11:25 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS PIDD] BMT for newborn with CGD


In my last CGD patient, diagnosed at birth (family history), I got him on the appropriate anti-microbials and waited until he was 6 months of age (for the reasons outlined below) and then used our Bu/Cy/ATG regimen (without any problems and using a UCB donor).

I would be careful with using fludarabine in a very young patient as well - and why we didn't consider the RIC approach in our young boy.

Since, I would not classify this as a "high-risk"  patient, not sure why he should be transplanted right now (or why a RIC would be the first option). The fact that a MSD is available should be taken into consideration as well, as far as preparative regimen is concenerd.

Jack Bleesing

-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Fleisher, Thomas (NIH/CC/DLM) [E]
Sent: Tuesday, August 28, 2012 2:12 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS PIDD] BMT for newborn with CGD


Advice from Harry Malech:

Most pediatric transplanters avoid busulfan in very early infancy, making the Gungor/Seger regimen likely not appropriate in the age group of this infant (7 weeks).  However, I am not familiar with what should be used.  I would refer them to Joann Kurtzberg at Duke for advice in this regard, and if she does not feel she has the best answer, she will know who has been transplanting infants of this age.  I do agree that this is a situation where going forward now is likely the right thing to do, even if it is not the best approach for CGD transplant in general. H.

Thomas A. Fleisher, M.D.
Chief, Department of Laboratory Medcine
NIH Clinical Center
Bethesda, MD 20892
301 496-5668 (tel)
301 402-1612 (fax)


-----Original Message-----
From: Jane Peake [mailto:j.peake at uq.edu.au]
Sent: Monday, August 27, 2012 10:39 PM
To: pagid at list.clinimmsoc.org
Subject: [CIS PIDD] BMT for newborn with CGD



Hi

I was wondering if I could canvas opinions. We have a  baby boy who is now 7 weeks old with confirmed  AR (p67) CGD that has been born to a family that has had 2 previous infants die with CGD. They come from a remote part of Australia and on presentation the other children had a large number of fungal organisms in their lungs and a lot of lung damage. One died  very suddenly with a febrile illness when they presented to their local hospital and  he could not be resuscitated. The family refused a postmortem. The other young boy underwent a matched sibling donot BMT buit died of respiratory failure.
I belive that this infant whilst he is still well should undergo BMT as we have a matched sibling donor sooner rather than later but I have some concerns regading the conditioning regieme in a baby so young both from the increased toxicity from full dose busulfan in neonatal population and long term neurocognitive outcomes.

I would be very interested in others thoughts.
Kind regards
Jane
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The CIS-PIDD listserv is supported by:
Clinical Immunology Society - The science & practice of human immunology

P: +1.414.224.8095
E: info at clinimmsoc.org

Not a member of CIS? Please visit www.clinimmsoc.org to join!
The CIS-PIDD listserv is supported by:
Clinical Immunology Society - The science & practice of human immunology

P: +1.414.224.8095
E: info at clinimmsoc.org

Not a member of CIS? Please visit www.clinimmsoc.org to join!