[CIS PIDD] [cis-pidd] 12yo boy with Hodgkins and ADA deficiency

Tue May 10 10:44:39 EDT 2016

              Given his late presentation and presenting T-cell count, he has a partial phenotype. As for the B-cells supporting EBV infection, I think that it is certainly possible that he has a reversion in B-cells, but I wouldn't say that that mechanism has to be invoked. The EBV-mediated transformation should give the neoplastic B-cells a selective advantage, helping them overcome adenosine mediated toxicity, which in any case is most significant in T-cells.
              I am not aware of IRIS being reported in patients treated with adagen, and the immune reconstitution provided by the drug is not very rapid. In any case, as with antiretroviral therapy, I would not withhold adagen for fear or IRIS. The boy has shown that his untreated ADA deficiency has actually led to life-threatening consequences, whereas the risk of IRIS is theoretical. Should he develop IRIS, I would use standard treatments. If the plan is to move quickly to allo BMT, consideration could be given to not using adagen, but this would not be an open and shut case, and I think that the decision for or against transplant should be made first, based on the normal factors of patient clinical condition and donor match and availability. It would be reasonable to keep him close by to monitor for IRIS, although that would depend on his parents' ability to stay near LA. Can speak by phone if you would like.

--
Rob Sokolic, MD
Medical Officer
Office of Cellular, Tissue and Gene Therapies
Center for Biologics Evaluation and Research
Food and Drug Administration
White Oak Building 71, Room 5261
10903 New Hampshire Ave
Silver Spring, MD 20993-0002
Robert.Sokolic at fda.hhs.gov<mailto:Robert.Sokolic at fda.hhs.gov>
(240) 402-5564
FAX: (301) 595-1305

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This communication does not constitute a written advisory opinion under 21 CFR 10.85, but rather is an informal communication under 21 CFR 10.85(k) which represents my best judgment at this time, but does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.

From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Tuesday, May 10, 2016 10:19 AM
To: CIS-PIDD
Subject: [cis-pidd] 12yo boy with Hodgkins and ADA deficiency

Colleagues:

About 18 months ago we consulted on an 11year-old boy with chronic lung disease, failure to thrive and a neck mass.  He had IgG=473, 46 B-cells, and 225 CD4+ T-cells with very poor antibody responses to routine immunizations and low mitogen and antigen responses on LPA.  The neck mass was EBV+ Hodgkin lymphoma.  He was treated for this, had a good response, and appears to be in remission.  The parents are from a small town in Mexico and are "distant cousins."  Microarray demonstrated multiple long contiguous stretches of homozygosity.  Exome sequencing showed a homozygous mutation (p.L107P) in ADA.

Given his chronic lung disease/bronchiectasis, do we run the risk of an IRIS-like response in his lungs or elsewhere if we give him PEG-ADA?

How could his B-cells support infection with EBV and transformation to Hodgkin lymphoma in the face of ADA deficiency?  Spontaneous reversion in the tumor?

Your thoughts/experiences are welcome.

Joe Church
Children's Hospital Los Angeles

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