[CIS PIDD] [cis-pidd] IPEX patient

[CIS-PIDD]

I'd appreciate advice regarding an IPEX patient we follow:

IPEX mutation:  FOXP3: X:49111939_A>G:NM_014009:exon8:c.T767C:p.M256T

Presented at 9 mo with:
- thrombocytopenia: plt initially 60-70, became transfusion dependent within a year, not immune/consumptive with good responses to plt transfusion (transfusion lasts 7-10 days, plt count to 40-80 post)
- moderate eczema, food allergies
- short stature and FTT (ht and wt both <3%).  Normal HC. I'm not convinced his short stature is just from malnutrition
- reticulocytopenic anemia, requiring RBC transfusion ~ q2-3 mo.  Not immune on work up.

Initial BMA - decreased megas with normal morphology, cellularity 70%, normal cytogenetics
1 yr later: decreased megas, cellularity 35%, normal cytogenetics

Trial of eltrombopag - elevated liver enzymes and iron studies, had to stop
Trial of romiplostim - no effect, but didn't get to full dose preBMT

At ~ 20 mo, he developed severe enteropathy following an adenovirus infection.  Became steroid and TPN dependent.  Tried tacrolimus - he developed nephrotic syndrome within 3 days, resolved in a week with stopping it.

After enteropathy developed, exome sequencing returned with IPEX mutation.  No other mutations identified (eg in hematopoietic genes)

Matched sib BMT at 28 mo (older sister), with reduced toxicity regimen campath/treo/flu (Newcastle regimen)
GVHD prophylaxis prednisone and MMF to day 40 then prednisone and CSA
Neutrophil engraftment at day +10
No GVHD.  No significant infections postBMT.
Enteropathy improved, now eating and weaning TPN and steroids

Currently 5 1/2 mo post BMT
- has not engrafted platelets (transfusion q5-10 days) or RBC (transfusion q4wk)
BMA: hypocellular, no megas, mostly normal erythropoiesis, mild left shifted granulopoiesis

Poor immune reconstitution:
CD3 110, CD4 80, CD8 30, no B cells, NK 290 x10E6
naïve CD3+CD4+CD45RA+ CD27+ 65%/ absolute 52

Donor chimerisms:
T cells 0% (highest its been is 4% at 0.7 months, 0 since)
NK cells 97%
myeloid 100%
insufficient B cells

Issues with elevated LFT's, likely due to meds - CSA +/- fluconazole +/- acyclovir +/- pentamidine.  (I think mostly likely CSA).  Almost normal off the above meds.

Currently on prednisone ~ 0.7 mg/kg/day
Admitted a few days ago with diarrhea but seems to be improving.  Infectious W/U pending and prednisone wean held.

Questions we have:
1) Suggestions for second transplant:
- use the sister again vs unrelated donor? Marrow was used for the 1st transplant; sister is likely too small to collect PBSC's.  Our center has very low rates of GVHD with PBSC's even with 9/10 MUD transplants.

- recommendations for conditioning regimen?

2) Any thoughts regarding his thrombocytopenia and anemia?  Why is he RBC and plt transfusion dependent despite good neutrophils and good myeloid engraftment?  How do we ensure we fix this with second transplant?

Greatly appreciate any advice.

Also happy to hear opinions on his cousin who will be coming to transplant shortly - has the same mutation, much milder presentation.  11 yo, mild enteropathy previously diagnosed as 'atypical celiac' (with normal transglutaminase; biopsies consistent with IPEX), eosinophilic esophagitis currently under good control, and psoriasis.  Older brother is his donor.

Thanks,
Nikki

Nicola Wright, MSc, MD, FRCPC
Pediatric Hematologist/Immunologist
Alberta Children's Hospital
2888 Shaganappi Trail NW
Calgary, AB, Canada T3B 6A8

Office Phone: (403) 955-3035
Clinic Phone: (403) 955-7155
Fax: (403) 955-3055

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