[CIS PIDD] [cis-pidd] T cell deficiency post chemo

[Issekutz, Thomas]

Dear Colleagues,

I have requested your kind help on this case some time ago and I would like to provide a bit of follow up andwould appreciate any  additional advice.

We were consulted by our hematology service about a  two and a half year old little girl who was being treated for Infantile ALL.  The child is of aboriginal background in Nova Scotia.  She presented with anemia and thrombocytopenia at four months of age and a CD10- pre- B cell ALL. She went through four cycles of very intense chemotherapy over 22 months according to a COG protocol for this very aggressive ALL.  We were consulted because after the last cycle she did not seem to be recovering clinically.

She developed disseminated varicella. She had norovirus in her stools that would not clear. She had repeated spiking fevers with negative cultures that only improved following amphotericin. She also developed pneumatosis intestinalis that persisted over months.  She also developed infections with HHV6 (despite protective isolation), Rhinovirus and Bocavirus.

Immunologically, her IgG and IgM were normal at the time of presentation and throughout most of her chemotherapy.  However, after 18 months of chemo IgG was consistently low. Her hemoglobin, platelet counts, ANC and ALC were all normal. Her ALC was 2000.  However, this consisted of 75% B cells and 0.4% CD3+CD4+,  0.4% CD3+CD8+, 23% NK cells. The few CD4s were only 6% CD45RA+ and 90% CD45RO+.  Thus virtually no CD4s. These measurements were done three and a half months after her last chemotherapy and have not appreciably changed over three months. She is IVIG dependent. She also receives po IVIG for the norovirus with initially some clinical benefit re diarrhea. Although she has a significant diarrhea with up to 12 stools per day. She had a long course of pneumatosis intestinalis that seemed to slowly resolve. She has developed a protein losing enteropathy requiring albumin regularly. She has had several episodes of venous  thrombosis associated with CVL insertions, so access issues are a major problem and hence parenteral nutrition is difficult.

Because the community she is from has had several children with SCID due to a mutation in RAG-2; she was checked for this and was normal (no heterozygosity even). Her first lymphocyte analysis at presentation and occasionally during follow up by hematology appeared to show normal numbers of T cells. Thus we think it is likely that she has had her T cells depleted and possibly her thymus severely injured by the intense chemo.  The possibility of a bone marrow transplant has been explored and a grandfather is a full 10 out of 10 match, because it is a fairly small community. He was not available as a donor for some time for health and personal reasons.

Based on literature showing promising results with IL-7 in patients treated with CD4 lymphopenia after retroviral therapy for HIV and post allogeneic HSCT with chronic lymphopenia, as well as some trials in idiopathic lymphopenia, we tried her on  IL-7 for three weeks. Unfortunately there was no increase in her CD4 counts. Our feeling has been that she needs a transplant and we now have the 10 out of 10 match ready. The problem is that she is a very high risk candidate and may not make it through conditioning and recover from it.  Our specific question is: Is conditioning required in her case with such profound T cell lymphopenia, close to that of an ADA patient? Would the use of ATG alone be an option?  Any thoughts would be very much appreciated.

I would also like to again thank the people who responded earlier re the likely course of her lymphopenia and transplant.

Sincerely

Thomas

Thomas Issekutz MD
Professor and Head, Division of Immunology,
Department of Pediatrics
Dalhousie University/IWK Health Center
5850 University Avenue
Halifax, Nova Scotia B3K 6R8
CANADA
ph 902-470-8933
fax 902-470-7812





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