Monday, June 27, 2005

Dr O'Reilly June 27 05

June 27, 2005
British of Columbia Ministry of Health Services
RE; Renee Dueck

Dear Sirs/Madams:
I am writing to request medical insurance coverage for Renee Dueck, a 21 -year-old Caucasian female from Manitoba who has recently been diagnosed with an M2 morphology acute myelogenous leukemia. This patient is a unique patient in that she was born with an autosomal form of severe combined immune deficiency and received an HLA haplotype disparate T cell depleted transplant from her mother after conditioning with busulfan and cyclophosphamide on July 26, 1984. This transplant resulted in durable engraftment of maternal lymphoid elements, both T cells and B Lymphocytes with full reconstitution of both T cell, mediated and antibody-mediated immunity.

She did not develop any graft vs. host disease. Thereafter, she enjoyed normal growth and development, without significant infections. The current state of myeloid chimerism at this time is not known. However, in all previous studies, the antigen responsive T and B cells in this child are maternal in origin. Her most recent assessment of T cell function dates to one month ago at which time she had a full complement of normally distributed T lymphocytes and normal responses to mitogens and antigens.

Over the last 2 weeks the patient developed a cellulitis of the legs as welt as multiple ecchymoses on the legs. At this time, she sought a medical evaluation at the Strongsville Division of the Cleveland Clinic, and was seen by Dr. Shawn He. She was noted to be severely neutropenic with a neutrophit count less than 500 mm with normal platelets. A marrow aspirate and biopsy performed by Dr. He demonstrated a marrow containing 32 % myeloid blasts, M2 type by morphology and by immunophenotype.

The patient will clearly need appropriate treatment for her acute myelogenous leukemia. The special circumstances of this child are such that accurate diagnosis of her disease is imperative. First, it is important that we ascertain the cell of origin of the leukemia. The patient was cytoreduced in 1984 with busulfan and cyclophosphamide. As a result there is the possibility of developing a late secondary

hematologic malignancy in her own cells. At this stage after the transplant, this would be rare since secondary leukemias, if they occur, usually develop within 15 years of the treatment. Nevertheless, this is the most likely possibility. In this case, it would be anticipated that the myeloid progenitor cells are derived from the patient. ALternatively, it is possible that the myeloid leukemia has evolved from the blood forming cells derived from the patient’s mother. The mother is healthy and hematologically normal. She is aLso HLA haplotype disparate from her daughter.

The implications in terms of treatment are quite important. If this AML has attributes of a chemotherapy associated secondary leukemia, it must be considered a high risk form of the disease. Such an AML would be appropriately treated with aggressive induction therapy with daunomycin and cytosirte arabinoside, possibly also including VP-16 and thioguanine since the DOCTER regimen has been associated with a particularly higher likelihood of sustained remission. An alternative regimen, potentially including only the daunomycin and ARA-C, could be considered for a primary AML. The treatment options for subsequent therapy also clinically depend upon these initial evaluations. If the patient has a secondary AML in her own hematopoietic cells, a transplant in first remission is clearly the treatment of choice. In this case the patient does not have an HLA matched sibling. However, the patient is durably engrafted with a lymphoid system that is entirely derived from her mother who is HLA A, B, DR disparate. For a transplant, we would propose to give a secondary graft after suitable cytoreduction from the mother who is the original donor.

A use of any other donor potentially matched to the patient entails a major risk of graft rejection by residual fully functional T cells derived from the haplotype disparate mother as well as the risk of a potentially lethal graft vs. host disease due to the fact that there are enough antigen presenting cells of maternal origin in this child to permit the stimulation of allo-reactive donor cells and subsequent generation of a lethal graft vs. host in the post transplant period. If the mother’s graft is used, a T cell depleted graft would be the only option. However, cytoreduction could be selected to maximize antileukemic effects, since the risk of the mother’s own T cells, already resident in the child, rejecting the grafts is minimal. Our studies here since 1980 have demonstrated no increase in the risk of leukemic relapse following a transplant for AML either in primary or secondary AMLs when a T cell depleted graft administered after myeloablative cytoreduction has been administered.

We would propose to have her come to Memorial Sloan-Kettering Cancer Center. Diagnostic marrows will be obtained. We will attempt to isolate, culture and identify the cell of origin of her AML. She will also have studies performed to determine her current state of chimerism, specifically to determine the origin of her T cells, B cells and normal progenitor cells. She could then be induced with a chemotherapeutic regimen. This could be started here at MSKCC and potentially maintained at home in Winnipeg.

I do feel, however, that if her disease warrants a transplant (at this point I expect that it will) that the transplant be performed at MSKCC because of our special expertise in transplants of HLA haplotype disparate T cell depleted marrow transplants, particularly for the treatment of severe combined immune deficiency and for leukemic disorders, The issues here are absolutely unique in the experience for severe combined immune deficiency. To my knowledge this is the first case of any leukemia occurring in SCID late after a transplant procedure. More importantly the unique chimeric state of this patient entails a significant number of difficult choices in the selection of treatment, transplant, cytoreduction and the type of transplant administered.
I would be happy to discuss this case further with you at any time. I urge your approval for insurance coverage for this unique patient so that we can define her disease adequately so as to be able to plan a potentially curative approach for this unique and potentially high-risk form of AML

Thank you for your consideration.
Sincerely yours,
Richard J. O MD
Chairman, Department of Pediatrics
Chief, Bone Marrow Transplantation Program
Memorial Sloan-Kettering Cancer Center

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