Dr O'Reilly writes

Richard J. O’Reilly, MD.
Chairman, Department of Pediatrics
Chief, Bone Marrow Transplantation Services
Claire L. Tow Chair in Pediatric Oncology Research

August 24, 2005
Mr. Roger Belton
Belton & Grom Financial Services
4-396 Assiniboine Avenue
Winnipeg, MB
R2M 0T4

Dear Mr. Belton:
I understand that Mr. Raymond Dueck has asked you to assist him and his daughter, Renee Dueck, in the insurance claim that they are making with respect to Renee’s recent medical treatment in the U.S.A.

I was contacted by several physicians treating Renee after admission to The Cleveland Clinic Foundation on June 24, 2005. At that time she presented with a two-week history of cellulitis of the legs as well as multiple ecchymoses. She had been seen by Dr. Shawn He and was noted to be severely neutropenic with a neutrophil count of less than 500 mm3. A marrow aspirate and biopsy demonstrated acute myelogenous leukemia of M2 type. The doctors consulted with me because of her exceptional history.

Renee 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 here at MSKCC on June 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 disease. In the interval between her transplant and her admission in Cleveland she had enjoyed good health, normal growth arid development and had no history of significant infections. She had been followed by her physicians in Manitoba.

However, at the time of her presentation in Cleveland there were no recent studies regarding her immune function or her state of chimerism. Because her original transplant had been performed by our Pediatric Marrow transplantation Service at Memorial Sloan-Kettering Cancer Center using a technique which we had developed and initially introduced in 1980 as a way to prevent graft vs. host disease following HLA disparate transplants, and, further because the family have maintained close contact with us because both Renee and her sister Karalee were transplanted here at Memorial Sloan-Kettering Cancer Center, Dr. Shawn He consulted with me along with Dr. Bow in Winnipeg concerning the most effective way to deal with this unprecedented occurrence of leukemia in a child with severe combined immune deficiency more than 20 years after her original transplant.

At the time, I conveyed to them the critical importance of determining the nature and origin of the leukemia since this would determine the most appropriate approach for her therapy. Our group was primarily concerned about the origin of this leukemia. We expected that it would be an AML that arose in the child’s own cells as a result of the known late effects of chemotherapy Were this the case, the AML would carry an exceptionally grave prognosis and would be appropriately treated with a marrow transplant alter achieving first remission, preferably using the mother as a secondary donor. At the time, I also raised the unlikely possibility that the leukemia would be derived from the maternal donor. In this case, if the leukemia had poor cytogenic features and required a transplant, a graft from an alternative donor would likely be the best treatment option, because the mother’s own cells would be unlikely to exert a significant negative effect against the regrowth of leukemic cells late after transplant. In fact the latter occurrence is the case.

We were able to test the patient’s leukemic cells and her marrow cells as to their origin. The cells were exclusively found to express the full maternal HLA genotype at the DNA Level. Thus this is a unique occurrence in the world’s experience with transplants for SCID. It is doubly of concern because the patient’s sister, Karalee, also received a depleted transplant from the mother. Thus far we have no evidence that the mother or the patient’s sister have any hematologic abnormalities. We are planning to assess these individuals, however, for rare cytogenically abnormal clones that might represent evidence of clonal disease.

On analysis, Ms. Dueck’s M2 AML also reveals cytogenetic characteristics that indicate a highly aggressive disease. Cytogenic evaluation reveaLed 11 metaphases with 48 chromosomes that contained extra copies of chromosomes 8 and 12. Fish evaluation further confirmed the presence of trisomy 8 in 19 % of the cells examined. DNA sequencing again revealed that the leukemia was derived from the maternal donor.

Because of the nature of her leukemia, and the likelihood that she would need a complex transplant procedure, she was initiated on chemotherapy here at Memorial Sloan-Kettering Cancer Center. She received 2 courses of DCTER and tolerated these induction courses well. She is currently in remission of disease with less than 1% blasts. It is planned to give her a consolidation on the DCTER protocol. Thereafter, she would best be treated with a marrow allograft. Because the leukemia is maternal in origin, we do not feel that the maternal donor would be the appropriate donor for a secondary graft.

We have initiated a search from the unrelated registries. If an unrelated donor is identified a secondary transplant from a matched unrelated donor would be appropriate, In this case, donor selection based on HLA compatibility with the patient’s own typing is critical. However, because the patient’s hematopoietic system is all derived from the mother and the antigen presenting cells in the various tissues of her body are also maternally derived, a transplant of unmodified marrow from such a donor, matched to the host, would likely lead to severe and probably lethal graft vs. host disease because of host-matched donor’s alloactivity against HLA disparate maternal antigen presenting cells.

For this reason, we consider it imperative to perform an adequately T cell depleted marrow transplant after myeloablative cyto-reduction. This would abrogate the potential for a lethal graft vs. host disease, or, more accurately graft vs. graft reaction, in this patient. At our center, procedures used here indicate that such transplants are associated with a highly favorable long-term disease-free survival with an extremely low incidence of leukemic relapse in the post-transplant period. Our studies, which have been published, also clearly indicate that the risk of relapse following such a transplant is no greater than that observed following an unmodified transplant. Furthermore, since a transplant from an HLA matched unrelated donor would differ by a full haplotype from the mother’s leukemic cells, we can anticipate that natural killer cells emerging from the secondary donor graft would exert potent anti-leukemic activity against the maternal AML cells.

Ms. Dueck, at the time of her initial transplant, was referred from Winnipeg to our center because we were uniquely able to perform HLA haplotype disparate T cell depleted transplant for her rare form of SCID. In the past, we have cooperated closely with the medical centers in Winnipeg and have trained them in our techniques of T cell depletion which they have since used successfully for the treatment of a significant series of children with SCID. However, this patient represents a unique instance of a leukemia developing in maternal cells. The complexity of her next transplant will be significant and will require special techniques for monitoring engraftment and any clinical evidence of GVHD.

Renee’s initial transfer to our center was agreed to by all the physicians at the time of diagnosis because of the rarity of a leukemia in patients transplanted for SCID and the critical need to define the origins of the leukemia in the patient. Knowing now that the leukemia is derived from the mother only further confirms the importance of these initial evaluations we were able to perform. These would not have been performed at other centers because they did not in have immediate access to laboratories able to isolate the leukemic blasts and thereafter perform the DNA sequence based HLA typing of the leukemic cells. Furthermore, because of the likely presence of mixed chimerism, VNTR typing would probably be inconclusive unless clean preparations of the leukemic blasts were isolated. Thankfully we were able to perform these assays and to our surprise found that the teukemic blasts were of maternal origin. This radically changes the treatment strategy most likely to provide this young woman with the possibility of cure.

I thank you for your help and understanding in this matter. At the time, of her diagnosis, her referral here to Memorial was felt by all to be in her best interest. The diagnostic studies which, we were able to perform here further confirm this opinion and for this reason we request your assistance in obtaining approval for the insurance claim made for Renee Dueck for her initial treatment here. We also further request that her subsequent therapy, particularly her transplant, which is likely the treatment of choice for her disease, also be performed at this institution.

Sincerely yours,

Richard J. O’Reilly, MD
Chairman, Department of Pediatrics
Chief, Bone Marrow Transplantation Program
Memorial Sloan-Kettering Cancer Center