July 30, 2009 — Italian researchers have described a series of patients with acute myeloid leukemia in whom the leukemic cells underwent some "genetic trickery" in order to escape immune surveillance, resulting in a relapse of the disease.
The finding is reported by Luca Vago MD, PhD, from Hospital San Raffaele–Telethon Institute for Gene Therapy in Milan, Italy, and colleagues in the July 30 issue of the New England Journal of Medicine.
They describe a series of patients with acute myeloid leukemia or myelodysplastic syndrome who were treated with a stem-cell transplant and an infusion of T cells from a donor who was a haploidentical family member. In these cases, only 1 of the donor's 2 human leukocyte antigen (HLA) haplotypes matched a haplotype of the recipient; the remaining haplotype was not a match.
This treatment approach — a haploidentical stem-cell transplant — is potentially curative in patients with high-risk hematologic cancers who do not have an HLA-matched donor, the researchers explain.
However, in their series of 43 patients treated this way, 17 went on to relapse.
Among these 17 relapsed patients, the researchers identified 5 patients (27%) in whom the leukemic cells had undergone a transformation after the transplant. What happened in these 5 cases is that the patient's leukemic cells underwent a mutation, during which they lost the patient-specific HLA haplotype that was a mismatch for the donor HLA haplotype, and replaced it with one that did match.
This switch made for a complete HLA match between the patient's leukemic cells and the donor's cells, thereby eliminating a major immunologic target on the leukemic cells, note John Barrett, MD, from the National Heart, Lung and Blood Institute in Bethesda, Maryland, and Bruce Blazar, MD, from the University of Minnesota in Minneapolis, in an accompanying editorial.
"The result of this genetic trickery was a failure of immune surveillance, a plausible reason for the recurrence of the leukemia," add the editorialists.
Implications for Treatment After Relapse
"Loss of the patient-specific HLA haplotype is easy to diagnose, and has important implications for selecting a treatment that is suitable for relapse after transplantation," the researchers write.
They report that among the 5 cases they identified, 2 were candidates for a subsequent transplantation of haploidentical hematopoietic stem cells from a different donor, who was mismatched for the HLA haplotype retained in the leukemic cells. "Remarkably, 1 of the 2 patients is alive and in complete remission more than 16 months after the second transplantation," they note.
Uniparental Disomy
The editorialists explain that the mutation that occurred is known as uniparental disomy. The cancer cell has lost an HLA haplotype that was inherited from one of the patient's parents and replaced it with a haplotype from the other parent. The loss occurs during mitotic recombination, leaving the daughter cell with the 2 HLA haplotypes derived from only 1 parent — hence the "uniparental" description. The chromosome number remains unchanged, and for this reason standard cytogenetic techniques fail to detect the swap, they add.
This finding has implications for the treatment of myeloid leukemia and perhaps other cancers that recur after hemopoietic stem-cell transplantation, the editorialists write. For example, donor lymphocyte infusions would most likely be ineffective, even if high numbers of lymphocytes were given, in cases of uniparental disomy of malignant cells that recur after transplantation.
This is the most important practical implication from this finding, corresponding author Fabio Ciceri, MD, director of the Hematology and Bone Marrow Transplant Unit at the San Raffaele Scientific Institute in Milan, told Medscape Oncology.
The usual treatment of relapsed leukemia after allograft is donor lymphocyte infusion, Dr. Ciceri explained. However, in view of this new finding, such a maneuver should be postponed until there is clear documentation of the absence of loss of heterozygosity, he emphasized. In cases of documented loss of heterozygosity, a second allograft from a donor mismatched for the HLA expressed by leukemia is more appropriate, he added. This was the approach his team took for the 2 patients described above who underwent a second transplantation.
Dr. Ciceri added that the frequency of this event is high, and "we suspect that it is even higher than actually detected."
Coauthor Chiara Bonini, MD, from the Cancer Immunotherapy and Gene Therapy Program at San Raffaele Scientific Institute in Milan, Italy, reports receiving consulting fees from MolMed. The remaining coauthors and the editorialists have disclosed no relevant financial relationships.
N Engl J Med. 2009;361:478-488 and 524-525.
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