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Journal of Clinical Oncology, Vol 23, No 19 (July 1), 2005: pp. 4473-4474 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.3581
Successful Use of Haploidentical Stem-Cell Transplantation With KIR Mismatch As Initial Therapy for Poor-Risk Myelodysplastic SyndromeBone Marrow Transplant Programme, Alfred Hospital, Melbourne, Australia To the Editor: Haploidentical transplantation is an innovative and promising field using stem-cell donors who are mismatched with the recipient at two or three of the major human leukocyte antigen (HLA) loci.1 The selection of donors who are also mismatched at the natural killer (NK) cell –receptor KIR allows for NK-cell alloreactivity to generate a graft-versus-disease outcome. KIR mismatch also leads to concurrent depletion of the recipient's antigen-presenting cells and residual T-lymphocytes, which has been proven to decrease graft-versus-host disease (GVHD) and graft rejection, respectively.2 We present here the first reported case employing this novel transplantation strategy as initial therapy to achieve a successful outcome for poor-risk myelodysplastic syndrome (MDS). It is also the first clinically described experience3 using the HLA-A3 KIR mismatch to accomplish this objective. A 21-year-old man presented with perianal sepsis. Initial investigations revealed pancytopenia. His CBC demonstrated a hemoglobin level of 9.5 g/dL (range, 12.5 to 17.5 g/dL), white cell count of 1.5 x 109/L (range, 4.0 to 8.0 x 109/L), neutrophils count of 0.1 x 109/L (range, 2.0 to 4.0 x 109/L), platelet count of 60 x 109/L (range, 150 to 380 x 109/L), and mean cell volume of 110 µm3 (range, 80 to 98 µm3). Continued pancytopenia 1 month following resolution of his septic crisis prompted a bone marrow aspirate and trephine. This revealed a hypercellular aspirate with trilineage dysplasia, less than 15% ringed sideroblasts, and less than 5% blasts. Cytogenetic analysis demonstrated monosomy 7, a poor prognosis karyotype in MDS. According to the International Prognostic Scoring System for MDS, his malignancy had a less than 10% 5-year survival rate and is essentially incurable without allogeneic transplantation.4 Despite an extensive search among his eight siblings, extended family, and unrelated donor registries, a full HLA-matched donor was not found. As a result of symptomatic pancytopenia, an HLA-haploidentical peripheral blood stem-cell transplantation (using his uncle as the donor) was performed as up-front therapy. The donor and recipient were mismatched at HLA A (DR and DQ), with the donor carrying an A3 allele and the recipient an A2 allele (Fig 1). This allowed for NK-cell alloreactivity in a graft-versus-disease direction. The transplantation schedule is illustrated in Figure 2. In vitro T-cell depletion was performed with Isolex CD34+ selection.5 The graft composition included 12.5 x 106/kg CD34+ cells and 5.0 x 104/kg CD3+ cells. The time to engraftment with neutrophil count more than 1.0 x 109/L was 11 days and platelet count to more than 50 x 109/L was 16 days. Time to CD4+ recovery to more than 400 cells/µL was 12 months. There was no acute GVHD. Significant transplant morbidities included sinusitis with Aspergillus fumigatus 8 days post-transplantation, which was successfully treated with amphotericin for 3 weeks followed by itraconazole for 6 months. Adenoviral colitis was diagnosed 20 months post-transplantation following colonoscopic investigation for diarrhea. This was successfully treated with ribavirin. The same colon biopsy also described grade 1 GVHD, managed with systemic steroids for 3 weeks. This was the only episode of GVHD noted. The patient is nearly 5 years post-transplantation with no active GVHD or evidence of MDS. He has subsequently married and conceived a child post-transplantation.
A haploidentical stem-cell transplant should be considered as initial therapy for patients with incurable MDS. The up-front strategy obviates the potential for jeopardizing this curative procedure secondary to colonization and infection with nosocomial microbes that is often a consequence of chemotherapy. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Aversa F, Tabilio A, Velardi A, et al: Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339:1186-1193, 1998
2. Ruggeri L, Capanni M, Urbani E, et al: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097-2100, 2002
3. Pende D, Biassoni R, Cantoni C, et al: The natural killer cell receptor specific for HLA-A allotypes: A novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer. J Exp Med 184:505-518, 1996
4. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997 5. Papadimitriou CA, Roots A, Koenigsmann M, et al: Immunomagnetic selection of CD34+ cells from fresh peripheral blood mononuclear cell preparations using two different separation techniques. J Hematother 4:539-544, 1995[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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