In 1997, a 55-year-old woman with Philadelphia chromosome positive CML in the first chronic phase received allogeneic peripheral blood SCT from her HLA-identical sister following a preparative regimen containing CY (total dose of 120 mg/kg) and fractionated TBI (2.4 Gy × 6). Standard GVHD prophylaxis was provided by methotrexate and CYA. Earlier transplantation donor examination showed a normal full blood count with a normal leukocyte count and normal lymphocyte percentage. From day +100 after transplant onwards, real-time PCR showed a bcr-abl/abl ratio consistent with complete molecular remission of CML and complete donor chimerism was found by molecular studies. Grades 1–2 acute and subsequently limited chronic GVHD of the skin and mouth mucosa had developed as transplant complication and responded well to steroid treatment. Until 2005, normal leukocyte counts and normal lymphocyte percentages were repeatedly found on follow-up blood tests.
In early 2005, a slightly elevated leukocytosis of 13.6/nl was detected for the first time but was not investigated further. One year later, the patient presented with elevated leukocyte count of 21/nl and a lymphocytosis at 78% while being without clinical symptoms. Haemoglobin level and platelet count were normal at 13.3 g per 100 ml and 247/nl, respectively. No palpable lymph nodes were found on clinical examination, spleen and liver were not enlarged, chest X-ray and abdominal ultrasound yielded unremarkable results. Immunophenotyping was performed on peripheral blood and showed a B lymphocyte clone with the immunophenotype CD19+/CD20+low/CD5+/CD22+low/CD23+/FMC7−/CD24+/CD79b−/CD43+/ZAP-70− compatible with CLL stratified stage A according to Binet classification. Cytogenetics showed a normal karyotype by banding techniques, whereas interphase FISH revealed a deletion at 13q14 and additional chromosomal material at 12q13, but was negative for 6q21, 8q24, 11q22.3 and 17p13 abnormalities. Immunoglobulin heavy chain gene sequencing of the CLL clone revealed a highly mutated gene status (>10% mutation rate, VH 4–34 DH 5–24 JH 4*02). Chimerism studies using short tandem repeats amplification of nine loci showed 100% donor chimerism in both the CD3-positive and in the CD19-positive cell fraction demonstrating donor origin of T-cells and B-cells. Subsequently, blood tests were performed on the 76-year-old stem cell donor. The leukocyte count was slightly elevated but no lymphocytosis was detected. Interestingly, immunophenotyping of donor's peripheral blood showed the presence of a B-cell clone with the immunophenotype CD19+/CD20+low/CD5+/CD22+/CD23+/FMC7−/CD24+/CD79b−/CD43+/ZAP-70− (13% of all lymphocytes). Clonal identity with the recipient's CLL clone was documented in the donor's blood samples by quantitative Ig heavy chain allele-specific oligonucleotide PCR using clone-specific forward primers in combination with heavy chain immunoglobulin J segment (JH) family-specific consensus reverse primers and probes as described earlier.1 Moreover, in both individuals identical Ig light chain rearrangements (Vκ 2-28-2 Jκ-5) were found after sequencing. Until today, donor and recipient remain without clinical symptoms and do not require specific treatment for CLL. We postulate that the CLL developed in donor-derived cells in the host microenvironment; moreover, negative real-time PCR for bcr-abl compatible with a complete molecular remission of CML reflects the loss of the original recipient's haematopoiesis.
Stem cell transplantation may be complicated by disease relapse or development of secondary malignancies. Donor cell leukaemia is a known complication of allogeneic SCT. A survey within the European Blood and Marrow Transplantation Group (EBMT) covering 10 489 allogeneic SCT revealed a total of 14 cases of donor cell leukaemia occurring between 1982 and 2003.2 Of those 14 cases, seven were AMLs, three ALLs, three myelodysplasias and one CML, but low grade B-cell lymphomas or CLL were not reported.2 However, Pavletic et al.3 found one case of donor-derived de novo CLL in a cohort of 19 patients who had undergone syngeneic SCT for CLL. Donor cell leukaemia following SCT still attracts much interest, whereas analysis of this phenomenon could potentially provide insight into the mechanisms of leukaemogenesis. Many hypotheses about the underlying mechanism have been generated including transfer of a dormant oncogene, induction or facilitation of leukaemia development by aberrant host homoeostasis, continued antigenic stimulation of a susceptible donor cell clone, transfer of an aetiologic agent such as a virus or genetic material from host to donor cells, factors of host microenvironment and stromal cells.4, 5, 6, 7 Considering the clonal identity observed here, our case supports the hypothesis on development of donor-derived CLL after the transfer of occult cells of a pathological B-cell clone from donor origin to the recipient's microenvironment.
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Perz, J., Ritgen, M., Moos, M. et al. Occurrence of donor-derived CLL 8 years after sibling donor SCT for CML. Bone Marrow Transplant 42, 687–688 (2008) doi:10.1038/bmt.2008.230
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