title: The occurrence of Philadelphia chromosome (Ph) negative leukemia after hematopoietic stem cell transplantation for Ph positive chronic myeloid leukemia: implications for disease monitoring and treatment.
abstract: Chronic myeloid leukemia (CML) is a clonal neoplastic disorder, characterized by t(9;22)(q34;q11) that results in the formation of the Philadelphia chromosome (Ph) and the BCR/ABL fusion gene. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CML. Much of its therapeutic efficacy is attributed to a graft-versus-leukemia (GVL) effect exerted by donor-derived lymphoid cells against the Ph positive (Ph+) clone. Post-HSCT monitoring by cytogenetic and molecular detection of the Ph+ clone is necessary, so that pre-emptive immunologic or pharmacologic treatment may be administered at an early stage of relapse. However, under rare circumstances a second Ph negative (Ph-) leukemia may evolve post-HSCT. The pathogenetic possibilities included leukemia arising from donor-derived hematopoietic stem cells (HSCs), or transformation of residual recipient-derived Ph- HSCs that have survived the conditioning chemotherapy and radiotherapy. Recipient-derived Ph- leukemia may be related to genetic alterations that precede the onset of CML, or myelotoxic effects of the HSCT conditioning regimen. The diagnosis of Ph- relapses requires detailed investigations by conventional karyotyping, fluorescence in-situ hybridization (FISH), and molecular analysis; as well as chimerism studies that help to document the donor or recipient origin of the leukemia. Although uncommonly reported in the past, Ph- relapses may in fact be more frequent if leukemic relapses post-HSCT are more thoroughly evaluated with these investigations. The recognition of Ph- relapses are important in several ways. Ph- relapses cannot be identified by monitoring investigations targeting the Ph+ clone, so that the early detection of Ph- leukemia is usually not possible. Furthermore, Ph- relapses will not respond to therapeutic strategies effective against the Ph+ CML clone.
authors.affiliation: University Department of Medicine, Queen Mary Hospital, Hong Kong, People's Republic of China.
authors.forename: W Y
authors.initials: WY
authors.lastname: Au
authors.forename: S K
authors.initials: SK
authors.lastname: Ma
authors.forename: Y L
authors.initials: YL
authors.lastname: Kwong
mesh_terms: D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000628:therapy*; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000209:etiology*