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.

• Chronic myeloid leukemia
• Relapse
• Philadelphia chromosome negative
• Allogeneic hematopoietic stem cell transplantation