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.

Not So Typical: Development of Atypical Chronic Myeloid Leukemia in a Patient With Chronic Myeloid Leukemia

“…There are no previous reports of atypical CML (aCML) arising in a patient with a history of BCR-ABLpositive CML. 3,[7][8][9]…”

Clinical outcome in chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation: the experience of the Bone Marrow Transplantation Unit of FUNFARME/BRAZIL using FISH

“…Especially when using a dual-color-dual-fusion probe, FISH can be used to monitor CML patients post-allo-HSCT regularly (Khan et al, 2004). Cytogenetic remission is critical to define engraftment and relapse and is a prerequisite in both myeloablative and non-myeloablative HSCT, in order to assess the graft status and decide future therapeutic strategies (Au et al, 2003;Khan et al, 2004). Therapeutic approaches for patients in relapse after allografting include α-interferon, chemotherapy, a second HSCT, and immunomodulation with donor lymphocyte infusions (Olavarria et al, 2003), as well as tyrosine kinase inhibitors (imatinib and dasatinib, for example) which block progenitor cell proliferation (Fausel, 2006).…”