Clonally unrelated BCR-ABL-negative acute myeloblastic leukemia masquerading as blast crisis after busulphan and interferon therapy for BCR-ABL-positive chronic myeloid leukemia

Abstract

We report a patient with Philadelphia (Ph)-positive, BCR-ABL rearrangement positive, chronic myeloid leukemia (CML) with a prolonged chronic phase of 24 years who was first prescribed alpha-2 interferon 22 years after initial diagnosis. This therapy was tolerated poorly on account of thrombocytopenia, but an eventual major cytogenetic response was followed soon afterwards by transformation to terminal acute myeloid leukemia (AML). Cytogenetic studies indicated that the transformed myeloblasts were karyotypically normal and Ph negative. Although polymerase chain reaction (PCR) analysis of total leukemic mRNA remained BCR-ABL positive, other molecular studies, including Southern blotting and fluorescent in situ hybridization (FISH) analyses, showed that myeloblasts were BCR-ABL rearrangement negative. PCR-based clonality studies using an X-chromosome-linked restriction fragment polymorphism within the phosphoglycerate kinase gene (PGK 1 ) further showed that the Ph-negative blast cells had a different clonal origin from the Ph-positive clone of chronic phase. We suggest that cases of underlying Ph-negative leukemic transformation in Ph-positive CML warrant further study and should be considered for trial of intensive remission induction therapy as appropriate for acute leukemia.

Granulocytic sarcoma of megakaryoblastic differentiation in the lymph nodes terminating as acute megakaryoblastic leukemia in a case of chronic idiopathic myelofibrosis persisting for 16 years

“…Busulfan may have worked as a causative agent in megakaryoblastic transformation in our case. The alkylating agent busulfan has been associated with clinical incidence of myelodysplasia (19), acute myeloblastic leukemia (20), increased incidence of DNA damage in mammalian cells in vitro (21) and damage to stem cell potential in cats (22).…”

Acute lymphoblastic leukemia without the Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosome

“…Fayad et al [4] suggested that the emergence of Phnegative abnormal clones in Ph-positive CML was related to the therapy or to the evolution of new clones other than the CML clone. In the reported cases, Ph-negative acute leukemia developed after the patients received busulphan, interferon, hydroxyurea, or bone marrow transplantation for CML [5][6][7][8]. Our patient was treated with interferon for 3 weeks and imatinib mesylate for 4 months.…”

“…Some authors have suggested that the selective suppression of the Ph-positive clone with CML treatment may induce an environment that allows the evolution and expansion of a new or previously silent leukemic clone, causing acute leukemia [4][5][6].…”

Philadelphia (Ph) chromosome‐positive chronic myeloid leukaemia relapsing as Ph‐negative leukaemia after allogeneic bone marrow transplantation

“…Fayad et al (1997)) described two cases of Ph − leukaemia (myeloproliferative disorder with 18p abnormality, and MDS with monosomy 5 and 7) after complete cytogenetic response to interferon. Manley et al (1999) reported a co‐existing Ph − leukaemic clone in a Ph + CML patient, also after complete CG response to interferon. Ph − cells with trisomy 8 had also been detected by FISH, after interferon therapy or autologous BMT (Bilhou‐Nabera et al , 1993; Ariyama et al , 1995).…”