BCR/ABL: The Clonal Bully
Authors: Deol Abhinav , Schiffer Charles A. 
Published: October 2019

Abstract 4417
Chronic myeloid leukemia (CML) is characterized by the presence of t(9;22) leading to the BCR/ABL fusion gene while other myeloproliferative disorders such as polycytemia vera (PV) and primary myelofibrosis (PMF) may have a point mutation at V617 F codon of janus kinase 2 gene. Myelodysplastic syndrome (MDS) is thought to arise from an abnormality in the hematopoietic stem cell leading to impaired production of blood cells. In these diseases an abnormal clone proliferates and then suppresses normal hematopoiesis. We present 3 very unusual patients in whom CML was diagnosed a few years after the diagnosis of another clonal hematological disorder and in whom there was re-emergence of the original disorder after successful treatment of the CML.
The first patient is an 88 yr old female who was diagnosed with PV in 1998 and treated with multiple phlebotomies, hydroxyurea and anagrelide. A bone marrow biopsy in 2002 showed the presence of the t(9;22) in 6 of 6 metaphases. She was treated with imatinib but failed to achieve a complete cytogenetic response and was switched to dasatinib which had to be stopped secondary to congestive heart failure. Nilotinib was then started but she developed QTc prolongation and failed to achieve a cytogenetic response. She was then managed with hydrea for many years and interestingly, manifested prominent cyclic leukocytosis. In 2010, analysis of blood showed a JAK2 mutation. She recently was begun on protocol treatment with ponatinib. Although moderate splenomegaly and leukocytosis persisted after 5 months of therapy, 0/26 metaphases demonstrated t (9;22) while gain/trisomy of 1q, an abnormality commonly seen in other myeloproliferative disorders and in particular, PV, was detected in 11/26 metaphases,
The second patient is a 64 year old man who was initially diagnosed with PV during workup for elevated hematocrit in 2002. A JAK2 mutation was detected subsequently. Phlebotomy was discontinued in 2007 and he was maintained on hydroxyurea. In 2010, he was noted to have a WBC of 100,000/ul and underwent a bone marrow biopsy which showed the t(9;22). He was found to be in accelerated phase of CML and was initiated on dasatinib. At last follow up visit, the patient is in a cytogenetic remission for CML but was noted to have elevated hemoglobin; a repeat JAK2 is pending.
The third patient is an 82 year old man who was diagnosed in 2005 with MDS with normal cytogenetics, when he was evaluated for macrocytic anemia. He was initially observed and subsequently treated with erythropoietin for decreasing hemoglobin. A bone marrow biopsy was repeated when his hemoglobin continued to decrease in 2009 and showed t(9;22) in 1/20 cells. He was started on imatinib and achieved a complete molecular response. About 3 months later he fractured his humerus and was found to have extramedullary acute myeloid leukemia which was positive by fluorescence in situ hybridization for BCR/ABL. His bone marrow at this time was negative for BCR/AB by RT-PCR but showed dysplatic changes. He was treated with radiotherapy to his arm and was switched to nilotinib. CML continues to be in a molecular remission, with low but stable blood counts.
These 3 patients had an antecedent diagnosis of a clonal hematological disorder prior to developing CML. In 2 of the patients the CML became the dominant “bully” clone suppressing the manifestations of the PV clone. With targeted therapy directed at BCR/ABL, the CML clone was suppressed and the underlying disease again became apparent. In one patient, the presumed PV clone had evolved further with typical cytogenetic changes. It is unclear whether the CML developed from the original MPD/MDS clone or whether it represents an entirely independent disorder. In either event, the ability to successfully suppress the CML with specific therapy provides insights into the competitive interactions amongst abnormal clones and indeed, with normal hematopoiesis.

Disclosures:
No relevant conflicts of interest to declare.