Contributions
Abstract: PB1954
Type: Publication Only
Background
Around 95% CML pts have breakpoints in the M-bcr, which result in b2a2 (e13a2) and/or b3a2 (e14a2) fusion mRNAs, both of which are translated into the p210 BCR-ABL protein, which in turn functions as a constitutively active Tyrosine Kinase (TK) leading to alterations in cell proliferation, differentiation, adhesion, and survival. Rarely, other breakpoints can occur - p190 BCR-ABL1 protein (m-bcr) or p230 BCR-ABL1 protein (μ-bcr), respectively, e1a2 and e19a2. There are other atypical breakpoints outside these cluster regions, usually associated with an aggressive clinical course.
Aims
To document a confirmed case of the co-expression of the p210 BCR-ABL1 and p195 BCR-ABL1 proteins in a CML patient, in order to draw attention to this rare diagnosis and its aggressive clinical course.
Methods
We report the case of a previously healthy 36 year-old man, with no relevant past diseases and a one-month history of fever and night sweats, on physical examination no hepatosplenomegaly or lymphadenopathy were found. Haemoglobin was 12.9g/dl, WBC were 58300/μL (90.8% neutrophils, 1.4% eosinophils, 0% basophils, 6.5% lymphocytes, 1.3% monocytes) and platelet count was 507000/μL. Bone marrow aspiration showed 1% blasts and FISH for BCR-ABL1 was 98% positive. A diagnosis of CML was made, with a Sokal score of 0.57, Hasford 58 and EUTOS 0. The patient initiated imatinib 400mg/day and a haematological response was achieved, with no cytogenetic response at 3 months of treatment, despite an increase of the imatinib dose to 600mg at 4 months and 800mg two weeks later. Treatment was switched to bosutinib at month 9. Cytogenetic response was achieved at 7 months after bosutinib initiation.
Results
The molecular analysis showed a rare co-expression of the p210 BCR-ABL1 and p195 BCR-ABL1, attributable to an alternative splicing of the transcript arising from the M-BCR chimeric oncogene. While waiting for related-donor survey for subsequent allogeneic transplantation, at month 11 of bosutinib, the disease progressed to a lymphoid blastic crisis, presenting with pancytopenia with 61% blastemia, and 96% bone marrow lymphoblasts; p210 remained in cytogenetic response yet p195 remained FISH positive. R-HyperCVAD+dasatinib+intra-thecal chemotherapy was initiated. At the end of the 1st A cycle a complete response was documented.
Conclusion
Different transcript co-expression has been reported by others in rare cases of CML, but with p210 and p190 BCR-ABL1. This is the first report of CML co-expressing p210 and p195 BCR-ABL1. Possibly, because of the shorter transcript lacking regulatory domains, p195 is associated with a dismal prognosis. Even though this patient initially presented in a chronic phase, the p195 clone remained positive in FISH and ultimately the disease progressed to a lymphoid blastic crisis.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): BCR-ABL, Chronic myeloid leukemia
Abstract: PB1954
Type: Publication Only
Background
Around 95% CML pts have breakpoints in the M-bcr, which result in b2a2 (e13a2) and/or b3a2 (e14a2) fusion mRNAs, both of which are translated into the p210 BCR-ABL protein, which in turn functions as a constitutively active Tyrosine Kinase (TK) leading to alterations in cell proliferation, differentiation, adhesion, and survival. Rarely, other breakpoints can occur - p190 BCR-ABL1 protein (m-bcr) or p230 BCR-ABL1 protein (μ-bcr), respectively, e1a2 and e19a2. There are other atypical breakpoints outside these cluster regions, usually associated with an aggressive clinical course.
Aims
To document a confirmed case of the co-expression of the p210 BCR-ABL1 and p195 BCR-ABL1 proteins in a CML patient, in order to draw attention to this rare diagnosis and its aggressive clinical course.
Methods
We report the case of a previously healthy 36 year-old man, with no relevant past diseases and a one-month history of fever and night sweats, on physical examination no hepatosplenomegaly or lymphadenopathy were found. Haemoglobin was 12.9g/dl, WBC were 58300/μL (90.8% neutrophils, 1.4% eosinophils, 0% basophils, 6.5% lymphocytes, 1.3% monocytes) and platelet count was 507000/μL. Bone marrow aspiration showed 1% blasts and FISH for BCR-ABL1 was 98% positive. A diagnosis of CML was made, with a Sokal score of 0.57, Hasford 58 and EUTOS 0. The patient initiated imatinib 400mg/day and a haematological response was achieved, with no cytogenetic response at 3 months of treatment, despite an increase of the imatinib dose to 600mg at 4 months and 800mg two weeks later. Treatment was switched to bosutinib at month 9. Cytogenetic response was achieved at 7 months after bosutinib initiation.
Results
The molecular analysis showed a rare co-expression of the p210 BCR-ABL1 and p195 BCR-ABL1, attributable to an alternative splicing of the transcript arising from the M-BCR chimeric oncogene. While waiting for related-donor survey for subsequent allogeneic transplantation, at month 11 of bosutinib, the disease progressed to a lymphoid blastic crisis, presenting with pancytopenia with 61% blastemia, and 96% bone marrow lymphoblasts; p210 remained in cytogenetic response yet p195 remained FISH positive. R-HyperCVAD+dasatinib+intra-thecal chemotherapy was initiated. At the end of the 1st A cycle a complete response was documented.
Conclusion
Different transcript co-expression has been reported by others in rare cases of CML, but with p210 and p190 BCR-ABL1. This is the first report of CML co-expressing p210 and p195 BCR-ABL1. Possibly, because of the shorter transcript lacking regulatory domains, p195 is associated with a dismal prognosis. Even though this patient initially presented in a chronic phase, the p195 clone remained positive in FISH and ultimately the disease progressed to a lymphoid blastic crisis.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): BCR-ABL, Chronic myeloid leukemia