ASSOCIATION OF 3?BCR GENE DELETION WITH LACK OF MOLECULAR RESPONSE IN CML PATIENTS WITH PH-VARIANTS TREATED WITH TYROSINE KINASE INHIBITORS
(Abstract release date: 05/19/16)
EHA Library. Spassov B. 06/09/16; 134711; PB1811
Dr. Branimir Spassov
Contributions
Contributions
Abstract
Abstract: PB1811
Type: Publication Only
Background
Chronic myeloid leukemia (CML) is a disease of the clonal hematopoietic stem cells caused by a balanced translocation t(9,22)(q34;q11) forming derivate 22 or Philadelphia chromosome (Ph), and molecularly BCR/ABL gene fusion. The standard for treatment of CML patients (pts) is therapy with tyrosine-kinase inhibitors (TKIs). About 8-10% of Ph+ CML pts have more composite rearrangements involving additional chromosomes (Ph-variants) or cryptic translocations. Ph-variants are accompanied more frequently by microdeletions in the regions of chromosome breakpoints than by standard t(9,22)(q34;q11). Although the proportion of CML pts with Ph-variants resistant to TKI therapy is the same as in the group with standard translocation, the specific mechanisms involving Ph-variants in TKI resistance are still unclear.
Aims
Evaluating the molecular-cytogenetic impact to resistance of TKIs treated CML pts with Ph-variants.
Methods
We have analyzed 13 CML cases, 12 of which were with Ph-variants and 1 of the patients was with cryptic translocation detected via G-banding cytogenetic analysis (CyG) and metaphase fluorescence in situ hybridization (met-FISH). The pts are aged 16 to 78 years and were treated with TKIs and followed for at least 18 months in hematology clinics in Sofia, Bulgaria. No less than 20 metaphases with CyG and no less than 10 with met-FISH were examined in each patient. Hematologic, cytogenetic and molecular responses were evaluated regularly.
Results
Our data showed that the following breakpoints were included in three- or four-way translocations: 1q42, 2q37, 3p25, 4p14, 4q33, 6q21, 7q34, 8q24, 11q11, 17q21, 19p13 (in 2 cases), 22q13 and Хq26. At diagnosis, two of the 13 pts had additional aberrations in the karyotype besides Ph-variants. The met-FISH technique allowed us to detect that the rearrangements in 10 of the cases are more complex than registered by CyG: additional chromosomes or additional regions in the visibly rearranged chromosomes were involved in 2 of the cases; loss of the 5' portion of ABL gene (5’ ABL) was observed in 3 of the cases, deletions in 3’BCR and 3’ABL genes were detected in 4 and 1 cases, respectively. Complete cytogenetic (CCgR) and major molecular response (MMR) were achieved in 61.5% (8/13) of the pts. The 3’BCR gene deletions were observed in 80% (4/5) of the pts without MMR. Two out of 5 resistant pts have the same t(9;19;22)(q34;p13;q11), but only one of them has a 3’BCR deletion with no achievement of CCgR and MMR. The the latter patient (without the 3’BCR deletion) has achieved CCgR and suboptimal molecular response on the 18 month after the start of the therapy.
Conclusion
We suggest that the lost of material in the chromosome 22 region including 3’BCR gene in CML pts with Ph-variants may be associated with TKIs resistance. Further research is necessary to confirm these results.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia
Type: Publication Only
Background
Chronic myeloid leukemia (CML) is a disease of the clonal hematopoietic stem cells caused by a balanced translocation t(9,22)(q34;q11) forming derivate 22 or Philadelphia chromosome (Ph), and molecularly BCR/ABL gene fusion. The standard for treatment of CML patients (pts) is therapy with tyrosine-kinase inhibitors (TKIs). About 8-10% of Ph+ CML pts have more composite rearrangements involving additional chromosomes (Ph-variants) or cryptic translocations. Ph-variants are accompanied more frequently by microdeletions in the regions of chromosome breakpoints than by standard t(9,22)(q34;q11). Although the proportion of CML pts with Ph-variants resistant to TKI therapy is the same as in the group with standard translocation, the specific mechanisms involving Ph-variants in TKI resistance are still unclear.
Aims
Evaluating the molecular-cytogenetic impact to resistance of TKIs treated CML pts with Ph-variants.
Methods
We have analyzed 13 CML cases, 12 of which were with Ph-variants and 1 of the patients was with cryptic translocation detected via G-banding cytogenetic analysis (CyG) and metaphase fluorescence in situ hybridization (met-FISH). The pts are aged 16 to 78 years and were treated with TKIs and followed for at least 18 months in hematology clinics in Sofia, Bulgaria. No less than 20 metaphases with CyG and no less than 10 with met-FISH were examined in each patient. Hematologic, cytogenetic and molecular responses were evaluated regularly.
Results
Our data showed that the following breakpoints were included in three- or four-way translocations: 1q42, 2q37, 3p25, 4p14, 4q33, 6q21, 7q34, 8q24, 11q11, 17q21, 19p13 (in 2 cases), 22q13 and Хq26. At diagnosis, two of the 13 pts had additional aberrations in the karyotype besides Ph-variants. The met-FISH technique allowed us to detect that the rearrangements in 10 of the cases are more complex than registered by CyG: additional chromosomes or additional regions in the visibly rearranged chromosomes were involved in 2 of the cases; loss of the 5' portion of ABL gene (5’ ABL) was observed in 3 of the cases, deletions in 3’BCR and 3’ABL genes were detected in 4 and 1 cases, respectively. Complete cytogenetic (CCgR) and major molecular response (MMR) were achieved in 61.5% (8/13) of the pts. The 3’BCR gene deletions were observed in 80% (4/5) of the pts without MMR. Two out of 5 resistant pts have the same t(9;19;22)(q34;p13;q11), but only one of them has a 3’BCR deletion with no achievement of CCgR and MMR. The the latter patient (without the 3’BCR deletion) has achieved CCgR and suboptimal molecular response on the 18 month after the start of the therapy.
Conclusion
We suggest that the lost of material in the chromosome 22 region including 3’BCR gene in CML pts with Ph-variants may be associated with TKIs resistance. Further research is necessary to confirm these results.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia
Abstract: PB1811
Type: Publication Only
Background
Chronic myeloid leukemia (CML) is a disease of the clonal hematopoietic stem cells caused by a balanced translocation t(9,22)(q34;q11) forming derivate 22 or Philadelphia chromosome (Ph), and molecularly BCR/ABL gene fusion. The standard for treatment of CML patients (pts) is therapy with tyrosine-kinase inhibitors (TKIs). About 8-10% of Ph+ CML pts have more composite rearrangements involving additional chromosomes (Ph-variants) or cryptic translocations. Ph-variants are accompanied more frequently by microdeletions in the regions of chromosome breakpoints than by standard t(9,22)(q34;q11). Although the proportion of CML pts with Ph-variants resistant to TKI therapy is the same as in the group with standard translocation, the specific mechanisms involving Ph-variants in TKI resistance are still unclear.
Aims
Evaluating the molecular-cytogenetic impact to resistance of TKIs treated CML pts with Ph-variants.
Methods
We have analyzed 13 CML cases, 12 of which were with Ph-variants and 1 of the patients was with cryptic translocation detected via G-banding cytogenetic analysis (CyG) and metaphase fluorescence in situ hybridization (met-FISH). The pts are aged 16 to 78 years and were treated with TKIs and followed for at least 18 months in hematology clinics in Sofia, Bulgaria. No less than 20 metaphases with CyG and no less than 10 with met-FISH were examined in each patient. Hematologic, cytogenetic and molecular responses were evaluated regularly.
Results
Our data showed that the following breakpoints were included in three- or four-way translocations: 1q42, 2q37, 3p25, 4p14, 4q33, 6q21, 7q34, 8q24, 11q11, 17q21, 19p13 (in 2 cases), 22q13 and Хq26. At diagnosis, two of the 13 pts had additional aberrations in the karyotype besides Ph-variants. The met-FISH technique allowed us to detect that the rearrangements in 10 of the cases are more complex than registered by CyG: additional chromosomes or additional regions in the visibly rearranged chromosomes were involved in 2 of the cases; loss of the 5' portion of ABL gene (5’ ABL) was observed in 3 of the cases, deletions in 3’BCR and 3’ABL genes were detected in 4 and 1 cases, respectively. Complete cytogenetic (CCgR) and major molecular response (MMR) were achieved in 61.5% (8/13) of the pts. The 3’BCR gene deletions were observed in 80% (4/5) of the pts without MMR. Two out of 5 resistant pts have the same t(9;19;22)(q34;p13;q11), but only one of them has a 3’BCR deletion with no achievement of CCgR and MMR. The the latter patient (without the 3’BCR deletion) has achieved CCgR and suboptimal molecular response on the 18 month after the start of the therapy.
Conclusion
We suggest that the lost of material in the chromosome 22 region including 3’BCR gene in CML pts with Ph-variants may be associated with TKIs resistance. Further research is necessary to confirm these results.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia
Type: Publication Only
Background
Chronic myeloid leukemia (CML) is a disease of the clonal hematopoietic stem cells caused by a balanced translocation t(9,22)(q34;q11) forming derivate 22 or Philadelphia chromosome (Ph), and molecularly BCR/ABL gene fusion. The standard for treatment of CML patients (pts) is therapy with tyrosine-kinase inhibitors (TKIs). About 8-10% of Ph+ CML pts have more composite rearrangements involving additional chromosomes (Ph-variants) or cryptic translocations. Ph-variants are accompanied more frequently by microdeletions in the regions of chromosome breakpoints than by standard t(9,22)(q34;q11). Although the proportion of CML pts with Ph-variants resistant to TKI therapy is the same as in the group with standard translocation, the specific mechanisms involving Ph-variants in TKI resistance are still unclear.
Aims
Evaluating the molecular-cytogenetic impact to resistance of TKIs treated CML pts with Ph-variants.
Methods
We have analyzed 13 CML cases, 12 of which were with Ph-variants and 1 of the patients was with cryptic translocation detected via G-banding cytogenetic analysis (CyG) and metaphase fluorescence in situ hybridization (met-FISH). The pts are aged 16 to 78 years and were treated with TKIs and followed for at least 18 months in hematology clinics in Sofia, Bulgaria. No less than 20 metaphases with CyG and no less than 10 with met-FISH were examined in each patient. Hematologic, cytogenetic and molecular responses were evaluated regularly.
Results
Our data showed that the following breakpoints were included in three- or four-way translocations: 1q42, 2q37, 3p25, 4p14, 4q33, 6q21, 7q34, 8q24, 11q11, 17q21, 19p13 (in 2 cases), 22q13 and Хq26. At diagnosis, two of the 13 pts had additional aberrations in the karyotype besides Ph-variants. The met-FISH technique allowed us to detect that the rearrangements in 10 of the cases are more complex than registered by CyG: additional chromosomes or additional regions in the visibly rearranged chromosomes were involved in 2 of the cases; loss of the 5' portion of ABL gene (5’ ABL) was observed in 3 of the cases, deletions in 3’BCR and 3’ABL genes were detected in 4 and 1 cases, respectively. Complete cytogenetic (CCgR) and major molecular response (MMR) were achieved in 61.5% (8/13) of the pts. The 3’BCR gene deletions were observed in 80% (4/5) of the pts without MMR. Two out of 5 resistant pts have the same t(9;19;22)(q34;p13;q11), but only one of them has a 3’BCR deletion with no achievement of CCgR and MMR. The the latter patient (without the 3’BCR deletion) has achieved CCgR and suboptimal molecular response on the 18 month after the start of the therapy.
Conclusion
We suggest that the lost of material in the chromosome 22 region including 3’BCR gene in CML pts with Ph-variants may be associated with TKIs resistance. Further research is necessary to confirm these results.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia
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