REL-PROTOCOL PHILOSOPHI34 CONFIRMS THAT NILOTINIB RAPIDLY INDUCES CD34+/LIN-PH+ CELLS DISAPPEARANCE IN PATIENTS WITH CHRONIC MYELOID LEUKAEMIA (CML) IN CHRONIC PHASE (CP).
(Abstract release date: 05/19/16)
EHA Library. Cairoli R. 06/09/16; 132646; E1097
Roberto Cairoli
Contributions
Contributions
Abstract
Abstract: E1097
Type: Eposter Presentation
Background
CML is a clonal disorder characterized by the presence of the Philadelphia (Ph) chromosome which encodes for the bcr-abl tyrosine-kinase (TK). Target therapy with the TK inhibitor (TKI) imatinib (IM) has greatly improved outcome in CML; however, only a minority of responsive pts can discontinue treatment without relapsing in the short term and even less pts can be considered free of disease. This data probably relates to persistence of quiescent CD34+Ph+ stem cells (SC) whose persistence has been documented even among pts in optimal response (Bocchia et al, 2008). Compared to IM, faster and deeper responses in CP-CML pts can be achieved with the second generation TKI Nilotinib (NIL); however, only preliminary data are available on NIL potential to eradicate Ph+ SC. Moreover, in vitro studies (Corbin AS, et al 2011; Hamilton A, et al 2012) suggest that CD34+Ph+SC may not be sensitive to TKI-mediated Bcr/Abl inhibition. However, in vivo data (Defina et al, 2012) have shown that, compared to IM treated pts, residual leukemic SC are very rarely detected among NIL treated pts in CCyR even after short-term NIL therapy and even if duration of treatment is shorter for NIL compared to IM treated pts (median 39 vs 22 mos). At present, no clear evidence of TKI effect on the leukemic SC clearance is available.
Aims
On behalf of the Rete Ematologica Lombarda (REL), the PhilosoPhi34 protocol (EudraCT: 2012-005062-34), an open label, single arm, phase II study, was designed to investigate the efficacy of NIL 300 mg BID in BM CD34+/lin-Ph+cells clearance at 3, 6 (primary objective) and12 months of treatment in newly diagnosed CP-CML pts.
Methods
Enrolled pts' BM cells were collected and stored at diagnosis and at 3,6 and 12 mos of treatment. CD34+/lin- cells were purified using a Diamond CD34 Isolation Kit Miltenyi (97% of purity). FISH analysis of selected unstimulated CD34+/lin- cells was performed according to standard method; considering the low sensitivity of the test, at least 200 nuclei were examined in order to define the test as negative. This phase II study was designed according to the A’Hern single stage design, where, at 6 mos, we assumed a proportion defining a poor response as PP = 0.10, and the proportion defining a good response as PG = 0.30, PA being the proportion of responders.The study required 41 subjects to decide, with a power of 95%, whether PA ≤ 0.10 or PA ≥ 0.30. To have 41 evaluable, 87 pts had to be enrolled, considering 80% of them being fully analysed and 60% of these reaching CCyR (according to ENESTnd data).
Results
Enrolment of 87 pts was completed by June 2015; the database hasn't been locked yet. At present, FISH analysis on CD34+/lin- cells at 6 mos of treatment is evaluable for 68 of 75 pts with a documented CCyR; 7 negative tests were not evaluable since less than 200 nuclei were analysed. Only 5/68 (7,3%) evaluable FISH tested positive. Results at 3 and 12 mos are as follows: 8/58 (13,8%) and 0/46 (0%) evaluable FISH respectively tested positive (7 and 6 negative test excluded respectively). Sokal score did not predict for FISH positive results at any time point.
Conclusion
These results strongly point to a role for NIL 300 mg BID in fast clearance of BM CD34+/lin-Ph+ cells in a high proportion of treated pts. In view of the potential clinical relevance of our data, the protocol was amended in order to revise our FISH data using a test with higher sensibility and specificity, i.e.: the gDNA PCR. These results might give insight into a possible correlation with depth and stability of molecular response. We acknowledge all REL Colleagues for their collaboration and Novartis SpA for the partial financial support to the study.
Session topic: E-poster
Keyword(s): CD34+ cells, Chronic myeloid leukemia, Targeted therapy
Type: Eposter Presentation
Background
CML is a clonal disorder characterized by the presence of the Philadelphia (Ph) chromosome which encodes for the bcr-abl tyrosine-kinase (TK). Target therapy with the TK inhibitor (TKI) imatinib (IM) has greatly improved outcome in CML; however, only a minority of responsive pts can discontinue treatment without relapsing in the short term and even less pts can be considered free of disease. This data probably relates to persistence of quiescent CD34+Ph+ stem cells (SC) whose persistence has been documented even among pts in optimal response (Bocchia et al, 2008). Compared to IM, faster and deeper responses in CP-CML pts can be achieved with the second generation TKI Nilotinib (NIL); however, only preliminary data are available on NIL potential to eradicate Ph+ SC. Moreover, in vitro studies (Corbin AS, et al 2011; Hamilton A, et al 2012) suggest that CD34+Ph+SC may not be sensitive to TKI-mediated Bcr/Abl inhibition. However, in vivo data (Defina et al, 2012) have shown that, compared to IM treated pts, residual leukemic SC are very rarely detected among NIL treated pts in CCyR even after short-term NIL therapy and even if duration of treatment is shorter for NIL compared to IM treated pts (median 39 vs 22 mos). At present, no clear evidence of TKI effect on the leukemic SC clearance is available.
Aims
On behalf of the Rete Ematologica Lombarda (REL), the PhilosoPhi34 protocol (EudraCT: 2012-005062-34), an open label, single arm, phase II study, was designed to investigate the efficacy of NIL 300 mg BID in BM CD34+/lin-Ph+cells clearance at 3, 6 (primary objective) and12 months of treatment in newly diagnosed CP-CML pts.
Methods
Enrolled pts' BM cells were collected and stored at diagnosis and at 3,6 and 12 mos of treatment. CD34+/lin- cells were purified using a Diamond CD34 Isolation Kit Miltenyi (97% of purity). FISH analysis of selected unstimulated CD34+/lin- cells was performed according to standard method; considering the low sensitivity of the test, at least 200 nuclei were examined in order to define the test as negative. This phase II study was designed according to the A’Hern single stage design, where, at 6 mos, we assumed a proportion defining a poor response as PP = 0.10, and the proportion defining a good response as PG = 0.30, PA being the proportion of responders.The study required 41 subjects to decide, with a power of 95%, whether PA ≤ 0.10 or PA ≥ 0.30. To have 41 evaluable, 87 pts had to be enrolled, considering 80% of them being fully analysed and 60% of these reaching CCyR (according to ENESTnd data).
Results
Enrolment of 87 pts was completed by June 2015; the database hasn't been locked yet. At present, FISH analysis on CD34+/lin- cells at 6 mos of treatment is evaluable for 68 of 75 pts with a documented CCyR; 7 negative tests were not evaluable since less than 200 nuclei were analysed. Only 5/68 (7,3%) evaluable FISH tested positive. Results at 3 and 12 mos are as follows: 8/58 (13,8%) and 0/46 (0%) evaluable FISH respectively tested positive (7 and 6 negative test excluded respectively). Sokal score did not predict for FISH positive results at any time point.
Conclusion
These results strongly point to a role for NIL 300 mg BID in fast clearance of BM CD34+/lin-Ph+ cells in a high proportion of treated pts. In view of the potential clinical relevance of our data, the protocol was amended in order to revise our FISH data using a test with higher sensibility and specificity, i.e.: the gDNA PCR. These results might give insight into a possible correlation with depth and stability of molecular response. We acknowledge all REL Colleagues for their collaboration and Novartis SpA for the partial financial support to the study.
Session topic: E-poster
Keyword(s): CD34+ cells, Chronic myeloid leukemia, Targeted therapy
Abstract: E1097
Type: Eposter Presentation
Background
CML is a clonal disorder characterized by the presence of the Philadelphia (Ph) chromosome which encodes for the bcr-abl tyrosine-kinase (TK). Target therapy with the TK inhibitor (TKI) imatinib (IM) has greatly improved outcome in CML; however, only a minority of responsive pts can discontinue treatment without relapsing in the short term and even less pts can be considered free of disease. This data probably relates to persistence of quiescent CD34+Ph+ stem cells (SC) whose persistence has been documented even among pts in optimal response (Bocchia et al, 2008). Compared to IM, faster and deeper responses in CP-CML pts can be achieved with the second generation TKI Nilotinib (NIL); however, only preliminary data are available on NIL potential to eradicate Ph+ SC. Moreover, in vitro studies (Corbin AS, et al 2011; Hamilton A, et al 2012) suggest that CD34+Ph+SC may not be sensitive to TKI-mediated Bcr/Abl inhibition. However, in vivo data (Defina et al, 2012) have shown that, compared to IM treated pts, residual leukemic SC are very rarely detected among NIL treated pts in CCyR even after short-term NIL therapy and even if duration of treatment is shorter for NIL compared to IM treated pts (median 39 vs 22 mos). At present, no clear evidence of TKI effect on the leukemic SC clearance is available.
Aims
On behalf of the Rete Ematologica Lombarda (REL), the PhilosoPhi34 protocol (EudraCT: 2012-005062-34), an open label, single arm, phase II study, was designed to investigate the efficacy of NIL 300 mg BID in BM CD34+/lin-Ph+cells clearance at 3, 6 (primary objective) and12 months of treatment in newly diagnosed CP-CML pts.
Methods
Enrolled pts' BM cells were collected and stored at diagnosis and at 3,6 and 12 mos of treatment. CD34+/lin- cells were purified using a Diamond CD34 Isolation Kit Miltenyi (97% of purity). FISH analysis of selected unstimulated CD34+/lin- cells was performed according to standard method; considering the low sensitivity of the test, at least 200 nuclei were examined in order to define the test as negative. This phase II study was designed according to the A’Hern single stage design, where, at 6 mos, we assumed a proportion defining a poor response as PP = 0.10, and the proportion defining a good response as PG = 0.30, PA being the proportion of responders.The study required 41 subjects to decide, with a power of 95%, whether PA ≤ 0.10 or PA ≥ 0.30. To have 41 evaluable, 87 pts had to be enrolled, considering 80% of them being fully analysed and 60% of these reaching CCyR (according to ENESTnd data).
Results
Enrolment of 87 pts was completed by June 2015; the database hasn't been locked yet. At present, FISH analysis on CD34+/lin- cells at 6 mos of treatment is evaluable for 68 of 75 pts with a documented CCyR; 7 negative tests were not evaluable since less than 200 nuclei were analysed. Only 5/68 (7,3%) evaluable FISH tested positive. Results at 3 and 12 mos are as follows: 8/58 (13,8%) and 0/46 (0%) evaluable FISH respectively tested positive (7 and 6 negative test excluded respectively). Sokal score did not predict for FISH positive results at any time point.
Conclusion
These results strongly point to a role for NIL 300 mg BID in fast clearance of BM CD34+/lin-Ph+ cells in a high proportion of treated pts. In view of the potential clinical relevance of our data, the protocol was amended in order to revise our FISH data using a test with higher sensibility and specificity, i.e.: the gDNA PCR. These results might give insight into a possible correlation with depth and stability of molecular response. We acknowledge all REL Colleagues for their collaboration and Novartis SpA for the partial financial support to the study.
Session topic: E-poster
Keyword(s): CD34+ cells, Chronic myeloid leukemia, Targeted therapy
Type: Eposter Presentation
Background
CML is a clonal disorder characterized by the presence of the Philadelphia (Ph) chromosome which encodes for the bcr-abl tyrosine-kinase (TK). Target therapy with the TK inhibitor (TKI) imatinib (IM) has greatly improved outcome in CML; however, only a minority of responsive pts can discontinue treatment without relapsing in the short term and even less pts can be considered free of disease. This data probably relates to persistence of quiescent CD34+Ph+ stem cells (SC) whose persistence has been documented even among pts in optimal response (Bocchia et al, 2008). Compared to IM, faster and deeper responses in CP-CML pts can be achieved with the second generation TKI Nilotinib (NIL); however, only preliminary data are available on NIL potential to eradicate Ph+ SC. Moreover, in vitro studies (Corbin AS, et al 2011; Hamilton A, et al 2012) suggest that CD34+Ph+SC may not be sensitive to TKI-mediated Bcr/Abl inhibition. However, in vivo data (Defina et al, 2012) have shown that, compared to IM treated pts, residual leukemic SC are very rarely detected among NIL treated pts in CCyR even after short-term NIL therapy and even if duration of treatment is shorter for NIL compared to IM treated pts (median 39 vs 22 mos). At present, no clear evidence of TKI effect on the leukemic SC clearance is available.
Aims
On behalf of the Rete Ematologica Lombarda (REL), the PhilosoPhi34 protocol (EudraCT: 2012-005062-34), an open label, single arm, phase II study, was designed to investigate the efficacy of NIL 300 mg BID in BM CD34+/lin-Ph+cells clearance at 3, 6 (primary objective) and12 months of treatment in newly diagnosed CP-CML pts.
Methods
Enrolled pts' BM cells were collected and stored at diagnosis and at 3,6 and 12 mos of treatment. CD34+/lin- cells were purified using a Diamond CD34 Isolation Kit Miltenyi (97% of purity). FISH analysis of selected unstimulated CD34+/lin- cells was performed according to standard method; considering the low sensitivity of the test, at least 200 nuclei were examined in order to define the test as negative. This phase II study was designed according to the A’Hern single stage design, where, at 6 mos, we assumed a proportion defining a poor response as PP = 0.10, and the proportion defining a good response as PG = 0.30, PA being the proportion of responders.The study required 41 subjects to decide, with a power of 95%, whether PA ≤ 0.10 or PA ≥ 0.30. To have 41 evaluable, 87 pts had to be enrolled, considering 80% of them being fully analysed and 60% of these reaching CCyR (according to ENESTnd data).
Results
Enrolment of 87 pts was completed by June 2015; the database hasn't been locked yet. At present, FISH analysis on CD34+/lin- cells at 6 mos of treatment is evaluable for 68 of 75 pts with a documented CCyR; 7 negative tests were not evaluable since less than 200 nuclei were analysed. Only 5/68 (7,3%) evaluable FISH tested positive. Results at 3 and 12 mos are as follows: 8/58 (13,8%) and 0/46 (0%) evaluable FISH respectively tested positive (7 and 6 negative test excluded respectively). Sokal score did not predict for FISH positive results at any time point.
Conclusion
These results strongly point to a role for NIL 300 mg BID in fast clearance of BM CD34+/lin-Ph+ cells in a high proportion of treated pts. In view of the potential clinical relevance of our data, the protocol was amended in order to revise our FISH data using a test with higher sensibility and specificity, i.e.: the gDNA PCR. These results might give insight into a possible correlation with depth and stability of molecular response. We acknowledge all REL Colleagues for their collaboration and Novartis SpA for the partial financial support to the study.
Session topic: E-poster
Keyword(s): CD34+ cells, Chronic myeloid leukemia, Targeted therapy
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