CLINICAL RESPONSE IN RELAPSED/REFRACTORY AML PATIENTS CORRELATES WITH LEUKEMIC BLAST MOBILIZATION AND DIFFERENTIATION INDUCED BY BL-8040, A POTENT CXCR4 ANTAGONIST; RESULTS OF A PHASE IIA STUDY
(Abstract release date: 05/19/16)
EHA Library. Pereg Y. 06/10/16; 133178; P190
Dr. Yaron Pereg
Contributions
Contributions
Abstract
Abstract: P190
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM retention of AML cells is dependent on CXCR4 and its ligand CXCL12 (SDF-1); high CXCR4 expression correlates with poor survival in AML patients. Blocking CXCR4 disrupts the interaction of AML blasts with the BM and augments the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a high affinity CXCR4 inhibitor with long receptor occupancy. Recent clinical trials have demonstrated BL-8040's robust hematopoietic cell mobilization from the BM. BL-8040's anti leukemic effect is mediated through robust leukemic blast mobilization, induction of leukemia cell differentiation and apoptosis. Here we report results of a phase 2a study evaluating BL-8040 in combination with cytarabine (Ara-C) for the treatment of relapsed/refractory AML patients (NCT01838395).
Aims
To assess the safety, efficacy and PK/PD parameters of BL-8040 in combination with Ara-C in relapsed/refractory AML patients.
Methods
The study included a dose escalation phase (3+3 design) followed by an expansion phase. Each patient received a once daily SC dose of BL-8040 as monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5g/m2 for patients ≥60; 3g/m2 for patients <60) on days 3-7. Six BL-8040 doses (0.5 – 2.0 mg/kg) were tested in the escalation phase with 1.5 mg/kg selected for the expansion phase. PD parameters such as extent of mobilization, induction of differentiation and apoptosis, CXCR4 expression and receptor occupancy were assessed by BM biopsy on day 3 and throughout the study. Remission was determined by BM biopsy on day 30.
Results
Forty five patients (median age, 61y; range, 23-75y) were treated with BL-8040 (including 3 patients treated on compassionate use basis). BL-8040 was escalated up to 2.0 mg/kg without reaching the MTD. Combination with Ara-C was safe and well tolerated at all doses. Three SAE’s (Sweet’s Syndrome, PCP pneumonia and allergic type reaction) were reported by the investigators as possibly related to BL-8040. Primary BL-8040 related AEs were transient, mild to severe injection site and systemic reactions, none of which were considered as DLT. The available composite complete remission (CR+CRi) rate is 38% in patients receiving BL-8040 doses of 1 mg/kg and higher (n=39). While baseline BM disease burden was comparable between responders (R) and non-responders (NR) (38% vs. 40% BM blasts, respectively), responders demonstrated significantly lower levels of circulating blasts at baseline compared to non-responders (2.9% vs. 19.3%, respectively). Furthermore, response to treatment was associated with higher mobilization of AML blasts following 2 days of BL-8040 monotherapy (CR=7.0, CRi=4.2, PD=1.1, SD=0.4, fold change) and with induction of granulocytic differentiation in the BM (R=3.2 vs. NR=1.4, fold change). PD analysis further confirmed BL-8040’s long receptor occupancy and its ability to induce apoptosis.
Conclusion
The results demonstrate that, in difficult to treat AML patients, sustained blockade of CXCR4 with BL-8040 combined with Ara-C may improve the clinical response rates achieved historically with Ara-C. In addition the data, for the first time, may suggest that better clinical responses are seen in patients with more efficient CXCR4 inhibition (reflected by higher mobilization and induction of granulocytic differentiation) and lower peripheral circulating blasts (despite comparable marrow blasts) at baseline. This finding may serve as a biomarker for patient selection in future BL-8040 studies in AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Apoptosis, CXCR4, Differentiation
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM retention of AML cells is dependent on CXCR4 and its ligand CXCL12 (SDF-1); high CXCR4 expression correlates with poor survival in AML patients. Blocking CXCR4 disrupts the interaction of AML blasts with the BM and augments the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a high affinity CXCR4 inhibitor with long receptor occupancy. Recent clinical trials have demonstrated BL-8040's robust hematopoietic cell mobilization from the BM. BL-8040's anti leukemic effect is mediated through robust leukemic blast mobilization, induction of leukemia cell differentiation and apoptosis. Here we report results of a phase 2a study evaluating BL-8040 in combination with cytarabine (Ara-C) for the treatment of relapsed/refractory AML patients (NCT01838395).
Aims
To assess the safety, efficacy and PK/PD parameters of BL-8040 in combination with Ara-C in relapsed/refractory AML patients.
Methods
The study included a dose escalation phase (3+3 design) followed by an expansion phase. Each patient received a once daily SC dose of BL-8040 as monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5g/m2 for patients ≥60; 3g/m2 for patients <60) on days 3-7. Six BL-8040 doses (0.5 – 2.0 mg/kg) were tested in the escalation phase with 1.5 mg/kg selected for the expansion phase. PD parameters such as extent of mobilization, induction of differentiation and apoptosis, CXCR4 expression and receptor occupancy were assessed by BM biopsy on day 3 and throughout the study. Remission was determined by BM biopsy on day 30.
Results
Forty five patients (median age, 61y; range, 23-75y) were treated with BL-8040 (including 3 patients treated on compassionate use basis). BL-8040 was escalated up to 2.0 mg/kg without reaching the MTD. Combination with Ara-C was safe and well tolerated at all doses. Three SAE’s (Sweet’s Syndrome, PCP pneumonia and allergic type reaction) were reported by the investigators as possibly related to BL-8040. Primary BL-8040 related AEs were transient, mild to severe injection site and systemic reactions, none of which were considered as DLT. The available composite complete remission (CR+CRi) rate is 38% in patients receiving BL-8040 doses of 1 mg/kg and higher (n=39). While baseline BM disease burden was comparable between responders (R) and non-responders (NR) (38% vs. 40% BM blasts, respectively), responders demonstrated significantly lower levels of circulating blasts at baseline compared to non-responders (2.9% vs. 19.3%, respectively). Furthermore, response to treatment was associated with higher mobilization of AML blasts following 2 days of BL-8040 monotherapy (CR=7.0, CRi=4.2, PD=1.1, SD=0.4, fold change) and with induction of granulocytic differentiation in the BM (R=3.2 vs. NR=1.4, fold change). PD analysis further confirmed BL-8040’s long receptor occupancy and its ability to induce apoptosis.
Conclusion
The results demonstrate that, in difficult to treat AML patients, sustained blockade of CXCR4 with BL-8040 combined with Ara-C may improve the clinical response rates achieved historically with Ara-C. In addition the data, for the first time, may suggest that better clinical responses are seen in patients with more efficient CXCR4 inhibition (reflected by higher mobilization and induction of granulocytic differentiation) and lower peripheral circulating blasts (despite comparable marrow blasts) at baseline. This finding may serve as a biomarker for patient selection in future BL-8040 studies in AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Apoptosis, CXCR4, Differentiation
Abstract: P190
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM retention of AML cells is dependent on CXCR4 and its ligand CXCL12 (SDF-1); high CXCR4 expression correlates with poor survival in AML patients. Blocking CXCR4 disrupts the interaction of AML blasts with the BM and augments the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a high affinity CXCR4 inhibitor with long receptor occupancy. Recent clinical trials have demonstrated BL-8040's robust hematopoietic cell mobilization from the BM. BL-8040's anti leukemic effect is mediated through robust leukemic blast mobilization, induction of leukemia cell differentiation and apoptosis. Here we report results of a phase 2a study evaluating BL-8040 in combination with cytarabine (Ara-C) for the treatment of relapsed/refractory AML patients (NCT01838395).
Aims
To assess the safety, efficacy and PK/PD parameters of BL-8040 in combination with Ara-C in relapsed/refractory AML patients.
Methods
The study included a dose escalation phase (3+3 design) followed by an expansion phase. Each patient received a once daily SC dose of BL-8040 as monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5g/m2 for patients ≥60; 3g/m2 for patients <60) on days 3-7. Six BL-8040 doses (0.5 – 2.0 mg/kg) were tested in the escalation phase with 1.5 mg/kg selected for the expansion phase. PD parameters such as extent of mobilization, induction of differentiation and apoptosis, CXCR4 expression and receptor occupancy were assessed by BM biopsy on day 3 and throughout the study. Remission was determined by BM biopsy on day 30.
Results
Forty five patients (median age, 61y; range, 23-75y) were treated with BL-8040 (including 3 patients treated on compassionate use basis). BL-8040 was escalated up to 2.0 mg/kg without reaching the MTD. Combination with Ara-C was safe and well tolerated at all doses. Three SAE’s (Sweet’s Syndrome, PCP pneumonia and allergic type reaction) were reported by the investigators as possibly related to BL-8040. Primary BL-8040 related AEs were transient, mild to severe injection site and systemic reactions, none of which were considered as DLT. The available composite complete remission (CR+CRi) rate is 38% in patients receiving BL-8040 doses of 1 mg/kg and higher (n=39). While baseline BM disease burden was comparable between responders (R) and non-responders (NR) (38% vs. 40% BM blasts, respectively), responders demonstrated significantly lower levels of circulating blasts at baseline compared to non-responders (2.9% vs. 19.3%, respectively). Furthermore, response to treatment was associated with higher mobilization of AML blasts following 2 days of BL-8040 monotherapy (CR=7.0, CRi=4.2, PD=1.1, SD=0.4, fold change) and with induction of granulocytic differentiation in the BM (R=3.2 vs. NR=1.4, fold change). PD analysis further confirmed BL-8040’s long receptor occupancy and its ability to induce apoptosis.
Conclusion
The results demonstrate that, in difficult to treat AML patients, sustained blockade of CXCR4 with BL-8040 combined with Ara-C may improve the clinical response rates achieved historically with Ara-C. In addition the data, for the first time, may suggest that better clinical responses are seen in patients with more efficient CXCR4 inhibition (reflected by higher mobilization and induction of granulocytic differentiation) and lower peripheral circulating blasts (despite comparable marrow blasts) at baseline. This finding may serve as a biomarker for patient selection in future BL-8040 studies in AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Apoptosis, CXCR4, Differentiation
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM retention of AML cells is dependent on CXCR4 and its ligand CXCL12 (SDF-1); high CXCR4 expression correlates with poor survival in AML patients. Blocking CXCR4 disrupts the interaction of AML blasts with the BM and augments the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a high affinity CXCR4 inhibitor with long receptor occupancy. Recent clinical trials have demonstrated BL-8040's robust hematopoietic cell mobilization from the BM. BL-8040's anti leukemic effect is mediated through robust leukemic blast mobilization, induction of leukemia cell differentiation and apoptosis. Here we report results of a phase 2a study evaluating BL-8040 in combination with cytarabine (Ara-C) for the treatment of relapsed/refractory AML patients (NCT01838395).
Aims
To assess the safety, efficacy and PK/PD parameters of BL-8040 in combination with Ara-C in relapsed/refractory AML patients.
Methods
The study included a dose escalation phase (3+3 design) followed by an expansion phase. Each patient received a once daily SC dose of BL-8040 as monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5g/m2 for patients ≥60; 3g/m2 for patients <60) on days 3-7. Six BL-8040 doses (0.5 – 2.0 mg/kg) were tested in the escalation phase with 1.5 mg/kg selected for the expansion phase. PD parameters such as extent of mobilization, induction of differentiation and apoptosis, CXCR4 expression and receptor occupancy were assessed by BM biopsy on day 3 and throughout the study. Remission was determined by BM biopsy on day 30.
Results
Forty five patients (median age, 61y; range, 23-75y) were treated with BL-8040 (including 3 patients treated on compassionate use basis). BL-8040 was escalated up to 2.0 mg/kg without reaching the MTD. Combination with Ara-C was safe and well tolerated at all doses. Three SAE’s (Sweet’s Syndrome, PCP pneumonia and allergic type reaction) were reported by the investigators as possibly related to BL-8040. Primary BL-8040 related AEs were transient, mild to severe injection site and systemic reactions, none of which were considered as DLT. The available composite complete remission (CR+CRi) rate is 38% in patients receiving BL-8040 doses of 1 mg/kg and higher (n=39). While baseline BM disease burden was comparable between responders (R) and non-responders (NR) (38% vs. 40% BM blasts, respectively), responders demonstrated significantly lower levels of circulating blasts at baseline compared to non-responders (2.9% vs. 19.3%, respectively). Furthermore, response to treatment was associated with higher mobilization of AML blasts following 2 days of BL-8040 monotherapy (CR=7.0, CRi=4.2, PD=1.1, SD=0.4, fold change) and with induction of granulocytic differentiation in the BM (R=3.2 vs. NR=1.4, fold change). PD analysis further confirmed BL-8040’s long receptor occupancy and its ability to induce apoptosis.
Conclusion
The results demonstrate that, in difficult to treat AML patients, sustained blockade of CXCR4 with BL-8040 combined with Ara-C may improve the clinical response rates achieved historically with Ara-C. In addition the data, for the first time, may suggest that better clinical responses are seen in patients with more efficient CXCR4 inhibition (reflected by higher mobilization and induction of granulocytic differentiation) and lower peripheral circulating blasts (despite comparable marrow blasts) at baseline. This finding may serve as a biomarker for patient selection in future BL-8040 studies in AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Apoptosis, CXCR4, Differentiation
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