Background: The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM homing of AML cells is dependent on CXCR4 and its ligand CXCL12; high levels of CXCR4 ...expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis with a potent CXCR4 antagonist will disrupt the interaction of the leukemic blasts with the BM and augment the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a short synthetic peptide which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukemic blasts from the bone marrow to the peripheral blood. BL-8040 also inhibits CXCR4/CXCL12 mediated pro-survival ERK/Akt signaling and alters balance of pro/anti-apoptotic Bcl-2 proteins. BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy, and, in contrast to other CXCR4 inhibitors, as a single agent induces apoptosis of leukemia cells ex-vivo in clinical samples. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of adult relapsed/refractory AML patients is currently ongoing (NCT01838395).
Objective: To assess the safety, efficacy and pharmacodynamics/pharmacokinetic parameters of BL-8040 in combination with Ara-C in first or second relapse and refractory AML patients.
Method: The study includes a dose escalation phase (3+3 design) followed by an expansion phase. Each patient receives a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5 g/m2 for patients ≥60; 3 g/m2 for patients <60) on days 3-7. Five dose levels of BL-8040 (0.5, 0.75, 1, 1.25 and 1.5 mg/kg) have been tested. Extensive pharmacodynamic parameters such as CXCR4 expression on the leukemic cells, receptor occupancy, mobilization of leukemic cells and induction of apoptosis are being assessed after monotherapy with BL-8040 using peripheral blood sampling (PB) and BM aspirates at baseline and on day 3 prior to Ara-C administration. Clinical response to treatment is evaluated by BM biopsy on day 30 (-/+ 2).
Results: Twenty two patients (median age, 61 y; range, 43-74 y) with relapsed/refractory AML were treated during the escalation phase. BL-8040 was escalated up to 1.5 mg/kg (recommended phase 2 dose) without reaching the MTD. Combination of BL-8040 with Ara-C was safe and well tolerated at all doses tested. Only one SAE (Sweet Syndrome) was reported as possibly related to study drug. The primary treatment related AEs were transient injection site and systemic reactions. The composite complete remission including complete remission (CR) and complete remission with incomplete blood count recovery (CRi) rate was 38% in subjects receiving BL-8040 doses of 1 mg/kg and higher (n=16). Two days of BL-8040 monotherapy triggered an average 40.2-fold (range 1.0-350.9) mobilization of immature AML progenitors (CD45+Low/CD34+/CD117+/HLA-DR+) from the BM to the PB. Moreover, a significant apoptotic effect on the immature leukemia progenitors in the BM following 2 days of BL-8040 monotherapy was noted. Flow cytometric evidence of apoptosis by BL-8040 was corroborated by an increase in cleaved caspase 3 positive blasts in day 3 bone marrow biopsies. In addition, BL-8040 treatment resulted in a median decrease of 57.7% (range, -10.4% to -96.2%) in the number of BM Leukemia progenitor cells (CD45+Low/CD34+/CD117+/HLA-DR+ out of total CD45+/CD34+ normal/progenitor cells) compared with the baseline biopsy. This decrease was accompanied with a 3.1 fold increase in granulocytes in the day 3 BM biopsy supporting differentiation effect. Finally, long receptor occupancy (up to 24 hours post dosing) was confirmed by FACS analysis measuring surface CXCR4 staining. Pharmacokinetics analysis confirmed dose incremental BL-8040 exposure with a short plasma half-life.
Conclusions: The current data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 has potent anti leukemic activity and in combination with Ara-C may improve the response typically achieved in this advanced AML population. Mechanistically, BL-8040 was able to induce apoptosis of leukemic progenitor cells, overcoming the stroma protection, inducing mobilization and differentiation.
Rowe:BioLineRx Ltd.: Consultancy; Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Novartis: Research Funding. Altman:Seattle Genetics: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; BMS: Consultancy. Peled:Biokine Ltd.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BiolineRX: Consultancy, Research Funding. Pereg:BioLineRx: Employment. Vainstein:BioLineRx: Employment. Aharon:BioLineRx: Employment. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.
Background: The bone marrow (BM) niche protects Acute Myeloid Leukemia (AML) cells from chemotherapy. BM homing of AML cells is dependent on CXCR4 and its ligand CXCL12, and high levels of CXCR4 ...expression correlate with poor survival in AML patients. It is postulated that blocking the CXCL12/CXCR4 axis with a potent CXCR4 antagonist will disrupt the interaction of the malignant blasts with the BM and augment the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a 14-residue, cyclic, synthetic peptide capped with an aromatic ring that acts as a selective inhibitor of the CXCR4 chemokine receptor. BL-8040 has strong affinity for the CXCR4 receptor and long receptor occupancy, resulting in a prolonged pharmacodynamic effect. BL-8040 has superior mobilization capacity, inverse agonism activity and direct pro-apoptotic activity against leukemia cells. Preclinical studies have shown that in addition to its activity as a mobilizer of hematopoietic cells, BL-8040 exhibits a CXCR4-dependent selective anti-tumor effect against malignant cells. A clinical trial for the treatment of adult relapsed/refractory AML patients using a combination of BL-8040 and cytarabine (Ara-C) is currently ongoing (NCT01838395).
Method: The phase II clinical trial in relapsed/refractory AML patients includes a dose escalation phase (3+3 design) followed by an expansion phase using the highest safe and efficacious dose group. Each patient receives a once daily SC dose of BL-8040 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. For each of the BL-8040 tested doses (0.5, 0.75, 1, 1.25 and 1.5 mg/kg) the safety and tolerability, pharmacokinetic profile and clinical responses are being evaluated. Additionally, CXCR4 expression on leukemia cells, receptor occupancy, timing of mobilization of leukemic blasts and stem/progenitor cells and induction of apoptosis are being followed using frequent peripheral blood sampling (PB) and BM aspirates at baseline and on day 3 prior to Ara-C administration.
Results: Preliminary results from the ongoing study suggest that administration of BL-8040, in combination with Ara-C, is safe and well tolerated at all doses tested to date (0.5-1 mg/kg). There have been no DLTs or SAEs and no delays in count recovery attributable to BL-8040. The primary treatment related AE has been a transient injection site reaction. FACS analysis revealed that 2 days of BL-8040 monotherapy triggered substantial mobilization of AML blasts (CD45+Low/CD34+/CD117+/HLA-DR+) from the BM to the PB. Data from the first 9 subjects revealed a 5.14 fold (range 1.0-8.09) median increase in AML blasts in the PB. Moreover, a dramatic decrease in the amount of AML blasts in the BM following 2 days of BL-8040 monotherapy was noted. FACS data from 7 subjects, for which BM aspirate samples were evaluable for analysis, revealed a median decrease of 70.65% range(-16.32%)-(-87.68%) in the number of AML blasts (CD45+Low/CD34+/CD117+/HLA-DR+ out of total CD45+/CD34+ normal/progenitor cells) compared with baseline. Importantly, this effect was specific to the AML blasts as the levels of normal/progenitor cells remained stable post BL-8040 monotherapy (5/7 patients). This decrease of BM AML blasts was evident regardless of whether the patient mobilized AML blasts or not. In support of induction of apoptosis by CXCR4 inhibition, an increase in the number of blasts with cleaved caspase3 was ascertained in day 3 BM biopsies from 6/8 patients. Long receptor occupancy (up to 24 hours post dosing) was observed by FACS analysis measuring surface CXCR4 staining. Pharmacokinetics analysis confirmed increase in BL-8040 exposure over doses with a short plasma half-life.
Conclusion: The current data demonstrate that BL-8040 induces mobilization of AML blasts from the BM and has sustained receptor occupancy. In addition, a direct effect on AML blast viability has been observed in samples obtained during BL-8040 monotherapy. Importantly, the data suggest a differential effect of BL-8040 monotherapy on AML blasts vs. normal progenitors. BL-8040 was found to be safe and well tolerated at all doses tested to date. The updated results of the dose escalation phase of this ongoing study will be presented.
Borthakur:BioLineRx: Research Funding. Nagler:BioLineRx: Research Funding. Peled:BioLineRx: Research Funding. Pereg:BioLineRx: Employment. Foley-Comer:BioLineRx: Consultancy. Russovsky:BioLineRx: Employment. Aharon:BioLineRx: Employment. Cortes:BioLineRx: Research Funding. Andreeff:BioLineRx: Research Funding.
Ataxia-telangiectasia (A-T) is a multi-system genomic instability syndrome that is caused by loss or inactivation of the ATM protein kinase. ATM is largely nuclear in proliferating cells, and ...activates an extensive network of pathways in response to double strand breaks (DSBs) in the DNA by phosphorylating key proteins in these pathways. The prominent symptom of A-T is neuronal degeneration, making the elucidation of ATM's functions in neurons essential to understanding the disease. It has been suggested that ATM is cytoplasmic in neurons and functions in processes that are not associated with the DNA damage response. Recently we showed that in human neuron-like cells obtained by
in vitro differentiation of neuroblastomas, ATM was largely nuclear and mediated the DSB response as in proliferating cells. We have now extended these studies to two additional model systems: neurons derived from human embryonic stem cells, and cortical neurons derived from neural stem cells. The results substantiate the notion that ATM is nuclear in human neurons and mediates the DSB response, the same as it does in proliferating cells. We present here unique and powerful model systems to further study the ATM-mediated network in neurons.
Cardiac rehabilitation improves prognosis and symptoms in cardiac patients. In 2020, due to the COVID-19 pandemic, cardiac rehabilitation services were temporarily suspended between April and August. ...We aimed to investigate the effect of cardiac rehabilitation suspension during the COVID-19 pandemic on patients' exercise capacity and metabolic parameters.
Included were patients undergoing cardiac rehabilitation following hospital admission for ACS. Exercise capacity, weight and body fat percentage were compared between baseline, pre- and post-lockdown visits.
A total of 281 patients participated in the cardiac rehabilitation program prior to its suspension. Of them, only 198 (70%) patients returned to the program on its renewal and were included in the analysis. Exercise capacity improved significantly in the pre-lockdown stress test compared to baseline. However, there was a significant decrease in exercise capacity in the post compared to pre-lockdown test (8.1±6.3 and 7.1±2.1 METs in pre- and post-lockdown measurements, respectively, p<0.001). Of the 99 (50%) of patients that demonstrated at least 10% improvement in exercise capacity in the pre-lockdown test, 48(48.5%) patients returned to their baseline values in the post-lockdown test. Post-lockdown assessment demonstrated a significant weight gain (80.3 and 81.1kg, in pre- and post-lockdown measurements, respectively, p<0.001) as well as an increase in visceral fat level and body fat percentage.
Cardiac rehabilitation suspension for 4 months during COVID-19 pandemic caused a significant reduction in exercise capacity and increased weight and body fat percent. These findings highlight the importance of remote cardiac rehabilitation services that can continue uninterrupted in times of pandemic.
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