Iclusig (ponatinib) / Takeda, Otsuka 
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  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte
    Preliminary Results of CML1214, a Survey on Ponatinib Compassionate Use in Italy By the Gimema CML Working Party (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_4117;    
    P=N/A
    After a median follow up of 46.6 months, ponatinib provided substantial benefits in a cohort of pts in a timeframe where, after failing 2nd generation TKIs, no other chances were available except transplantation, and T315I positive patients were practically orphan of treatment before ponatinib . Aside from the large prospective PACE trial, results from GIMEMA CML1214 pair with other real-life experiences like the French PEARL (Heiblig M, Exp Hematol 2018) or the Spanish GELMC (Garcia-Gutierrez V, EHA 2016) reports, thus confirming the manageability and the effectiveness of this therapy in challenging clinical situations.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Sprycel (dasatinib) / BMS, Otsuka, Inhibikase
    Prognostic Significance of IKZF1, PAX5, and CDKN2A Deletions in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD/MA with Dasatinib or Ponatinib (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_3930;    
    However, patients with IKZF1 deletion (del) has been shown to manifest poor prognosis when treated with imatinib-based regimens (Martinelli et al...Methods We studied 62 patients with previously untreated Ph+ B-ALL who were part of the phase II clinical trials of Hyper-CVAD alternating with high-dose methotrexate and cytarabine (Hyper-CVAD/MA) plus dasatinib (N = 27) or Hyper-CVAD/MA plus ponatinib (N = 35)...In the patients harboring IKZF1 del, ponatinib-treated subgroup had better prognosis than dasatinib-treated subgroup. Further investigation is needed to determine the prognostic significance of IKZF1 del in individual treatment subgroup.
  • ||||||||||  S81694 / Nerviano Medical Sciences, Servier, Survector (amineptine) / Servier, Pfizer
    Preclinical Activity of the MPS1 Inhibitor S81694 in Acute Lymphoblastic Leukemia (ALL) (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_3804;    
    Mps1i S81694 yields significant preclinical activity in T-and B-cell ALL including BCR-ABL1+ models. Interestingly S81694 was efficacious in a TKI resistant cell line.
  • ||||||||||  Activation of AKT/mTOR Pathway in Ph+ Acute Lymphoblastic Leukemia (ALL) Leads to Non-Mutational Resistance (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_3740;    
    Successful targeting of BCR/ABL by selective tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, Dasatinib and Ponatinib are used for the treatment of Philadelphia chromosome-positive (Ph+) leukemias...All approved AKIs and allosteric inhibitors like GNF-2, ABL001 and Crizotinib were unable to inhibit growth of these cells, except for Dasatinib (IC50 40nM), a multi-target kinase inhibitor...We targeted the AKT/mTOR pathway using BKM-120 (PI3 Kinase inhibitor), BEZ-235 (PI3 Kinase and mTOR pathway) and Trorin1/Torin2 (mTORC1 and mTORC2) and found that Torin-1 and Torin-2 significantly inhibited proliferation of SupB15RT, in a dose dependent manner, with an IC50 of 11–20 nM... Our experiments revealed an additional pathway involved in the evolution of non-mutational resistance in Ph+ ALL which could assist in developing novel targeted therapy for Ph+ ALL patient(s) with non-mutational resistance.
  • ||||||||||  Combined Targeting of the Menin-MLL1 Chromatin Complex and FLT3 As a Novel Therapeutic Concept Against NPM1 Mutant or MLL-Rearranged AML with Mutated FLT3 (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_2267;    
    As the murine Npm1mutFlt3ITD AML cells harbor the Flt3ITD F692L gatekeeper mutation that conveys drug resistance to most FLT3 inhibitors, we used Ponatinib as a combination partner for MI503 in these cells and found similar synergistic suppression of proliferation and colony formation...Of note, we observed the most pronounced pFLT3 reduction with combo treatment, most likely reflecting the cooperative effect of direct pFLT3 inhibition with AC220 and transcriptional suppression of total FLT3 via MI503...In summary, we demonstrate synergistic on-target activity against mutant FLT3 signaling with combined menin-MLL1 and FLT3 inhibition in leukemias with NPM1mut or MLL-r in vitro and in vivo . This concept may represent a novel therapeutic opportunity against these AMLs harboring a prognostically adverse FLT3-ITD.
  • ||||||||||  paclitaxel / Generic Mfg.
    High-Throughput Drug Screening of FDA-approved Antineoplastic Drugs for the Treatment of Aggressive Meningiomas (Ballroom Lawn) -  Oct 29, 2019 - Abstract #SNO2019SNO_414;    
    Drug concentrations of 10xIC50 values resulted in an inhibition of migration in Ben-Men-1 cells for Bortezomib, Carfilzomib, and Omacetaxine by 49%, 30%, and 23%, respectively (P< .05). In conclusion, we identified 5 promising drugs for the treatment of aggressive meningiomas by applying a high-throughput drug screening of 147 FDA-approved antineoplastic drugs.
  • ||||||||||  Clinical, Review, Journal:  Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy. (Pubmed Central) -  Oct 29, 2019   
    Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.
  • ||||||||||  Review, Journal:  The 8p11 myeloproliferative syndrome: a review of recent literature (Pubmed Central) -  Oct 28, 2019   
    Therefore, at present, allo-hematopoietic stem cell transplantation is the only curative methods for EMS. Very recently, a phase-2 study with pemigatinib, an inhibitor for FGFR1, showed clinical benefits for EMS patients, including major cytogenetic response, suggesting a new therapeutic option for EMS.
  • ||||||||||  Review, Journal:  Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors. (Pubmed Central) -  Oct 24, 2019   
    Although all TKIs are associated with high survival rates, newer TKIs have been associated with lower disease progression rates and, importantly, deeper treatment responses and, potentially, a greater chance of future treatment-free remission. Finally, we consider the unmet needs of patients with CML, including the challenges remaining for those without optimal responses during TKI therapy and new therapies and strategies to identify such patients at diagnosis.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Tasigna (nilotinib) / Novartis, Inhibikase, Sprycel (dasatinib) / BMS, Otsuka, Inhibikase
    Journal:  Coronary artery spasms due to tyrosine kinase inhibitors used in chronic myeloid leukemia. (Pubmed Central) -  Oct 8, 2019   
    Coronary artery spasm (CAS), although encountered during treatment with other chemotherapeutic drugs, have to our knowledge never been reported during TKI treatment. Here, we describe two cases of coronary artery spasms which are likely due to TKIs.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte
    Clinical, Journal:  Ponatinib: A Review of Efficacy and Safety. (Pubmed Central) -  Oct 2, 2019   
    In this review, clinical trials data about the use of ponatinib in CML and Ph+ ALL patients will be discussed. It will be focused also about the Ph+ safety and tolerability profile of the drug and future perspectives of employment.
  • ||||||||||  Actemra IV (tocilizumab) / Roche, JW Pharma
    Improvement of the prediction of cytokine release syndrome (CRS) in patients with CAR-T therapy (M8) -  Sep 30, 2019 - Abstract #DGHO2019DGHO_1344;    
    These preliminary results suggest that residual lymphoma/leukemia burden and early increase of Kymriah ® -specific TCR in PB and of IL-6 serum levels may identify patients at increased risk of CRS. We will continue this diagnostic program in subsequent CAR-T recipients to optimize in- and outpatient management.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte
    Large vessel vasculitis as a potential mechanism for vascular side effects of ponatinib (M4 / M5) -  Sep 30, 2019 - Abstract #DGHO2019DGHO_869;    
    This interim analysis shows first data of the real-life treatment with ponatinib in CML patients which have not only been collected from various clinical studies. Introduction: Arterial occlusive events (AOEs) are known side effects of ponatinib, due due to rapid development of arteriosclerosis, while the definite patho-mechanisms are still unclear. 1 We present a case of large vessel vasculitis and discuss this as a possible mechanism. Patients: A 60-year-old Ph + ALL female was put on ponatinib in subsequent relapse with detection of T315I mutation after two alloSCT and several salvage therapies, including other TKIs. On ponatinib, she achieved a complete molecular remission, but developed symptoms of intermittent claudication. Ultrasound (US) revealed stenosis of bilateral femoro-iliac and subclavian arteries, with typical pattern for large vessel vasculitis and no arteriosclerosis. After stop of ponatinib and initiation steroids, symptoms improved rapidly, as well as the US signs of vasculitis. Due to a meningeal relapse 16 months later, ponatinib was restarted (15 mg / d) and symptoms of claudication recurred. Steroids were administered again and ponatinib was continued, resulting in slight improvement. Three months later, due to abdominal pain, a CT showed a distanced caecum (7 cm) and a complete occlusion of the superior mesenteric artery (SMA). The presence of collaterals is a chronic stenosis or occlusion. No signs of intestinal arteriosclerosis on CT and no evidence of atrial fibrillation in the ECG that might suggest a thromboembolic event. Immediate bowel-resection what performed. However, the patient died due to septic complications. The histo-pathological evaluation showed only minimal signs of both arteriosclerosis and inflammation.  Large vascular vasculitis as a possible mechanism for AOE's following ponatinib has been described in a patient with cerebral ischemia. 2 In accordance with this report, the present case, this patho-mechanism by way of typical symptoms of claudication and US signs of vasculitis, as well as by rapid improvement after steroids and stopping ponatinib. After re-exposure claudication re-appeared, and the patient finally died out of otherwise unexplained ischemic bowel disease. In lack of other obvious reasons, intestinal vasculitis in the context of re-exposure to ponatinib was suspected as a trigger for occlusion of SMA. The missing clear proof of inflammation in histology in our case may be explained by the prior restart of steroids.
  • ||||||||||  asciminib (ABL001) / Novartis, Iclusig (ponatinib) / Takeda, Otsuka, Incyte
    Journal:  Asciminib with Ponatinib Lowers Resistance in Chronic Myeloid Leukemia. (Pubmed Central) -  Sep 29, 2019   
    The clinical value of these drug combinations in CMML remain to be determined in forthcoming studies. Asciminib with ponatinib was more effective than either alone in chronic myeloid leukemia (CML).
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte
    Review, Journal:  Ponatinib for Treating Chronic Myeloid Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. (Pubmed Central) -  Sep 26, 2019   
    In BP-CML, the cost effectiveness of ponatinib ranged from £5033 per QALY gained to dominated compared with allo-SCT, although it was likely to be at the more favourable end of this range, and dominant in all scenarios compared with BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of NHS resources in the considered population, subject to the company providing the agreed discount in the Patient Access Scheme.
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte
    A Genome-Wide CRISPR/Cas9 Screen Identifies Druggable Targets that Synergize with TKIs for Potential Combination Treatment of Leukemia (Acute Lymphoblastic Leukemia) -  Sep 26, 2019 - Abstract #SOHO2019SOHO_301;    
    We are currently studying the ex vivo efficacy of these combination treatments in primary cells from BCR-ABL+ ALL patients. Furthermore, we will characterize the molecular role of these epigenetic factors in resistance mechanisms by performing transcriptomic and epigenomic assays.Conclusions We have identified novel small molecule inhibitors that synergize with ponatinib, providing a potential novel treatment strategy for treatment of leukemia patients that have developed drug resistance.
  • ||||||||||  doxorubicin hydrochloride / generics, cyclophosphamide intravenous / generics
    Dynamic Prediction of Outcome with Longitudinal BCR-ABL1 Levels in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Acute Lymphoblastic Leukemia) -  Sep 26, 2019 - Abstract #SOHO2019SOHO_296;    
    For the estimation of parameters of the joint model, a Bayesian approach was used with Markov Chain Monte Carlo methods. Overall, the median follow-up was 72 months (range, 0.2-199.4).Setting MD Anderson Cancer Center from April 2001 to June 2017.Patients 223 patients enrolled in frontline trials of the combination of intensive therapy with TKI were analyzed (HCVAD [hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone] + imatinib, 54 patients; HCVAD + dasatinib, 72 patients; HCMAD [hyper-fractionated cyclophosphamide, liposomal vincristine, doxorubicin and dexamethasone] + TKI, 21 patients; HCVAD + ponatinib, 68 patients), including 2445 measurements of BCR-ABL1 transcripts by reverse transcriptase polymerase chain reaction.Interventions TKI, intensive chemotherapy, and ASCT.Main Outcome Measure Overall survival.Results Multivariate joint model identified age at the start of therapy (p<0.001; post-mean, 0.0167; 95% credible interval [CI], 0.0150 – 0.0175), type of transcript (P210 or P190) (p=0.030; post-mean, 2.5375; 95% CI, 1.3568 – 3.9252), BCR-ABL1 transcripts levels at diagnosis (p<0.001; post-mean, 0.0083; 95% CI, 0.0072 – 0.0097), TKI therapy (imatinib, dasatinib, or ponatinib) (p<0.001; post-mean, -0.4929; 95% CI, -0.5543 – -0.4532), time-dependent logarithmic P190 levels (p=0.006; post-mean, 0.0407; 95% CI, 0.0300 – 0.0605), time-dependent logarithmic P210 levels (p<0.001; post-mean, 0.0599; 95% CI, 0.0423 – 0.0812), and the use of ASCT (p=0.020; post-mean, 0.1276; 95% CI, 0.0869 – 0.2371) as prognostic factors for OS.Conclusions Dynamic personalized assessment of outcome is feasible to optimize treatment decision in patients with Ph+ALL.