Glucocorticoid Receptor 

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  • ||||||||||  lenalidomide / Generic mfg.
    Maintenance Therapy with Single-Agent Lenalidomide for POEMS Syndrome (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_6372;    
    Lenalidomide with dexamethasone (Rd) can lead to rapid hematological and neurological responses, however, progression-free survival (PFS) after Rd treatment remains unsatisfactory...Conclusion Maintenance therapy with lenalidomide is a practical approach to increase responses and reduce the risk of progression, especially in high-risk patients and in those with inadequate remission. Maintenance therapy may be considered part of the standard therapy in these patients in POEMS syndrome.
  • ||||||||||  Darzalex (daratumumab) / J&J
    Optimal Sequencing Determination in Relapsed Multiple Myeloma (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_6334;    
    Therefore, either regimen remains reasonable in the second line setting, and there is no optimal sequence in the current era of available therapies in RMM. Additional data is needed to determine if combining the two drugs at first relapse results in improved outcomes.
  • ||||||||||  bortezomib / Generic mfg., dexamethasone / Generic mfg., lenalidomide / Generic mfg.
    Post-Hoc Analysis of Efficacy and Safety in the SWOG S0777 Trial Stratified By Age (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_6323;    
    In patients aged <65 years at enrollment (n=269), median PFS was 55.4 and 36.6 months for VRd and Rd patients, respectively (HR=0.63, 95% CI: 0.46, 0.87); median OS was not reached and 68.9 months (HR=0.61, 95% CI: 0.39, 0.97). The incidence of grade =3 TEAEs and treatment discontinuation due to toxicity was 87% and 29% in VRd patients as compared with 79% and 18% in Rd patients.
  • ||||||||||  Circulating RAS/RAF and DNA-Repair Gene Mutations Associates with High-Risk/Treatment Resistance in Primary Refractory Multiple Myeloma (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_6285;    
    Real-world data reveals that 23% of transplant eligible newly diagnosed MM patients relapse within 12 months of starting first-line bortezomib (1LB) based therapy and of these ~50% will fail secondary therapy and die within 18 months of diagnosis...Methods A total of 186 paired peripheral blood plasma and BM samples were obtained at baseline, cycle 3 day 1 (C3D1), end of study (EOS) and/or relapse, whichever appeared earlier, from a Phase II single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible ND MM patients who were refractory or had a suboptimal response to 1LB (Australasian Leukaemia and Lymphoma Group MM17 trial)...Conclusions These data demonstrate that combining ctDNA mutational profiling with available platforms for MM risk-stratification significantly enhances the identification of high-risk patients. Moreover, the impact in this context of RAS/RAF and DDR mutations provides a rationale for the design and implementation of novel treatment paradigms utilising RAS/RAF inhibitors or DNA-repair modulators in these high-risk MM patients.
  • ||||||||||  Xpovio (selinexor) / Karyopharm, Menarini, FORUS Therap
    Selinexor in Combination with R-GDP/R-ICE Regimen for Refractory Aggressive Large B-Cell Lymphoma Patients with TP53 Alterations (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_6111;    
    The prognosis of LBCL patients (pts) with TP53 mutations is poor in R-CHOP era, even treated with autologous stem-cell transplantation (ASCT) or anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy...Selinexor was administered orally (40 mg day 1, 8, 15) plus R-GDP (R 375mg/m2 d0, gemcitabine 1g/m2×d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4) or R-ICE (R 375mg/m2 d0, ifosfamide 1.5g/m2×3d, carboplatin (AUC 5) and etoposide 100mg/m2×3d) every 3 weeks as per physician’s choice...In addition, clinicians should be cautious to its GI toxicities with more proactive prevention and management measures. Selinexor (40mg qw) with R-GDP/R-ICE is worthy of further study based on the preliminary efficacy results.
  • ||||||||||  Dual Targeting of MDM2 and BCL2/Bclxl Demonstrates Potent Synergistic Activity in High-Risk Adult Acute Lymphoblastic Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5948;    
    These included clinical ALL drugs dexamethasone and daunorubicin, proteasome inhibitor carfilzomib, BCL2/BCLxL inhibitor navitoclax, and histone deacetylase inhibitors romidepsin and pracinostat...Combination of idasanutlin with navitoclax exhibited both the greatest and most consistent synergistic interaction (d = 24.7±8.7, n=11) of the candidate combinations (n=10) across an extensive landscape of dose combinations; additionally alluding to synergy indiscriminate of ALL subtype...Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes. The proposed combination of two clinical-stage compounds could have considerable positive clinical impact for the treatment of adult ALL.
  • ||||||||||  Hansoh Xinfu (flumatinib) / Jiangsu Hengrui Medicine, Jiangsu Hansoh Pharma
    A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia in Adults:Preliminary Results from RJ-ALL2020.2A Trial (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5857;    
    It has been demonstrated better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL...Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly...Central nervous system (CNS) prophylaxis is regularly performed by intrathecal injection of methotrexate, cytarabine, and dexamethasone after remission induction course...Conclusion The combination of the second-generation TKI flumatinib and chemotherapy is quite effective and safe in Chinese adult pts with newly diagnosed Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated.
  • ||||||||||  Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
    Inotuzumab Ozogamicin (InO) Combined with UKALL-R3 Modified Chemotherapy in Pediatric Patients with B-Cell Precursor CD22+ Acute Lymphoblastic Leukemia (BCP-ALL) – Results from the ITCC-059 Phase 1B Trial (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5855;    
    P1/2
    InO (fractionated in 3 doses/cycle, days 1, 8, 15) was combined with vincristine 1.5 mg/m2 (days 3, 10, 17, 24), two blocks (days 1-5 and 15-19) of dexamethasone 20 mg/m2 (in 2 daily doses), and intrathecal (IT) therapy (methotrexate ± steroids and cytarabine as per local practice; days 1 and 8)...Post study therapy data were available for 22 responders; 14 proceeded directly to HSCT and 6 to CAR-T-cell therapy; 1 received blinatumomab and 1 proceeded to maintenance chemotherapy...The ORR seems comparable to the SA cohorts, but the sample size is small. SA InO is randomized against UKALL R3 in the upcoming trial B1931036 for high-risk first relapsed ALL; a phase 2 study in very-high-risk first relapsed ALL is ongoing (ITCC-059).
  • ||||||||||  dexamethasone / Generic mfg.
    The RNA Binding Protein Musashi-2 (MSI2) Sustains the Growth and the Leukemogenic Potential of MLL-Rearranged Acute Lymphoblastic Leukemia, and It Is Involved in Glucocorticoid Resistance (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5782;    
    Further validation studies in vitro demonstrated that MSI2 KO cells were significantly (100-fold) more sensitive to Prednisolone or Dexamethasone than their MSI2-expressing counterpart...The putative role of MSI2 in regulating the energy metabolism of leukemia is a novel finding not previously investigated, which may pave the way for targeting the metabolic vulnerabilities of ALL as a novel therapeutic approach. In conclusion, our study demonstrates that MSI2 sustains the growth in vitro and the leukemogenic potential in vivo of MLLr ALL cells, and it is involved in GC-resistance by regulating the energy metabolism of leukemia.
  • ||||||||||  dexamethasone / Generic mfg., lenalidomide / Generic mfg., cytarabine / Generic mfg.
    Targeting PLZF Enhances Glucocorticoid Sensitivity in Acute Myeloid Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5780;    
    To better characterize GC-response in AML, we compared gene expression landscape of GC-resistant versus GC-sensitive AML cell lines exposed to dexamethasone (Dex) for different time points...Combination of Dex and Lenalidomide appeared more effective in samples harboring NPM1 mutation, independently of recurrent additional mutations of FLT3 or DNMT3A...PLZF suppression induces inflammatory response and sensitizes AML cells to anti-inflammatory effects of glucocorticoids. Based on our results, potent PLZF degrading compounds hold promises to potentiate GC-response in AML.
  • ||||||||||  Tavalisse (fostamatinib) / Rigel, Kissei
    SYK Kinase As a Master Regulator of Netosis (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5513;    
    Conclusions The ability of SYK inhibitors to block both NETosis and platelet activation (in case of platelets, via CLEC2 and GPVI – two receptors involved in thrombosis yet dispensable for hemostasis) is consistent with possibility that, in addition to anti-inflammatory properties, SYK inhibition has potential anti-thrombotic effects (Harbi et al.). Indeed, the latter might be behind the lower than expected rates of thrombotic events in ITP patients observed in clinical trials of fostamatinib (Cooper et al.).
  • ||||||||||  COVID-19 Outcomes at a Comprehensive Sickle Cell Center: A Two-Year Report (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5505;    
    Chronic pain was defined in the patients experiencing daily pain episodes for more than 4 days a week for the last 3 months and calculation of daily morphine equivalents was reported based on the clinic follow-ups and the narcotic database utilization...The treatment utilized for the patients was most commonly Remdesivir in 33, dexamethasone in 26, red cell products in 21 and monoclonal antibody in 13 patients...To circumvent that, the SC center resorted to virtual visits utilization to deliver the needed healthcare visits to the patients. This measure has aided in protecting patients against COVID-19 during the multiple COVID-19 peaks occurring in the last 2 years and has accordingly reduced the mortality and morbidity of the patient population.
  • ||||||||||  Maintenance Therapy Cessation for Sustained MRD Negative Multiple Myeloma Patients (ENMCC - La Nouvelle Orleans Ballroom AB) -  Nov 4, 2022 - Abstract #ASH2022ASH_5408;    
    P=N/A
    Introduction Maintenance therapy with lenalidomide (len) and other drugs is a cornerstone therapeutic strategy for sustaining deep durable remissions in multiple myeloma (MM)...These pts have transitioned to new regimens: Pt 13 initiated carfilzomib, pomalidomide, and dexamethasone with VGPR; Pt 2 with a plan to initiate daratumamab-based therapy locally...One such trial includes SWOG 1803, which randomizes maintenance continuation vs. discontinuation in two-year MRD negative sustained patients. While maintenance therapy demonstrates clear benefit for MM patients, feasibility of treatment-free periods remain an unanswered critical question in the field.
  • ||||||||||  dexamethasone / Generic mfg.
    Variable Frailty Categorization Among Real-World Patient with Multiple Myeloma: A Prospective Cohort Study (MFRAIL) (ENMCC - La Nouvelle Orleans Ballroom AB) -  Nov 4, 2022 - Abstract #ASH2022ASH_5407;    
    Empiric dose reduction outside the product monograph was observed in 17.5% of the patients with the majority of dose reductions (80%) done for agents other than dexamethasone alone among those patients...Additionally, prevalence of patients classified as frail versus fit varies depending upon the assessment tool utilized with no uniform definition of frailty in routine clinical practise. Further work is needed in both evaluating and standardizing frailty assessment tools in different clinical settings and with different therapeutic modalities to further optimize outcomes in this high-risk patient subgroup.
  • ||||||||||  bortezomib / Generic mfg., dexamethasone / Generic mfg., lenalidomide / Generic mfg.
    Minimal Residual Disease Monitoring By Targeted Mass Spectrometry Allows Early Relapse Detection in Multiple Myeloma (ENMCC - 278-282) -  Nov 4, 2022 - Abstract #ASH2022ASH_5383;    
    P3
    Future perspective The dynamic information on disease activity that is provided by the MS-MRD can provide patients with feedback on their disease status after each checkup, and can provide clinicians options for evidence based treatment escalation or de-escalation. While the overall patient benefit of such personalized treatment still needs to be assessed in clinical trials, we expect that this can improve patient quality of life and allow for more efficient use of pharmacotherapy.
  • ||||||||||  isatuximab subcutaneous (SAR650984 SC) / Sanofi
    Bone Marrow Immune Signatures in Multiple Myeloma Are Linked to Tumor Heterogeneity and Treatment Outcome (ENMCC - Hall E) -  Nov 4, 2022 - Abstract #ASH2022ASH_5249;    
    P3
    Anti-CD38 monoclonal antibodies increase efficacy when added to standard-of-care (SOC) regimens as reflected by minimal residual disease-negativity (MRD-neg) rates of >50 % after induction therapy in newly diagnosed MM (NDMM) patients treated with SOC plus isatuximab within the GMMG-HD7 trial (Goldschmidt et al...NDMM patients were treated with lenalidomide/bortezomib/dexamethasone (RVd) alone or in combination with isatuximab (isa-RVd, NCT03617731)...BME signatures at baseline and during treatment as defined by our reference atlas enable risk stratifications of MM patients and can identify patients at high risk for early relapse. Longitudinal monitoring of the BME can support clinical decision making, as a compromised CD8+ memory compartment in patients may impact on the efficacy of novel immunotherapies.