- |||||||||| Rinvoq (upadacitinib) / AbbVie
Upadacitinib exposure during pregnancy in seronegative Rheumatoid arthritis () - Nov 8, 2024 - Abstract #BSRCBC2024BSR_CBC_12;
She has no history of spontaneous abortions.At the time of her RA diagnosis, the patient was considering pregnancy and was initially started on sulfasalazine...Despite this treatment, she exhibited only a partial response with ongoing disease activity, leading to a change to etanercept in August 2021.When etanercept proved ineffective, adalimumab was considered in January 2022...She was subsequently started on certolizumab...Access to a medical obstetrician team is invaluable in managing such cases.
- |||||||||| Actimmune (interferon gamma-1 b) / Clinigen, Amgen
Trial completion date, Trial primary completion date: Safety and Efficacy of Interferon-Gamma 1b in Patients With Candidemia (clinicaltrials.gov) - Nov 8, 2024
P2, N=200, Recruiting,
She has no history of spontaneous abortions.At the time of her RA diagnosis, the patient was considering pregnancy and was initially started on sulfasalazine...Despite this treatment, she exhibited only a partial response with ongoing disease activity, leading to a change to etanercept in August 2021.When etanercept proved ineffective, adalimumab was considered in January 2022...She was subsequently started on certolizumab...Access to a medical obstetrician team is invaluable in managing such cases. Trial completion date: Jan 2025 --> Jun 2027 | Trial primary completion date: Jan 2025 --> Jan 2027
- |||||||||| Neupogen (filgrastim) / Kyowa Kirin, Amgen
Enrollment change, Trial completion date, Trial withdrawal, Trial primary completion date: Phase I Study of TH1 Dendritic Cell Immunotherapy for the Treatment of Cutaneous Angiosarcoma (clinicaltrials.gov) - Nov 8, 2024
P1, N=0, Withdrawn,
Trial completion date: Nov 2024 --> Jan 2026 | Trial primary completion date: Nov 2024 --> Jan 2026 N=24 --> 0 | Trial completion date: Dec 2029 --> Nov 2024 | Recruiting --> Withdrawn | Trial primary completion date: Dec 2029 --> Nov 2024
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal, Combination therapy: KRAS inhibitors in drug resistance and potential for combination therapy. (Pubmed Central) - Nov 7, 2024
Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Ibrance (palbociclib) / Pfizer
Trial primary completion date, Metastases: PALVEN: Palbociclib, Letrozole & Venetoclax in ER and BCL-2 Positive Breast Cancer (clinicaltrials.gov) - Nov 7, 2024
P1, N=17, Active, not recruiting,
In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors. Trial primary completion date: Jun 2024 --> Jun 2025
- |||||||||| briquilimab (JSP191) / Jasper Therap
Trial completion date, Trial primary completion date: JSP191 Antibody Targeting Conditioning in SCID Patients (clinicaltrials.gov) - Nov 7, 2024
P1/2, N=40, Recruiting,
Trial primary completion date: Jun 2024 --> Jun 2025 Trial completion date: Aug 2027 --> Jun 2028 | Trial primary completion date: Aug 2024 --> Jun 2025
- |||||||||| Imdelltra (tarlatamab-dlle) / Amgen
Review, Journal: Tarlatamab-dlle: A New Hope for Patients with Extensive-Stage Small-Cell Lung Cancer. (Pubmed Central) - Nov 6, 2024
It might be possible that Tarlatamab-dlle received accelerated FDA approval for extensive-stage SCLC, leaving some questions unanswered at this stage. This manuscript is focused on clinical, pre-clinical, and other pharmacological aspects of Tarlatamab-dlle for extensive-stage SCLC.
- |||||||||| tolimidone (MTX228) / Bukwang Pharma, Biodexa Pharma
Trial primary completion date: An Adaptive Design Study of MTX228 (clinicaltrials.gov) - Nov 6, 2024
P2, N=24, Not yet recruiting,
No abstract available Trial primary completion date: Oct 2024 --> Oct 2026
- |||||||||| Krazati (adagrasib) / BMS
Journal: Adagrasib in KRYSTAL-12 (Pubmed Central) - Nov 6, 2024
Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.
- |||||||||| Vectibix (panitumumab) / Amgen
Differential Efficacy of Panitumumab in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase-Deficient Renal Cell Carcinoma () - Nov 6, 2024 - Abstract #IKCS2024IKCS_113;
The RMC PDX model was generated from a 28-year-old male with sickle cell trait who had previously received cisplatin plus paclitaxel followed by carboplatin plus paclitaxel...The FH-deficient PDX model was generated from a 24-year-old female with HLRCC (hereditary leiomyomatosis and renal cell carcinoma syndrome), who had been previously treated with first-line bevacizumab plus erlotinib with excellent response of her metastatic disease, which allowed subsequent cytoreductive nephrectomy of the left-sided primary mass from which the PDX model was derived...We observed disease control but not tumor regression with panitumumab in our FH-deficient RCC PDX model. Based on these data, panitumumab-based therapy is currently being prospectively investigated in a multi-center cohort of patients with treatment-refractory RMC.
- |||||||||| Neupogen (filgrastim) / Kyowa Kirin, Amgen, Promacta (eltrombopag) / Novartis
Incidence, Time to Diagnosis, and Therapeutic Landscape of Aplastic Anemia: Results from a Large United States Claims Database (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_6286;
Stem cell transplant (6.5%), horse antithymocyte globulin (hATG; 1.4%), and eltrombopag (0.3%) were recorded less frequently...Treatment patterns suggest infrequent use of direct therapy within 6 months of diagnosis, which may reflect the overall management of pts with AA in the US. These findings require further evaluation, but could present opportunities for earlier intervention, diagnosis, and treatment.
- |||||||||| Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Extranodal (EN) B-Cell Non-Hodgkin Lymphoma (NHL): Results from a Multicenter Analysis (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_6132;
Methods : We performed a retrospective multi-center analysis of pts with R/R aggressive B-cell NHL who had EN disease and received treatment with anti-CD19 CAR-T...99% (278 of 281 available) of pts received a commercial CD19 CAR (43% axicabtagene ciloleucel, 30% tisagenlecleucel, 25% lisocabtagene maraleucel, 2% brexucabtagene autoleucel), while the remaining 1% (n=3) received a bispecific or allogeneic CAR...Transfusion support (PRBC and platelets) and filgrastim beyond the first 30 days post CAR-T was needed in 18% (50 of 272 available), 20% (54 of 272 available), and 34% (93 of 272 available) of pts, respectively...TCT 2024). Further analysis including comparison of single-site versus multi-site EN disease as well as multivariate analysis of factors with significant impact on survival is ongoing.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Blincyto (blinatumomab) / Astellas, Amgen, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Real-World Outcomes and Disparities in the Era of Novel Therapies, 2010-2021 (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_6050;
Subsequent new agents, including ponatinib, a 3rd generation TKI introduced in 2012 which retains activity against all imatinib resistant mutations, and blinatumomab (Blin) and inotuzumab ozogamicin (Ino), both approved in 2017, have rapidly changed the treatment landscape of Ph+ B-ALL...Kaplan-Meier and Cox regression methods compared OS by time period of dx, corresponding with approved therapies (dasatinib, 2010-2011, ponatinib 2012-2016, Blin and Ino 2017-2021), and by age group (18-39, 40-64, 65-74, 75+ yrs)...We found considerable survival disparities in underinsured pts and pts from low-income areas, signaling that access to care may be a significant barrier to optimal outcomes. Efforts to optimize treatment regimens, such as novel chemotherapy-free regimens in elderly and frail pts, and improved access to novel therapies, are critically needed in Ph+ B-ALL to replicate the success observed in clinical trials in a real-world population.
- |||||||||| Real-World Outcomes of CD19-Targeted CAR T-Cell Therapy in Adult and Pediatric Patients with B-Cell Acute Lymphoblastic Leukemia (B-ALL): Insights from the GoCART Coalition on Behalf of the PDWP, ALWP, and CTIWP of the EBMT (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_6049;
Results : A total of 345 patients (173 adults and 172 pediatrics) received therapy from 2016 to 2023 with tisagenlecleucel (65.2%), varnimcabtagene autoleucel (25.8%), brexucabtagene autoleucel (5.5%), and others (3.5%)...Bridging therapy was administered in 86.4% (298) of patients based on high or low intensity chemotherapy (32.1% or 26.5%, respectively), inotuzumab-ozogamicin (13.4%), TKI (8.2%), involved-site therapy (intrathecal chemotherapy, radiotherapy, orchiectomy) (3.5%), and blinatumomab (2.6%), alone or in combination...Lymphodepletion was performed in all but one patient, based on fludarabine and cyclophosphamide regimens...These findings support the continued use and further investigation of CAR T-cell therapy in diverse clinical settings, emphasizing the importance of post-infusion strategies to sustain long-term remission. This will provide deeper insights into the factors influencing outcomes and help refine treatment protocols to improve patient care.
- |||||||||| SB202190 / Amgen
The c-MAF/SLP76 Axis Modulates Immune Evasion and Drives Malignancy in Multiple Myeloma Via Epigenetic Reprogramming (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5381;
The use of ERK or p38 inhibitors (STE-MEK1 or SB 202190) enhances the suppression of PDL1 by SLP76 knockdown...Knockdown of c-MAF reduced H3K27ac deposition, indicating that c-MAF-mediated super-enhancer remodeling establishes the c-MAF-SLP76-PDL1 axis to modulate immune responses and drive MM malignancy. In summary, we demonstrate that c-MAF plays a non-canonical role in epigenetics, which is related to the regulation of cellular immune status, and suggest that immunotherapy combined with MAPK-targeted therapy represents a novel therapeutic direction for t(14; 16) multiple myeloma.
- |||||||||| Ibrance (palbociclib) / Pfizer, iberdomide (CC-220) / BMS
CDK4/6 Inhibition Reverses MEIS2 Inhibition of CRL4CRBN By Both Disrupting MEIS2-CRBN Association and Opposing Regulation of MEIS2 and CRBN Synthesis That Enhances IMiD Therapy in Multiple Myeloma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5337;
The immunomodulatory drugs (IMiDs) lenalidomide (Len) and pomalidomide (Pom) are standard of care for multiple myeloma (MM)...Indeed, induction of prolonged early G1 arrest by CDK4/6 inhibition with palbociclib 1) enhanced Len and Pom killing in model MM cell lines; 2) reduced the MEIS2 protein by transcriptional repression and increased the CRBN protein by post-transcriptional regulation in cooperation with Len; 3) this led a > 5 fold reduction in the MEIS2/CRBN protein ratio, exacerbated loss of IKZF1/3 and IRF4, and enhanced apoptosis (caspase- cleavage)...In this study, we provide the first evidence that CDK4/6 inhibition reverses MEIS2 inhibition of CRBN that has a potential to enhance the clinical response to IMiD. The prospect that through cell cycle control CDK4/6 inhibition may also enhance the anti-MM activity of CELMoDs, the newly developed IMiDs such as iberdomide, in relapsed-refractory setting is exciting and warrants future investigation.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, RPT1G / Remedy Plan
The Hyperbolic NAMPT Inhibitor RPT1G Synergizes with BCL-2 Family Inhibitors and Helps Overcome Venetoclax Resistance in Acute Myeloid Leukemia Cells (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5297;
Moreover, RPT1G strongly synergizes with olaparib, a poly(ADP-ribose) polymerase inhibitor, and olaparib further enhanced the synergy between RPT1G and venetoclax...Of note, navitoclax or AMG-176 further enhanced the synergy between RPT1G and venetoclax in MV4; 11-VR cells...In summary, the first-in-class hyperbolic NAMPT inhibitor RPT1G exhibited strong synergy with agents targeting anti-apoptotic BCL-2 family proteins in AML cells, both alone and in the presence of other standard-of-care agents. Given the crucial roles of NAMPT and BCL-2 family proteins in the survival and treatment-resistance of LSCs, RPT1G is emerging as an ideal candidate to be included in novel combinatorial therapies to enhance treatment efficacy of BCL-2 family inhibitors and overcome therapy resistance, improving overall outcome in a wide range of patients with AML and potentially other hematological malignancies.
- |||||||||| ulocuplumab (BMS-936564) / BMS
Combined CXCR-4 Inhibition with Novel Agent GPC-100 (burixafor) and Beta 2 Adrenergic Receptor Blockade Enhances Cytarabine Response for Acute Myeloid Leukemia Blasts on Stroma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5275;
P1
Clinical trials of CXCR4 inhibitors have been conducted to mobilize AML out of the protected BM niche, including plerixafor with 7+3 or MEC, BL-8040 with cytarabine (araC), LY2510924 with idarubicin/araC, and ulocuplumab (human IgG4 antibody) with MEC...In addition, high throughput drug screening of AML on stroma, but not in suspension or on CXCL12 coated plates, revealed that combination of the CXCR4 inhibitor GPC-100 and beta blocker propranolol, with araC, increased drug sensitivity (reduced IC50 by ?4 to >10 fold) as compared to araC alone for AML cells on HS-5 human stromal cell line or autologous patient mesenchymal stromal cells...Conclusions : These studies support further investigation of whether simultaneous blockade of CXCR4 and ADRB2 may potentiate chemotherapy response in AML, perhaps by disrupting microenvironment mediated chemotherapy protection. Patients with new diagnosis AML may be more susceptible to this approach than R/R AML due to higher CXCR4 expression by both blasts and LSCs.
- |||||||||| Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5196;
Relapsed disease has poor prognosis, especially after immunotherapeutic approaches have failed, including blinatumomab (bispecific T cell engager BITE) and chimeric antigen receptor T-cell (CAR-T) therapy...Methods : Venetoclax, alvocidib, S63845 (MCL1i), dexamethasone and tyrosine kinase inhibitors (TKIs) were from Selleckchem...Conclusions : Simultaneous inhibition of BCL-2 and CDK9 represents an effective approach for targeting Ph+, KMT2AR and CD19-/- B-ALL without need for additional DNA-damaging chemotherapy or kinase inhibition. Taken together, this provides strong rationale for the clinical translation of venetoclax combined with alvocidib in patients with poor prognosis ALL, thereby offering a promising novel combination treatment for CAYA.
- |||||||||| Darzalex (daratumumab) / J&J
Synergistic Induction of Senescence-Driven Immune Responses and Myeloma Cell Cytotoxicity By CDK4/6 Inhibitors and Daratumumab Combination Therapy (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5187;
Conclusion : Strategies to exploit and enhance NK cell immune surveillance may complement existing efforts to harness adaptive immune surveillance in MM. Our results suggest that cytostatic agents inducing senescence such as CDK4/6 inhibitors can be combined in MM with CD38 antibody-based therapy to enhance NK cell activity and the clearance of senescent cells, providing the basis for clinical evaluation of this combination therapy to further improve patient outcome in MM.
- |||||||||| Neupogen (filgrastim) / Kyowa Kirin, Amgen
Enhancing Hematopoietic Stem and Progenitor Cell Mobilization with 27-Hydroxycholesterol and Cyp7b1 Inhibitors (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4362;
In turn, we found that four-day intravenous treatment of mice with voriconazole, an antifungal medication used for treatment post-HSC transplant in clinics, similarly enhanced AMD3100-induced HSPC mobilization. Our findings indicate that Cyp7b1-inhibiting azoles clinically used for antifungal treatment can enhance HSPC mobilization, offering a new strategy for developing novel HSPC mobilization options for donors and patients, especially those with SCD undergoing gene therapies.
- |||||||||| In Vitro Drug Profiling to Guide Treatment for Relapse/Refractory AML (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4284;
Importantly, in vitro drug sensitivities of AML samples were correlated with in vivo anti-leukaemia effect in respective patient-derived xenogarafts e.g. entrectinib, venetoclax, alectinib and ponatinib in combination with azacitidine...Cancer Cell. 2022; 40(8) : 850-64 e9.
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen
Obinutuzumab Is a Promising Alternative for the Treatment of Relapsed or Refractory Autoimmune Hematological Disorders (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4198;
All patients had failed steroid treatment and had undergone a median of two additional immunosuppressive therapies, including Rituximab in seven cases...Among the ITP cohort, all five patients were on low-dose steroids and received TPO receptor agonists (Eltrombopag, Avatrombopag, Romiplostim) before Obinutuzumab...For ITP patients, concurrent use of TPO-RAs mitigates bleeding risks, tapering or discontinuation of TPO-RAs may be feasible after the onset of Obinutuzumab's therapeutic effect. Infection was the primary side effect observed, highlighting the need for enhanced prophylaxis.
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