Results for Phase II Clinical Trial of LCL161, a SMAC Mimetic, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF) or Post-Essential Thrombocytosis Myelofibrosis (post-ET MF)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3105-3105 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Bing Z Carter ◽  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Myeloproliferative Neoplasm ◽  
Advisory Board ◽  
Janus Kinase ◽  
Common Reason ◽  
Jak Inhibitor ◽  
Jak Inhibitors

Abstract Background: There is no standard therapy for patients (pts) with intermediate (Int)-2 or high risk myelofibrosis (MF) who have failed or are intolerant to Janus kinase (JAK) inhibitors such as ruxolitinib. Second mitochondria-derived activator of caspases (SMAC) mimetics, or inhibitors of apoptosis (IAP) antagonists, lead to increased apoptotic cancer cell death, especially in high TNFα-expressing tumor models. An emerging concept in myeloproliferative neoplasm (MPN) tumor pathobiology is the finding of significantly increased levels of TNFαin pts with MF(Fleischman AG et al, Blood 2011). Objectives: Primary objective: to determine efficacy (IWG-MRT, 2013) of LCL161 as monotherapy for pts with MF. Secondary objectives: to determine safety, durability of response, and changes in symptom burden [Myeloproliferative Neoplasm (MPN)-Total Symptom Score]. Exploratory objectives: to assess JAK2V617F and CALR allele burden; 28-gene panel for molecular mutations via next generation sequencing; and markers of IAP pathway degradation. Methods: We conducted an investigator-initiated, single-center, phase II study of LCL161 for pts with MF in a Simon's Optimal two-stage design. Pts age ≥18, PS=0-2, Int to high risk MF, who were intolerant to, ineligible for, or relapsed/refractory to JAK inhibitors were eligible. There was no threshold requirement for spleen size or platelet (plt) count, and pts with prior allogeneic stem cell transplant (SCT) were eligible. LCL161, an oral (po) drug, was given at starting dose 1500mg po once weekly. Each cycle=28 days. After 3 cycles, bone marrow exam and objective response assessments were performed. Results: From January 2015 to July 2016, 21 pts have been enrolled. Baseline characteristics: Median Age: 72 years [56-81], 86% with primary MF. Baseline laboratory values: Hb 9 g/dL (6.3-12); WBC 5.3 K/uL [1.1-38]; platelets 45 K/uL [6-1365]. JAK2V617F mutations were present in 14(67%), CALR mutations in 3(14%), and MPLW515L mutation in 1(5%) pt. Additionally, the most common other molecular mutations were: TET2(n=4); DNMT3A(n=3); RAS(n=1); EZH2(n=1). 17 (81%) had ≥2 prior therapies. Most common prior therapy was a JAK inhibitor (67%). 2 pts had prior SCT. By IPSS, 14 (67%) were high risk MF; 6(28%) were Int-2. Median number of cycles received=3[1-19], median treatment duration=2.8 months (mos)[0.2-16.7]. 19 pts are alive, with median follow-up of 7 mos[0.2-17.7]. Among 21 pts, 5 have been recently enrolled and have not yet reached 12-week evaluation period; among 16 evaluable pts, 6 pts had 9 objective responses (3 pts achieved 2 separate IWG-MRT 2013 response categories): Clinical improvement (CI) (anemia) in 2 pts; CI (Symptom) in 5 pts; CI (Spleen) in 1 pt; Cytogenetic remission in 1 pt. Grade 3/4 non-hematologic adverse events: syncope, n=2. No pts had cytokine release syndrome. Most common grade 1/2 non-hematologic toxicities: fatigue (n=10), nausea (n=10), dizziness/vertigo (n=9). Dose reductions: 7 pts: 6 pts to dose -1 level (1200 mg po once weekly) and 1 pt to dose -2 (900mg po once weekly); importantly, the most common reason was due to grade 2 fatigue (n=6). 10 pts are now off study [n=5 no response; n=3 toxicity; n=1 transformation to AML; n=1 patient on study proceeded to SCT]. Preliminary, ongoing correlative studies demonstrate on-target inhibition (by Western blot) of CIAP1 in eight pts: strong (n=4) or moderate (n=4); among the 6 clinically responding pts, 4 of 4 of these pts with viable/available samples for analysis demonstrated strong on-target CIAP1 inhibition. Conclusions: In this study, in a cohort of older pts with MF, 67% IPSS high risk, with median plt count of 45 at study entry, in whom 81% had received ≥2 prior therapies, we have observed objective responses in 38% (6/16 evaluable for response). LCL161 has a convenient (po, weekly) dosing schedule, represents a novel target for pts with MPNs, and is able to be administered to pts who have failed or intolerant/ineligible for JAK inhibitor therapy. Notably, grade 2 fatigue was commonly observed, and represents the most common reason for dose reduction and study discontinuation. Based on early responses observed, this study has met criteria for the pre-planned analysis for efficacy (Simon Stage 1) and therefore is able to proceed to Simon Stage 2. This clinical trial is registered at www.clinicaltrials.gov/ct2/show/NCT02098161. Disclosures Carter: PRISM Pharma/Eisai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Bose:Novartis: Research Funding. Verstovsek:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding.

scholarly journals Final Results of a Dual-Institution Phase I Clinical Trial of Targeted Marrow Irradiation (TMI) Intensification of Reduced-Intensity Fludarabine/Busulfan (Flu/Bu) Conditioning for Allogeneic Hematopoietic Cell Transplantation for Medically Frail Patients with High-Risk Hematological Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Naveed Ali ◽  
Ana Carolina Pires de Rezende ◽  
Folashade Otegbeye ◽  
Mariana Nassif Kerbauy ◽  
Brenda W. Cooper ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Board ◽  
Matched Sibling ◽  
Grade 3 ◽  
One Year ◽  
Reduced Intensity

Background Reduced-intensity conditioning (RIC) regimens provide insufficient disease control in patients with high-risk hematological malignancies who are ineligible for myeloablative hematopoietic cell transplantation (HCT) due to advanced age or comorbidities. RIC fludarabine/busulfan (Flu/Bu) is generally well tolerated, but is associated with high relapse rates. We hypothesized that intensification of RIC Flu/Bu with targeted marrow irradiation (TMI) would be feasible and improve outcomes in such patients. Methods This dose escalation phase I clinical trial incorporated 3+3 design with expansion. The primary endpoint was to estimate safety and feasibility of TMI combined with Flu/Bu. Secondary endpoints included transplant-related mortality (TRM), disease free survival (DFS) and overall survival (OS). Eligible patients were ≥ 18 years diagnosed with high-risk hematological malignancies who were not candidates for myeloablative HCT. The conditioning regimen consisted of TMI (dose levels: 3 Gy, 4.5 Gy and 6 Gy) delivered at 1.5 Gy/fraction in twice daily fractions on days -10 through -7, fludarabine (30 mg/m2) on days -6 through -2 and busulfan (AUC 4800 µM*minute) on days -5 and -4. Radiation was targeted to bone marrow and spleen using intensity modulated radiation therapy (IMRT) technique while minimizing injury to organs at risk. GVHD prophylaxis included tacrolimus and methotrexate for matched sibling and unrelated donors (UD), and tacrolimus, mycophenolate mofetil and post-cyclophosphamide for haploidentical donors. Antithymocyte globulin (ATG) was added for recipients of UD transplants. Dose limiting toxicity (DLT) was defined as engraftment failure, grade ≥ 4 mucositis and grade ≥ 3 other non-hematological adverse events (AEs) from day -10 to day +32. Results A total of 26 patients (median age 64 years [range, 25-76]; 61% females) were enrolled in two transplant centers (Table 1). Diagnoses included AML (n=15), MDS (n=5), T-PLL (n=2), CLL (n=1), DLBCL (n=1), multiple myeloma (n=1) and myeloproliferative disorder (n=1). Sixteen (61%) patients had intermediate/high HCT-comorbidity index and high/very high disease risk index (DRI). At the time of HCT, 19 (73%) patients had active or residual disease. Donors were UD (n=18), matched sibling (n=5) and haploidentical (n=3). All patients engrafted neutrophils (median, 16 days [range, 10-29]). Most frequent AEs were mucositis (65%), gastrointestinal toxicity (62%), hepatotoxicity (hyperbilirubinemia and/or increased transaminase levels) (65%) and fatigue (69%). Twenty-four grade ≥ 3 AEs occurred in 13 patients; 2 patients experienced reversible DLT (mucositis and hepatotoxicity) at 6 Gy TMI dose level. Additional escalation was halted and 6 Gy cohort was expanded. Only 1 patient experienced reversible hepatotoxicity in the expansion cohort. Grade II-IV and III-IV acute GVHD rates at day +100 were 57% (95% CI, 39%-84%) and 22% (95% CI, 9%-53%), respectively. The 1-year cumulative incidence of chronic GVHD was 42% (95% CI, 24%-74%). The 1-year cumulative incidence of TRM and relapse was 8% (95% CI, 2%-32%) and 26% (95% CI, 13%-52%), respectively (Figure 1A). The overall TRM for 3 Gy, 4.5 Gy and 6 Gy cohorts was 25%, 12.5% and 12%, respectively. With a median follow up of 12.7 months (range, 1.1-36.8), 1-year DFS was 55% (95% CI, 34%-76%) and OS was 65% (95% CI, 46%-85%) (Figure 1B). One-year DFS was equivalent for patients transplanted in CR or with active disease (54% [95% CI, 14%-93%] vs 55% [95% CI, 29%-80%]; p=0.83) (Figure 1C). While no difference in DFS was observed between the 4.5 Gy and 6 Gy cohorts, the 3 Gy cohort was associated with inferior DFS (p=0.004) (Figure 1D). One-year DFS and OS for 6 Gy cohort was 58% (95% CI, 30%-87%) and 82% (95% CI, 59%-100%), respectively. Conclusion Intensification of RIC Flu/Bu with TMI is feasible, with low incidence of TRM in medically frail patients. Reversible mucositis and hepatotoxicity prevented dose escalation beyond 6 Gy. DFS and OS at 6 Gy are promising and deserve further investigation. Disclosures Malek: Janssen: Other: Advisory board, Speakers Bureau; Medpacto: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau.

scholarly journals JAK Be Nimble: Reviewing the Development of JAK Inhibitors and JAK Inhibitor Combinations for Special Populations of Patients with Myelofibrosis

2021 ◽  
Author(s):  
Andrew T. Kuykendall ◽  
Rami S. Komrokji
Keyword(s):  
Myeloproliferative Neoplasm ◽  
Unmet Need ◽  
Extramedullary Hematopoiesis ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Long Term Outcomes ◽  
Increased Risk ◽  
Inhibitor Combination

ABSTRACT Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by uncontrolled blood counts, constitutional symptoms, extramedullary hematopoiesis, and an increased risk of developing acute myeloid leukemia. Janus kinase (JAK) inhibitors are the most common treatment for MF due to their ability to reduce spleen size and improve disease-related symptoms; however, JAK inhibitors are not suitable for every patient and their impact on MF is limited in several respects. Novel JAK inhibitors and JAK inhibitor combinations are emerging that aim to enhance the treatment landscape, providing deeper responses to a broader population of patients with the continued hope of providing disease modification and improving long-term outcomes. In this review, we highlight several specific areas of unmet need within MF. Subsequently, we review agents that target those areas of unmet need, focusing specifically on the JAK inhibitors, momelotinib, pacritinib, itacitinib, and NS-018 as well as JAK inhibitor combination approaches using CPI-0610, navitoclax, parsaclisib, and luspatercept.

scholarly journals Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis

2021 ◽  
Vol 5 (16) ◽  
pp. 3163-3173 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Bing Z. Carter ◽  
Prithviraj Bose ◽  
Nitin Jain ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Objective Response ◽  
Severe Thrombocytopenia ◽  
Jak Inhibitor ◽  
Phase 2 ◽  
Jak Inhibitors ◽  
Phase 2 Clinical Trial ◽  
Smac Mimetics ◽  
Smac Mimetic

Abstract Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.

scholarly journals Overall and Progression Free Survival from the Mcrn-003/Myx.1 Trial: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1871-1871 ◽  
Author(s):  
Christopher P Venner ◽  
Richard Leblanc ◽  
Irwindeep Sandhu ◽  
Darrell J White ◽  
Andrew Belch ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Light Chain ◽  
Research Funding ◽  
Free Light Chain ◽  
High Dose ◽  
Advisory Committees

Background: Carfilzomib is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Questions remain regarding optimal dosing strategies and combinations. The MCRN-003/MYX.1 single arm phase II clinical trial of high-dose once weekly carfilzomib in combination with dexamethasone and cyclophosphamide (wCCD) in RRMM met its primary endpoint with an overall response rate (ORR) ≥ 80% after 4 treatment cycles [Venner, Blood 2018 132:1984]. This abstract focuses on previously unreported protocol specified secondary and exploratory endpoints including progression free (PFS) and overall survival (OS). Methods: This multi-centre clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had 1-3 prior lines of therapy and without proteasome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. Secondary endpoints included toxicity, depth of response, PFS and OS as defined by International Myeloma Working Group Uniform Response Criteria (2016). Exploratory endpoints included the impact of cytogenetics (CG) and prior PI or lenalidomide exposure on efficacy, and the novel endpoint of serum free light chain (sFLC) escape, defined as a > 25% change in the difference of involved to uninvolved light chain with the absolute rise > 100mg/L, in individuals with disease previously measurable by serum or urine protein electrophoresis. This analysis is based on the locked database of 19 June, 2019. Results: Of 76 patients accrued, 75 were included in the analysis. One was ineligible due to prior bortezomib refractoriness. Thirty-nine percent received 1 prior line, 44% two prior lines and 17% three prior lines of therapy. High-risk cytogenetics (t(4;14), t(14;16) and/or del P53, considered positive at any level above local accepted threshold) were identified in 32%. Twenty percent had ISS stage III disease. The majority of participants were previously exposed to PI (87%) and lenalidomide (83%). The median duration of follow-up was 25 months. The ORR at any time was 85% (1 patient achieved a response after 4 cycles) with ≥ VGPR achieved in 68% and ≥ CR in 29%. The presence of high-risk CG conferred a worse ORR (75% vs 97% respectively, p = 0.013). Thirty-one patients have died with a median OS and median PFS of 27 months and 17 months respectively (figure 1). High risk CG conferred a worse median OS (18 months vs NR, p = 0.002) and a trend toward a worse median PFS with high risk CG (14 months vs 22 months, p = 0.06; figure 1). For patients with prior PI exposure the median OS and PFS were 27 and 17 months respectively. For patients with prior lenalidomide exposure median OS and PFS were 26 and 16 months respectively. Free light chain escape events were noted in 11 patients (15%) but was the only progression event in 3 (4%). For the remaining 8 patients the sFLC rise was a harbinger of traditional relapse by electrophoresis. The median PFS when sFLC escape was included as a progression event was 17 months. With updated toxicity data the most common ≥ grade 3 non-hematologic events were infection (40%), cardiac (15%, including 5 dyspnea and 1 pulmonary edema) and vascular (17%, including 7 with hypertension and 3 with thrombotic microangiopathy). To date 57 (76%) patients have discontinued carfilzomib, including 34 due to disease progression and 14 due to toxicity. Conclusion: This phase II trial demonstrates that wCCD remains a safe and effective regimen for RRMM. The survival data presented here is comparable to current phase II and III studies examining the weekly dosing strategy. No new toxicity signals are observed but cardiovascular risks remain an important factor in the use of carfilzomib-based therapies. Using sFLC escape does not negatively affect PFS outcomes but likely better characterizes progression as a harbinger of more traditional events detected by electrophoresis. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to lenalidomide and otherwise ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: J&J: Research Funding. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; gilead: Honoraria. White:Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Reece:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Louzada:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Janssen: Honoraria; Celgene: Honoraria. Hay:Janssen: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Kite: Research Funding; Takeda: Research Funding; Roche: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding. OffLabel Disclosure: While Carfilzomib is approved for use in relapsed and refractory myeloma the combination with cyclophosphamide is not approved.

scholarly journals Myelofibrosis Drug Development through the Decade: Novel JAK Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5477-5477
Author(s):  
Ali Younas Khan ◽  
Muhammad Junaid Tariq ◽  
Muhammad Usman ◽  
Awais Ijaz ◽  
Abdul Rafae ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Phase Iii ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Phase Iii Trial ◽  
Grade 3

Abstract Introduction Myelofibrosis (MF), a BCR-ABL negative myeloproliferative neoplasm (MPN), has an annual incidence of 1 in 100000 for the primary MF and 0.3-0.7 in 100000 for secondary MF in the USA. MF patients have a median survival of 6.5 years. The primary mutation, JAK2V617F, occurs in 40-60% of MF cases. Ruxolotinib, a JAK inhibitor, has been the mainstay in treating high risk, debilitating MF but largely clinical needs are unmet. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade ( Jan 2007 till Dec 2017) were screened for relevant studies. After screening by 2 independent reviewers, 212 articles were finalized for our final analyses. We have reviewed the mechanism of action, safety and efficacy of 2nd generation JAK inhibitors in this review. Results JAK1 inhibitor: Itacitinib reduced total symptom score (TSS) ≥ 50% in 15/42 (36%) patients. Mild gastrointestinal (GI) disturbances and some grade 3-4 myelosuppression (anemia: 33%, thrombocytopenia: 29%) were reported. JAK2 inhibitors: In PERSIST-1, pacritinib when compared to best available therapy (BAT) showed SVR ≥ 35% in 19.1% vs. 4.7% patients, with lower rates of myelosuppression (thrombocytopenia: 17%, anemia: 11%). In PERSIST-2, a phase III trial of pacritinb vs. BAT in patients with baseline cytopenias, similar efficacy was demonstrated (SVR ≥ 35%: 18% vs. 3%). Increasing rates of heart failure and intracranial hemorrhages led to a temporary hold which was lifted in August 2017. Lestaurtinib showed CI in 7 (44%) patients in a phase I trial (n=16) and 6 (27%) patients in a phase II trial (n=22). Most notable toxicities were G 1/2 GI disturbances, anemia occurred in 14% and thrombocytopenia in 23% of patients. In a phase III trial (n=193), fedratinib showed a SVR ≥ 35% and a TSS ≥ 50% in 40% and 36% patients, respectively. However, incidence of significant neurotoxicity and Wernicke's encephalopathy led to its suspension. Similarly, a trial of XL019 was terminated due to emergence of central and peripheral neurotoxicity. In a phase I trial (n=48), NS-018 exhibited a spleen length reduction (SLR) ≥ 50% in 20 (56%) patients along with prompt improvement in bone marrow fibrosis (37%). Anemia and thrombocytopenia were reported in 15% and 27% of patients, respectively. Dizziness (23%) and nausea (19%) were also reported. Gandotinib demonstrated SLR ≥50% in 62% patients, in a phase I trial (n=38). G1 diarrhea (55.3%) and nausea (42.1%) were the most common toxicities. JAK 1/2 inhibitors: SIMPLIFY-1 (S1), a phase III clinical trial (n=432) of momelotinib vs. ruxolotinib in JAK inhibitor-naïve patients, demonstrated non-inferiority for momelotinib, in spleen volume reduction (SVR) ≥ 35% (26.5% vs. 29%; p=0.01). However, SIMPLIFY-2 trial (S2), that compared these two drugs in JAK inhibitor exposed patients did not achieve similar responses with momelotinib (6.7% vs. 5.8%; p=0.90). Interestingly, momelotinib excelled at achieving transfusion independency in both trials (S1: 66.5% vs. 49.3%; p=0.001, S2: 43.3% vs 21.2%; p=0.001). Grade ≥ 3 infections and peripheral neuropathy were the major toxicities noted. These trials were suspended after 89% of patients failed to achieve the primary endpoint of SVR. AZD1480 demonstrated clinical improvement (CI) in four (11%) patients in a phase I trial (n=35). Most common adverse events included grade (G) 1-2 dizziness and anemia. Conclusion Novel JAK pathway inhibitors have shown promising efficacy in MF but safety concerns regarding the hematological (cytopenias) and non-hematological adverse effects needs to be addressed until their use in clinical practice is established. Momelotinib success in achieving anemia related endpoints is note-worthy and should be further explored in this regard. A phase II study [NCT03165734] evaluating pacritinib monotherapy as a second line treatment in patients with baseline thrombocytopenia is ongoing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation and Maintenance in Subjects with High Risk Smoldering Multiple Myeloma (SMM): Initial Analysis of Safety Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Shaji K. Kumar ◽  
Al-Ola Abdallah ◽  
Ashraf Z. Badros ◽  
Betsy Laplant ◽  
Binod Dhakal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Research Funding ◽  
Advisory Board ◽  
Phase 2 ◽  
Phase 3 ◽  
Phase 2 Trial ◽  
Risk Of Progression ◽  
M Spike

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

A Phase II Randomized Dose-Ranging Study of the JAK2-Selective Inhibitor SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, or Post-Essential Thrombocythemia (ET) MF.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2837-2837 ◽  
Author(s):  
Moshe Talpaz ◽  
Catriona Jamieson ◽  
Nashat Y Gabrail ◽  
Claudia Lebedinsky ◽  
Guozhi Gao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Jak2 V617f ◽  
Spleen Volume ◽  
Employment Equity ◽  
Symptom Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2837 Introduction: Treatment with the JAK2 selective inhibitor SAR302503 reduced spleen size, disease-related symptoms, and the JAK2 V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF in a Phase I/II study (J Clin Oncol 2011;29:789, ASH 2011; Abs 3838). The objective of this Phase II study is to assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 3 doses of SAR302503. Methods: Patients with intermediate-2 or high-risk primary MF, post-PV MF, or post-ET MF were randomized to 1 of 3 dose groups of SAR302503 (300, 400, or 500 mg per day). Eligibility criteria included age ≥18 years, ECOG PS 0–2, and an enlarged spleen (length ≥5 cm). SAR302503 was taken orally, once a day, in consecutive 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint is the absolute change in spleen volume at the end of cycle 3 assessed by MRI with independent central review. Secondary endpoints include spleen response (≥35% reduction in spleen volume vs baseline), safety, symptom response (MPN-SAF), PK, and PD (changes in leukocyte pSTAT3). Results: From August–December 2011, at total of 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status (intermediate-2 vs high) was balanced in the 400 mg and 500 mg groups (∼50%), whereas the 300 mg group had more high-risk patients (70%). The majority of patients (88% to 91%) had the JAK2 V617F mutation and most (∼80%) were blood transfusion independent. Mean (median) percentage reductions in spleen volume vs baseline at the end of cycle 3 were 30% (26%) in the 300 mg group, 33% (31%) with 400 mg, and 42% (38%) with 500 mg. A spleen response at the end of cycle 3 was seen in 30% of patients (3/10) in the 300 mg group, 50% (5/10) in the 400 mg group, and 64% (7/11) in the 500 mg group. Patients with constitutional symptoms at baseline in all groups reported a symptom response at the end of cycle 3, with at least a 2-point improvement in or resolution of night sweats in 93% (14/15) of patients, itching in 71% (10/14), early satiety in 56% (10/18), abdominal pain in 56% (10/18), and abdominal discomfort in 50% (10/20). Safety was evaluated in all patients. The most common grade 3–4 hematological adverse event (laboratory) was anemia, with rates across the 300, 400, and 500 mg doses of 33%, 30%, and 55%, respectively. Rates of grade 3–4 thrombocytopenia were 20%, 0, and 9%. There was no grade 3–4 neutropenia. Most common grade 3–4 nonhematological events were diarrhea (10%, 20%, 0), nausea (10%, 10%, 0), and vomiting (10%, 10%, 0). Adverse events in the 300 mg group led to discontinuation in 2 patients: 1 patient had grade 3 anemia, and 1 patient with pre-existing intermittent mild transaminase elevations and polyarthritis had hepatic failure, but completely recovered after discontinuation. No other grade 3–4 increases of AST, ALT, or bilirubin were observed. No deaths were due to an adverse event. Following repeated once-daily oral doses, SAR302503 exposure increased in a dose-dependent manner, with a median time to maximum plasma concentration of 2 to 3 hours. Steady state was achieved by cycle 1 day 15 (C1D15), with a 2.95- to 3.88-fold accumulation of drug. Time-dependent pSTAT3 inhibition was observed at all doses, with the highest mean percentage decreases from baseline (range) occurring at C1D15 (44% to 52%) and C2D1 (40% to 51%). The relationship between PK and PD pSTAT3 suppression can be described by an Emax model. There was also a correlation between percentage of pSTAT3 inhibition and spleen response rate at C1D15 and C2D1 and evidence of a steady state exposure-response relationship for spleen volume reduction at the end of cycle 3. Conclusions: In this Phase II trial, treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly and improvements in constitutional symptoms. SAR302503 was generally well tolerated in this trial and adverse events were consistent with the known safety profile. Time-dependent decreases in pSTAT3 and exposure-response correlations can be demonstrated across the three doses tested. Sponsored by Sanofi (NCT01420770) Disclosures: Talpaz: Novartis: Research Funding, Speakers Bureau; BMS: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding. Gabrail:Sanofi: Research Funding. Lebedinsky:Sanofi: Employment, Equity Ownership. Gao:Sanofi: Employment, Equity Ownership. Liu:Sanofi: Employment, Equity Ownership. Pardanani:YM BioSciences: Clinical trial support, Clinical trial support Other; BMS: Clinical trial support, Clinical trial support Other; Sanofi: Clinical trial support Other.

A Phase I/II Clinical Trial of the First-in-Class GPCR Antagonist ONC201 in Relapsed/Refractory Acute Leukemias

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3997-3997
Author(s):  
Gautam Borthakur ◽  
Jo Ishizawa ◽  
Courtney D DiNardo ◽  
Tapan M. Kadia ◽  
Katherine Weise ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Phase Ii ◽  
Conflict Of Interest ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Equity Ownership ◽  
Md Anderson ◽  
Refractory Aml

Abstract ONC201 is a highly selective G protein-coupled receptor (GPCR) antagonist that is the first-in-class member of the imipridone class of anti-cancer compounds. Preclinical studies have shown that ONC201 is highly effective in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), regardless of resistance to standard-of-care therapies, TP53 mutations, or complex karyotypes. Furthermore, ONC201 equally induces cell death in both the bulk tumor and cancer stem cells (CSC) in a range of malignancies. The anti-CSC activity has been validated in preclinical hematological malignancy models in vitro and in vivo, as well as in primary relapsed/refractory AML patient samples using CD34+CD38- as leukemia stem cell marker (Ishizawa et al, Science Signaling, 2016). On the basis of robust preclinical activity, a phase I/II clinical trial of single agent ONC201 is ongoing that enrolls adult patients with relapsed/refractory AML, ALL, or high-risk myelodysplastic syndrome. Phase I dose escalates from 125 to 625mg in 3 schedules; once a week, twice a week and once every 3 weeks, using an accelerated titration design. The primary endpoint of Phase I is to determine the recommended Phase II dose and the primary endpoint of phase II is to determine the overall response rate. Secondary endpoints include pharmacokinetics, pharmacodynamics, and other clinical outcomes. Between December 2015 and July 2016, 6 relapsed/refractory AML patients (median of 4 prior therapies) have been enrolled in dose cohorts ranging from 125 to 625mg ONC201 administered every 3 weeks and one additional AML patient received weekly ONC201 at 125mg. All patients have successfully cleared the DLT window, dose escalation has proceeded uninterrupted, and no drug-related adverse events have been reported. Pharmacokinetic results indicate that all patients achieved a Cmax of >1.4 ug/mL (3.6 uM) that exceeds therapeutic thresholds in preclinical models. The second patient with relapsed/refractory AML and prior therapies that included decitabine, fludarabine and cytarabine and two investigational IDH2 inhibitors showed a reduction in circulating blasts from 78% to 3% after one dose of 250mg ONC201. Furthermore, a >2-log reduction in circulating CD34+CD38- cells was observed in parallel in a time-dependent manner after the first dose of ONC201 in this patient. The fifth AML patient remains on study with stable disease after 5 cycles of 500mg ONC201 despite prior treatments that included azacitidine, eltrombopag, bortezomib, ruxolitinib, and decitabine. Patient enrollment in the weekly schedules and pharmacodynamics, are ongoing. In agreement with Phase I results in advanced solid tumors (NCT02250781), these early results suggest that ONC201 is a very well tolerated investigational therapy that achieves therapeutic plasma concentrations and shows encouraging preliminary signs of biological activity. Note: The research being reported in this abstract is research in which The University of Texas MD Anderson Cancer Center has an institutional financial conflict of interest. Because MD Anderson is committed to the protection of human subjects and the effective management of its financial conflicts of interest in relation to its research activities, MD Anderson has implemented an Institutional Conflict of Interest Management and Monitoring Plan (Plan) to manage and monitor the conflict of interest with respect to MD Anderson' s conduct of this research. Disclosures DiNardo: Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding. Allen:Oncoceutics: Employment, Equity Ownership. Oster:Oncoceutics: Employment, Equity Ownership. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Kantarjian:Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Topical Tofacitinib: A Janus Kinase Inhibitor for the Treatment of Vitiligo in an Adolescent Patient

2021 ◽  
pp. 190-194
Author(s):  
Sineida Berbert Ferreira ◽  
Rachel Berbert Ferreira ◽  
Afonso Cesar Neves Neto ◽  
Silvana Martins Caparroz Assef ◽  
Morton Scheinberg
Keyword(s):  
Case Report ◽  
Skin Disease ◽  
Kinase Inhibitor ◽  
Effective Therapy ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Adolescent Patient ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitor ◽  
History Of

Vitiligo is an autoimmune skin disease presenting with areas of depigmentation. Recent reports suggest that Janus kinase (JAK) inhibitors may be an effective therapy. In this case report, we show our experience with an adolescent patient with a long history of generalized and refractory vitiligo, for which treatment with topical tofacitinib, a JAK inhibitor, associated with phototherapy for 9 months, resulted in near complete repigmentation.

scholarly journals Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 797-797
Author(s):  
Talha Badar ◽  
Mark R. Litzow ◽  
Rory M. Shallis ◽  
Jan Philipp Bewersdorf ◽  
Antoine Saliba ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Advisory Board ◽  
Novel Therapies ◽  
Advisory Committees ◽  
Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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