No abstract

The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study’s objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T–related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.

FLT3-ITD mutations in newly diagnosed acute myeloid leukemia (AML) are associated with worse overall survival (OS). FLT3-ITD diversity can further influence clinical outcomes. Addition of FLT3 inhibitors to standard chemotherapy has improved OS. The aim of this study is to evaluate the prognostic impact of FLT3 diversity and identify predictors of efficacy of FLT3 inhibitors. We reviewed prospectively collected data from 395 patients with newly diagnosed FLT3-ITD mutant AML. 156 (39%) patients received FLT3 inhibitors combined with either high or low intensity chemotherapy. There was no statistically significant difference in clinical outcomes among patients treated with FLT3 inhibitors based on FLT3 numerical variation (p = 0.85), mutation length (p = 0.67). Overall, the addition of FLT3 inhibitor to intensive chemotherapy was associated with an improved OS (HR = 0.35, 95% CI: 0.24-0.5, p = 0.0005), but not in combination with lower intensity chemotherapy (HR = 0.98, 95%CI: 0.7-1.36, p = 0.85). A differential effect of FLT3 inhibitor on OS was more pronounced in younger patients with FLT3 allelic ratio ≥0.5 (HR = 0.41, 95% CI: 0.25-0.66, p < 0.001), single ITD mutation (HR = 0.55, 95% CI: 0.34-0.88, p = 0.01), diploid cytogenetics (HR = 0.52, 95% CI: 0.35-0.76, p = 0.001), NPM1 co-mutation (HR = 0.35, 95% CI: 0.19-0.67, p = 0.001). Our analysis identifies predictors of survival among diverse FLT3 related variables in patients treated with FLT3 inhibitor.

Background Internal tandem duplication (ITD) mutation of the FMS-like tyrosine kinase-3 (FLT3) receptor gene occurs in about 25% patients with acute myeloid leukemia (AML) and confers a poor prognosis. Several studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Methods Adult patients with FLT3-ITD mutated AML treated at our institution from January 2001 to January 2018, who had quantified FLT3-ITD allele burden, were identified. Patients with acute promyelocytic leukemia and core-binding factor AML were excluded.Patients were assigned into 2 groups; Group 1 included patients who received idarubicin and cytarabine (IA) containing induction and Group 2 included patients who received sorafenib in addition to IA containing regimens at induction. Mutant allelic burden was expressed as the ratio of area under the peak of mutant allele to total FLT3. Relapse free survival (RFS) for patients achieving complete response (CR)/CR with incomplete recovery (CRi) was defined as time from CR/CRi to relapse or death. Overall survival (OS) was defined as time from treatment to death. Patients were censored at last follow up. Time from therapy to allogeneic hematopoietic cell transplant (AlloHCT) was handled as a time-dependent variable. The optimal cutoff of mutant FLT3-ITD allelic burden was defined as the cutoff to divide the whole cohort with the highest statistical significance. Results A total of 183 patients withFLT3-ITD mutated AML were identified including 104 (57%) in Group 1 and 79 (43%) in Group 2. Baseline characteristics are summarized in Table 1. The median age was 52 years (range, 17-64). The median allelic burden of mutant was 33% (range, 0.3% to 88%). This was comparable between the two groups (p=0.6). The CR/CRi rates following induction for Group 1 vs Group 2 were 85% vs 99%, respectively (p=0.004). Overall, 111 (61%) patients received an AlloHCT, at any time during the follow up, more frequently in Group 2 than in Group 1 (67% vs 56%, respectively, p=0.1). The median RFS for Group 1 and 2 were 12 and 45 months, respectively (p=0.02); the median OS was 17 months in Group 1 and has not been reached in Group 2 (p=0.008) (Table 2). The optimal mutant allele burden cutoff for OS and RFS in the entire cohort was 1.55% (p=0.002) confirming the adverse effect of FLT3-ITD even at low level. The cutoff was 6.9% in Group 1, with no optimal cutoff value in Group 2 (Figure 1) confirming the value of sorafenib inFLT3-ITD mutated AML. When censored for AlloHCT; the FLT3-ITD cutoff for OS and RFS was 60% and 60% in the entire group. For Group 1 the cutoff values where 59% and 7.9% for OS and RFS, respectively. For Group 2 the cutoff values were 46% and 46%, respectively (Figure 2). On multivariate analysis, AlloHCT (HR 0.52; 95%CI 0.33-0.82; p=0.005), sorafenib (HR 0.6; 95%CI 0.38-0.93; p=0.02) and white blood cell count (HR 1.005; 95%CI 1.002-1.009) were independent predictors of OS with no impact by cytogenetics, concurrent NPM1, TP53, FLT3-D835 mutations or the FLT3-ITD allelic burden. Conclusion Although a higher FLT3-ITD allele burden is associated with a worse RFS and OS in patients with FLT3-ITD mutated AML treated with IA-based chemotherapy, it is no longer prognostic when sorafenib is added to the therapeutic regimen. Addition of sorafenib to intensive chemotherapy as well as AlloHSCT are associated with a significant improvement in OS on multivariate analysis. Disclosures Kadia: Novartis: Consultancy; BMS: Research Funding; Takeda: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy. Sasaki:Otsuka Pharmaceutical: Honoraria. Daver:BMS: Research Funding; ImmunoGen: Consultancy; Karyopharm: Consultancy; Sunesis: Research Funding; Novartis: Consultancy; Otsuka: Consultancy; Karyopharm: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Kiromic: Research Funding. DiNardo:Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Short:Takeda Oncology: Consultancy. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria.

Introduction: For transplant-eligible patients (pts) with newly diagnosed multiple myeloma (NDMM), autologous stem cell transplant (ASCT) is the standard of care treatment (tx). However, ASCT, which includes a standard melphalan conditioning regimen that is associated with systemic toxicity, is not always feasible due to various reasons including advanced age, co-morbidities, and pt frailty. ASCT-eligible pts may also opt to defer the procedure as initial therapy. For pts with NDMM who are ineligible or unwilling to pursue ASCT, the VRd regimen is an effective tx option; however, pts continue to have inferior outcomes, and there is a need for more effective tx strategies, including ones with a curative intent. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T cell (CAR-T) therapy with 2 B-cell maturation antigen (BCMA)-targeting single-domain antibodies. In the phase 1b/2 CARTITUDE-1 study, a single infusion of cilta-cel resulted in deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma with a manageable safety profile (Berdeja, Lancet, 2021). At a median follow-up of 18 months (mo), the overall response rate was 98% (80% with stringent complete response), and the 18-mo overall survival (OS) rate was 81%. Objective: The randomized phase 3 CARTITUDE-5 study (NCT04923893) will compare the efficacy of VRd induction followed by cilta-cel versus VRd induction followed by Rd maintenance in pts with NDMM for whom ASCT is not planned as initial therapy. Methods: Eligible pts (target recruitment: N=650) are ≥18 years of age with documented MM diagnosis per International Myeloma Working Group criteria, measurable disease at screening, and Eastern Cooperative Oncology Group performance status ≤1. Pts are eligible 1) if they are not candidates for high-dose chemotherapy with ASCT due to advanced age or comorbidities that are likely to have a negative impact on tolerability of this procedure or 2) if they choose to defer high-dose chemotherapy with ASCT as initial treatment. Pts with a frailty index ≥2 based on the Myeloma Geriatric Assessment Score, prior CAR-T or BCMA-targeting therapy, or any prior therapy for MM or smoldering myeloma (with the exception of a short course of steroids or one cycle of VRd) will be excluded. All enrolled pts will receive five to six 21-day (d) cycles of the VRd regimen (one cycle allowed prior to screening): 1.3 mg/m 2 subcutaneous bortezomib on d 1, 4, 8 and 11; 25 mg oral lenalidomide on d 1-14; and 20 mg oral dexamethasone on d 1, 2, 4, 5, 8, 9, 11, and 12. Pts without disease progression will then be randomized 1:1 to the cilta-cel arm or Rd maintenance (control) arm (Figure). In the cilta-cel arm, pts will undergo apheresis and receive two more 21-d cycles of VRd as bridging therapy; pts will then be administered cilta-cel (target dose: 0.75×10 6 CAR+ viable T cells/kg) 5-7 d after lymphodepletion chemotherapy (intravenous cyclophosphamide 300 mg/m 2 and fludarabine 30 mg/m 2 daily for 3 d) followed by a tx-free observation phase. In the control arm, pts will receive two additional 21-d cycles of VRd followed by Rd maintenance in 28-d cycles (25 mg oral lenalidomide on d 1-21 and 40 mg oral dexamethasone on d 1, 8, 15, and 22) until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints include sustained minimal residual disease (MRD)-negative complete response (CR), as assessed by next-generation sequencing; MRD-negative CR rate at 9 mo; overall MRD-negative CR rate; OS; proportion of pts who achieve ≥CR; time to subsequent anti-myeloma therapy; PFS on next-line therapy (PFS2); incidence and severity of adverse events; pharmacokinetic and pharmacodynamic markers; and changes in health-related quality of life. Results from this study will provide insights into the efficacy and safety of VRd followed by cilta-cel in pts with NDMM. Additionally, VRd tx followed by a single infusion of cilta-cel vs continuous tx with Rd until disease progression may offer pts the benefit of a tx-free period. Figure 1 Figure 1. Disclosures Dytfeld: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Current Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees. Manier: Celgene/BMS: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Amgen: Research Funding. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Kuppens: Janssen: Current Employment. Afifi: Janssen: Current Employment. Deraedt: Janssen: Current Employment. Taraseviciute-Morris: Janssen: Current Employment. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Gilbert: Janssen: Current Employment. Yalniz: Janssen: Current Employment. Florendo: Legend Biotech: Current Employment. Pacaud: Legend Biotech: Current Employment. Hungria: Abbvie: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Other: Support for attending meetings/travel ; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel . Usmani: Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau. Mateos: AbbVie: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.