Higher Complete Remission Rate Research Articles

Phospholipase A2 Receptor Antibodies and Clinical Prognosis in Patients with Idiopathic Membranous Nephropathy: An Updated Systematic Review and Meta-Analysis

Background: Idiopathic membranous nephropathy (IMN) is the most common form of primary nephrotic syndrome in adults. Antibodies against the M-type phospholipase A2 receptor (PLA2R-ab) are considered as diagnostic biomarkers of IMN. Objective: Here, we performed an updated meta-analysis to assess the diagnostic value of PLA2R-ab for clinical remission in IMN patients. Method: PubMed, Embase, and Cochrane databases were searched for relevant studies published before September 2022. Odds ratios and corresponding 95% confidence intervals were determined using a fixed or random effects model. The heterogeneity among studies was explored by subgroup analysis. Results: Sixteen studies involving 1,761 IMN participants were included. There were significant differences between PLA2R-ab (+) and PLA2R-ab (−) patients in terms of complete remission (CR) and spontaneous remission. The rates of partial remission (PR) and relapse were similar between the two groups. Patients with PLA2R-ab (−) were at a higher CR rate when treated with a calcineurin inhibitor or a treatment course for 3 months and 6 months, while the spontaneous remission rate was higher in PLA2R-ab seronegative patients from Asia. However, the CR and spontaneous remission rate only significantly declined in IMN patients with the highest titer, but not a middle titer, when compared to those with the lowest titer. Conclusion: In contrast with previous meta-analyses, our results verified that PLA2R-ab can likely predict CR and spontaneous remission in IMN patients, instead of PR and relapse. Race, immunosuppressive agents, and duration of treatment may affect the prognostic value of PLA2R-ab. Considering that the remission rate of IMN patients with a middle level of PLA2R-ab was not different from that of patients with the lowest level, a proper cut-off value of PLA2R-ab for prognosis should be clarified.

Infantile Takayasu: clinical features and long-term outcome.

Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and infants. Most articles on paediatric TAK have not focused on infants. We present the largest case series of infantile TAK, aiming to identify its demographic and clinical characteristics and compare them with existing data on older children. We conducted an international multicentre retrospective cohort study. Epidemiological and clinical data were collected from patients' charts from six rheumatology centres. All patients met both the EULAR/PReS 2008 criteria and the 1990 ACR/EULAR criteria and were diagnosed with TAK at age <5 years. Twelve patients were included (50% female). Median age of symptom onset was 11 months, with a diagnostic delay of 4 months. The most common symptoms at presentation were hypertension, blood pressure differences between limbs, and fever. The most commonly involved arteries were the abdominal aorta and renal artery. Medications included steroids, conventional and biologic DMARDs, and other immunosuppressive therapies. Half of the patients received biologic agents, of which infliximab had the highest complete remission rate (40%). Other medications resulting in complete remission were CYC (40%) and MTX (38%). Invasive procedures were required for 58% of patients. The most common complications were cardiac (50%), stroke (42%), and serious infections (33%). No patients died. This study presents the largest series of infantile TAK. Compared with other reported series on older children, infants with TAK have more severe disease and were more likely to receive biologic agents, develop complications, and require invasive interventions.

TRICIN: A Phase II Trial on the Efficacy of Topical TRIchloroacetic Acid in Patients with Cervical Intraepithelial Neoplasia

Data on non-surgical treatment approaching persistent cervical intraepithelial neoplasia (CIN) are scarce. Retrospective analysis suggest high efficacy of topical treatment with trichloroacetic acid (TCA). This prospective phase II study set out to investigate the efficacy of a single application of 85% TCA in the treatment of CIN I/II. Patients with CIN I/II were treated a single time with 85% TCA. After three and six months colposcopic, histologic, and HPV evaluation was performed. The primary endpoint was treatment efficacy defined as complete histologic remission six months after treatment. The secondary endpoint was HPV clearance six months after treatment. A total of 102 patients with CIN I/II were included into this trial. Complete histologic remission rates were 75.5% and 78.4% three and six months after TCA treatment, respectively. Clearance rates of HPV 16, 18 and other high risk types were 76.5%, 91.7%, 68.7% after six months, respectively. Side effects of TCA were mild and lasted usually less than 30 min. This is the first prospective trial reporting high histologic complete remission rates in patients with CIN I/II after a single 85% TCA treatment. In the future, TCA may represent an effective and feasible non-surgical treatment approach for CIN.

Comparing the efficacy of salvage regimens for relapsed/refractory B-cell acute lymphoblastic leukaemia: a systematic review and network meta-analysis.

The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future.

Venetoclax Plus "2 + 5" Modified Intensive Chemotherapy with Daunorubicin and Cytarabine in Fit Elderly Patients with Untreated De Novo Acute Myeloid Leukemia: A Single-Center Retrospective Analysis

Background: Therapeutic options remain limited for elderly acute myeloid leukemia (AML) considering the poor tolerance to intensive chemotherapy. Venetoclax in combination with hypomethylation agents (HMAs) or low-dose cytarabine (LDAC) has been shown achieved significantly improved efficacy in elderly AML patients. Recently, we reported that an intensive chemotherapy regimen of venetoclax plus daunorubicin and cytarabine (DAV regimen) showed high complete remission (CR) rates of 91% after one cycle of induction therapy in newly diagnosed adult young AML patients, indicating the strong potential of the venetoclax-based intensive therapy to induce rapid remission (Lancet Hematol, 2022). For fit elderly AML patients, a prospective, phase Ib study demonstrated that venetoclax plus "2 + 5" (idarubicin and cytarabine) regimen achieved high CR rates of 68% (CR and CR with incomplete count recovery [CRi] rate 97%) in fit elderly patients with de novo AML. Unfortunately, delayed hematologic recovery, especially prolonged thrombocytopenia, was observed during consolidation therapy. Thus, an optimized venetoclax-based modified intensive therapy with the hope to achieve higher CR rates and better tolerance and improve long-term survival are urgently needed. Objective: To evaluate the efficacy and safety of modified intensive induction of venetoclax in combination with "2 + 5" (daunorubicin and cytarabine) chemotherapy and the following intermediate-dose cytarabine plus venetoclax consolidation in untreated fit de novo elderly AML. Design, setting and participants: Retrospective clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (≥60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since March 9, 2021, with final follow-up in July 15,2022. Interventions: Patients were treated with induction chemotherapy included daunorubicin (60mg/m2 days 1-2, intravenously), cytarabine (100mg/m2 days 1-5, intravenously), and venetoclax (100mg day 3, 200mg day 4, 400mg days 5-10, orally), followed by 3 consolidation cycles of venetoclax (400mg days 1-14, orally) in combination with intermediate-dose cytarabine (1g/m2 days 1-3, intravenously) and post-remission bone marrow transplantation when applicable. Venetoclax was administered for the maintenance therapy for one year (200mg days 1-14 in each 28-day cycle, orally). Main outcomes and measures: The primary endpoints included the rate of composite complete remission (CRc) after one cycle of induction treatment, including CR/CRi. The secondary endpoints were measurable residual disease detected by muti-parameter flow cytometry (MFC-MRD), adverse events, event-free survival (EFS) and overall survival (OS). Results: Twelve patients were enrolled. Median age was 64 years old (range, 61-71), with poor-risk in 33.3% (4/12) of patients (European LeukemiaNet 2022 risk). Other characteristics of patients were listed in Table 1. The CR rate were 91.7% (11/12) (Table 1). All patients with poor-risk achieved CR. Measurable residual disease-negative composite CR was attained in 100.0% (11 out 11) of total patients achieved CR (Table 1, Figure 1). Common adverse events (>30%) included thrombocytopenia. neutropenia, anemia, febrile neutropenia, nausea, and pneumonia. The main grade ≥ 3 hematologic toxicities during induction were neutropenia (100%), anemia (100%) and thrombocytopenia (100%). The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (41.7%) and pneumonia (33.3%) (Table 1). No tumor lysis syndrome was observed. The median follow-up was 108 days. The median EFS was 398 days, with an estimated 1-year EFS rate of 75.0%. The median OS was not achieved, with an estimated 1-year OS rate of 100% (Table 1). 9 out of 11 patients achieving CR maintained the MRD-negative status until the last follow-up (Figure 1). No deaths occurred among the patients during follow-up. Conclusions: The novel combination of "2+5" (daunorubicin and cytarabine) with venetoclax (modified DAV regimen) showed encouraging efficacy and good tolerability in untreated fit elderly patients with de novo AML, with high CR rate and deep remission. Figure legends Figure 1 The clinical outcome of the 12 elderly patients with newly diagnosed acute myeloid leukemia who were treated with modified DAV. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Feature and Effect of Demethylation Therapy in Pediatric Patients with Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Objective:To better understanding of the clinical and biological features of childhood AML-MRC, in this study we retrospectively investigated 70 children with AML-MRC admitted to our hospital and compared with AML-NOS. We also analyzed the effect of demethylation drugs in introduction therapy among these patients. Study design: This retrospective cohort study was conducted at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS). Newly diagnosed AML patients at our hospital between January 2009 and December 2021 with complete data regarding baseline characteristics and treatment outcomes were reevaluated as having AML-NOS or AML-MRC according to the 2016 WHO classification of myeloid neoplasms and acute leukemia, strictly excluding cases of therapy-related myeloid neoplasms and AML with recurrent genetic abnormalities. Patients with acute megakaryocytic leukemia were also excluded. Clinical and laboratory data were searched in electronic medical records. Follow-up information was obtained from electronic records or by contacting family members and was initialized from the day of diagnosis to May 31, 2022, or the day of death. Results: Among the 779 newly diagnosed AML patients in our center, 70 patients met the diagnostic criteria of AML-MRC and 73 patients were AML-NOS. Patients with AML-MRC had lower white blood cell count (9.1 (IQR 3.0~30.0) ×109/L vs.17.6 (IQR 5.9~86.8) ×109/L, p=0.002), lower hemoglobin level (74.5 (IQR 63.5~ 86.0) g/L vs. 80.0 (71.0, 94.0) g/L, p=0.025) and lower bone marrow proliferation level (p=0.001) compared with patients with AML-NOS. More FLT3-ITD positive patients were found in AML-NOS patients than AML-MRC patients (33.8% vs. 7.1%, p<0.001). Among the 70 AML-MRC patients, 41(58.6%) were diagnosed by myelodysplasia-related cytogenetics, 10(14.2%) from MDS history, and 19 (27.1%) from a multilineage dysplasia. Monosomy 7 or deletion 7q(-7/7q-) is the most frequent cytogenetic abnormality (21.6%) followed by complex karyotype (18.8%) in AML-MRC patients. Totally 56 AML-MRC patients and 71 AML-NOS patients accepted chemotherapy in out center. Induction treatment for 69 AML-NOS patients were idarubicin/ cytarabine/ etoposide (IAE) or mitoxantrone/cytarabine/ etoposide (MAE) therapy. For AML-MRC patients, demethylation drugs alone or demethylation drugs combined above regime were also used (15 case) besides IAE/MEA therapy (35 case). Six AML-MRC patients and 2 AML-NOS patients accepted homoharringtonine/cytarabine/ granulocyte colony-stimulating factor (HAG) and 3 patients received hematopoietic stem cell transplantation (HSCT) without induction chemotherapy. Overall complete remission (CR) rate of 1 course were 51.0% in AML-MRC and 68.2% in AML-NOS patients. In IAE/MAE group, higher CR rate were seen in AML-NOS patients (70.3%) than AML-MRC patients (48.4%) p= 0.06). AML-MRC patients treated with demethylation drugs seemed to have higher CR rate than introduced by IAE/MAE (64.2 % vs. 48.3%, p= 0.39). HSCT in CR1 were conducted in 29 AML-MRC patients and 19 AML-NOS patients. Median follow-up periods were 2.17 in AML-MRC group and 2.43 years in AML-NOS. Three-year overall survival (OS) and event-free survival (EFS) were 54.4% (95%CI 42.4%~69.8%) and 75.7% (95%CI 62.8%~91.1%) for AML-MRC, 42.3% (95%CI 30.2%~59.2%) and 45.8% (95%CI 32.8%~63.9%) for AML-NOS patients. Cox analysis revealed that HSCT were associated with higher OS (HR 0.21,95%CI 0.1~0.41, p< 0.001). In AML-MRC patients, 3-year OS in HSCT group were significantly higher than that in non-HSCT group [83.4% (95%CI,69.6%~99.8%) vs. 28.0% (95%CI,14.6%~53.9%), p<0.001]. AML-MRC patients with myelodysplasia-related cytogenetics exhibited lower 3-year OS (41.9% ,95%CI,27.5%~63.8%) compared with MDS history group (64.8% (95%CI,39.3%~100.0%) and multilineage dysplasia (77.1% (95%CI,57.3%~100.0%). complex karyotype (41.9% ,95%CI,27.5%~63.8%) and -7(7q-) (40.0% ,95%CI,21.5%~74.3%) AML-MRC patients had lower 3-year OS than normal karyotype (42.3%, 95%CI,21.8%~82.0%) and the other abnormal karyotype (63.5% ,95%CI,37.3%~100.0%) but without statistical difference. Conclusions: Childhood AML-MRC exhibited a comparable adverse outcome with AML-NOS which can be significantly improved by HSCT therapy. Demethylation may help improve the CR rate of AML-MRC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of 5-Day Vs. 10-Day Decitabine in Combination with Venetoclax in Newly Diagnosed AML Patients Ineligible for Induction Chemotherapy

BACKGROUND. Standard dosing of decitabine 20mg/m 2 daily given over 5 days in combination with the Bcl-2 inhibitor venetoclax (5-day DEC/VEN), in elderly or chemotherapy ineligible patients with Acute Myeloid Leukemia (AML), induces both a high rate of complete remission (CR/CRi rate 71%) and prolonged survival (median OS 14.2 months). (DiNardo CD et al. Blood. 2019) Extending the duration of decitabine treatment to 10-days (10-day DEC/VEN) may increase efficacy of the combination. In a phase 2 study of newly diagnosed chemotherapy ineligible AML patients aged ≥ 60 years, 10-day DEC/VEN led to a high CR/CRi rate of 89%, with 67% of these being negative for measurable residual disease and a median OS of 18 months. (DiNardo, CD et al. Leukemia. 2020). As a prospective clinical trial comparing efficacy of the different dosing schedule of decitabine in combination with venetoclax is unlikely to be performed, we conducted a single center retrospective analysis comparing 5-day and 10-day DEC/VEN outcomes. METHODS. We retrospectively studied patients with newly diagnosed AML receiving either 5-day or 10-day DEC/VEN between January 2016 to May 2022 at City of Hope National Medical Center. Patients receiving prior AML therapies including hypomethylating agents were excluded. Responses were evaluated per the ELN criteria (Dohner, H et al. Blood. 2017) Measurable residual disease (MRD) flow cytometry was performed at the University of Washington. Patient characteristics were summarized by frequency and associations between overall response and patient and disease characteristics were tested by Fisher's exact test. Overall Survival (OS) was evaluated by the Kaplan-Meier method and the difference between groups was determined by log-rank test. All statistical analyses were performed using R software. RESULTS. 139 patients were included: 48% (n=67) treated with 5-day decitabine and 52% (n=72) treated with 10-day decitabine. The baseline characteristics of the patients are summarized in table 1. At baseline, 5-day decitabine + venetoclax treated patients were older with a median of age of 73 vs. 70 years (p=0.01). The 5-day and 10-day groups were otherwise well balanced with no significant difference in AML type, ELN risk or adverse molecular features. Rates of CR/CRi, CR/CRi, MRD negativity, and the percentage of responders proceeding to allogeneic stem cell transplant were similar between regimens (Table 1). There was also no difference in 8-week mortality (p = 0.44). With a median follow-up of 12 months for responding patients, the median OS (figure 1) and RFS for 5-day and 10-day DEC/VEN were 14 vs. 27 months, p=0.091 and 12.9 vs. 14.3 months, p= 0.75 respectively. In subgroup analysis, patients without therapy- related AML (non-tAML) receiving the 10-day-regimen had a longer median OS (42.5 vs. 14.6 months, p= 0.03). No other subgroups, including those with high-risk molecular (eg.TP53) or cytogenetic risk factors (e.g. complex karyotype) demonstrated a significant difference between the 5 and 10-day DEC/VEN regimen. CONCLUSION. Among newly diagnosed AML patients receiving venetoclax in combination with either 5-day or 10-day decitabine, there was no significant difference in response (CR/CRi or MRD negativity) or survival outcomes (OS or RFS). Although a significant difference was not observed, 10-day DEC/VEN led to an increased median OS, which may reach significance with more patients and longer follow-up. Additionally, the 10-day DEC/VEN regimen may benefit certain subpopulations; it demonstrated longer median OS in patients without t-AML. Further analysis to confirm a survival benefit among patients without t-AML receiving either 5-day or 10-day DEC/ VEN is needed and will be presented at ASH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single-Cell Proteomic Analysis Defines Metabolic Heterogeneity in Response to Venetoclax in AML

Acute myeloid leukemia (AML) is among the deadliest blood cancers with over 10,000 patients dying annually in the U.S. Despite high rates of complete remission after conventional frontline genotoxic chemotherapy, patient prognosis remains poor with a 5-year overall survival of only 28%, which is largely attributable to frequent relapses. The standard chemotherapy for AML has changed little during the past 40 years. However, several new drugs have been approved by the FDA over the last 10 years including venetoclax (VEN), BH3 mimetic protein that selectively inhibits the anti-apoptotic function of BCL2. Combining VEN with the hypomethylating agent azacytidine (AZA) or with low-dose cytarabine (AraC) demonstrated promising results, leading to approval of these combinations by the FDA. However, durable response remains a challenge as resistance has emerged. Metabolic flexibility and intratumoral heterogeneity (both genetic and non-genetic) are key components of resistance. Resistance to VEN combination therapies has implicated alternative anti-apoptosis proteins such as MCL1, monocytic differentiation state, and remodeling of mitochondrial electron transport chain complex I. TP53 or RAS mutations are also associated with resistance. To better understand the interplay between differentiation state, metabolism, and signaling pathways in resistance to VEN and its combinations, we analyzed 36 primary AML samples (31 adult, 5 pediatric) and 2 healthy bone marrow controls using single-cell mass cytometry after ex vivo treatment for 24h with VEN, AraC, AZA and VEN+AraC and VEN+AZA. Across two antibody panels we measured myeloid phenotypic markers, key signaling pathways, transcription factors and metabolic proteins relevant to glycolysis, TCA cycle, fatty acid oxidation, amino acid transport, and mitochondrial dynamics, for a total of 76 unique markers. For more than 80% of the patients, we observe, at baseline, highly metabolic subpopulations with high expression of ATPA5, a subunit of mitochondrial ATP synthase, and glutathione synthetase (GSS), necessary for redox homeostasis as well as strong expression of mitochondrial proteins related to oxidative phosphorylation and TCA cycle. A small subset of these cells also highly express glycolytic enzymes, in particular enolase 1 (ENO1) and lactate dehydrogenase (LDHA) which converts pyruvate to lactate. This demonstrates the presence of cells with dual glycolytic and oxidative metabolism possibly reflecting a high demand for NAD+ to support oxidation reactions. These metabolic features do not correlate with specific phenotypic markers and is highly variable between patients. As expected, ex vivo treatment with VEN eradicates more immature subpopulations (CD34+ and/or CD117+) while sparing monocytic populations. In general, cells with the highest levels of BCL2 respond well to VEN (Panel A). However, defining populations solely with phenotypic proteins fails to adequately identify persistent and emerging populations after VEN or its combinations. Instead, clustering based on metabolic pathways identifies persistent or emerging populations. In several patients, expression of mitochondrial cristae-shaping protein (OPA1) and NADPH-producing enzymes isocitrate dehydrogenase (IDH1) or glucose-6-phosphate dehydrogenase (G6PD) defines BCL2+ subpopulations that persist through VEN treatment, likely through maintenance of mitochondrial integrity. In other patients, we observe selection of cells expressing monocarboxylate transporter 1 (MCT1), which facilitates lactate uptake, suggesting these cells undergo metabolic reprogramming to counteract the decrease in amino-acid uptakes following VEN. Interestingly, 4 of the 5 pediatric AML samples demonstrated VEN-resistant subpopulations characterized by co-expression of glucose transporter GLUT1, fatty acid transporter CD36, and alternative anti-apoptotic protein BCL-xL (Panel B). Very little is known about metabolic dependencies in pediatric AML and VEN is an emerging therapy in this patient group. Altogether, our data indicate that single-cell metabolic analysis may better organize intratumoral heterogeneity in AML and enables discovery of new pathways defining resistance or persistence to VEN and its combinations. Further analyses and integration of clinical data including mutational patterns are underway and will be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ELN Risk Stratification Is Not Predictive of Outcomes for Treatment-Naïve Patients with Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine

Background: Venetoclax (Ven), a highly selective oral BCL-2 inhibitor, in combination with hypomethylating agents (HMAs) such as azacitidine (Aza), is approved for the treatment of patients (pts) with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy (IC). An open-label, non-randomized phase 1b trial (NCT02203773) and the confirmatory VIALE-A phase 3 randomized trial (NCT02993523), both enrolling pts with intermediate and poor risk cytogenetics per NCCN Guidelines, demonstrated that the combination of Ven+Aza led to high rates of complete remission and longer overall survival (OS) than Aza alone (median OS of 14.7 months [mo] vs 9.6 mo), with similar safety profiles. In this exploratory post hoc analysis of the pooled treatment-naïve, IC ineligible pts treated with Ven+Aza in the phase 1b and phase 3 trials, patients were stratified according to the 2017 ELN risk classification system (which is based on data from patients receiving IC and utilizes cytogenetic and molecular determinants commonly associated with AML). We report clinical outcomes for these patients per ELN 2017 risk group, which will also be updated using the newly published ELN 2022 criteria. Methods: For the phase 1b trial, our analysis includes pts who were enrolled to evaluate safety and efficacy of Ven+Aza at a daily dose of 400 mg for VEN. For the phase 3 trial, pts were randomly assigned in a 2:1 ratio to the Ven+Aza group or placebo (Pbo)+Aza group. All pts received a standard dose of Aza (75 mg/m2 SC or IV on days 1-7 every 28-day cycle). Ven (400 mg) or Pbo was administered orally, once daily, in 28-day cycles. Pts with favorable risk cytogenetics such as t(8;21), inv(16), t(16;16) or t(15;17) as per the NCCN Guidelines Version 2 were excluded from the study. The pooled group of pts from the two trials having both site-reported cytogenetic data and bone marrow aspirate with centrally determined molecular data allowing for ELN genetic risk classification were included in this analysis. Pts were retrospectively classified per the ELN 2017 criteria as favorable-, intermediate-, or adverse-risk AML. Results: Inclusion of central molecular data allowed the reclassification of patients according to ELN 2017 recommendations (Figure 1). 63 of the 67 Ven 400mg + Aza pts enrolled in the phase 1b trial, and 329 of the 431 total pts enrolled in the VIALE-A trial were evaluable for inclusion in this analysis (279/353 in the pooled Ven+Aza group and 113/145 in the Pbo+Aza control group from the phase 3 study). In the Ven+Aza and Pbo+Aza groups, 46 (16.5%) and 20 (17.7%) pts had favorable-risk AML, 65 (23.3%) and 19 (16.8%) had intermediate-risk AML, and 168 (60.2%) and 74 (65.5%) had adverse-risk AML, respectively, by ELN. In favorable-risk AML pts, CR+CRi was achieved in 69.6% with VEN+AZA vs in 20% with Pbo+Aza; for intermediate-risk AML, CR+CRi was achieved in 75.4% vs 42.1%; for adverse-risk AML, CR+CRi was achieved in 61.3% vs 25.7%. Median OS was longer with Ven+Aza in all three risk categories when compared to Pbo+Aza: 21.09 vs. 12.96 mo, HR = 0.45 [95% CI: 0.24, 0.83] in the favorable-risk group; 23.26 vs. 13.14 mo, HR = 0.62 [95% CI: 0.35, 1.08] in the intermediate-risk group; 11.53 vs. 7.43 mo, HR = 0.59 [95% CI: 0.43, 0.82] in the adverse-risk group. The median OS was similar for favorable and intermediate risk groups who received Ven+Aza (21.09 mo and 23.26 mo, respectively; Figure 2). While the median OS of the Ven+Aza adverse risk group was lower (11.53 mo), two subgroups with distinct outcomes are apparent: adverse risk pts with a TP53 mutation (36.3% [61/168]) and adverse risk pts with a RUNX1 mutation (40.5% [68/168]) (one pt had both TP53 and RUNX1). The median OS for adverse risk pts with a RUNX1 mutation and TP53 WT was 22.9 mo while the median OS for adverse risk pts with a TP53 mutation and RUNX1 WT was 5.42 mo. Conclusions: ELN 2017 risk groups, based on younger patients who received IC regimens, are not prognostic in patients receiving Ven+Aza. This exploratory analysis suggests little OS distinction between favorable and intermediate risk groups. Furthermore, adverse risk ELN groups can be further refined to determine mutationally-defined cohorts with more favorable outcomes. A modified risk stratification system is needed for pts receiving newer therapies, such as Ven+Aza, that uses determinants that are prognostic for pts treated in the context of these regimens with distinct mechanisms of actions from IC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatric Acute Lymphoblastic Leukemia with Pdgfrb Fusions: A Multicenter Retrospective Study

Objective: PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. PDGFRB fusions was mainly observed in B-ALL, but also in T-ALL. Previous studies were mostly limited to anecdotal cases, suggesting that this subtype of ALL had low rate of remission and poor prognosis. The addition of tyrosine kinase inhibitor (TKI) to intensive chemotherapy may improve the outcome, but lack of long-term survival data. Herein, we retrospectively analyzed the clinical characteristics, survival and prognostic factors for 28 pediatric patients with PDGFRB fusions ALL. Methods: This multicenter, retrospective study included pediatric patients with newly diagnosed PDGFRB fusion ALL after treatments according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 10 hospitals in China. All patients completed the followed up. The baseline characteristics and treatment outcomes of these patients, including complete remission, drug resistance, relapse, treatment-related mortality and minimal residual disease (MRD) at end of induction therapy, as well as hematopoietic stem cell transplantation (HSCT) were collected. The outcome was compared between patients treated with and without TKI. Fisher test and nonparametric rank sum test were used for comparative analysis. 4-year event-free survival (EFS) and 4-year overall survival (OS) were estimated by use of Kaplan-Meier methods, and the 4-year cumulative incidence of relapse was calculated by use of a competing risk model gray test. Univariate and multivariate analyses were performed by use of Cox regression. Results: We identified 28 pediatric patients with newly diagnosed PDGFRB fusion ALL, which accounted for approximately 0.5% of childhood ALL. In all 28 patients, 21 (75%) were male and 7 (25%) were female; the median age was 10 (1-16) years old; median white blood cell (WBC) was 29.8 (1.6-627.7) × 10^9/L; 24 (85.7%) were acute B-lymphoblastic leukemia and 4 (14.3%) were acute T-lymphoblastic leukemia; one case (3.5%) was observed accompanied by the CNS involvement at diagnosis. Twenty of the patients received TKI treatment. Only 6 patients underwent hematopoietic stem cell transplantation. For all 28 patients, the median follow-up was 25.5 (3-77) months, the 4-year EFS was 29.2% (95% CI, 13.6-36.4), the 4-year OS was 42.1% (95% CI, 30.6-61.4), and the 4-year cumulative incidence of relapse was 58% (95% CI, 45·6-70·1). Patients in TKI group had a high rate of complete remission after induction therapy compared with those in no-TKI group (90% vs 63.6%). However, no significant differences were observed in the 4-year EFS and 4-year OS between TKI group and no-TKI group (EFS, 21.1% vs 43.8%, P=0.925; OS, 50.1% vs 36.5%, P=0.807). The cumulative incidences of relapse between these two groups also have no remarkable differences (P >0.05). Among the 6 patients who underwent HSCT, 2 patients who achieved CR1 survived and 4 died. Univariate analysis showed that minimal residual disease (MRD) ≥10-4 after induction therapy for D46 and IKZF1 positive had a poor prognosis (all P <0.05). MRD≥10-4 at the end of induction therapy is an independent risk factor for poor prognosis (hazard ratio of event-free, 9.101 [95% CI 2.03-40.86], P =0·004, compared to those with a MRD of <10-4). Conclusion: Pediatric ALL patients with PDGFRB fusions have a poor outcome. This subtype of ALL is associated with high-risk clinical features such as older age, high WBC count at diagnosis, high MRD after induction therapy, and increased risk of leukemia relapse. The addition of TKI to chemotherapy can improve the early remission rate of treatment, but does not improve the long-term survival. Profitably, the TKI treatment can provide an opportunity for subsequent treatment, including HSCT. Additionally, HSCT has indeed potential to reduce the relapse rate for this subtype patients. HSCT is recommended for this subtype patients who achieve CR1. The MRD≥10-4 or more at the end of induction therapy was independently predictive factor for unfavorable outcome and stratified treatment based on MRD may improve survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Addition of Sorafenib to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone (CLAG-M) in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and High-Grade Myeloid Neoplasms Independent of FLT3-Mutation Status: Final Results of a Phase 1/2 Study

BACKGROUND: We previously showed that cladribine, cytarabine, G-CSF and dose-escalated mitoxantrone (CLAG-M) led to a higher rate of complete remissions without measurable residual disease (MRDneg CR) than 7+3. Recently, a randomized trial demonstrated addition of the multikinase inhibitor sorafenib to 7+3 improved event free survival (EFS) irrespective of FLT3 mutation status. Here, we report the results of a phase 1/2 study (NCT02728050) evaluating addition of sorafenib to CLAG-M (CLAGM+S) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms (≥10% blasts). Phase 1 results were reported previously. METHODS: Patients aged 18-60 years were eligible if they had a treatment-related mortality score (TRM) of ≤13.1 (corresponding to a predicted <13.1% risk of death by day 28 following intensive induction chemotherapy) and adequate organ function. Patients with uncontrolled infection or concomitant illness with expected survival <1 year were excluded. Cohorts of 6-12 patients were assigned to 1 of 6 dose levels of mitoxantrone (10, 12, 15, or 18 mg/m2/day, days(d) 1-3) and sorafenib (200 to 400 mg twice daily [BID] on d10-20 with induction and 8-27 with consolidation). G-CSF dose was 300 or 480 μg/day (weight-based, d0-5), cladribine 5 mg/m2/day (d1-5), and cytarabine 2 g/m2/day (d1-5). Up to 4 cycles of post-remission therapy with CLAG+S (mitoxantrone omitted) were allowed, followed by 12 months of maintenance sorafenib. Patients were taken off trial if they underwent allogeneic transplant. As primary endpoint in Phase 2, the rate of MRDneg CR following CLAGM+S was compared to a matched historical control population who received CLAG-M alone. Secondary endpoints included rate of CR, overall response rate (ORR defined as CR+CR with incomplete hematologic recovery [CRi]), overall survival (OS), EFS and the toxicity profile. EFS and OS were estimated using the Kaplan-Meier method and compared using Cox regression models. RESULTS: 84 patients were enrolled from 12/8/2016-10/7/2021. In Phase 1, CLAG-M with mitoxantrone at 18 mg/m2/day and sorafenib 400 mg BID was established as the recommended phase 2 dose (RP2D). Sixty-one patients with a median age of 50 [range: 21-60] years were treated at the RP2D. ELN2017 risk category was favorable in 28%, intermediate in 36%, and adverse in 34%. FLT3-ITD and TKD mutations were present in 28% and 7% respectively. Mortality within 28 days was 2%. At the RP2D, a response of MRDneg CR occurred in 49/61 patients (80%, 95% CI: 68-89%). Additional responses of MRDpos CR and CRi (3 patients each) led to an ORR of 90%. The MRDneg CR rate in patients with and without FLT3-mutations was similar (90% vs. 83%, p=0.30). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 29 and 25 days. Besides infections/neutropenic fever, rash was the most common grade ≥3 adverse event. With a median follow up of 35 months, median OS was not reached; 12-month OS was 82%. There was no difference in OS and EFS in the FLT3-mutated and FLT3-wild type patients. We next compared CLAGM-S to a historical cohort of 71 newly diagnosed patients treated with CLAG-M alone, matched for mitoxantrone dose, age and TRM score (Table 1). In univariate analysis, rates of MRDneg CR, OS and EFS were similar (p=0.83, 0.16, and 0.37 respectively). Likewise, there was no difference in OS (p=0.54) or EFS (p=0.63) in FLT3-mutated patients who received CLAGM+S vs CLAG-M. In subgroup analysis, we observed a benefit favoring CLAGM+S for both OS (p<0.01) and EFS (p=0.03) among ELN2017 intermediate risk patients (Figure 1). No benefit of CLAGM+S vs CLAG-M alone in either OS or EFS was observed among adverse risk patients. Analysis of the favorable-risk cohort was limited by small sample size. Multivariate models comparing CLAGM-S to CLAG-M alone (reference) and controlling for age, secondary disease, FLT3 status and cytogenetic risk showed improved OS (HR=0.38, 95%CI 0.17-0.84, p= 0.02) and EFS (HR= 0.43, 95% CI 0.22-0.85 p=0.02) following CLAGM-S; MRDneg CR was also more likely with CLAGM-S though not statistically significant (OR= 2.56, 95% CI 0.68-9.61, p= 0.16). CONCLUSION: Addition of sorafenib to CLAG-M produces high rates of MRDneg CR in newly diagnosed AML patients ≤60 and prolongs OS and EFS in multivariate analysis compared to historical, matched control cohort receiving GLAG-M alone, a benefit that was particularly evident in patients with intermediate-risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Tandem Duplications of the UBTF gene in Adult AML: A Rare but Recurrent Alteration Associated with Myelodysplasia and Poor Outcome

The upstream binding transcription factor (UBTF) is a nucleolar protein that regulates the transcription of ribosomal genes as a component of the RNA Pol I pre-initiation complex. Recently, tandem duplication mutations of the UBTF gene (UBTF-TDs) were identified as recurrent alterations in pediatric AML (Umeda et al., 2022), potentially representing a new subtype-defining lesion. UBTF-TDs were found to be associated with normal karyotype (NK) or trisomy 8 (+8), FLT3-ITD and WT1 mutations as well as poor prognosis. Data on the role of UBTF-TD in adult AML are limited. In the present study, we therefore analyzed the prevalence and prognostic significance of UBTF-TDs in a large cohort of adult AML patients (pts). Methods: Pts included were registered and treated in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003, AML60+, SORAML) or the SAL-registry. Screening for UBTF-TDs was done by PCR covering exon 13 of the UBTF gene with 6-FAM labelled primers followed by high-resolution fragment analysis using genomic DNA isolated at diagnosis. Mutations were confirmed by Sanger sequencing. All UBTF mutant samples were further analyzed by targeted next generation sequencing (Archer Myeloid Panel) for the presence of co-occurring alterations. Results: Somatic mutations in UBTF were identified in 52 (1.2%) of 4247 pts. Mutations varied in size (3 to 309 bps), all yielding in-frame insertions, duplications or deletions in exon 13 of the UBTF gene. UBTF-TD AMLs frequently presented with a normal karyotype (46%) or +8 (36.5%). Similar to findings in pediatric pts, the co-mutation profile showed significant differences between UBTF-mut and UBTF-wt pts, i.e. UBTF-TDs were significantly associated with FLT3-ITD (48%, p<.001) or WT1 mutations (52%, p<.001), while DTA co-mutations were exceedingly rare (DNMT3A 1.9%; TET2 3.8%; ASXL1 3.8%) (Fig. 1A). Furthermore, UBTF-TDs and several class-defining lesions, i.e. reciprocal translocations such as RUNX1::RUNX1T1,DEK::NUP214 or mutations in CEBPA or NPM1 were mutually exclusive. The prevalence of UBTF-TDs showed a strong negative correlation with increasing age, ranging from 10% in patients <20 years (yrs) to 0.05% in patients >70 yrs, respectively. Accordingly, pts with UBTF-TDs were significantly younger (median age 41 yrs; range 17-77 yrs) than wt pts (med. 57 yrs; range 15-90 yrs, p<.001). Association with clinical parameters revealed significantly lower hemoglobin levels and platelet counts at diagnosis for UBTF-mut pts compared to UBTF-wt pts (median Hb 8.7 vs. 9.2 g/dL; p=.02; median PLT 31.5 vs 53 x 109/L; p=.003). Although UBTF-TDs mainly affected younger pts, cytomorphologic assessment revealed a clear association with myelodysplastic changes in about 60% of patients. Univariate analysis showed a significantly higher rate of complete remissions (CR) in UBTF-mut pts (92.3%) compared to UBTF-wt pts (70.8%) (p<.001). However, UBTF-mut pts had shorter overall (OS) and event-free survival (EFS). This effect was particularly pronounced in the subgroup of pts under 60 years of age (median OS 20.4 months in UBTF-mut pts vs. 45.3 months in UBTF-wt pts, p=.079; median EFS 6.7 months in UBTF-mut pts vs. 11 months in UBTF-wt pts, p<.001) (Fig.1B), who represented the majority (45/52, 87%) of UBTF-TD patients, and in patients with co-mutations of the WT1 gene (data not shown). AlloSCT performed in CR1 in 11 pts (21%) did not improve outcome. In multivariable analyses, the presence of UBTF-TD was associated with a trend for shorter OS (HR: 1.39; 95% CI 0.98-2, p=.06) and significantly worse EFS (HR: 1.68; 95% CI 1.24-2.3; p<.001). Conclusions: This analysis of a large cohort of adult patients with newly diagnosed AML revealed that UBTFmutations can be found in about 1% of all patients with AML, but are considerably more common in young adults. As in pediatric patients, they are associated with a specific cytogenetic and molecular profile, i.e. high rate of +8, FLT3-ITD and WT1 mutations. As a novel finding, adult UBTF-TD patients frequently showed signs of myelodysplasia. The distinct molecular genotype and the fact that UBTF-TDs were associated with a dismal outcome, even in patients treated with alloSCT in CR1, support the classification of this group as a new disease entity and indicate that novel treatment strategies are needed in this subgroup of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mogamulizumab-Associated Rash (MAR) Correlates with Longer Progression Free Survival in Cutaneous T Cell Lymphoma (CTCL)

Background: Mogamulizumab-kpkc (mogamulizumab) is an anti-CCR4 monoclonal antibody approved for relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS). In the Phase III MAVORIC trial comparing mogamulizumab to vorinostat, mogamulizumab-associated rash (MAR) was reported in 25% of patients (pts) and was more common in responders than in non-responders. Since then, several small case series have suggested that MAR is associated with response to the drug and prolonged remission. Methods: We collected retrospective data from 8 academic centers on pts diagnosed with CTCL as defined by 2018 WHO-EORTC classification, who received at least one dose of mogamulizumab from 1/1/2000 to 1/31/2022. Primary endpoints were PFS and overall survival (OS) as calculated by Kaplan-Meier, compared with log rank test. Secondary endpoint was response to mogamulizumab in accordance with ISCL/EORTC 2011 criteria. MAR was graded with NCI CTCAE version 5.0. Categorical variables were compared between groups using Fisher test. Quantitative variables are presented with means and standard deviation or median and interquartile range (IQR). Univariate analysis was performed to calculate the hazard ratios (HR) for PFS. Results: A total of 159 pts were included in analysis: 80 (50%) pts had a diagnosis of MF, 67 (42%) had SS, and 11 (7%) had other CTCLs. Median age was 70 (IQR 59.5-76), 65 (41%) were female, 124 (78%) were non-Hispanic Caucasian, 22 (14%) were Black. Median of prior lines of therapy was 3 (0-14). ECOG was 0-1 in 80% of pts at start of mogamulizumab. Majority of pts (70%, n=111) had advanced stage disease (Stage III or IV). Extranodal disease other than skin was present in 111 (70%) and LDH was elevated in 80 (50%) of pts. MAR occurred in 72 (45%) pts. Majority of rash was grade 1-2 (76%, n=55) but 14% (n=10) developed grade 3 rash. Median time to onset was 3.7 months (mo) (IQR 2.1, 7.6) and median time to resolution was 4.3 mo (IQR 1.4, 7.5). Skin biopsy was obtained in 51 of 72 pts who developed MAR. Histologic patterns ranged from spongiotic/psoriasiform (40%, n=29), interface (19%, n=14), lichenoid (28%, n=20), granulomatous (7%, n=5) or a combination of patterns. Location of rash occurred in extremities (78%, n=56), trunk (69%, n=50), face/scalp (39%, n=28), buttocks/groin (8%, n=6) or combination of places. Of the pts who developed MAR, 24 (33%) were treated with topical steroids, 13 (18%) with systemic steroids, 16 (42%) with both topical and systemic steroids and 12 (17%) with other therapies, while 4 (6%) did not receive any treatment. Median follow up was 20.9 mo, IQR: (12.0, 38.4). Median PFS was 30.5 mo (95% CI: 27.0 mo to not reached) for pts who developed MAR vs. 8.6 mo (95% CI: 5.7-20.9) for those who did not (HR=0.38, 95% CI: 0.24-0.62, p<0.0001). Three-year OS for pts with MAR vs. those without was 84% vs 55% (HR 0.3, 95% CI: 0.14-0.63, p=0.0008). Complete remission (CR) was higher in pts with MAR (64%; n=46) than those who did not develop MAR (26%; n=23). Overall response rate (ORR) was also higher in those with MAR vs those without, 85% (n=61) vs. 54% (n=47), p<0.0001. Odds ratio of CR in pts with MAR was 4.64 (95% CI: 2.37-10.25), p<0.0001. CR and partial remission (PR) in the blood were the most predictive of longer PFS on univariate analysis with HR of 0.05 (95% CI: 0.02, 0.14, p<0.001) and 0.07 (95% CI: 0.03, 0.20, p<0.001), respectively. Advanced stage CTCL at the start of mogamulizumab was also associated with improved PFS compared with early stage, HR 0.61 (95% CI: 0.37, 1.00), p=0.05. At last follow-up, mogamulizumab had been discontinued in 114 pts due to rash (n=38), immune event (n=2), progression (n=56) or other adverse outcome (n=22). Mogamulizumab was held in 40 pts with drug rash. Of the pts who permanently discontinued mogamulizumab due to rash, 16 of 38 pts (42%) remain off systemic therapy at last follow up with ongoing response; median time off of systemic therapy for these pts was 7.8 mo (IQR: 6.1, 16.5). Conclusions: The development of MAR in patients with CTCL is associated with higher rates of CR and ORR and significantly longer PFS and OS. CR/PR response in blood were associated with improved PFS. Additionally, 40% of patients who developed MAR and discontinued mogamulizumab had ongoing responses without additional systemic therapy. Rash may be a surrogate marker of favorable outcome with mogamulizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults < 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P<0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Wierzbowska et al, 2008; Jaglal et al, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. The trial schema is shown in Figure 1. The trial was initiated in July 2017; 408 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. The CR, CRi, CRh after single or double induction were achieved in 63.4%, 16.5% and 0.6% patients, respectively leading to an overall composite CR (cCR) rate 80.5%. Thirty-day mortality, mainly due to infectious complications in aplasia, were observed in 5% and 14.5% did not achieved cCR. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Impact of Chimeric Antigen Receptor T Cell Quality to Clinical Safety and Efficacy in Non-Hodgkin Lymphomas

Background: Immunotherapy has become increasingly important in modern cancer treatments. It has become evident that chimeric antigen receptor-modified T (CAR-T) cells may be a promising treatment for hematological malignancies. Malignancies affecting B cells have been successfully treated using CAR-T cell therapies. Many studies have explored the influence of various factors on the efficacy and survival of CAR-T therapy from different aspects, including the patient's disease state, general condition, tumor burden, and even the dose of CAR-T cells infused. Few researchers have explored the effect of CAR-T cell quality on disease treatment impact on remission, survival, and prognosis. This study combines the essential condition of patients and quality data of CAR-T cells, such as transduction efficiency, killing efficiency, and the ratio of CD4+ and CD8+ subsets, to analyze CAR-T's safety and clinical efficacy in the treatment of non-Hodgkin's lymphoma in our center. Methods: This was a retrospective, single-center, investigator-initiated study. A total of 179 patients with NHL were included. Patients' baseline data were obtained from electronic medical records and telephone follow-ups. Laboratories provided data on the quality of patients' CAR-T cells. We conducted a multivariate analysis to determine the independent factors that influence treatment response and patient prognosis. Results: In our study, the median age of 179 NHL patients was 52 (range 17-78) years, and 51 (28.5%) were ≥60 years old. Before CAR-T treatment, 22 (12.3%) patients remained in complete remission (CR), and 83 (46.4%) patients were in progressive disease (PD). Among the available data, 105 (61.4%) patients had CAR-T cell killing efficiency (KE) <30%, while 66 (38.6%) patients had killing efficiency (KE) ≥30%. There were 101 (58%) patients with CAR-T cell transduction efficiency (TE) <40% and 73 (42%) with transduction efficiency (TE) ≥40%, respectively. CD4+/CD8+ ratio of CAR-T cells <1 in 32 (18.4%) patients and CD4+/CD8+ ratio of CAR-T cells ≥1 in 142 (81.6%) patients. Overall, the median event-free survival (PFS) was 10.6 months (95% CI: 4.064-17.136months), and the median overall survival has not yet been reached. The 6-month OS was 80.2%, and the 1-year OS was 70.6%. 2-year 0S is about 59.8%. In addition, we divided patients into different subgroups according to the TE and KE of CAR-T cells, and the results of multivariate logistic regression analysis were as follows. The subgroup with TE<40% had a higher complete remission rate than the subgroup with TE≥40%. And the subgroup with KE≥30% had a higher rate of complete remission than the subgroup with KE<30%, with p-values equal to 0.007 and 0.022, respectively. There was statistical significance, so TE and KE independently influenced efficacy factors. Multivariate cox regression analysis showed that the subgroup of CAR-T CD4+/CD8+<1 had better overall survival than CAR-T CD4+/CD8+≥1, p=0.039 (95% CI: 0.114-0.947). Therefore, the ratio of CAR-T CD4+/CD8+ was an independent factor for OS, while the subgroups of transduction efficiency and killing efficiency did not show statistical significance. Conclusion: In general, CAR-T therapy has shown significant efficacy in NHL, and the quality of CAR-T cells plays a vital role in treatment. Screening suitable CAR-T cells in future treatment will Make the treatment effect more satisfactory. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Influence of Molecular Abnormalities on Treatment Response of Venetoclax Plus Azacytidine and Homoharringtonine Versus Venetoclax Plus Hypomethylating Agent in Relapsed/Refractory Acute Myeloid Leukemia

Purpose: Aim to explore the impact of molecular and cytogenetic abnormalities on the response of venetoclax (VEN)-based therapies in relapsed/refractory acute myeloid leukemia (R/R-AML). Method: 231 patients with RR-AML were included from an exploratory study (n=29), an prospective single-arm study (n=40) and a randomized controlled trial study (n=162) and analyzed the influence of molecular and cytogenetic abnormalities on the response of VEN-based therapies. Results: 98 patients received VEN+hypomethylating agent (HMA) therapy. 138 cases were treated with VEN+azacytidine and homoharringtonine (VAH). There was not significantly different in the clinical characteristics and the treatment after acquiring response, except for remarkably higher rate of prior allogeneic hematopoietic stem cell transplantation and higher incidence of ASXL1 and RUNX1 mutation, -5/5q- and -7/7q- in VAH group versus VEN+HMA group. VAH group had significantly higher rate of complete remission (CR)/CR with incomplete count recovery (CRi) (63.8% vs 40.9%, P=0.003), overall survival (OS) (no reach vs 16.0 months, P=0.023) and event-free survival (EFS) (7.1 vs 2.3 months, P<0.001) than VEN+HMA group. Patients with TET2 (P=0.041), NPM1 (P=0.039), ASXL1 (P=0.044), FLT3-ITD/TKD (P=0.008), DNMT3A (P<0.001) or RAS (P=0.006) mutation or co-mutation of DNMT3A and FLT3 (P=0.020, DNMT3A and NPM1 (P=0.020) or DNMT3A and IDH/2 (P=0.016) acquired statistically higher rate of CR/CRi with VAH therapy as compared with VEN+HMA trerapy. AML1-ETO-positive AML patients poorly responded to VEN+HMA therapy (0/7), but responded much better to VAH treatment (5/7, P=0.005). Patients with complex chromosome had low CR/CRi rate with either VEN+HMA or VAH therapy (1/10 vs 6/17, P=0.148). Conclusion: Combination of HHT with VEN+HMA could significantly improve the treatment response and long time survival in the patients with R/R-AML, especially benefit more in those with some special molecular and cytogenetic abnormalities. Key words: relapsed/refractory acute myeloid leukemia, venetoclax, HHT, molecular mutation, cytogenetic abnormalities

In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time. In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions. Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively. Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001). Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001). The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked. Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004). Conclusions In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CD58 Could be As a Leukemic Marker in Relapsed/Refractory B-ALL Patients after Multiline Therapies

It has been verified that CD58, a member of the immunoglobulin superfamily, is expressed in B-cell lymphoblastic leukemia (B-ALL) at a higher level and is a marker of minimal residual disease in B-ALL. A study reported that CD58 was expressed in 99.4% of B-ALL cases at diagnosis. Nevertheless, little is known regarding CD58 expression in relapsed/refractory (r/r) B-ALL patients having received multiline therapies especially chimeric antigen receptor (CAR) T-cells. Although CD19-specific CAR-T therapy resulted in high complete remission (CR) rates, some patients relapsed after CAR-T and part of them showed CD19 loss, under this circumstance, additional B-cell antigen specifically expressed on the B-ALL cells could help us to identify the leukemia cells. In this study, we investigated the CD58 expression in r/r B-ALL patients before CAR-T, and the influence of CAR-T cells on CD58 antigen of lymphoblasts in patients failed or relapsed after CAR-T. CD58 on leukemic cells of r/r B-ALL patients has been routinely detected by flow cytometry in our center. Data of r/r B-ALL patients were collected from May 2019 through May 31, 2022. Samples were detected on an 8-color BD FACSCanto II flow cytometer, and analyzed by FACS Diva software from BD or Kaluza software from Beckman Coulter. Antigen full expression, partial expression and no expression were defined as >80%, 20%-80% and <20% of gated cells displaying the antigen of interest, respectively. A total of 274 r/r B-ALL patients planned to be administered CD19 CAR-T cells were assayed CD58 antigen before CAR-T, all of them had received multiline chemotherapies, 61 (22.3%) underwent allogeneic hematopoietic cell transplant (allo-HCT) and 6 cases had a history of antibody (CD20, CD19 or CD22) treatment. The median age was 12 years (range, 1-75 years), including 97 adults and 177 children younger than 18 years. Among all 274 patients, 228 (83.2%, 228/274) showed CD58 expression, consisting of 180 (78.9%, 180/228) cases with full expression and 48 (21.1%, 48/228) with partial expression; whereas 46 (16.8%, 46/274) patients were CD58-negative, demonstrating that CD58 was expressed on the majority (83.3%) of r/r B-ALL patients after treated by multiple intensive chemo drugs and even allo-HCT. Then, we observed the influence of CAR-T cells on the expression of CD58 antigen of lymphoblasts. We followed-up 57 patients who had CD58 expression before CD19 CAR-T but failed or relapsed after CAR-T. Of them, 45.6% (26/57) cases received the further treatment as a consolidation following CD19 CAR-T (CD22 CAR-T, 14; allo-HCT, 12). Among 57 patients, 10 were CD58-negative while 47 cases still showed CD58-positive, the frequency of CD58 expression was 82.5% (47/57) after treated by CAR-T cells and allo-HCT. When we excluded the 26 patients who received following CD22 CAR-T or allo-HCT, and only considered the 31 patients exposed to one-time CD19 CAR-T cells, the CD58 expression rate was 87.1% (27/31). It was reported that CD58 loss in tumor cells induced resistance to CAR-T therapy in cell lines and mouse models. We therefore analyzed the influence of CD58 expression on the treatment response of CAR-T cells. Among 274 r/r B-ALL patients received CD19 CAR-T, 6 were unable to evaluate the treatment response due to death or hospital discharge within 15 days after cell infusion, the remaining 268 patients had evaluation data including 223 cases with CD58 expression (full or partial expression) and 45 without CD58 expression. After CD19 CAR-T therapy, the CR (including MRD+CR) rate in patients with CD58 expression was 91.9% (205/223) while it was 95.6% (43/45) in patients without CD58 expression, indicating that CD58 negativity was irrelevant to CAR-T treatment failure in r/r B-ALL. In conclusion, CD58 antigen was expressed in the majority (83.2%) of r/r B-ALL cells without exposing to CAR-T treatment, and still expressed on the lymphoblasts of most patients (>80%) failed or relapsed after CAR-T, therefore, it could be as a leukemic marker for identifying tumor cells in r/r B-ALL patients who have received multiline therapies including allo-HCT and CAR-T. Additionally, CD58-negative patients achieved a similar high CR rate as CD58-positive patients did after CD19 CAR-T.

A Phase Ib Study of the Safety and Efficacy of Venetoclax When Combined with Escalating Doses of Omacetaxine in Patients with Relapsed/Refractory Acute Myeloid Leukemia Failing Treatment with Venetoclax-Containing Regimens (VEN-OM)

Background: Venetoclax (VEN) combined with hypomethylating agents (HMA) are increasingly used as first line (1L) treatment in AML patients (pt) intolerant of intensive chemotherapy, due to the high complete remission (CR) rate (66.4%), tolerance of therapy and a median duration CR of 17.5 months. However, >60% of pts discontinued VEN/HMA (n=286) during the VIALE-A trial, mostly due to disease progression (DiNardo et al.N Engl J Med2020; 383:617-29). Outcomes for such pts receiving 2L and 3L therapies for relapsed/refractory (R/R) AML are poor and may be due to development of resistance to BCL-2 inhibition through mechanisms including the upregulation of the anti-apoptotic proteins BCL-XL or MCL1. In vitro studies demonstrate that VEN-resistant leukemia stem cells (LSC) are re-sensitized to BCL-2 inhibition when MCL-1 is also inhibited (Ramsey et al. Cancer Discov 2018; 8:1566-81). Novel MCL-1 inhibitors are thus in phase 1 clinical trials in R/R AML (e.g. NCT02675452), however there have been concerns for cardiotoxicity. Metabolic studies (Stevens et al. Nat Commun 2018: 9, 3694) indicate that the CD123+ malignant stem cell compartment of pts with high-grade MDS rely on upregulation of the protein synthesis machinery and mitochondrial oxidative phosphorylation (OxPhos). Omacetaxine (OM), a protein translation inhibitor both inhibits OxPhos and down-regulates (other) proteins with a short half-life such as MCL1. Treatment of a xenograft AML model with a combination of OM and VEN indicates in vivo synergistic effects in impairing mitochondrial respiration, ATP production, BCL-2 inhibition and MCL-1 downregulation (Fig 1A). We hypothesize this combination will prove effective in pts with R/R AML including those resistant to VEN-containing regimens. A similar drug combination is being studied by Dinardo et al. in R/R AML and MDS pts with RUNX1 mutations. Methods: VEN-OM is a single arm, open-label, phase Ib dose-escalation study in R/R AML pts (18-75y). The trial utilizes an innovative Bayesian Optimal Interval (BOIN) adaptive design (Yuan et al. Clin Cancer Res 2016)to determine the maximum tolerated dose (MTD), with a target dose-limiting toxicity (DLT) rate of 2%, and 4 pre-specified dose levels of OM, involving 24-30 pts. Major eligibility: ECOG 0-2, adequate organ function, R/R AML having progressed on ≥ 1L of therapy, which must have included a VEN-containing regimen. Exclusion criteria: Prior use of OM, peripheral blast count > 25 × 109/L, unresolved ≥ grade 2 clinically significant nonhematologic toxicities from prior anticancer therapy, unresolved ≥ grade 2 disseminated intravascular coagulation (DIC), other active malignancy within 1 year before study entry, or active infections. Induction Phase: Beginning with the first pt treated at the lowest dose of OM (0.625 mg/m2 q12h), OM dose escalation and de-escalation will involve comparison of the observed DLT rate at the current dose with a pair of fixed, pre-specified boundary rates. After a VEN ramp-up phase (days 1-3), the VEN dose is fixed at 400mg daily on days 4-28. OM doses are given days 1-7. OM dose will be escalated for each subsequent pt until the first DLT occurs, whereupon the current dose cohort is expanded to 3. In simulations of these conditions with a target DLT rate of 20%, the percentage correct selection of the MTD is between 60% with enrollment of 20 pts and 70% with 24 pts. Consolidation Phase: OM dose will be as per induction dose for days 1-7 of each cycle. VEN dose is 400mg days 1-21. Regimen comprises 3 cycles: Induction cycle x 1 and Consolidation cycles x 2 (Fig 1B). Primary endpoint is MTD of the combination of VEN and OM. Secondary endpoints include overall response rate after 3 cycles, characterization of adverse effects, and estimates of EFS and OS at 12 months. Exploratory objectives include measurement of validated markers of early renal injury including urine TIMP-2 x IGFBP7 and KIM-1 to identify pts susceptible to OM-induced nephrotoxicity and potential correlation with OM efficacy. Our previous experience with OM added to 7+3 ("AML-02", ASH 2022 abstract submitted) suggests that quantification of BM leukemia blast protein synthesis rates (Walker et al. Clin Cancer Res 2021, 27:819-30) and 'BH3 profiling' at presentation predicts outcomes, and these correlative studies will also be performed. The study recently opened, with the first patient completing induction without complications. Trial registered as (NCT04926285). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax (VEN) Plus Intensive Chemotherapy (IC) with FLAG-IDA in Patients (Pts) with Newly Diagnosed (ND) and Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Background: Despite the high complete remission (CR) rates achieved with IC, relapse rates remain high underscoring the need for novel combination regimens capable of inducing deeper remissions via eradicating measurable residual disease (MRD). Recently, several studies have shown promising clinical activity of VEN when combined with different IC regimens in pts with ND AML with composite CR rates (CRc) above 90% and MRD-ve rates exceeding 80% (Wang 2022; Kadia 2021). FLAG-IDA + VEN has also shown significant clinical activity in pts with ND AML with a CRc rate of 89% and MRD-ve remission rate of 93% (DiNardo 2022). Methods: We conducted a single-center retrospective study to assess the clinical activity of FLAG-IDA + VEN in pts with AML. During induction, VEN was initially given for 14 days which was later on reduced to 7 days due to encouraging results by Kadia et al. Standard cytogenetic (CN) analysis was performed and molecular data was obtained using a 40-gene NGS platform. Responses were assessed using the modified International Working Group response criteria and included CR, CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR). Time-to-event analyses were estimated using the Kaplan-Meier method and compared using the log rank test. Results: From March 2020 to May 2022, 24 pts with AML (17 ND and 7 R/R) were treated using FLAG-IDA + VEN (Table 1). Median age was 48 years (range, 21-68) with male predominance (67%). Among the 17 pts with ND AML (8 de novo, 5 AML-MRC, 2 treated-secondary, 2 therapy-related), 3 had extramedullary disease (EMD). The most common ELN CN risk groups were complex (N=5), KMT2A-rearranged (N=4), other adverse (N=3), and diploid (N=3). Eight pts (47%) harbored a RAS mutation. Median time to initiation of therapy was 5 days (range, 2-14). Twelve pts (71%) [KMT2A-rearranged, N=4; complex CN, N=3; diploid, N=3; other adverse, N=1; other intermediate, N=1] achieved CR/CRi including 1 pt with EMD. Median time to ANC (≥ 500) and platelet (≥ 50,000) recovery were 29 days (range, 19- 42) and 25 days (range, 17- 42), respectively. Median number of consolidation cycles given were 1.5 (range, 1- 5). MRD status was available in 6 out of 12 pts and all 6 pts achieved MRD negativity using flow cytometry (<10-3). Median follow-up among ND AML pts was 4.3 months (mths) (range, 0.7- 13.2). Among the 12 responders: (1) 3 pts received allo-SCT [KMT2A-rearranged, N=2; (-7), N=1] after 7, 4, and 3 mths, respectively, and remain alive in CR 10+, 7.5+, and 3+ mths, respectively, after initiation of therapy, (2) 6 pts with ELN favorable (N=3), intermediate (N=2), and adverse (N=1) risk AML remain in CR/CRi for 6+, 4+, 1+, 3+, 2+, and 2+ mths, respectively, (3) 3 pts with ELN adverse risk AML (including 1 pt with de novo MLLr AML and EMD) achieved CR and relapsed after 0.7, 1.7, and 7.6 mths, respectively. One pt died due to progressive disease (PD) 4.7 mths after relapse and the remaining 2 pts are receiving salvage therapy and alive 4.3+ and 5.2+ mths after relapse, respectively. All nonresponders (N=5) had ELN adverse risk AML including 2 pts with EMD and 2 pts with treated secondary AML. All 5 nonresponders died due to PD including 3 pts who had no response to HMA+VEN based salvage therapy. Among the 7 pts with R/R AML, 6 were in salvage 1 and 1 pt received prior allo-SCT. Responses were observed in all pts: 4 CR, 1 CRi, 1 MLFS, and 1 PR. Median time to count recovery in R/R AML pts was 33 days (range, 24-78). Median follow-up in R/R AML pts was 6.2 mths (range, 1.5- 15.6). Of the 5 pts who achieved CR/CRi, 4 were bridged to allo-SCT and 1 pt died in CR after 3 cycles of consolidation due to sepsis. Of the 4 SCT recipients: (1) 2 pts relapsed 2 mths after allo-SCT and died 4 and 6.5 mths, respectively, after allo-SCT; (2) 2 pts (KMT2A-rearranged and NPM1mut) remain alive in CR for 8+ and 14+ mths, respectively. Two pts with complex CN achieved MLFS and PR after 1 cycle of therapy and died due to PD and fungal pneumonia after 5.3 and 1.5 mths of starting therapy, respectively. Median overall survival (OS) for pts with ND AML and R/R AML were 13.2 mths (95% CI: Not reached) and 6.2 mths (95% CI: 5-7), respectively (p=0.62; Figure 1). Among pts with ND AML, median OS was not reached among responders and was 2.6 mths in non-responders (p=0.002). Conclusion: FLAG-IDA + VEN is a feasible and active regimen in AML. Longer follow-up and larger multicenter studies are needed to confirm the efficacy of this regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal