Poor Risk Cytogenetics Research Articles

Real World Clinical Characteristics, Treatment Patterns and Outcomes of R/R B-Cell ALL Adult Patients in Latin America

Introduction. Acute lymphoblastic leukemia (ALL) frequently affects mainly children and young adults. ALL has seen important progresses in diagnosis techniques and treatment approaches in the last decade. However, in some developing countries, there are inequalities in ALL management, such as heterogeneous access to diagnosis technologies (e.g., cytogenetic and molecular profiling) and access to target therapies treatments. To date, there is scarce data on those impacts in treatment patterns and real-world outcomes of adult relapsed/refractory (R/R) B-cell ALL (R/R ALL) patients in Latin America (LA). Therefore, this study aims to describe treatment patterns, clinical characteristics, and outcomes of R/R ALL adult patients treated in LA. Methods. This was a retrospective multicenter non-interventional study to evaluate treatment patterns, clinical characteristics and outcomes conducted in Argentina, Brazil, and Colombia. The study included patients ≥ 18 years old at diagnosis with confirmed R/R ALL between January 1, 2015, to December 31, 2019 that received at least one line of treatment for R/R ALL. Data collected from medical records was considered for the analysis, which was descriptive in nature, as no hypothesis has been tested. Results: A total of 71 patients diagnosed with R/R ALL were included in the study (23 from Argentina, 27 from Brazil, and 21 from Colombia). Table 1 shows the demographics and clinical characteristics. The median age at diagnosis was 31 years (Q1-Q3: 24.0-46.0), 56.3% were male, and 50% were White/Caucasian patients. At diagnosis, the most common comorbidities were diabetes, hypertension, gastrointestinal disease, and thyroid disease, with 11% each. At diagnosis, most patients presented with poor or intermediate cytogenetic risk prognosis, in 55.1% and 31.6%, respectively. Most of the patients presented with good performance status, 50.9% ECOG 0 and 36.8% ECOG 1. As for treatment patterns, patients received up to six treatment lines (LOT-1 to LOT-6), with a median of 2.0 LOTs (Q1-Q3: 1.5-3.0) within the R/R setting. Fifty-three (74.6%) out of the 71 patients enrolled in the study received two lines of R/R treatment (up to LOT-2), and 27 patients (38%) received 3 lines (up to LOT-3). The median treatment duration of LOTs were 3.4 months (Q1-Q3: 1.14 - 5.7), 1.4 months (Q1-Q3: 0.62 - 2.6) and 0.9 months (Q1-Q3: 0.4 - 2.1) for LOT-1, -2 and -3, respectively. The most frequently used treatment regimens at LOT-1 were the Hyper-CVAD (22.9%), BFM (20.0%) and GRAAL (15.7%). The most reported reasons for patients discontinuing their regimen in LOT-1 were progression of disease (37.5%), followed by adverse events (25%). For LOT-2 discontinuation, adverse events and/or toxicity (33.3%) were most frequently reported, followed by progression of the disease (25%). Of the total number of R/R ALL patients, 26 (36.6%) underwent stem cell transplantation (SCT), with a median time from diagnosis to transplantation of 9.6 months. All those patients (n=26) received allogeneic hematological SCT (100%), and haploidentical donors were most common (42.3%), followed by identical (matched) related (34.6%), mismatched unrelated donor (15.4%), and identical (matched) unrelated donors (7.7%). For R/R ALL patients, the median overall survival (mOS) was 18.96 months, with a probability of survival of 66.6% at 1 year, 32.3% at 3 years, and 16.2% at 5 years. Philadelphia Chromosome (Ph) molecular results were reported in 53 patients: 38 (71.7%) were Ph- and 15 (28.3%) were Ph+. The mOS in Ph+ patients was 31.5 months, numerically longer than the 17.7 months seen in Ph- patients (p = 0.500); however, the Kaplan-Meiers crossed over and separation was not clearly evident within the follow-up period (Figure 1). Conclusions: This study enabled a better understanding of R/R ALL in LA in the real-world. Data from this study demonstrate the high heterogenicity within first salvage (LOT-1) treatment patterns in R/R ALL, likely due to no established single standard of care in the region and highlights that only a fraction of the patients undergo SCT, which should be the treatment goal following induction therapy. In addition, our study reinforces already published data that overall survival on R/R ALL adult patients remain poor. Consistent guidelines and access to new treatments and are needed to remove inequalities in the management of ALL in LA.

Improved Survival with Venetoclax in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Cohort Study

Background: Venetoclax in combination with azacitidine or low-dose cytarabine has become standard treatment for newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML). Since approval of venetoclax in 2020 in Japan, venetoclax combination therapy have been also used for relapsed or refractory patients although its role in relapsed or refractory disease is not well defined. The survival impact of chemotherapy with venetoclax combination therapy compared with that without venetoclax combination therapy on AML patients in a real-life setting is scarcely reported. Objective: The aim of this retrospective study was to evaluate chemotherapy with or without venetoclax combination therapy in patients with newly diagnosed AML in our institution. Patients and Methods: This study included 234 non-M3 newly diagnosed AML patients who were treated with or without venetoclax combination therapy between February 2008 and July 2023 in our hospital. We evaluated overall survival and composite complete remission (complete remission or complete remission with incomplete hematologic recovery). Overall survival was compared with the use of a cox proportional-hazards regression model adjusted for age (1-year increase) and cytogenetic risk (favorable or intermediate vs. adverse). Composite complete remission was compared between the treatment groups with the use of a logistic regression model adjusted for the same prognostic factors. Subgroup analyses of overall survival was performed according to variables based on disease characteristics at baseline to assess whether the beneficial effect of venetoclax combination therapy varied among specific patient subgroups. Results: We identified 41 patients who were treated with venetoclax as first-line or later treatment and 193 patients who were treated without venetoclax. In the venetoclax group, 26 (63.4%) received venetoclax combination therapy as first-line and 15 (36.6%) as second- or later-line treatement. Twenty (48.8%) were treated with venetoclax combined with azacitidine, 12 (29.3%) with low-dose cytarabine and 9 (22.0%) with both in their course of treatment. Patients in the venetoclax group was older than those in the non-venetoclax group (median age, 76 years vs. 67 years, respectively; P<0.001). FLT3, NPM1, TP53 and IDH1/2 mutational status was comparable between groups. The percentage of patients classified as poor cytogenetic risk category according to the NCCN guidelines for AML, 2021 was higher in the venetoclax group than that in the non-venetoclax group (51.2% vs. 28.0%, respectively; P=0.005). The percentage of patients who umderwent allogeneic hematopoietic stem cell transplantation was lower in the venetoclax group than that in the non-venetoclax group (2.4% vs. 16.6%, respectively; P=0.014). Composite complete remission was achieved in 46.3% (95% CI, 30.7 to 62.6) of the patients in the venetoclax group and 54.4% (95% CI, 47.1 to 61.6) of the patients in the non-venetoclax group (P=0.199). In a Cox model adjusting for age and cytogenetic risk, the 1-year overall survival rate was 79.4% (95% confidence interval [CI], 66.5 to 87.8) in the venetoclax group, as compared with 68.0% (95% CI, 59.6 to 75.0) in the non-venetoclax group (adjusted hazard ratio, 0.64; 95% CI, 0.41 to 1.00; P=0.049). Subgroup analysis of overall survival showed a greater survival benefit in the venetoclax group than in the non-venetoclax group in patients who were 70 years of age or older (P=0.003 for interaction) and in patients with de novo AML (P=0.022 for interaction) after adjustment for age and cytogenetic risk. Conclusions: These real-world data suggested that incorporation of venetoclax combination therapy into existing therapies improved survival in patients with AML. The survival benefit of venetoclax combination therapy was greater in elderly patient and in de novo AML patients than secondary AML patients. Interpretation of the results must be careful because the sample size in the venetoclax group was small. To confirm our findings, further investigation in a larger patient population is required.

Reduced-Dose Chemotherapy Followed By Blinatumomab As Induction Therapy in Treatment of Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia - Interim Results from a Multicenter, Single-Arm, Phase 2 Study

Introduction: Although intensive pediatric chemotherapeutic regimens have shown good efficacy in the treatment of Philadelphia Chromosome-negative (Ph-negative) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults, the high incidence of chemotherapy-related toxicities limits their use. Blinatumomab, a CD3/CD19 bispecific T-cell antibody, has shown high efficacy in relapsed/refractory or minimal residual disease (MRD) positive BCP-ALL; however, the efficacy of single-agent blinatumomab does not meet the treatment needs of adult patients. Therefore, combining low-intensity chemotherapy with blinatumomab could be a better induction regimen for newly diagnosed adult patients with BCP-ALL. Methods: This multicenter, single-arm, phase 2 trial (NCT05557110) enrolled adult patients (aged 15-59 years) with newly diagnosed Ph-negative BCP-ALL. The induction regimen comprised reduced intensity chemotherapy (idarubicin 8 mg/m 2 on day 1, vindesine 4 mg on day 1, and dexamethasone 9 mg/m 2/day from day 1-7) followed by 2 weeks of blinatumomab (9 ug/day from day 8-14, 28 ug/day from day 15-21). The primary endpoint was to assess the overall response rate (ORR=complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]) of this induction regimen. Secondary endpoints were MRD negativity (<1x10 -4 by flow cytometry), event-free survival (EFS), overall survival (OS) and safety. Bone marrow evaluation and one intrathecal injection chemotherapy were performed on day 22±2. Patients not achieving ORR continued blinatumomab for another 2 weeks (28 ug/day from day 1-14), followed by bone marrow re-evaluation. Consolidation therapy was given after achieving ORR with recommended multidrug combination chemotherapy (including high-dose methotrexate or cytarabine combined with asparaginase) or alternating with blinatumomab (28 ug/day for 28 days). If allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not performed, consolidation therapy needs at least 4 courses before 2 years of maintenance therapy. Results: Interim results are presented here.By July 6, 2023 (data cut-off), 25 patients were enrolled with a median age of 42 years (range: 15-53); 68% were females. The Eastern Cooperative Oncology Group Performance Status score ranged from 0-1. Eight (32.0%) patients had poor cytogenetic risk factors, including 3 with P2RY8::CRLF2, 2 with hypodiploidy, 2 with KMT2A rearranged and 1 with alterations of IKZF1 (Table 1). The bone marrow evaluation done in 19 patients on day 8 prior to blinatumomab treatment showed that none of the patients had got ORR. All 21 (100%) patients evaluable for the primary endpoint attained CR/Cri - 19 at the end of 2 weeks of blinatumomab and the remaining 2 after another 2 weeks of blinatumomab (Table 2). The MRD negativity rate was 90.5% (19/21) after 2 weeks of blinatumomab which increased to 95.5% (20/21) after another 2 weeks of treatment with blinatumomab. In 21 patients evaluated for safety, blinatumomab-related cytokine release syndrome was reported in 10 (47.6%) patients (grade 1: n=6, grade 2: n=3 and grade 3: n=1). No incidence of neurotoxicity was reported. Febrile neutropenia was reported in 4 (19%) patients (all ≥grade 3). The non-hematological AEs reported were fever in 7 (33.3%) patients (any grade), increased ALT in 10 (47.6%) patients (any grade) and infections in 4 (19%) patients, including pneumonia in 2 and sepsis in 2 (all ≥grade 3). The median duration of neutrophil deficiency (<0.5×10 9/L) and platelet deficiency (<20×10 9/L) during induction therapy was 9 days (range: 0-20) and 1 day (range: 0-18), respectively. The median follow-up time was 4 months and no relapse or leukemia-related deaths were observed. The median EFS and OS were not yet reached. All enrolled patients are alive except one who died of infection after multidrug combination consolidation chemotherapy. The median cycles for consolidation were 2 (range: 1-5) with 3 patients undergoing allo-HSCT. Conclusion: Thesepreliminary results indicate that the reduced intensity chemotherapy followed by blinatumomab is an effective regimen in adults with newly diagnosed Ph-negative BCP-ALL, resulting in favorable response rates, deep remission, and low-grade treatment-related AEs. These promising findings may provide a rationale for integrating blinatumomab into future induction therapy recommendations.

Prognostic Impact of Conditioning Intensity on Outcomes after Allogeneic Transplantation for MDS with Low Blasts

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). The blast percentage in MDS is one of the important factors to utilize allo-HSCT, and the other disease-related factors, such as transfusion dependency and chromosomal risk, are crucial to consider whether patients harboring MDS with less than 5% of marrow blasts (MDS-Lo) undergo to allo-HSCT. However, the prognostic impacts of conditioning intensity in MDS-Lo patients are still unclear. We here conducted a nationwide retrospective study to clarify the prognostic factor and investigate the optimal conditioning intensity for MDS-Lo. Methods In this study, patients diagnosed as the other than refractory anemia with excess blasts (RAEB)-1 and -2 according to the WHO classification (marrow blasts <5% and peripheral blood blasts <1%) were considered to be MDS-Lo. The clinical data of 1,229 de novo MDS-Lo patients (i) who had stayed MDS-Lo from diagnosis to transplantation and (ii) who underwent their initial allo-HSCT between January 2001 and December 2020 were collected from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In a total of 1,229 patients, 651, 397, and 181 patients received myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), and non-myeloablative conditioning (NMAC) groups, respectively. The estimated 3-year OS rates were 63.3%, 61.0%, and 69.7% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CRFS rates were 41.1%, 43.9%, and 47.2% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year GRFS rates were 27.5%, 33.4%, and 35.4% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CIR were 11.9%, 14.2%, and 16.0% in MAC, RIC, and NMAC groups, respectively; and the estimated 3-year NRM were 29.8%, 31.0%, and 24.7% in MAC, RIC, and NMAC groups, respectively. The multivariate analyses revealed four factors affecting lower OS: older recipient's age (Hazard ratio (HR) [95% confidential interval], 1.70 [1.28-2.24]; P<0.001 for 40-59 years)(HR, 2.32 [1.71-3.15]; P<0.001 for 60 years or older), performance status 2-4 at HSCT (HR, 1.84 [1.32-2.57]; P<0.001), the history of infection before HSCT (HR, 2.12 [1.55-2.89]; P<0.001), and high number of red blood cell (RBC) transfusion before HSCT (HR, 1.65 [1.35-2.02]; P<0.001). These factors also negatively affected CRFS, GRFS, and NRM. In addition, poor cytogenetic risk group was associated with worse OS (HR, 1.66 [1.32-2.09]; P<0.001), CRFS (HR, 1.48 [1.22-1.80]; P<0.001), and GRFS (HR, 1.36 [1.14-1.64]; P=0.001) but not CIR. There was no significant difference of OS, CRFS, GRFS, CIR, and NRM in either RIC or NMAC group compared to MAC group. We next performed the subgroups analysis based on the prognostic factors. The subgroup analysis for the comparison between MAC and RIC regimens showed the better OS of MAC regimen among patients with low number of RBC transfusion (HR, 1.33 [1.01-1,75]; P=0.039). The subgroup analysis for the comparison between RIC and NMAC regimens revealed the better OS of NAMC regimen among patients aged <40 years (HR, 0.43 [0.19-0.96]; P=0.038), no history of infection (HR, 0.67 [0.50-0.91]; P=0.009), and good cytogenetic risk (HR, 0.54 [0.38-0.83]; P=0.004). Conclusion This study showed the prognostic factors on the post-transplant outcomes among MDS-Lo patients, and no significant difference of conditioning intensity in the entire population. Furthermore, we found the factors (the number of RBC transfusion, patient's age, the history of infection, and cytogenetic risk) potentially affecting the selection of conditioning intensity. These findings would improve the management for transplant candidates with MDS-Lo.

Clinical Outcomes and Cardiovascular Adverse Events of Patients with Acute Myeloid Leukemia Treated with Venetoclax Plus a Hypomethylating Agent or Low-Dose Cytarabine in the Veterans Health Administration: A National Retrospective Cohort Study

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a median age at diagnosis of 68 years. Standard curative treatment consists of intensive induction chemotherapy followed by consolidation, allogeneic stem-cell transplantation, or both. However, older patients may be ineligible for intensive chemotherapy due to impaired performance status or significant comorbidities. For those medically unfit, the combination of venetoclax plus a hypomethylating agent (VEN + HMA) can be used based on the results of the phase 3 VIALE-A clinical trial (PMID: 32786187). With a median follow-up of 20.5 months, azacitidine-venetoclax achieved superior OS than azacitidine monotherapy (14.7 versus 9.6 months; HR 0.66; 95% CI 0.52-0.85; P<0.001). The only cardiac event reported was atrial fibrillation in 5% of patients. Our retrospective study explores real-world clinical outcomes and new cardiovascular adverse events of patients treated with venetoclax plus either azacitidine, decitabine, or LDAC (VEN + LDAC) in the Veterans Health Administration (VHA). Methods Medical records of 198 veterans who were patients in the VHA and treated with VEN + HMA or VEN + LDAC between January 1, 2016, and December 31, 2021, were randomly selected and reviewed. Patients with a diagnosis of AML who received front-line therapy were included. Patients with acute promyelocytic leukemia were excluded. Overall survival (OS) was defined as the period between the date of diagnosis and the date of death from any cause and was estimated using the Kaplan-Meier method. Cardiovascular adverse events were characterized as those that occurred from the first dose until 30 days after discontinuation of treatment. Results A total of 101 patients were included. The median age at diagnosis was 74 years, 98% were male, 48% presented with de novo AML, 64% had an Eastern Cooperative Oncology Group performance-status score ≤ 1, and 52% had poor cytogenetic risk according to the European LeukemiaNet (ELN) 2017 stratification. Azacitidine was used in 62% of patients, decitabine in 34%, and LDAC in 4%. Based on the common terminology criteria for adverse events (CTCAE) version 5, 28% of the cohort had grade ≥3 (≥G3) anemia, 36% ≥G3 thrombocytopenia, and 62% ≥G3 neutropenia. The median OS was 8.5 months (95% CI:6.4-12.3). Those who received azacitidine had an OS of 7.7 months (95% CI: 5.6 - 12.4) versus 10.7 with decitabine (5.3 - 19.9), however the difference was not significant (p=0.29). Twenty-five percent of patients experienced at least one new cardiovascular adverse event. Of those, 11% already had a cardiovascular comorbidity at baseline. The most common adverse events were atrial fibrillation in 9%, non-ST elevation myocardial infarction in 4%, cardiopulmonary arrest in 3%, cardiogenic pulmonary edema in 2%, and LVEF decrease in 2%. Conclusion This is the first study to analyze the OS and the array of new cardiovascular events of patients with AML treated with VEN + HMA or VEN + LDAC in the VHA. Our national retrospective cohort study showed an inferior median OS and more new adverse cardiovascular events in patients treated with VEN + HMA than what was seen in the VIALE-A study. This is likely due to the clinical design of the phase 3 trial. Furthermore, we had a higher percentage of patients with secondary AML and poor cytogenetic risk which are known adverse prognostic factors. The limitations of this study include its retrospective and observational nature with data that was created for patient care, not research, and might contain missing information. Besides, the VHA sites are exclusively located in the United States and the cohort is mainly composed of male patients which is not fully applicable to the general population. Further studies are needed to determine the real-world OS and profile of cardiovascular adverse events of venetoclax combination therapy.

Early Results Indicate Acceptable Safety and Promising Efficacy of Venetoclax in Combination with Pola-R-CHP for Untreated High-Risk BCL-2-Positive B-Cell Lymphoma Including Double/Triple Hit Lymphoma

Background: The Phase II CAVALLI study assessed the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven; 800mg for 10 days [Ds]) + rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisolone (P; R-CHOP), for first line treatment of diffuse large B-cell lymphoma (DLBCL). The end of treatment (EOT) complete response (CR) rate was 64% in patients (pts) with BCL-2 overexpression by immunohistochemistry (BCL-2 IHC+); there was a 2-year progression-free survival (PFS) benefit compared with R-CHOP (GOYA trial; 78% vs 62%); but a higher incidence of Grade (Gr) 3/4 adverse events (AEs; 86% vs 66%, respectively; Morschhauser et al. Blood 2021). In the Phase III POLARIX study, polatuzumab vedotin (Pola)-R-CHP had a prolonged PFS vs R-CHOP, establishing Pola-R-CHP as standard of care for untreated DLBCL (Tilly et al. N Engl J Med 2022; Morschhauser et al. EHA 2022). Thus, we explored whether adding Ven to Pola-R-CHP could further improve outcomes in BCL-2 IHC+ DLBCL. Here, we report early safety and efficacy results from a Phase Ib study (BO42203; NCT04790903), evaluating the optimal dose/schedule of Ven+Pola-R-CHP. Methods: BO42203 is an ongoing open-label, multicenter study of pts with untreated BCL-2 IHC+ DLBCL (including Grade 3b follicular lymphoma). Pts enrolled had an International Prognostic Index (IPI) of 2-5, and BCL-2 IHC+ defined as ≥50% expression (by local pathology). The primary endpoint is to determine the recommended Phase II dose (RP2D) for Ven+Pola R-CHP based on the rate of dose-limiting toxicity (DLT) during the first 2 cycles (42 Ds), with tolerability assessed by dose modifications/delays and discontinuation. Secondary endpoints include percentage of pts with AEs, and PET-based response rates/duration. Pts are enrolled in 5 cohorts (n=10 pts each). Safety data are reviewed by an internal monitoring committee (IMC) who can alter the Ven dose/schedule for the next cohort. Pts receive 6 21-D cycles of treatment. Pola-R-CHP is administered on D1 of each cycle at the following doses: Pola 1.8mg/kg, R 375mg/m 2, C 750mg/m 2, H 50mg/m 2, and P 100mg/D for 5 Ds. All pts in Cohort 1 were assigned to Ven 800mg/D for 5 Ds/cycle; doses start on D4 of Cycle 1 and D1 of subsequent cycles (Schedule A) with optional escalation to 10 Ds/cycle from Cohort 2 onwards (Schedule B), depending on IMC assessment. Results: At the time of analysis (data cutoff: May 2, 2023), 4 cohorts were enrolled (n=40). At baseline, the median age was 64.0 years, 14 (35.0%) pts were female, and 5 (12.5%) had an Eastern Cooperative Oncology Group performance status of 2. Thirty-six (90.0%) pts had Ann Arbor Stage III-IV; 30 (75.0%) had an IPI score of ≥3; and 10 (25.0%) had poor risk cytogenetics (double/triple hit lymphoma [DHL/THL]). Thirty-eight pts have completed the DLT period; 2 pts withdrew prior to this due to meningitis and a COVID-related AE. No DLTs have been observed. Gr ≥3 myelosuppression was observed in Cohort 1 after the DLT period: neutropenia (n=5 pts [50.0%]), neutrophil count decreased (n=2 [20.0%]), and febrile neutropenia (n=1 [10.0%]). Hence, after IMC review of Cohorts 1-3 it was decided that Schedule A will be maintained/received by all future pts, as the benefit-risk of increasing the Ven schedule may not be favorable. Safety and efficacy analyses were performed on Cohorts 1-3 (n=30) as they have reached the EOT. All pts had ≥1 AE; 21 (70.0%) and 11 (36.7%) pts had at least one Gr ≥3 AE ( Table) and serious AE (SAE), respectively; 2 (6.7%) pts died due to treatment-related SAEs (investigator-assessed; sudden cardiac death [related to Ven] and sepsis [related to Ven+Pola-R-CHP]). AEs leading to dose modification/delay of any drug occurred in 11 (36.7%; 23 events) pts; 21 (91.3%) AEs led to Ven modification in 10 pts (33.3%); and 3 (10.0%) pts had an AE that led to discontinuation of any study drug. Response was evaluated in 30 pts, with an EOT PET-CT based objective response rate and CR of 86.7% (n=26; including all pts with DHL/THL [n=8; CR: 100%]); 1 pt had progressive disease [PD], and 3 were not assessed due to death (n=2) and early discontinuation (n=1; Figure). Three (10.0%) pts died due to PD. Conclusions: Ven 800mg/D for 5 Ds/cycle + Pola-R-CHP has been determined as the RP2D; early results show acceptable safety and promising efficacy for untreated BCL-2 IHC+ DLBCL. High CR rates were observed across all cohorts at EOT, including pts with DHL/THL. Updated results, including circulating tumor DNA, will be presented.

Inb-100: A Pilot Study of Donor Derived, Ex-Vivo Expanded/Activated Gamma-Delta T Cell (EAGD) Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-Transplant Cyclophosphamide (PTCy)

Background: Gamma-delta (gd) T cells are MHC unrestricted lymphocytes that recognize and lyse malignant cells in allogeneic settings. Although haploidentical transplant with PTCy has reduced the risk of graft-versus-host disease (GvHD); the incidence of relapse remains up to 50% at year 1. Early post-transplant infusion of haploidentical EAGD cells may decrease relapse risk through a graft-versus-leukemia (GvL) effect without severe GvHD. We present updated clinical and correlative data from our Phase I trial using our recommended phase 2 dose (RP2D). Methods: Adults with newly diagnosed or relapsed ALL, CML, AML undergoing first haploidentical transplant with reduced-intensity flu/cy/TBI conditioning received EAGD intravenously within 7 days of neutrophil engraftment. Peripheral blood was collected at EAGD infusion and monthly through day 90, with additional collections every 6 months through 1 year. Primary endpoints include dose-limiting toxicities (DLT), grade (G) 3-4 adverse events including GvHD with secondary endpoints of relapse and overall survival. Biologic parameters included multiparameter flow cytometric immunophenotyping and additional serum cytokine analysis using the Olink ® 48 target panel. Results: 14 subjects were enrolled with 4 treated at Dose Level (DL) 1 of 1 x 10 6 EAGD/kg and 6 subjects treated at the RP2D of DL2 (3 x 10 6 EAGD/kg). Untreated subjects included: One screen failure, a manufacturing failure, one subject who died prior to dosing, and one subject who received an out of study specification product. Treated subjects were 60% male, median age of 68, and primarily AML subjects in CR1. RP2D was defined by an acceptable toxicity profile, no DLT's, prolonged RFS and elevated gd levels. Peripheral lymphodepletion persisted through the first 100 days post-BMT followed by T cell recovery from a CD45+CD27-effector phenotype to central and effector memory phenotype. Notably, DL2 showed significant increases in gd T cell count recovery at days 60, 100 and 180 post-BMT vs. DL1 and historically untreated Haplo/PTCy patients, p = <0.05. NK cells remained within the low normal range and <3% of circulating T cells were Tregs. Preliminary serum cytokine analysis revealed elevated IL-6 and IL-15 in serum post- transplant prior to EAGD infusion, but dropped to normal median levels at day 60, 20-30 days after EAGD infusion. One subject received intermittent hypomethylating therapy for emergence of recipient chimerism. Treatment emergent AE's included transient WBC and ANC decreases (100% each), platelet count decrease and anemia (88.9% each) and maculopapular rash, hypomagnesemia and blood creatine increased (55.6% each). EAGD related toxicities were primarily G1-2, included G1-2 skin acute GvHD and gastrointestinal GvHD, and one case of G3 platelet count decrease. Treatment related serious AE's of G3 nausea and G2 rash were reported. No DLTs, neurotoxicity, cytokine release syndrome or treatment related deaths were reported. Conclusions: Post-BMT infusion of donor-derived, EAGD cells has demonstrated manageable safety with no infusional toxicity or ≥G3 acute GvHD or extensive chronic GvHD. Durable relapse free survival at a maximum of >3 years in subjects with poor risk cytogenetics and adverse clinical risk factors combined with ongoing homeostatic reconstitution of increasing gd T cell effectors post-BMT suggests this therapy may be an effective measure in mitigating relapse after HaploBMT. NCT03533816

Allogeneic Stem Cell Transplantation with Myeloablative Compared with Reduced- Intensity Conditioning for AML and Mds; 20 Years Later

Background. Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) regimens is effective therapyin AML and MDS. However, the relative merits of each may differin different settings and at different time-points after SCT. We have previously reported on the role of dose intensity in a group of 112 patients with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). At that time we showed that MAC was associated with lower relapse rate, higher non-relapse mortality (NRM) and similar overall survival (OS) as RIC. MAC was associated with survival advantage in patients with active leukemia at SCT. There is paucity of data on the comparison of these 2 approaches very late after SCT (beyond 20 years). Methods. We have now updated SCT outcomes in the same cohort with a median follow up of 20 years (range, 15-22) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. Updated follow-up is available for all but one patient. Results. The median age at SCT was50 years (18-70). Eighty-five patients had AML and 17 had MDS (IPSS int2 or high). Fifty-eight hadactive disease at SCT (>10% marrow blasts) and 54 were inremission. The donor was HLA-matched sibling (n=58), 1-Ag mismatchedrelated (n=6) or matched-unrelated (n=48). Twenty-nine patients (26%) had poor risk cytogenetics. Forty-five patients meteligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide(BuCy). Sixty-seven patients were considered non-eligible for standardMAC and were given RIC with fludarabineand ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative dosesof ivBu (12.8 mg/kg, FB4, n=26). The medianage of RIC, RTC and MAC recipients was 57, 51 and 42 years at transplantation, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelateddonors (p=0.01). In all, 31 patientsare alive and 81 have died, 50 of relapse and 31 of NRM.The median age at last follow-up was 66 years (35-81). The 20-year OS rate was 29% (20-37). The rate was 40% (26-54), 19% (7-31) and 19% (7-31) after BuCy, FB4 and FB2, respectively (P=0.19). The 20-year NRM was 29% (18-45), 27% (14-51) and 27% (16-45) respectively (Figure 1, P=0.94). The 20-year relapse mortality was 31% (20-48), 54% (38-77) and 54% (40-71), respectively (Figure 2, P=0.12). Five patients with relapse in the first 5 years are very long-term survivors with no recurrent disease following additional treatments. Forty patients were alive and disease-free 5 years after SCT with a 5-year OS of 42% (33-51). Fourteen patients died beyond 5 years, 3 from late relapse (6.6 -11.8 months after SCT) and 11 due to NRM. The causes of late NRM were second malignancies (n=6), cardiovascular disease (n=3), pulmonary disease (n=1) and liver disease (n=1). The risk of late NRM was 17% (6-47), 25% (7-83) and 44% (24-81) after BuCy, FB4 and FB2, respectively (P=0.29). The risk of late NRM was 14% (4-52) and 35% (21-59) in patients younger and older than 55 years at SCT, respectively (P=0.18). Late relapse mortality was low; 6 (8-37), 13% (2-78) and 7% (1-5), respectively (P=0.81). In all, the subsequent 15-year OS in those who were alive and disease-free 5-years after SCT was 78% (59-97), 63% (29-96) and 49% (22-76), respectively. The small number of events did not allow a meaningful multivariate analysis. Conclusions. With a long-term follow-up of 20 years, RIC/RTC is an acceptable alternative to MAC in ineligible patients. NRM is lower after RIC in the early post SCT period, but late NRM negates this early advantage and at longer follow-up there is no difference between the regimens. Relapse after RIC is higher at the first 5 years after SCT. However, late relapses beyond 5 years from SCT are rare after all regimens. In all, the very long-term OS is better after MAC. However, older age at SCT for RIC may be a major cause of these observations. Longer follow up of randomized studies is needed for more definite conclusions.

Tagraxofusp in Combination with Azacitidine and Venetoclax in Newly Diagnosed CD123+ Acute Myeloid Leukemia, Expansion Cohort of a Phase 1b Multicenter Trial

Background: CD123 is a subunit of the interleukin 3 (IL3) receptor expressed on the surface of blasts in most acute myeloid leukemias (AMLs). Tagraxofusp (TAG), a CD123-directed therapy, is a recombinant protein drug consisting of IL3 fused to a truncated diphtheria toxin payload approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We found TAG resistance in AML cells was mediated by DNA methylation and silencing of diphthamide genes (e.g., DPH1), which causes resistance to diphtheria toxin (Togami, JCI 2019). The hypomethylating agent azacitidine (AZA) reversed TAG resistance, and TAG plus AZA prolonged survival vs. either alone in xenograft models. TAG-exposed AML cells were also sensitized to the BCL2 inhibitor venetoclax (VEN). We performed a phase 1b trial combining these agents in myeloid malignancies and reported acceptable safety in dose escalation of TAG with AZA-VEN (ASH 2021). Here, we report an expansion cohort in newly diagnosed AML treated with TAG-AZA-VEN. Methods: Patients (pts) were adults with AML ineligible or declining intensive induction chemotherapy. CD123+ blasts were required (tested locally by flow or IHC, any level). Eligibility included albumin >3.2 g/dL and normal cardiac ejection fraction. Pts were treated on 28-day cycles with AZA 75 mg/m2 d1-7, VEN 400 mg d1-21 with ramp up in cycle 1, and TAG 12 µg/kg d4-6 ( Fig A), with cycle 1 hospitalization to mitigate risks of capillary leak syndrome (CLS). Also included are 3 pts who received TAG 7 µg/kg (n=2) or 9 µg/kg (n=1) in escalation. TAG was given on d4 to avoid VEN ramp up overlap and because preclinical data showed AZA pretreatment can sensitize AML cells to TAG. Results: 26 pts with AML were treated; median age 71 (range 60-81). All were adverse risk per ELN 2022 criteria, including 13 (50%) with a mutation in TP53 and others with 1 or more of ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, or U2AF1. Eight (31%) had complex karyotype, 8 (31%) secondary AML, and 5 (19%) therapy-related AML. Adverse events (AEs) were like those seen with TAG or AZA/VEN, without evidence of exacerbation by combination. Grade 3+ AEs occurring in >15% of pts regardless of attribution included thrombocytopenia (54%), leukopenia (54%), febrile neutropenia (35%), and anemia (31%). CLS, a known TAG side effect, occurred in 19% (n=5; three grade 2, one gr 3, one gr 4; all in cycle 1) and was manageable by albumin supplementation and diuresis. Mortality at 30 days was 11.5%, with causes of death of sepsis (n=2), multiorgan system failure (n=1). 18 of 26 pts (69%) achieved a best response of CR (10; 39%), CRi (5; 19%), or MLFS (3; 12%). Of the 13 with TP53 mutation, 7 (54%) achieved CR/CRi/MLFS (CR=4, CRi=2, or MLFS=1). Bone marrow blasts decreased in all pts who had a biopsy after starting treatment ( Fig A). For the 18 achieving CR/CRi/MLFS, the median duration of response was 12.4 months (mo) (95% CI, 6.1-NA). 13 of 26 (50%) proceeded to allogeneic stem cell transplantation, which included 6/13 (46%) with TP53 mutation. The median number of cycles was 3 for both pts who did (range 1-15) and did not (range 2-4) proceed to transplant. The median follow-up was 10.7 mo, including post-transplant timepoints. Median overall survival (OS) was 14 mo (95% CI, 9.5-NA) and progression-free survival (PFS) was 8.5 mo (95% CI, 5.1-NA). In pts with TP53 mutation, median OS was 9.5 mo (95% CI, 1.8-NA); and not reached (NR) without ( Fig B). PFS for pts with TP53 mutation was 5.1 mo (95% CI, 1.8-NA), and 13.3 mo (95% CI, 8.6-NA) without. Measurable residual disease (MRD) was assessed by flow cytometry in 17 pts who achieved CR/CRi/MLFS; 12/17 (71%) were MRD negative (<0.1%). 4/7 (57%) with TP53 mutation achieving CR/CRi/MLFS were MRD negative. Median OS for pts who became MRD negative was NR. Median OS for the 13 pts who received allogeneic transplant was 18.2 mo (95% CI, 14.0-NA). Median PFS for the transplanted pts was 13.3 mo (95% CI, 8.2-NA). Conclusions: Treatment of AML with triplet TAG-AZA-VEN is feasible and shows encouraging activity as up-front therapy in adverse risk AML, including in pts with TP53 mutation. These data (OS 14 mo; TP53 mutant OS 9.5 mo) compare favorably to HMA/VEN in ELN adverse risk (OS 12 mo; Lachowiez, BloodAdv 2023) or TP53 mutant AML with poor risk cytogenetics (OS 5.2 mo; Pollyea, CCR 2022), albeit with some differences between populations. No new safety signals were observed. Further development of this combination is warranted, including directly compared to AZA-VEN.

Efficacy and Safety of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naive, Higher-Risk Myelodysplastic Syndromes

Introduction: Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk myelodysplastic syndrome (HR MDS) compared to lower-intensity, conventional treatment regimens; however, improvement in clinical outcomes are needed. Clinical data on the synergy of Aza with venetoclax (Ven)-a selective, potent BCL-2 inhibitor-in the treatment of myeloid malignancies and the unmet need in HR MDS provide a rationale to evaluate Ven in combination with Aza in treatment-naive HR MDS. Here, we report efficacy and safety data in patients with treatment-naive HR MDS treated with Ven+Aza at the recommended Phase 2 dose (RP2D) in the safety expansion part of the Phase 1b study (NCT02942290). Methods: Adult patients were enrolled with de novo treatment-naive HR MDS defined by the Revised International Prognostic Scoring System (IPSS-R) score of >3 with an Eastern Cooperative Oncology Group performance status of ≤2, and bone marrow (BM) blasts <20% at baseline. Patients received Ven 400 mg orally daily on Days 1-14 and Aza 75 mg/m 2 intravenously or subcutaneously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle (RP2D). The primary objective was to assess the complete remission (CR) rate. Key secondary objectives included determining marrow CR (mCR), overall response rate (ORR), hematologic improvement (HI), postbaseline red blood cell (RBC) and platelet transfusion independence (TI), overall survival (OS), duration of CR, time to next treatment (TTNT), transformation to acute myeloid leukemia (AML), and time to AML transformation. Responses were assessed by International Working Group 2006 criteria. Prophylactic antibiotics were mandated in Cycle 1 and recommended for Grade ≥3 neutropenia thereafter. Safety was analyzed in patients who received ≥1 dose of study treatment. Results: At thedata cutoff of May 31, 2023, 107 patients had received Ven+Aza at the RP2D. Key baseline characteristics for all treated patients are shown in Table 1A. Median age was 68 years (range, 26-87), 64% of patients had intermediate or poor cytogenetic risk, and >89% had ≥5% BM blasts. Median number of treatment cycles before transplantation was 3.0 (range, 1.0-11.0). At the median follow-up of 31.9 months (95% CI, 30.4-42.5), CR rate was 29.9% (95% CI, 21.4-39.5), with a median CR duration of 16.6 months (95% CI, 10.0-not reached [NR], Table 1B). Median OS was 26 months (95% CI, 18.1-51.5), with an estimated 12-month OS of 71.2% (95% CI, 61.4-78.9)and 24-month OS of 51.3% (95% CI, 41.2-60.5). Median OS for CR was NR. Median TTNT including transplantation was 6.8 months (95% CI, 5.6-8.3). Sixty-two (57.9%) patients received subsequent treatment, including transplantation in 42 (39.3%) patients; the median time to transplantation was 4.8 months (range, 1.4-16.8). Among patients who received transplantation post-study, 17 were transplant ineligible at study entry. Postbaseline TI rate was 61.7% for RBC and 72.0% for platelets. Median maximal duration of TI achieved was 5.4 months (range, 1.8-50.8) and 5.4 months (range, 1.9-56.0) for RBC and platelets, respectively. Postbaseline overall hematologic improvement (HI) was achieved in 51 (49.0%) of 104 evaluable patients, and specific responses included erythroid (40/93; 43.0%), platelet (32/74; 43.2%) and neutrophil (10/57; 17.5%) indices. All patients experienced ≥1 treatment-emergent adverse event (TEAE), with 94.4% of patients reporting grade ≥3 TEAEs. Serious adverse events (SAEs) occurred in 68.2% of patients. Common TEAEs of any grade were constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), diarrhea (41.1%), anemia (39.3%), vomiting (36.4%), and hypokalemia (26.2%). Grade ≥3 TEAEs reported in ≥20% of patients were neutropenia (48.6%), thrombocytopenia (43.0%), febrile neutropenia (42.1%), and anemia (34.6%). Infections were reported in 57% of patients, including SAEs in 40.2% of patients. Of the 59 deaths (55.1%) reported, 23 (21.5%) were due to disease progression and 7 (6.5%) to adverse events. Within 60 days after study start, 7 deaths (6.5%) were reported. Conclusion: Ven 400 mg for 14 days plus Aza combination was well tolerated with favorable responses of CR+PR+mCR in >80% and HI in nearly 50% of patients with treatment-naïve HR MDS. A separate Phase 3 study of this combination is ongoing to confirm survival benefit.

Outcomes in Chemotherapy-Ineligible Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Plus Azacitidine: A Pooled Analysis

Introduction: Elderly patients (aged ≥75 years), with newly diagnosed acute myeloid leukemia (ND AML) frequently are ineligible to receive intensive chemotherapy (IC) and therefore have limited treatment options. The BCL-2 inhibitor venetoclax (Ven) in combination with azacitidine (Aza) was approved for the treatment of patients with ND AML who are ineligible for IC due to age or comorbidities based on the phase 3 VIALE-A trial. Treatment with Ven+Aza demonstrated rapid and durable remissions, with improved median overall survival (OS) versus placebo (Pbo)+Aza (14.7 vs 9.6 mo; hazard ratio [HR] 0.64) in patients enrolled in the VIALE-A trial (median age, 76 years). Although a subgroup analysis showed improvement in patients aged ≥75 years (HR 0.54; DiNardo C, et al. N Engl J Med. 2020;383:617), detailed analyses are lacking to further understand the impact of advanced patient age on the safety and efficacy of Ven+Aza. Here, we evaluate the outcomes of Ven+Aza across elderly age cohorts in patients with ND AML pooled from the open-label, single-arm, Phase 1b M14-358 trial of Ven plus hypomethylating agents in patients with ND AML who were ≥65 years old and IC-ineligible (NCT02203773) and the Phase 3 VIALE-A trial of Ven+Aza versus Pbo+Aza in patients with ND AML who were IC-ineligible (NCT02993523). Methods: This analysis included IC-ineligible patients aged ≥75 years with ND AML pooled from the Ven+Aza arm of the M14-358 trial (NCT02203773) and the Ven+Aza and Pbo+Aza arms of the VIALE-A trial (NCT02993523). In both studies, patients received Ven daily (400 mg) with 75 mg/m 2 subcutaneous (SC) or intravenous (IV) Aza on Days 1-7 of 28-day cycles). In VIALE-A, patients were randomized 2:1 to Ven+Aza or Pbo+Aza and received Ven (400 mg) or Pbo daily with Aza at the same schedule. For this post hoc analysis, patients were stratified by age (75-79 years, 80-84 years, and ≥85 years) to evaluate efficacy and safety, including complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate, minimal residual disease (MRD) response (<10 -3) rate, OS, and Grade ≥3 treatment-emergent adverse events (TEAEs). Results: A total of 216 patients treated with Ven+Aza and 87 patients treated with Pbo+Aza were included, with n=120 and n=54 aged 75-79 years, n=75 and n=27 aged 80-84 years, and n=21 and n=6 aged ≥85 years ( Table 1). Baseline disease characteristics were largely similar across age cohorts, including ECOG performance status and poor cytogenetic risk ( Table 1). Baseline grade 3/4 neutropenia was more prevalent in patients aged ≥85 years. Across the 75-79, 80-84, and ≥85 age cohorts, the CR/CRi rate was higher with Ven+Aza (67%, 68%, and 81%) vs Pbo+Aza (19%, 22%, and 17%) ( Table 1). Ven+Aza also elicited a higher rate of MRD response (<10 -3;30%, 29%, and 29%) vs Pbo+Aza (13%, 11%, and 17%). Median OS (95% CI) was 14.1 mo (10.2-24.9) for those aged 75-79 years, 12.2 mo (8.0-21.8) for those aged 80-84 years, and 16.2 mo (9.3-20.5) for those aged ≥85 years in the Ven+Aza arm; in the Pbo+Aza arm, median OS (95% CI) was 8.5 mo (6.8-10.7), 10.1 mo (2.3-14.5), and 2.6 mo (0.2-not reached), respectively. In the Ven+Aza arm, median Ven dosing per cycle was 21 days across all age cohorts, with a median time from Day 1 of a cycle until Day 1 of the next cycle (including dose holds), of 31, 35, and 31 days for the 75-79, 80-84, and ≥85 age cohorts, respectively. Rates of Grade ≥3 non-hematologic TEAEs were similar between age cohorts ( Table 2). Consistent with the known safety profile of Ven+Aza, the most frequently reported hematologic TEAEs for the 75-79, 80-84, and ≥85 age cohorts included anemia (30%, 26%, and 48%), febrile neutropenia (43%, 38%, and 52%), neutropenia (34%, 37%, and 29%), and thrombocytopenia (36%, 48%, and 43%). Conclusions: Ven+Aza led to higher rates of remission, including higher rates of MRD response, and longer median OS vs Pbo+Aza, while maintaining consistent safety data across all older patient cohorts (Table 1). Findings were consistent with data from the overall population in VIALE-A (median age of 76 years), emphasizing the benefit of Ven+Aza in the older population. Although the post hoc nature of the analysis and limited sample sizes require careful interpretation of differences between cohorts, these findings confirm Ven+Aza provides benefit across elderly patient cohorts with ND AML who are ineligible for IC.

AK117 (anti-CD47 monoclonal antibody) in Combination with Azacitidine for Newly Diagnosed Higher Risk Myelodysplastic Syndrome (HR-MDS): AK117-103 Phase 1b Results

Background: CD47, an immune checkpoint overexpressed by tumor cells, plays a crucial role in evading the antitumor immune response. AK117, an IgG4 monoclonal antibody (mAb) targeting CD47, has emerged as a potential best-in-class therapy with high affinity binding to CD47 and without inducing hemagglutination effects. By blocking CD47, AK117 effectively triggers macrophage-mediated phagocytosis of hematological malignancy cells, and in combination with azacitidine (AZA), it synergistically enhances the activation of “eat me” signals. In this study, we present the Phase 1b data from the AK117-103 study conducted in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS). Methods: Eligible patients with newly diagnosed intermediate/high/very high-risk MDS, determined by the Revised International Prognostic Scoring System (IPSS-R) prognostic risk score >3, were enrolled to receive combination therapy with AK117 and AZA. AK117 was administered intravenously (IV) following various dosing regimens (20-30 mg/kg once weekly [QW], or 20-45 mg/kg every 2 weeks [Q2W], or 30 mg/kg every 4 weeks [Q4W]), whereas AZA was administered subcutaneously (SC) at the standard dosage (75 mg/m 2, Day 1-7, Q4W). The primary endpoints of this study were safety/tolerability and the complete remission (CR) rate based on the International Working Group (IWG) 2006 response criteria. Results: As of June 9, 2023, 72 patients were enrolled (median age: 66 years, 69.4% males). Most patients exhibited abnormal hematologic conditions at baseline, including decreased hemoglobin, neutrophil count, and platelet count. Specifically, 69.4% of patients had Grade ≥3 anemia, 61.1% had Grade ≥3 neutrophil count decrease, and 47.2% had Grade ≥3 platelet count decrease. For the recommended phase 2 dose (RP2D) group, treated with a combination of AK117 30 mg/kg Q2W and AZA, 30 patients were enrolled with a median age of 67 years, 80.0% of whom were males. According to IPSS-R risk assessment, 33.3%, 23.3%, and 43.3% of patients had intermediate, high, and very high risk, respectively. 30.0% of patients had poor-risk cytogenetics, with 23.0% of those being complex. After a median follow-up of 6.6 months (ranging from 0.4-17.2 months), anemia (a primary adverse event associated with CD47 blocking antibodies) occurred in 30.6% (22/72) of the patients, of which Grade ≥ 3 anemia accounted for 22.2% (16/72). Other commonly observed treatment-emergent adverse events (TEAEs) (≥30%) included decreased neutrophil count (77.8%), decreased white blood cell count (72.2%), decreased platelet count (69.4%), pyrexia (58.3%), decreased lymphocyte count (41.7%), constipation (41.7%), and vomiting (31.9%). Three patients (4.2%) discontinued treatment due to TEAEs. The efficacy of AK117 was compared at different dosages, and ultimately, 30mg/kg Q2W was chosen as the RP2D. As of June 21, 2023, among 27 evaluable patients, the CR rate was 48.1%. 8 patients achieved marrow CR (5 also with hematologic improvement [HI]), and 2 patients achieved HI alone. Among 24 evaluable patients with ≥ 3 months follow-up, the CR rate further escalated to 54.2%. Of 13 evaluable patients who initially required red blood cells (RBC) transfusions, 8(61.5%) became independent of RBC transfusion. Conclusions: AK117 in combination with AZA was well tolerated with low incidence of anemia and demonstrated promising efficacy in patients with newly diagnosed HR-MDS.

Oral Decitabine/Cedazuridine with Venetoclax in High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Analysis By Different Response Criteria

Introduction: Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival. The standard of care for HR-MDS are hypomethylating agents (HMA). The addition of venetoclax (Ven) to HMA has been shown to improve outcomes in acute myeloid leukemia (AML) and potentially in HR-MDS. The combination of oral decitabine/cedazurridine (DEC-C) with Ven has been shown to induce high response rates in patients with HR-MDS. Herein we analyze the responses of patients treated with DEC-C with Ven according to different response criteria. Additionally, we analyze the cytogenetic responses and mutation dynamics. Methods: We analyzed patients included in a phase I/II single center clinical trial (NCT04655755). diagnosed with treatment-naïve MDS (IPSS intermediate-2 or high) or CMML with excess blasts. Responses were analyzed by the International Working Group (IWG) criteria for MDS of 2006 and 2023, as well as the European LeukemiaNet (ELN) criteria for AML (2022). Cytogenetic responses and mutations were analyzed by conventional cytogenetics/FISH and NGS, respectively. Results: Between January 2021 and January 2023, 39 patients were enrolled. The median age of the entire cohort was 71 years old (range, 27-94), with 26 (70%) male patients. The WHO 2016 diagnosis was MDS with excess-blasts 1 (n=6, 16%), MDS with excess-blasts 2 (n=24, 65%), CMML-2 (n=6, 16%) and atypical chronic myeloid leukemia (n=1, 3%). The cytogenetic risk according to IPSS was good (n=11, 30%), intermediate (n=12, 32%) and adverse (n=14, 38%). The most common mutations found were ASXL1 (n=18, 49%), RUNX1 (n=14, 38%), SRSF2 (n=11, 30%), TET2 (n=8, 22) and TP53 (n=7, 19%). According to the IWG-2006 classification, the overall response rate was 95%, with 17 (43%) patients achieving complete remission (CR) and 20 (52%) patients achieving marrow CR (mCR). When using the IWG-2023 criteria, the overall response rate was 82%, with 23 (59%) patients achieving CR and 9 (23%) achieving CR with limited count recovery/CR with partial hematologic recovery. Of note, 5 patients achieved mCR according to the IWG-2006 but did not achieved CR by the IWG-2023 due to the peripheral blood count. Moreover, we did not find differences in overall survival (OS) between CR and mCR (OS of 60% for both groups, p=0.5). When using the ELN 2022 criteria for acute myeloid leukemia, the ORR was 80% with 2 patients not responding and 2 patients in a morphologic leukemia-free status (MLFS) (Figure 1). Both IWG-2006 and 2023 define cytogenetic response as complete disappearance of chromosomal abnormalities present at diagnosis. 14 patients out of 29 (48%) with cytogenetic abnormalities achieved cytogenetic response after a median of 2 courses of treatment (1-9). The IPSS cytogenetic risk of patients responding was good in 1 (7%) patient, intermediate in 8 (57%) patients and poor in 5 (36%) patients, including 3 patients with complex karyotype. Among patients not achieving cytogenetic response, 5 (33%) and 10 (67%) patients had an intermediate and adverse IPSS cytogenetic risk, respectively. Although molecular responses are not defined in the IWG-2023, we studied the molecular dynamics between diagnosis and best response. 23 patients of the study had molecular data in paired samples at diagnosis and at CR while on treatment. When analyzing the dynamics of each individual mutation, STAG2 (11/11, 100%), NRAS (3/3, 100%), BCOR (4/5, 80%) and IDH1 (2/3, 67%) showed the higher rate of clearance from diagnosis to CR. On the contrary, ZRSR2 (3/4, 75%), U2AF1 (3/4, 75%), TP53 (3/4, 75%), SRSF2 (5/7, 71%) and ASXL1 (10/14, 71%) showed the higher rate of persistence from diagnosis to CR (Figure 2). Among all patients in the study, 19 (49%) proceeded to hematopoietic stem cell transplantation (HSCT). Eleven patients had molecular data after HSCT, all achieving complete mutation clearance after HSCT. Conclusion: DEC-C with Ven achieves a high rate of responses, although with the IWG-2023 criteria responses are lower due to the disappearance of mCR and more strict criteria in terms of peripheral blood count recovery. Almost half of patients with cytogenetic abnormalities can acquire cytogenetic responses, including poor risk cytogenetics. Subclonal mutations (like STAG2 or NRAS) can be cleared with this combination while founding mutations (like ASXL1 or TP53) tend to persist, although HSCT has a potential to eliminate them.

Pivekimab Sunirine (PVEK, IMGN632), a CD123-Targeting Antibody-Drug Conjugate, in Combination with Azacitidine and Venetoclax in Patients with Newly Diagnosed Acute Myeloid Leukemia

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; <0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in > 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, <0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

Real World Outcomes of CPX-351 Compared to Traditional Chemotherapy with Cytarabine Consolidation for Treatment of Secondary Acute Myeloid Leukemia

Introduction: Outcomes in patients with secondary AML (sAML) are inferior to those with de novo AML which has led investigators to seek alternatives to traditional treatment. Liposomal daunorubicin and cytarabine, or CPX-351, for the treatment of sAML has shown superior complete remission/complete remission with incomplete count recovery (CR/CRi), event-free survival (EFS), and overall survival (OS) compared to the traditional non-liposomal formulations of daunorubicin and cytarabine (“7+3”). However, this agent was originally studied in combination with a suboptimal consolidation regimen which did not include standard of care high dose cytarabine (HiDAC). This is often cited as a limitation of the study and may have contributed to the significantly lower response rates reported when compared to historical data. Here we present a real-world comparison of the efficacy and safety of patients with sAML receiving CPX-351 versus traditional 7+3 with HiDAC consolidation. Methods: Patients were at least 18 years of age with sAML, defined as: t-AML, AML-with Myelodysplasia-Related Changes (MRC), or AML with a history of chronic myelomonocytic leukemia (CMML). Patients were included if they had received induction (and consolidation, if applicable) with CPX-351 or induction with 7+3 (daunorubicin 60 mg/m 2 for 3 days and cytarabine 100 mg/m 2 for 7 days), followed by consolidation with cytarabine (≥1000 mg/m 2 x 6 doses). Nominal data were analyzed using chi squared tests or Fisher's exact tests. Continuous data were analyzed using the Mann-Whitney U test. A Kaplan Meier estimator was used for survival outcomes. Results: Overall, 58 patients with sAML were included, with 36 (62%) receiving CPX-351 and 22 (38%) receiving 7+3 followed by cytarabine-based consolidation between April 2013 and June 2022. Patients in the CPX-351 were older (67.5 vs 62 years, p=0.04) and had a higher prevalence of poor-risk cytogenetics (p=0.22). Other baseline characteristics were similar (Table 1). The rate of CR/CRi following induction was significantly higher in patients who received 7+3-based induction vs patients who received CPX-351 (81.8% vs 44.4%, p=0.01). Twenty-five percent of patients achieved CR/CRi in the CPX-351 arm with one induction cycle, compared to 95.5% in the 7+3 group. Median progression-free survival (PFS) was 3 vs 6.1 months (p=0.67) and median OS was 18.3 vs 9.3 months (p=0.73) in the CPX-351 and 7+3 cohorts, respectively (Figure 1). Thirty-nine percent of patients in the 7+3 cohort proceeded to allogeneic stem cell transplant compared to 81% in the CPX-351 cohort, however median OS in patients who underwent transplant was similar between the two cohorts (16.8 vs 15.8 months). Median OS was longer in the CPX-351 cohort however this was not statistically significant (Figure 1). Rates of both febrile neutropenia (94.3% vs 95.5%; P>0.99) and confirmed infections (54.3% vs 50%) were similar amongst those treated with CPX-351 and 7+3. Bacteremia and pneumonia were the most common infections in both cohorts. Median duration of neutropenia was significantly longer in the CPX-351 cohort (43 days vs. 27 days, p=0.002) with no major difference in duration of thrombocytopenia. In the 7+3 cohort, 11 deaths were directly attributed to progression, while 5 were associated with infection. In the CPX-351 cohort, 6 deaths were directly attributed to progression, while 8 were attributed to infection. At day 60, two deaths were observed in the CPX-351 cohort and there were no deaths in the 7+3 cohort. Conclusion: These findings suggest use of traditional 7+3 induction followed by HiDAC consolidation may be an alternative to CPX-351 for patients with sAML. Although median PFS was longer in the 7+3 cohort, this did not translate into longer median OS, likely due to the low rate of patients proceeding to transplant. Similar rates of overall survival in patients undergoing allogeneic stem cell transplantation support the hypothesis that transplant should be the goal for most patients with sAML. The retrospective nature of the study may limit broader application of this data.

Cytogenetic risk explored within an electronic patient reported outcomes (ePROs) remote symptom monitoring platform among patients with acute myelogenous leukemia (AML).

349 Background: Patients with AML and poor-risk cytogenetic abnormalities often have suboptimal treatment response and poor long-term survival, Electronic Patient Reported Outcomes (ePROs) integration into routine oncology practice have been shown to improve patient time on therapy, survival, and resource utilization. This study explores the use of an ePRO platform to explore differences in treatment experience and ePRO compliance in patients with AML and poor and other-risk cytogenetics. Methods: Adult patients with AML undergoing treatment were enrolled in the Carevive remote symptom monitoring (RSM) platform between March 1, 2021 and April 20, 2023. Patients received baseline and weekly surveys to assess patient-reported symptom burden, physical function, overall health, and survey compliance throughout treatment. Baseline characteristics included age, sex, race, frailty status (modified Geriatric Assessment, CARE survey item, and/or self-reported activity level), comorbidities, and social determinants of health. Symptoms (derived from the PRO-CTCAE), physical function (PROMIS 4a), and quality of life (QoL) (EORTC QLQ-C30, items #29-30) were assessed weekly. Results were stratified by poor vs. other cytogenetic risk. As this was an exploratory study, statistical significance was not reported. Results: Of a total of 124 patients, 47 (38%) had poor-risk and 77 (62%) had other-risk disease by cytogenetics. Weekly survey compliance was comparable (68% vs 69%), and median age was 66 (range 35-88) and 69 (range 21-88), respectively. About 50% of all patients were male, 76% were White, and 69% had ≥1 comorbidity. Patients with other-risk were younger with 40% fewer comorbidities (mean 0.95, median 0, range 0-5) than patients with poor cytogenetic risk (mean 1.36, median 1, range 0-5). Overall symptoms were reported 12% more frequently among patients with other risk (1.49 symptoms per patient-week) compared to patients with poor risk (1.33 symptoms per patient-week). Fatigue was reported by 20% of patients across all patient-weeks for both risk groups; shortness of breath was reported 6% and 10% across all patient-weeks for poor and other risk groups, respectively. Although baseline treatment bother was 17% higher for poor risk patients, over time, QoL and treatment bother were comparable between both groups, and physical function was directionally higher. Conclusions: This study illustrates the feasibility of using remote symptom monitoring for evaluating patients with poor vs. other cytogenetic risk in routine care, with relatively high survey compliance in a real-world setting. Despite poor prognostic status, the experience of poor cytogenetic risk patients was comparable to other cytogenetic risk patients and reported directionally lower levels of symptom burden and higher levels of function over time.

Serum circRNA_100199 is a Prognostic Biomarker in Acute Myeloid Leukemia.

An aberrant level of serum microRNA expression has been demonstrated to be a prognostic marker for acute myeloid leukemia (AML). The therapeutic relevance of serum circRNA 100199 remained unknown, however. This research aimed to investigate the probable prognostic significance of serum circRNA_100199 for AML. This study included a total of 200 participants consisting of 114 AML-diagnosed patients and 86 healthy people. Blood samples were taken, and the level of circRNA_100199 in the serum was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) to explore its potential clinical significance. Our study demonstrated that circRNA_100199 expression in the serum was substantially higher in AML subjects than in healthy persons. This increase in serum circRNA_100199 levels was particularly noticeable in M4/M5 subtype AML patients, and those with poor cytogenetic risk or higher white blood cell counts. Using receiver operating characteristic (ROC) analysis, AML cases were effectively differentiated from healthy persons based on the level of serum circRNA_100199. Furthermore, it was found that high serum circRNA_100199 expression was strongly linked with shorter survival times and more severe clinical features. Our study also confirmed that high serum circRNA_100199 expression was an independent predictor of relapse-free survival (RFS) and overall survival (OS) in AML patients. Interestingly, the serum expression level of circRNA_100199 was significantly reduced following treatment, and its levels were substantially lower in AML patients who achieved complete remission (CR) than those who did not. Overall, these findings suggest that serum circRNA_100199 has the potential to be a favorable prognostic biomarker for AML.

Cluster of Differentiation 38 Protein Significantly Adds to the Prognostic Value of Cytogenetic Risk in Patients with Acute Myeloid Leukemia.

There is some controversy regarding the clinical significance of cluster of differentiation 38 (CD38) protein in acute myeloid leukemia (AML). We aimed to study the prognostic value of CD38 expression in relation to the standard cytogenetic risk stratification in AML patients. In this prospective study, adult patients with AML were diagnosed based on the finding of ≥ 20% blasts in the bone marrow and the flow cytometry. The control group was selected from normal bone marrow samples examined at the same period in the lab. The CD38 expression levels were assessed by immunophenotyping the bone marrow samples of the patients prior to therapy, as well as those from the controls. The subjects were N = 52 newly diagnosed adult AML patients, while n = 25 sex-and-age matched normal volunteers served as the control. The CD38 expression among AML patients ranged from 3.6% to 79.9%, significantly higher levels than in the control population (p =0.001). Positive CD38 expression was higher in AML patients with favorable cytogenetics when compared to those with intermediate and poor cytogenetics (75.0%, 57.1%, and 68.2%, respectively) (p =0.007). Median CD38 expression in AML patients was higher in the favorable cytogenetic group and lower in intermediate and poor cytogenetic groups, though lacking in significance (p =0.578). Patients with poor cytogenetic risk were associated with significantly shorter median overall survival when compared to favorable and intermediate cytogenetic risk (p =0.010). The expression of CD38 significantly adds to the prognostic value of cytogenetic risk stratification at diagnosis of AML patients.

P26 Leukaemia cutis as the first manifestation of acute myeloid leukaemia

Abstract Leukaemia is the most frequent malignancy of childhood, accounting for approximately 30% of all malignancies. Acute leukaemia may present in a variety of extramedullary manifestations, the commonest being leukaemia cutis (LC). LC is the infiltration of the epidermis, dermis or subcutis by neoplastic leukocytes with skin lesions preceding the development of leukaemia in the peripheral blood or bone marrow in just 2–3% of cases. A 6-month-old baby girl was reviewed due to multiple skin lesions which appeared on her left forearm 2 months previously, and spread widely, showing over 50 in the following weeks. They were well-circumscribed, nontender, violaceous nodules. She was clinically well and thriving with no lymphadenopathy or organomegaly. Blood tests and abdominal ultrasound were normal. A skin biopsy of a nodule demonstrated an infiltrate of medium-sized atypical cells involving the dermis and subcutis. Immunostaining showed CD45 expression and the Ki67 proliferation index was high, in keeping with a leukaemic infiltration. Cytogenetics performed on the skin biopsy showed KMT2A rearrangement by FISH. Bone marrow aspirate confirmed the diagnosis of acute myeloid leukaemia with monoblastic morphology, and cytogenetics confirmed the rearrangement as a KMT2A–MLLT10 fusion, which is classified as poor cytogenetic risk. Cerebrospinal fluid analysis was negative. It is vital to get a histological diagnosis (with cytogenetics) in a child presenting with violaceus nodular lesions even if the child is well. Importantly, LC can present with a normal full blood count. A bone marrow aspiration is paramount to confirm the diagnosis. Once leukaemia is diagnosed, cytogenetics plays a key role in stratifying treatment intensity.

Prognostic impact of complex and/or monosomal karyotypes in post-transplant poor cytogenetic acute myeloid leukaemia: Aquantitative approach.

To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics.