Therapy-related Acute Myeloid Leukemia Research Articles

A phase 1/2 study of NS-87/CPX-351 (cytarabine and daunorubicin liposome) in Japanese patients with high-risk acute myeloid leukemia.

NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML. This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60-75years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351. In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7-74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated. NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.

Rare NUP98::PRRX1 fusion transcript in a therapy-related acute myeloid leukemia associated with del(7q) following chemotherapy for diffuse large B-cell lymphoma

BackgroundTherapy-related acute myeloid leukemia (t-AML) is increasingly recognized as a treatment complication in patients receiving chemotherapy, radiotherapy, or immunosuppressive agents for primary neoplasms. NUP98::PRRX1 fusion gene, caused by t(1;11)(q23;p15), is a rare recurrent cytogenetic alteration in leukemia, and only seven cases with NUP98::PRRX1 were reported so far. MethodsA 53-year-old female patient was diagnosed with t-AML after 20 months of complete remission (CR) from diffuse large B-cell lymphoma (DLBCL). Conventional karyotype, fluorescence in situ hybridization (FISH), and DNA/RNA next-generation sequence (NGS) were used to detect genetic abnormalities. ResultsAbnormal karyotype of 46, XX, t(1;11)(q25;p15), del(7)(q22) was revealed. NUP98 gene rearrangement and del(7)(q22) were verified by FISH. Further, RNA NGS detected NUP98::PRRX1 fusion transcript, and DNA NGS detected KRAS gene mutation. The patient achieved CR after a combined chemotherapy regimen containing BCL-2 inhibitor and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but she died of leukemia recurrence 14 months later. ConclusionsNovel targeted drugs may provide opportunities for patients with NUP98::PRRX1 to undergo allo-HSCT. However, since the cases of carrying the NUP98::PRRX1 are limited, more patients with this genetic change need to be investigated to elucidate the prognostic significance.

Successful use of Palbociclib combined with Venetoclax and Azacitidine in an adult with refractory/relapsed therapy-related acute myeloid leukemia.

Therapy-related acute myeloid leukemia (t-AML) is considered high risk as it related to prior exposure to cytotoxic chemotherapy agents for solid tumors or hematologic malignancies. Compared with de novo AML, t-AML is associated with lower remission rates, inferior overall survival (OS) and higher relapse rates. Many efforts have been devoted to improving the overall but with limited success, and novel strategy is thus highly needed. We reported one patient with refractory/relapsed t-AML was successfully treated with Palbociclib combined with Venetoclax and Azacytidine (AZA). In this case, a 47-year-old patient with t-AML recurred during Venetoclax in combination with AZA therapy. However, the patient achieved morphological, immunophenotypic and molecular complete remission again after Palbociclib combined with Venetoclax and AZA. Although only one successful case is presented here, three-drug combination regimens should be considered as another treatment option for t-AML in the future.

FLT3 Mutated Acute Myeloid Leukemia after CD19 CAR-t Cells.

Chimeric Antigen Receptor T-cells have improved the life expectancy of severely pretreated patients with aggressive hematological cancers; for this reason, therapy-related myeloid leukemias are becoming of great concern in this field, despite their clonal phylogenesis and mutational landscape have not been fully explored yet. This case discusses a 33-year-old man with refractory large B-cell lymphoma, treated with Chimeric Antigen Receptor T-cell (CAR-T) therapy as the 7th line of treatment. Despite a persistent partial response, the patient developed therapy-related acute myeloid leukemia (t-AML) six months post-CAR-T, revealing pre-existing clonal hematopoiesis. The myeloid malignancy exhibited an unusual hypocellular/dysplastic pattern, progressing to an established blast phase with cytopenia. Treatment with demethylating agents and BCL2 inhibitors proved ineffective, leading to t-AML with hyperleukocytosis and FLT3-ITD gain, resulting in the patient's death. This case underscores the impact of severe pretreatment and bone marrow impairment in CAR-T-associated t-AML, emphasizing their role over insertional mutagenesis. Furthermore, it highlights the retention of classic therapy-related leukemia characteristics, including the potential for acquiring FLT3 mutations and displaying dysplastic morphology in these secondary leukemias.

Recent Advances towards the Understanding of Secondary Acute Myeloid Leukemia Progression.

Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy related AML, tAML). sAML is diagnosed when the number of blasts is ≥20% in the bone marrow or peripheral blood, and it is characterized by poor prognosis, resistance to therapy and low overall survival rate. With the recent advances in next generation sequencing technologies, our understanding of the molecular events associated with sAML evolution has significantly increased and opened new perspectives for the development of novel therapies. The genetic aberrations that are associated with sAML affect genes involved in processes such as splicing, chromatin modification and genome integrity. Moreover, non-coding RNAs' emerged as an important contributing factor to leukemogenesis. For decades, the standard treatment for secondary AML has been the 7 + 3 regimen of cytarabine and daunorubicin which prolongs survival for several months, but modifications in either dosage or delivery has significantly extended that time. Apart from traditional chemotherapy, hematopoietic stem cell transplantation, CAR-T cell therapy and small molecule inhibitors have also emerged to treat sAML.

CPX-351 and allogeneic stem cell transplant for a therapy-related acute myeloid leukemia that developed after treatment of acute promyelocytic leukemia: a case report and review of the literature

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.

CPX-351 exploits the gut microbiota to promote mucosal barrier function, colonization resistance, and immune homeostasis

AbstractCPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, because it improves survival and outcome of patients who received hematopoietic stem cell transplant compared with the continuous infusion of cytarabine plus daunorubicin (referred to as “7 + 3” combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily affects the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 vs “7 + 3” combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and “7 + 3” combination on mucosal barrier function, gut microbial composition and function, and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with “7 + 3” combination, protected from gut dysbiosis, mucosal damage, and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor–interleukin-22 (IL-22)–IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.

Epigenetic signature of ionizing radiation in therapy-related AML patients

Therapy-related acute myeloid leukaemia (t-AML) is a late side effect of previous chemotherapy (ct-AML) and/or radiotherapy (rt-AML) or immunosuppressive treatment. t-AMLs, which account for ∼10–20 % of all AML cases, are extremely aggressive and have a poor prognosis compared to de novo AML. Our hypothesis is that exposure to radiation causes genome-wide epigenetic changes in rt-AML. An epigenome-wide association study was undertaken, measuring over 850K methylation sites across the genome from fifteen donors (five healthy, five de novo, and five t-AMLs). The study predominantly focussed on 94K sites that lie in CpG-rich gene promoter regions. Genome-wide hypomethylation was discovered in AML, primarily in intergenic regions. Additionally, genes specific to AML were identified with promoter hypermethylation. A two-step validation was conducted, both internally, using pyrosequencing to measure methylation levels in specific regions across fifteen primary samples, and externally, with an additional eight AML samples. We demonstrated that the MEST and GATA5 gene promoters, which were previously identified as tumour suppressors, were noticeably hypermethylated in rt-AML, as opposed to other subtypes of AML and control samples. These may indicate the epigenetic involvement in the development of rt-AML at the molecular level and could serve as potential targets for drug therapy in rt-AML.

Haploidentical and Matched Sibling Transplantation for Acute Myeloid Leukemia: A Hospital-Based Study.

Allogeneic peripheral blood stem cell transplantation (PBSCT) has been increasing for the last years in Latin America. The objective of this study was to describe clinical outcomes in acute myeloid leukemia (AML) receiving allogeneic PBSCT between 2013 and 2019 in a single center of Cali, Colombia. A retrospective cohort study was conducted in Fundacion Valle del Lili. Patients diagnosed with AML who received an allogeneic PBSCT between 2013 and 2019 using human leukocyte antigen (HLA)-matched sibling donors (MSDs) or haploidentical related donors (HRDs) with myeloablative conditioning regimen were included. Cases with diagnosis of promyelocytic leukemia, myelodysplastic syndrome-related AML and therapy-related AML were excluded. Data were obtained directly from the hospital PBSCT database and clinical records. A total of 50 patients were included (HRD, n = 32; MSD, n = 18). Sixty-two percent was in the first complete remission (CR1) at the time of the transplant, of which 26% were MSD and 74% were HRD. The European Group for Blood and Marrow Transplantation (EBMT) risk score was: 44% vs. 50% low, 28% vs. 28% intermediate and 28% vs. 22% high for MSD vs. HRD, respectively. Overall survival at 5 years for MSD was 62% (95% confidence interval (CI): 31-83%) and 43% (95% CI: 25-60%) for HRD. Event-free survival was 56% (95% CI: 26-78%) and 35.6% (95% CI: 18-53%), respectively. Non-relapse mortality at day-100 was 6% (95% CI: 0.8-35%) and 20% (95% CI: 9-39%). Relapse at5 years was 18% (95% CI: 4-58%) and 25% (95% CI: 10-52%). Overall mortality rate was 46%. The grade II-IV, III-IV acute graft-versus-host disease and severe chronic graft-versus-host disease was 44%, 11% and 12% for MSD, and 43%, 9% and 0% for HRD. These results underline that MSD remains the first donor choice for AML patients in CR1 when available. HRDs are still our next option among alternative donors. It is necessary to find strategies that have a positive impact on those outcomes that markedly affect the quality of allogeneic PBSCT and the prognosis of patients. Comparative, randomized, prospective studies with longer follow-up of haploidentical allogeneic PBSCT with other donor types are required to definitely establish its role among alternative donors.

Therapy-Related Acute Myeloid Leukemia After Chemotherapy For Osteosarcoma: Report of 2 Cases and Review of The Literature

Abstract Introduction/Objective Therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS) are rare but well-established late complications of chemotherapeutic agents or radiation therapy used to treat various malignancies. Many cases of t-AML/t-MDS have been described secondary to Hodgkin, non-Hodgkin lymphoma, and other solid tumors. However, only a few cases of t-AML and t-MDS have been reported following osteosarcoma treatment. We describe two patients diagnosed with osteosarcoma who developed t-AML after receiving multiple chemotherapeutic agents. Methods/Case Report A 12-year-old male with Li-Fraumeni syndrome was diagnosed with osteosarcoma of the left ilium and sacrum with pulmonary metastases. Despite multiple lines of chemoradiation therapy including doxorubicin and ifosfamide, tumor progressed at the primary tumor site. The patient subsequently presented with altered mental status and pancytopenia. Bone marrow biopsy demonstrated AML. He died despite supportive care. A 14-year-old female was diagnosed with left tibial osteosarcoma with bony and pulmonary metastases. She was treated on standard osteosarcoma chemotherapy including doxorubicin, cisplatin, methotrexate, ifosfamide and etoposide, surgery, and radiation. 1 year following therapy, she had local recurrence of osteosarcoma without progression despite not starting chemotherapy. However, 3 years later, she developed pancytopenia, and immature white blood cells were identified on peripheral smear. Bone marrow biopsy revealed AML-M7. Despite supportive care and zoledronic acid, she ultimately died from sepsis and disseminated intravascular coagulation. Results (if a Case Study enter NA) NA Conclusion With improved therapy and survival for osteosarcoma patients, these patients should be monitored for secondary malignancies. T-AML is rare following osteosarcoma treatment, but outcome remains poor, despite treatment. Underlying Li-Fraumeni syndrome may influence the risk of development of secondary malignant neoplasms. Literature review of types and prognosis of t-AML following osteosarcoma will be reviewed and compared to our cases, including related genetic predisposing factors and chemotherapeutic agents. Our second patient is the first reported case of AML-M7 secondary to osteosarcoma treatment.

Association between Molecular Profile and Outcome after Intensive Chemotherapy in Patients > 60 Years with Adverse Cytogenetic Risk and/or Secondary Acute Myeloid Leukemia - a Filo Study

Background: Recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary acute myeloid leukemia (AML), i.e., arising from prior cytotoxic therapy and/or an antecedent hematologic disorder (AHD), is now considered a diagnostic qualifier rather than a separate disease entity (Döhner, Blood 2022). To assess the relationship between clinical history and/or adverse cytogenetics and outcome, we report herein the molecular profile of AML patients >60 years with secondary AML and/or adverse cytogenetics included in a multicentric prospective trial. Methods: Fit patients >60 years with secondary AML and/or adverse cytogenetics according to the European LeukemiaNet, included in the Rev-5-Aza trial (NCT01301820), received induction therapy with lomustine 200 mg/m 2 day 1, idarubicin 8 mg/m 2 days 1-5, and cytarabine 100 mg/m 2 days 1-7. Patients in complete remission (CR) after one induction cycle received consolidation therapy with 12 cycles of alternating azacitidine 75 mg/m 2 days 1-7 and lenalidomide 10 mg days 1-21 every 28 days (Hunault-Berger M, Blood Cancer J 2017). Mutational profile was determined by targeted sequencing of complete coding regions, including splice sites, of 77 genes recurrently mutated in myeloid malignancies using custom SureSelect QXT capture system (Agilent, Santa Clara, CA, USA) on NextSeq500 platform (Illumina, San Diego, CA, USA). As a validation cohort, we determined the molecular profile of 73 patients with adverse cytogenetic risk and/or secondary AML in first CR after the same induction therapy but who received standard chemotherapy consolidation with 6 cycles of idarubicin 8 mg/m 2 day 1 and cytarabine 50 mg/m 2/12 hours days 1-5. Results: Between March 2011 and February 2013, 117 fit patients >60 years included in the Rev-5-Aza trial received induction therapy with 56% reaching first CR and four patients undergoing allogeneic hematopoietic cell transplantation. The molecular profile could be established in 97 of these patients (83%; median age 70 years, interquartile range (IQR): 65-73; therapy-related AML, 32%; AHD, 46%; adverse cytogenetic risk, 70%). Secondary-type mutations were the most frequently observed (49%; ASXL1, 12%; BCOR, 16%; EZH2, 2%; RUNX1, 18%; SF3B1, 8%; SRSF2, 14%; STAG2, 10%; U2AF1, 8%; and ZRSR2, 0%) followed by TP53 mutations (44% of patients). Patients with TP53 mutations were more likely to have adverse risk cytogenetics (95%) in comparison to patients with secondary-type mutations (64%). No clinical or biological characteristic was associated with the achievement of CR (secondary-type mutations, 51%, TP53 mutation, 49%). Clinical history was not associated with overall survival (OS) as patients with therapy-related AML had the same outcome as other patients (hazard ratio [HR]=1.04, P=0.9) and patients with AHD had a more favorable outcome (HR=0.57, P=0.02). On the other hand, adverse cytogenetics was associated with decreased OS (HR=3.32, P<0.001). Whereas TP53 mutations were associated with decreased OS (HR=3.71, P<0.001), secondary-type mutations were not (HR=0.64, P=0.049; Figure A). After multivariable analysis, both complex karyotype (CK; HR=0.006, P=0.006) and TP53 mutations (HR=2.12, P=0.03) were independently associated with OS. Considering both CK and TP53 mutations identified three groups of patients with differential OS (median 1.57 vs. 0.91 vs. 0.45 years, P<0.001; Figure B). Similar results were observed in the validation cohort. Patients in first CR from both cohorts were then compared to identify molecular subgroups for which a lenalidomide/azacitidine consolidation was associated with improved OS in comparison to standard chemotherapy. No molecular subgroup had increased OS with lenalimomide/azaciditine consolidation while standard chemotherapy was associated with improved outcomes in patients with adverse risk cytogenetics. Conclusion: Together, these data suggest that the clinical history contains limited prognostic value compared to genetics, supporting the most recent approach to use cytogenetic and molecular data to assess disease risk. In this patient population, complex karyotype and TP53 mutations, rather than secondary-type mutations, were associated with outcome. Figure. (A) Overall survival according to secondary-type and TP53 mutations status. (B) Overall survival according to complex karyotype (CK) and T P53 mutation status.

Selinexor in Combination with Venetoclax and Azacitidine for Newly Diagnosed (ND) Unfit Acute Myeloid Leukemia (AML): A Multicenter, Open-Label Prospective Study

Introduction: Acute myeloid leukemia (AML) predominantly affects the elderly, with a median age at diagnosis around 68 years (Bhansali, 2023). Due to existing or potential comorbidities and frailty, many patients are unable to undergo conventional intensive chemotherapy at the time of diagnosis. The combination of venetoclax with azacytidine has shown improved clinical response rates of 64% with a median overall survival of 14.7 months (DiNardo, 2020). However, subgroup data demonstrated no significant benefits in the Chinese population, in pts with poor risk, or in those with TP53 mutations. Therefore, managing AML in elderly or unfit pts remains a significant challenge. Selinexor has shown promising tolerability and clinical activity in AML through various phase 1/2 trials. The triple regimen of selinexor, venetoclax, and azacytidine (SAV) has demonstrated favorable results in AML pts with severe co-morbidities in real-world settings. To further evaluate its efficacy and safety, we have designed a prospective study (NCT05736965) to assess the SAV regimen for ND AML pts who are ineligible for intensive therapy. Methods: To report the efficacy and safety of ND AML pts ineligible for intensive chemotherapy, treated with a triple regimen from 6 sites. The study enrolled pts who were unfit for intensive chemotherapy, ≥75 years, had significant comorbidities, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥3, organ dysfunction, or had abandoned intensive chemotherapy. The primary study objectives were the complete response (CR)/complete response with incomplete count recovery (CRi) rate and overall response rate (ORR). Responses were assessed according to the ELN2022 criteria. Pts received the following treatment regimen: Selinexor 60mg on days 3, 10, and 17; Azacitidine 75mg/m2 on days 1-3, 8-9, and 15-16; Venetoclax 100mg on day 1, 200mg on day 2, and 400mg on days 3 to 14. Each treatment cycle lasted for 28 days. Pts who achieved CR, CRh, or CRi, as per the center's treatment guidelines, were eligible for transplantation at any time point. Remaining pts continued to receive the SAV regimen until disease progression or intolerable toxicity. Results: From March 2023 to the data cutoff on June 10, 2023, a total of 20 pts were enrolled in the study, of which 16 had de novo or therapy-related AML, and 4 had secondary AML with a history of myelodysplastic syndrome. Table 1 displays the baseline characteristics and responses of the newly diagnosed AML pts. The median age of the 20 pts was 64 years (range: 28-80), and the majority of them had high-risk disease: 12/20 (60%) had intermediate-risk, and 8/20 (40%) had adverse-risk according to the ELN 2022 criteria. Additionally, 4/20 (20%) of the pts had therapy-related AML, 6/20 (30%) were aged ≥75 years, 12/20 (60%) had ≥2 high-risk molecular mutations, and a significant proportion had high blast counts. All pts completed at least 1 cycle of treatment (range: 1-4). Specifically, 1patient completed 4 cycles, 2pts completed 3 cycles, and 7pts completed 2 cycles. The remaining 10pts have just completed their first cycle of treatment and evaluation. With the exception of one patient with disease progression (PD), all other pts are still undergoing treatment. As the treatment duration extends, the depth of remission in pts may further deepen. The CR/CRi rates and ORR across the ELN 2022 risk groups for all pts, intermediate-risk group, and adverse-risk group were as follows: 80% (16/20) and 90% (18/20), 75% (9/12) and 91.7% (11/12), 87.5% (7/8) and 87.5% (7/8), respectively. In comparison, the VIALE-A data showed a CR/CRi rate of 52.9% for adverse-risk pts, indicating a higher remission rate observed in this study. As of now, 3 pts were MRD-negative. The reported adverse events of grade 3 or higher occurring in ≥10% of pts in the triple regimen were thrombocytopenia (35%), neutropenia (35%), and infections (15%). The most frequently reported adverse events of Grade 1-2 included anemia, nausea, fatigue, anorexia, and hyponatremia. All adverse events could be managed and improved through dose adjustments and supportive treatment. Conclusions: The SAV regimen has been found to be safe and effective, with encouraging complete response (CR) rates in newly diagnosed AML pts, especially in adverse risk patients. Further trial enrollment and correlative analysis are currently underway to thoroughly observe the efficacy and safety of the SAV regimen.

CLAG-Based Chemotherapy in Previously Untreated AML Patients: 12 Year Follow-up

Introduction: The 7+3 combination of cytarabine plus an anthracycline is the most commonly used induction regimen for AML in the US. There is evidence FLAG-IDA may be superior to 7+3 (Solh et al Leuk Res 2020), and that cladribine is superior to fludarabine (Holowiecki et al JCO 2012). Currently we report the results of CLAG-based chemotherapy in newly-diagnosed AML patients. Methods: This single-center retrospective cohort studied all patients with newly-diagnosed AML who received CLAG-based induction therapy (with or without an anthracycline, depending on cardiac function) between February 2011 and June 2023. Chemotherapy consisted of cladribine 5 mg/m 2 daily times 5 days, cytarabine 2 gm/m 2 over 4 hrs daily times 5 days (given 2 hours after the completion of each cladribine dose), plus G-CSF 300 ug daily during chemotherapy and then based on weight after that. Patients with adequate cardiac function also received 3 days of mitoxantrone 12 mg/m 2 (CLAG-M) or idarubicin 12 mg/m 2 (CLAG-IDA) on days 1-3 or 2-4. Many of these patients were treated prior to the current era of targeted therapies and thus most received chemotherapy without targeted agents. Post-remission therapy was given at the physician's discretion based on the patient's tolerance of induction chemotherapy. Complete response (CR) was defined as less than 5% blasts in the marrow with recovery of ANC >1000/mm 3 and platelets >100,000/mm 3. Lesser responses included CRi, CRp and PR. All others were considered failures or early deaths (within 30 days). This study was approved by the IRB of New York Medical College. Results: We analyzed all 87 newly-diagnosed AML patients that were treated with CLAG-based induction therapy (CLAG alone: 10%, CLAG-IDA: 87%, CLAG-M: 3%). 4 patients with a FLT-3 mutation received a FLT-3 inhibitor concurrently. Post-remission therapy included allo transplant (13%), further CLAG+/- IDA, reduced to 4+2 days (84%), HiDAC (27%), and hypomethylators (36%), in that order of priority. The intensity of the post-remission therapy was matched with the perceived ability of the patient to tolerate it. Many patients received more than one post-remission therapy in sequence. The median age of the cohort was 65 (33-85) years. 59% were male, 47% were smokers, 6% had prior MDS and 13% had therapy-related AML. The median baseline WBC was 9.7 (0.4-392) k/mm 3. 10% of patients were stratified as favorable ELN cytogenetic risk, 45% as intermediate, and 45% as adverse. TP53 mutation was present in 22% patients and FLT3 mutation in 14% patients. CR was obtained in 67% of patients overall and did not differ significantly by age (<60: 65%, 60-70: 70%, >70: 64%). Early deaths (within 30 days) were more common in older patients (<60: 3%, 60-70: 3%, >70: 8%). The CR rate was similar across all cytogenetic risk groups (good risk: 67%, intermediate risk: 68%, poor risk: 62%) and was favorable in patients with a TP53 mutation (68%), as well as those with therapy-related AML (69%). The median overall survival (OS) was 13 months. By cytogenetic risk the median OS was good: not reached, intermediate: 25.6 months and poor: 6.8 months (Figure 1). It should be noted that two patients with good risk cytogenetics who expired included an 80-year-old woman with therapy-related AML after treatment for breast cancer who declined further therapy after cycle 1 and survived 20 months with no further therapy, as well as a second unvaccinated patient who expired due to complications of COVID. Median OS by age was <60: 18 months, 60-70: 25.6 months and >70: 8 months (Figure 2). Median overall survival for patients with TP53 mutation was 5.6 months. Conclusion: CLAG provides an alternative induction regimen to 7+3. Interestingly, in contrast to 7+3, CR rates did not differ significantly by age or cytogenetic risk group. The older patients treated on this trial were a select group that were considered eligible for intensive chemotherapy. Many of the patients on this trial would be treated differently today, with the availability of more targeted therapies. However the relatively high response rates in patient with poor risk cytogenetics and/or TP53 mutation gives fit patients the opportunity of pursuing stem cell transplantation.

Socioeconomic Status Is a Mediator of Overall Survival in Acute Myeloid Leukemia (AML)

Introduction: AML is a morbid disease with a five-year overall survival (OS) rate of 30.5%. Despite increasing treatment options and improved OS, inequities exist. Some studies cite a 3-year OS difference between Black and White AML patients (pts) at 34% versus 43% (p < 0.001) (Bhatnagar 2021). This study examines data from AML pts in community and academic centers across the United States to assess for differences in outcomes by demographic factors. Methods: This study used the nationwide Flatiron Health electronic health record derived de-identified database with a data cutoff date of June 30, 2022. Pts were over 18 years old with a diagnosis of AML were included. Pts with acute promyelocytic leukemia or therapy related AML were excluded. The primary outcome was OS defined as time between date of diagnosis and date of death or last follow up stratified by demographic factors of race, ethnicity, sex, and socioeconomic status (SES). Area-level SES is an index quintile based on an area-level measure providing insight into pts' neighborhood SES conditions with a score of 1 representing the lowest SES and 5 representing the highest (Guadamuz 2022). Secondary outcomes included first line (1L) treatment stratified by demographic factors. Results: 3338 pts were included in the analysis. 59.8% of pts were age 65 or older, 55.9% were male, and 93.5% were non-Hispanic. 75.2% reported as White, 7.9% as Black or African American, 14.7% as other and 2.1% as Asian. Table 1 highlights key demographic features of the pts with European Leukemia Net (ELN) risk stratification. With a median follow up of 3.33 years, the median OS for the population was 15.9 months (mos) (95% CI 15, 16.9). When broken down by race, median OS was 21.4mos for Asian pts (95% CI 12.6, 23), 18.4mos for Black pts (95% CI 15, 24), 15.4mos for other pts (95% CI 13.6, 18.2), and 16.1mos for White pts (95% CI 14.9, 17.1). These results were not statistically significant (p = 0.67). When stratified by age group, there was a marginally significant difference in OS with Black pts showing a decreased OS in the age group 18-40 years. Median OS for Hispanic pts was higher at 22.7mos (95% CI 17.4, 35.9) compared to non-Hispanic pts at 15.3mos (95% CI 14.4, 16.4) (p = 0.0010). Female sex was associated with improved OS at 17.7mos (95% CI 15.6, 19.3) versus 15mos for male (95% CI 13.8, 16.1) (p < 0.0001). Median OS by SES had improved OS for pts with SES status 4 or 5 at 17.2mos (95% CI 15.7, 18.6) compared to pts with SES 1 or 2 at 16.1mos (95% CI 14.1, 18.0) (p = 0.03) (Fig.1). The mediating effect of SES on race was explored using Cox regression analysis, multivariate models, mediation analysis, and multivariate logistic regression. Analysis indicated no significant mediating effect (p = 0.3142, p = 0.1377, p = 0.3929 for cde/nde, nie, and total effect respectively). 1L treatment analysis showed greater use of 7+3 in Black versus White pts (25% vs 21%) and greater use of hypomethylating agent (HMA) or HMA+venetoclax in White versus Black pts. Similar findings were seen in the Hispanic versus Non-Hispanic pts, with higher use of 7+3 in Hispanic pts (32.5% vs 21.5%). These findings will be further stratified by age group and ELN risk category. There were no significant differences in the use of 7+3, HMA or HMA+venetoclax based on SES category. Discussion: This is a population-based study of AML pts in academic and community centers. Prior studies demonstrated Black pts have worse OS versus White pts. Similarly, we saw a non-statistically significant trend of decreased OS in young Black pts compared to White pts, but no difference when comparing races when assessing patients with an age cut off of 65 years. Hispanic White pts had statistically significant improved OS versus non-Hispanic pts, a finding not noted previously. It is possible with novel regimens such as HMA/venetoclax are responsible for improved outcomes, particularly in the elderly population, although this needs to be further explored. Molecular analysis could yield additional information on the effect of certain mutations and OS. Abraham et al (2022) demonstrated structural racism played a significant role in AML treatment outcomes in pts treated at Chicago academic centers. In our study, lower SES had a negative impact on OS, even when accounting for other factors. These findings are similar to a study by Rebechi et al (2023) and reveal the need for prospective research to mitigate structural barriers to care for AML pts.

T-Cells Immune Cluster Analysis Using Cytof Identifies Unique Patient Subgroups with TP53 Mutation and Predicts Complete Remission (CR) in Patients with Acute Myeloid Leukemia (AML) Receiving Venetoclax Plus Hypomethylating Agent Therapy

Introduction The advent of venetoclax (VEN) based chemotherapy has revolutionized the treatment of elderly acute myeloid leukemia (AML), with improvement in remission rates from historical 10%-20% to 60%-70%. However, remission duration is short-lived in patients (pts) with high-risk AML with consequent dismal outcome. As our knowledge of genomic landscape of AML expands and more immunotherapies become available, exploration of the immune tumor microenvironment (TME) of AML may allow identification of subsets of pts that may benefit from immune based therapy. We conducted an investigator initiated prospective study to evaluate TME of pts receiving VEN plus hypomethylating agent (HMA; azacitidine or decitabine) combination. We hypothesize that these pts will cluster into immune-infiltrated vs. immune-depleted sub-types by high-definition immune cell profiling. Methods In 26 newly diagnosed AML pts, who were planned to receive VEN plus HMA therapy, we isolated bone marrow (BM) and peripheral blood (PB) derived mononuclear cells (MC) by density gradient centrifugation and cryopreserved. We performed CyTOF (cytometry time-of-flight) analysis to study their immune signatures. Thawed cells were labeled with metal-conjugated antibodies that bind CD33, CD196, CD19, CD127, CD11b, CD4, IgD, CD11c, CD14, CD56, CD123, TCRgd, CD185/CXCR5, CD45RA, CD27, CD28, CD66b, CD183 (CXCR3), CD161, CD45RO, CD197 (CCR7), CD8a, CD25, CD3, CD20, CD38, HLA-DR, CD194 (CCR4), CD57, CD16 and CD45. We performed a Rphenograph clustering on 25 paired BMMC and PBMC samples (one patient only had PBMC) to create 35 unique clusters for each ( Figure 1). Then we broke down the distribution of cluster by two different groupings: pts with TP53 mutation (m) and those who achieve complete remission. Statistical significance of clusters calculated using t-test. We performed Pearson correlation test on the paired BMMC and PBMC samples to assess correlation between BMMC and PBMC samples. Results Baseline characteristics The median age of the pts was 74 years (range, 53-88), and 17 (65%) pts were male. Ten (37%) pts had secondary AML, and 12 (46%) pts had ELN adverse risk disease (n=6; TP53m). There was no significant difference in median age (p= >0.99), proportion of pts with secondary AML (p= 0.64), acute myelomonocytic leukemia (p= 0.14) white blood cell count (WBC) ≥ 100 (10 9/L) (p= >0.99), and frequency of commonly occurring co-mutations ( ASXL1 [p=0.35]), FLT3 ITD [p=0.54], splicing [p=0.29], IDH1/2 [p=0.28], DNMT3A [p=0.29], NPM1 [p=0.29], TET2 [p=0.35]) in TP53m and TP53 wild-type group. Response 12/20 (60%) evaluable pts achieved complete remission with or without count recovery (CR/CRi). There was no significant difference in median age (p= 0.06), proportion of pts with secondary AML (p= 0.16), therapy related AML (p= 0.60) WBC ≥ 100 (10 9/L) (p= 0.40), and frequency of commonly occurring mutations ( TP53 [p=0.60], ASXL1 [p > 0.99]), FLT3 ITD [p=0.54], splicing [p > 0.99], IDH1/2 [p=0.60], DNMT3A [p=>0.99], NPM1 [p=0.61], TET2 [p >0.99]) in CR/CRi and no-CR/CRi group. CyTOF analysis and Rphenograph clustering on 25 paired BMMC and PBMC samples We found significant clustering with high expression of B-cell activated (cluster 2; p= 0.005), NK cell rich (cluster 1; p= 0.005, cluster 35; p= 0.0009), CD8 T-cells (cluster 31; p= 0.01) and CD4 effector cells (cluster 17; p= 0.005) phenotype among TP53m AML ( Table 1). Among pts who achieved CR/CRi, significant clustering with low expression of B-cell activated (cluster 29; p= 0.01), CD8 cytotoxic (cluster 14; p= 0.01) CD4 activated (cluster 21; p= 0.03) phenotypes observed. Correlation between BMMC and PBMC clustering Among clusters which showed significance for a particular phenotype, we performed Pearson correlation (R 2) and observed strong correlation between BMMC and PBMC samples clustering in cluster 1 (R 2 = 0.99), cluster 2 (R 2 = 0.95), cluster 17 (R 2 = 0.96), cluster 21 (R 2 = 0.99) and cluster 29 (R 2 = 0.93). Conclusion In this single institutional study using CyTOF analysis we have identified novel clustering with immune- infiltrated phenotype among pts with TP53m AML and conversely immune-depleted phenotype among AML pts who responded to VEN plus HMA. Moreover, we found strong correlation in CyTOF analysis conducted from BMMC and PBMC samples. Future studies with larger sample size needed to validate our findings.

Li-Fraumeni Syndrome: The Two Faces of a Coin in Myeloid Malignancies

Background Li-Fraumeni Syndrome (LFS) is a rare, autosomal dominant genetic disorder caused by germline mutations in the TP53 tumor suppressor gene. It is characterized by a predisposition to a wide range of cancers, including hematological malignancies. Hematological malignancies account for approximately 3-4% of all LFS-related cancers of which are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Myelodysplastic syndromes (MDS) and lymphomas. Method and Results We retrospectively analyzed our clinical data for patients with hematological malignances from the period of Jan 2016-Jan 2022 at the national center for cancer care and research (NCCCR), the only tertiary hematology center in the country. We report on two cases with Li Fraumeni syndrome with acute leukemia and their variable spectrum of the disease manifestations and prognosis. Case 1: 16 years old male known case of rheumatic heart disease presented with double malignancy; left mandible osteosarcoma and lymphoblastic leukemia/ lymphoma concurrently in 2020. For his Leukemia he received BFM*2009 protocol and after remission he underwent surgical resection and received radiotherapy for the osteosarcoma. Patient has family history of breast cancer in his maternal aunt and his paternal great aunt. Germline Genetic testing from buccal swab revealed a pathogenic variant in TP53 gene confirming Li Fraumeni syndrome which is most likely De novo as it was not detected in both parents and his 3 siblings. In 2022 patient presented with pancytopenia and therapy related AML/MDS with complex Karyotype. He was started on salvage therapy and was planned for allogenic stem cell transplant (SCT) from his HLA matched brother, however, unfortunately, patient didn't achieve complete remission thus could not receive the SCT and he passed away one year later in 2023. Case 2: 60-year-old female known case of hypertension who was diagnosed with right breast cancer in 2011 for which she underwent surgery, chemotherapy, and radiotherapy. A year later, patient was diagnosed with left upper lobe squamous cell lung carcinoma, and underwent left upper lobectomy, chemotherapy and radiotherapy. Patient was in remission for 6 years, until 2018 when she presented with pancytopenia and therapy related AML with complex monosomic Karyotype. Due to patient's age and comorbidities, she was unfit for intensive therapy, thus she received hypomethylation agent (Azacitidine) till disease progression and was referred to genetic counseling. Patient has a family history of unknown cancer in her paternal half-sister at the age of 77 and an unknown cancer in her paternal cousin. Genetic testing reveled a mosaic pathogenic variant in TP53 gene present in 17% of the 1137 next generation sequencing reads. Shortly later, patient passed away without confirmatory fibroblast testing. Conclusion: Genetic testing indications for Li-Fraumeni syndrome present challenges as patients with full mutationin TP53 often but not always present with the full spectrum of the disease, whereas patients with mosaic profilepresent with a later onset of the disease and might not be identified early. In both scenarios, patients can be miss-identified and exposed to radiotherapy thus testing criteria warrants further evaluation. Acute Leukemia in Li-Fraumeni syndrome is associated with poor prognosis and usually presents in the context of therapy related myeloid malignancies . Identification of patients with Li-Fraumeni syndrome early on is crucial to avoid exposures to radiotherapy whenever possible thus reducing the risk of subsequent malignancies and the tragic outcomes of the disease. There are unmet clinical needs in Li-Fraumeni syndrome diagnostic and therapeutic approaches which needs further attention.

Long-Term Real-World Experience of CPX-351 in Combined French-Italian Cohorts Identified High Rate of Negative Measurable Residual Disease (MRD) and Prolonged Overall Survival

Introduction CPX-351 is a liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio. This drug has been approved by the FDA and EMEA for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML) according to the WHO 2016 AML classification. Real world experience from several countries (France, Italy, Germany, UK and US) showed similar results of phase 3 clinical registration but with short follow-up. Lancet et al. published a long-term update of phase 3 clinical trial and confirmed long-term remission and improvement of overall survival (OS) ( Lancet Haematology 2021). Thus, the primary objective of this study was to analyze the efficacy of CPX-351 in a real-life setting with a longer follow-up, evaluating the impact of measurable residual disease (MRD) in responding patients. Methods We retrospectively collected data from patients treated with CPX-351 in thirty-six centers in France and Italy. Overall response rate (ORR) was defined by complete remission (CR) and CR with incomplete hematological recovery (CRi). Among the patients in CR or CRi, 62 (61%) had MRD evaluation assessed by next-generation sequencing (NGS) or flow cytometry. OS was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analysis were performed using SPSS v.22 software (IBM SPSS Statistics). Results Between April 2018 and October 2019, 170 patients treated with CPX-351 were included in this study. The sex ratio male/female was 80/90 and the median age was 66 years (range 20-83). AML subtypes were MRC-AML in 117 (69%) and t-AML 48 (28%) patients. According to the European LeukemiaNet (ELN) 2017 classification, genetic risk was favorable, intermediate, and adverse in 8 (5%), 61 (36%), and 98 (58%) (missing for 3 patients), respectively. According to the ELN 2022 classification, genetic risk was favorable, intermediate, and adverse in 8 (5%), 16 (9%) and 143 (84%), respectively. Thirty percent and 19% of patients had complex and monosomal karyotypes, respectively. Assessed by NGS the most frequent mutated genes were: TP53 (n=35, 21%), RUNX1 (n=30, 18%), ASXL1 (n=22, 13%) and TET2 (n=18, 11%) among the XX were NGS was available (sinon ca fait des % qui ne tombe pas juste sur les 170 pts). According to a genetic ontogeny-based classifier (Lindsley et al., Blood 2015), 28 %, 39% and 33% had de novo/pan-AML, secondary type mutations AML, and TP53 mutated AML, respectively. The ORR was 102/170 (60%) after one (n=91) or two (n=11) inductions including 53% CR and 6% CRi. Among the 102 CR/CRi patients, 62 (61%) were evaluable for MRD after induction or after first consolidation. Forty (65%) patients had MRD below the threshold of 10 -3. ELN2017 and ELN2022 were identified as factors predicting CR/CRi rate ( P=0.032 and P=0.043, respectivelyà but the Lindsley classifier did not predict response ( P= 0.060). After 3-years of follow-up, in a univariate analysis, only MRD >10 -3 ( P=0.031); ELN 2017 classification ( P=0.027) and presence of TP53 mutation ( P=0.017) but not ELN 2022 or the Lindsley classifier; were associated with a significantly poorer median OS. In a multivariate analysis, only MRD >10 -3 was associated with a poorer OS (hazard ratio [HR]=2.6, 95% CI 1.2-5.5, P=0.013). Median OS was 40.9 months vs. 10.6 months for patients with MRD <10 -3 vs. ≥10 -3, respectively ( P=0.006). Sixty (35%) patients underwent an allogeneic hematopoietic stem cell transplant (HSCT) with an improved median OS compared to non-transplanted patients (not-reached vs. 9.1 months, P<0.0001). We also observed a trend towards a better median OS in transplanted patients who underwent an HSCT with MRD <10 -3 (not reached vs. 26.0 months, P=0.06). Conclusion After 3 years of follow-up, the improved OS with CPX-351 was confirmed in the real- life setting. Achievement of MRD negativity contributed to improvement of OS in the overall population and, maybe, in transplanted patients. These data provide the rationale for the ongoing ALFA-2101 phase III clinical trial evaluating CPX-351 vs. 3+7 (daunorubicin and cytarabine) in non-MRC-AML and non-t-AML using MRD as the primary endpoint.

Real-World Outcomes with CPX-351 Induction in Adults with Newly Diagnosed Acute Myeloid Leukemia

Introduction: CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine with a fixed molar ratio of 1:5. CPX-351 is approved for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia related changes (AML-MRC) in the U.S. and Europe for adult patients (pts) eligible for intensive chemotherapy. In a randomized phase 3 study of older pts ages 60-75, CPX-351 induction showed improved CR rates and OS compared to conventional 7+3 induction, with the greatest benefit seen in pts with t-AML and those without prior hypomethylating agent (HMA) use. There is limited data on the use of CPX-351 in younger pts, although the U.S. FDA approval was not age-restricted. This study examined real-world CPX-351 usage, including patient selection, clinical outcomes, and complications during induction hospitalizations. Methods: We identified previously untreated AML pts who received CPX-351 induction chemotherapy at the University of Kansas Medical Center via retrospective chart review from August 2017 - May 2023. Determination of t-AML and AML-MRC was made by patient history, bone marrow morphology, and available cytogenetic and molecular information at the time of therapy selection. We excluded pts who received CPX-351 as part of a clinical trial. Data was collected for baseline demographics, disease characteristics, outcomes, and safety profile. The composite complete remission rate (CRc) was defined as CR+CRi+CRh at recovery marrow after induction. Primary refractory disease included pts who failed to achieve CR, CRi, or CRh after 2 courses of intensive induction and excluded those who died in aplasia or due to an indeterminate cause. Results: 74 pts with previously untreated AML who received CPX-351 were identified. Median age was 64 years (21-78): 29% of pts were <60 years old, 50% were males, 84% were Non-Hispanic White, 32% had t-AML, 68% had AML-MRC, 20% had prior HMA treatment, and 22% had prior anthracycline exposure. ELN 2022 risk categories were 13% favorable, 20% intermediate, and 68% adverse. 21 pts had complex karyotype (28%), and 16% were TP53 mutant (Table 1). Indications for induction with CPX-351 versus 7+3 included history of prior chemotherapy (n=24), prior MDS (n=32), or MDS-related changes in bone marrow morphology (n=50). The CRc for the total study population was 61% (45/74). Of these, 29% (13/45) achieved MRD negativity by multiparameter flow cytometry <10 -4. CRc in the ELN adverse risk group was 54% (27/50), 73% (11/15) in the intermediate-risk group, and 78% (7/9) in the favorable risk group. Among TP53 mutant pts, CRc was 42% (5/12). CRc in the t-AML group was 71% (17/24), 56% (28/50) in the AML-MRC group, and 53% (8/15) in the prior HMA treatment group. The CRc in pts ≥60 was 63%, 15% were primary refractory, and 37% underwent alloSCT in CR1. In pts <60, the CRc was 54%, 32% were primary refractory, and 27% underwent an alloSCT in CR1 (Table 2). A second course of induction therapy was given for persistent disease at day 14 or similar time point in 36% (n=27) of pts. Among those, 55% (15/27) had primary refractory disease, 20% of the cohort. At a median follow-up of 11 mos, the mOS was 10.8 mos (0.4-54). The mOS for t-AML was 13 mos, whereas the mOS for the group with prior HMA treatment was 10.4 mos. For pts that achieved CR, mOS was 13.6 mos; for pts that achieved MRD negativity, mOS was 13.8 mos. The mOS for pts <60 was 16 mos, and for pts ≥60 was 10 mos (p=0.39). The mOS for pts that achieved CRc in the group <60 was 20.3mos, and for ≥60 was 11.2 mos (p=0.27). Pts that underwent alloSCT in CR1 <60 had mOS of 25 mos; for ≥60, it was 14.2 mos (p=0.37). During induction hospitalization, febrile neutropenia was the most common adverse event in 84% (n=62). ICU treatment was required in 14% (N=5). There were 2 deaths during induction: one due to respiratory failure and one attributed to sepsis. Conclusion: The use of CPX-351 demonstrated efficacy across subgroups, especially in t-AML and pts without prior HMA exposure, as shown in larger studies. In pts <60 years, even though CRc rates were lower, CPX-351 led to longer mOS in those who achieved CRc and in those who underwent alloSCT compared to pts ≥60 years, although it didn't reach statistical significance in this small cohort. Induction therapy outcomes and treatment-related complications in our study corroborate the data for prior CPX-351 studies.

Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

INTRODUCTION: Hypomethylating agents (HMAs) are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). HMA failure (HMA-F) is associated with poor outcomes and median survival of 4 to 6 months. CPX-351 is a drug liposomal encapsulation of cytarabine (araC) and daunorubicin (dauno) at a synergistic 5:1 molar ratio approved for the treatment of pts with therapy-related acute myeloid leukemia (AML) or AML with MDS-related changes. Here we present the results of a phase I-II study of lower dose CPX-351 for HR-MDS and CMML after HMA-F. METHODS: We conducted a phase I/II clinical trial of CPX-351 for pts with MDS or CMML after HMA-F with Int-2 or High risk by IPSS, or Int-1 with >10% bone marrow (BM) blasts. The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 4 dose levels of CPX-351: 10 units/m 2 (dauno 4.4mg/m 2 and araC 10mg/m 2), 25 units/m 2 (dauno 11mg/m 2 and araC 25mg/m 2), 50 units/m 2 (dauno 22mg/m 2 and araC 50mg/m 2) and 75 units/m 2 (dauni 33mg/m 2 and araC 75mg/m 2). Therapy was administered intravenously on days 1, 3 and 5 of 28-day cycles during induction and on days 1 and 3 of re-induction or consolidation. Re-induction was allowed in pts not achieving response after induction. The primary end point was to evaluate safety and determine the maximum tolerated dose of CPX-351. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between June 2019 and September 2022, 23 pts have been treated: 15 in the phase I portion, and 8 in the phase II. A total of 17 pts had MDS, and 6 had CMML. Four (17%) pts had intermediate-1 risk IPSS and >10% blasts, 15 (65%) had intermediate-2 and 4 (17%) had high-risk IPSS. Median number of prior therapies was 1 (range 1-4) including 4 (17%) pts with failure to prior venetoclax therapy and 2 (9%) with prior HSCT. In the phase I portion, 3 pts received CPX-351 at dose level 1, 3 at dose level 2, 3 at dose level 3 and six at dose level 4. One pt treated at dose level 4 developed grade 2 congestive heart failure with grade 2 reduction in left-ventricular ejection fraction (LVEF). No additional DLTs were detected during the 28-day DLT evaluation window. The initial two pts treated at the P2RD of 75units/m 2 during phase II experienced cardiac complications: grade 3 congestive heart failure without reduction in LVEF and grade 3 right-sided heart failure, respectively. Study was amended to continue further treatment in phase II at dose level 3 (50units/m 2). Most common adverse events (AEs) were lower extremity edema (n=12, 52%), febrile neutropenia (n=11, 48%), dyspnea (n=10, 44%), mucositis (n=10, 44%), constipation (n=9, 39%), diarrhea (n=9, 39%), and generalized muscle weakness (n=9, 39%). Most common grade 3-4 AEs were febrile neutropenia (n=11, 48%), neutropenia (n=5, 22%), lung infection (n=4, 17%), diarrhea (n=4, 17%) and thrombocytopenia (n=3, 13%). The 4-week and 8-week cumulative incidences of mortality were 0% and 4%, respectively. Median number of days to cycle 2 was 47 days (range 30-83). Dose reductions of CPX-351 occurred in 4 (17%) pts. Median number of cycles was 3 (range 1-9). Median cycles to best response was 1 (range 1-3). Among pts with HR-MDS, the ORR was 71% (n=12): CR in 1 (6%), mCR with HI in 1 (6%) and mCR in 11 (59%) pts (Fig 1A). Among pts with BM blast reduction to <5% by the end of cycle 1, 11 (65%) and 9 (53%) had ANC recovery to >0.5x10 9/L and >1x10 9/L, respectively, and 8 (47%) and 6 (35%) had platelet recovery to >50x10 9/L and >100x10 9/L, respectively. Based on 2023 IWG response criteria, the ORR was 59% (n=10) including CR in 1 (6%), CR bilineage (CRbi) in 4 (24%) and CR unilineage in 5 (29%). Of 11 (65%) pts with baseline cytogenetic abnormalities, 2 (18%) and 2 (18%) achieved complete and partial cytogenetic responses, respectively. Three (13%) pts underwent HSCT at time of best response. Among pts with CMML (n=6), only one (17%) achieved response. Median response duration was 4.5 months (95% CI 0.7-8.2 months) and the median OS was 12.6 months (95% CI 3.6-21.7 months) (Fig 1B). CONCLUSIONS: Lower doses of CPX-351 in HR-MDS after HMA-F can induce clinically meaningful responses and be used as a bridge to allogeneic stem-cell transplant. Therapy is associated with median OS of 12.6 months in this population with expected survival of 4-6 months.

Venetoclax Plus Azacitadine for Middle Aged and Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase 2 Trial

Background: “7+3” induction is the standard regimen in newly diagnosed young patients (pts) with acute myeloid leukemia (AML) fit for intensive chemotherapy with 60-80% complete remission rate. However, middle aged and elderly pts may experience more severe complications during induction therapy and overall survival is shorter than that of younger pts. Recently, venetoclax with azacitadine as induction therapy was approved as the first line therapy for pts with aged more than 75 years or unfit pts with composite complete remission (CRc) of 60-70%. We hypothesize that venetoclax with azacitadine as induction therapy in fit middle aged and elderly pts may have similar CRc rate and less complications. This study aims to evaluate the safety and efficacy of venetoclax plus azacitadine as induction therapy in fit middle aged and elderly newly diagnosed AML pts. Methods: This is an interim analysis of an ongoing phase 2 clinical trial (NCT05471700) of a planned 40 untreated AML pts aged 45-65 who were fit for intensive chemotherapy according to Ferrara Criteria. In cycle 1, pts received azacitadine 75mg/m2/day on d1-7 and venetoclax escalated from 100mg to 200mg to 400mg until 28-day cycle was finished. For pts with FLT3-ITD positive, sorafenib was optional administered at a dose of 400mg twice daily. Bone marrow assessments were performed on d28. Pts who achieved CRc (defined as complete remission[CR] and CR with incomplete hematologic recovery[CRi]) with intermediate or adverse risk groups received 1 or 2 cycles of consolidation with venetoclax plus azacitadine or center-specific cytarabine-based consolidation. Allogeneic stem cell transplantation (HSCT) was performed if a donor was available. Pts in favorable risk gruop received 3 to 4 cycles of center-specific intermediate or high dose cytarabine-base consolidation. Non-responders or pts who achieved partial remission received 1 more cycle of venetoclax plus azacitadine. Who could not get CRc after 2 cycles of induction would be withdrawn from the study. The primary objective is to determine the CRc rate. The secondary objective is safety, MRD negative rate, duration of remission (DOR), the rate of allo-HSCT, event free survival (EFS), and overall survival (OS). The endpoint is to show that venetoclax plus azacitadine is not inferior to “3+7” induction in fit pts with newly diagnosed AML aged 45-65. Results: From 10/9/2022 to 6/30/2023, a total of 32 pts was enrolled to this study, comprising 18 males and 14 females. There were 27 (84%) pts with de novo AML, 2(6%) pts were secondary AML, 3 pts (9.4%) were therapy-related AML. Median age was 58 years (range, 45-64 years). There were 2(6%), 14(44%) and 16(50%) pts were in the favorable, intermediate and adverse risk group, respectively. The baseline patient characteristics are summarized in Table 1. Outcome data were updated as of June 30, 2023, for a median follow-up of 2.2(0.2-8.8) months. Among 27 evaluable pts, 21(77.8%) achieved CRc with 11(40.8%) in CR and 10(37.0%) in CRi, 2(7.4%) achieved PR in cycle1, while 23(85.2%) achieved CRc with 14(51.9%) in CR and 9(33.3%) in CRi, 4(14.8%) got induction failure after 2 cycles(Figure 1). A total of 16 (61.5%) pts got MRD negative among the pts with CRc after cycle1, and 17 (65.4%) after cycle2. CRc rate after 2 cycles in ELN2017 favorable, intermediate, adverse risk group was 100%, 83.3% and 85.0%, respectively, and MRD negative rate was 100%, 88.9% and 55.6%, respectively. The regimen was well tolerated. No mortality occurred during induction therapy. The most common non-hematological grade 3/4 AE were febrile neutropenia (n=13, 40.6%)，followed by pneumonia (n=3, 9.4%).Sepsis occurred in 1 (3.1%) pt. With a median follow-up of 2.2(0.2-8.8) months, the median remission duration, EFS and OS have not been reached. Conclusions: Preliminary results indicate that venetoclax plus azacitadine as an induction regimen for fit middle aged and elderly pts with newly diagnosed AML is promising with high CRc and low toxicity. Recruitment of adults with newly diagnosed aged 45-65 AML pts for this trial is ongoing.