Antecedent Hematologic Disorder Research Articles

Haploidentical transplantation in primary refractory/relapsed secondary vs de novo AML: from the ALWP/EBMT

AbstractWe compared the outcomes of haploidentical stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) in 719 patients with primary refractory (PR) or first relapse (Rel) secondary acute myeloid leukemia (sAML; n = 129) vs those with de novo AML (n = 590), who received HSCT between 2010 and 2022. A higher percentage of patients with sAML vs de novo AML had PR disease (73.6% vs 58.6%; P = .002). In 81.4% of patients with sAML , the antecedent hematological disorder was myelodysplastic syndrome. Engraftment was 83.5% vs 88.4% in sAML and de novo AML, respectively (P = .13). In multivariate analysis, haplo-HSCT outcomes did not differ significantly between the groups: nonrelapse mortality hazard ratio (HR), 1.38 (95% confidence interval [CI], 0.96-1.98; P = .083), relapse incidence HR, 0.68 (95% CI, 0.4.7.-1.00; P = .051). The HRs for leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)–free, and GVHD and relapse–free survival were 0.99 (95% CI, 0.76-1.28; P = .94), 0.99 (95% CI, 0.77-1.29; P = .97), and 0.99 (95% CI, 0.77-1.27; P = .94), respectively. We conclude that outcomes of haplo-HSCT with PTCy are not different for PR/Rel sAML in comparison with PR/Rel de novo AML, a finding of major clinical importance.

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.

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.

Prognostic Significance of NCAM1 (CD56) Expression in AML Patients Treated with HMA+Venetoclax

Introduction : NCAM1 (CD56) is a cellular adhesion molecule highly expressed on natural killer (NK) cells and other immune cells. NCAM1 is aberrantly expressed in 20% of patients with acute myeloid leukemia (AML) and is associated with resistance to chemotherapy, upregulation of the MAPK pathway, and poor prognosis. The significance of NCAM1 in the setting of venetoclax (VEN) therapy has not been explored. We set out to determine the functional and prognostic role of CD56 in vitro and in newly diagnosed (ND) patients receiving VEN-based therapy. Methods : OCI-AML2, KG-1, and MOLM-14 cell lines were purchased from ATCC and maintained in RPMI, 10% or 20% FBS, L-Glutamine, and penicillin/streptomycin. Ex vivo drug testing on cell viability was performed using an MTS assay. Briefly, AML cells were plated for 72 hours in replicates of six at 1,250 cells/well in R20 and titrated using a log scale over 7 doses (0-1000 nM) of VEN. After 3 days of culture at 37 °C in 5% CO2, MTS reagent was added, optical density was measured at 490 nm, and raw absorbance values were adjusted to a positive control and (normalized to untreated wells to produce cell viability estimates). VEN-resistant (VR) OCI-AML2 cells were generated by continuous incubation with escalating doses of VEN. Viability was monitored by Guava EasyCyte. Cells maintained resistant by co-culture with 1 µM of VEN twice weekly. Flow for NCAM1 was performed with commercially available antibodies on parental and VR cells. NCAM1 expression on parental vs. VR OCI-AML2 cells was compared with student's T test. Inactivation of NCAM1 in OCI-AML2 cells was carried out by CRISPR/Cas9 using sgRNAs cloned into plentiCRISPRv2 (Addgene, #52961). AUC was derived from 4-parameter logistic regression curves fit to normalized cell viability values for the 7 tested drug doses. Clinical outcomes including overall survival (OS) were assessed in a retrospective cohort of ND AML patients treated with a hypomethylating agent (HMA)+VEN at Oregon Health & Science University (OHSU). CD56 positivity on AML blasts was based on surface immunophenotype determined by multiparameter flow cytometry. OS was measured from AML diagnosis (with time from diagnosis to VEN start as left-truncation), estimated by Kaplan-Meier, compared with the log-rank test, and modeled with Cox regression to estimate unadjusted and adjusted hazard ratios (HRs) for CD56. Results : Across the 3 AML cell lines evaluated, higher baseline NCAM1 expression levels correlated with increased ex vivo resistance to VEN. The MOLM14 cell line was most resistant with highest median NCAM1 expression (90%), followed by OCI-AML2 with median NCAM1 expression (55%) and then KG-1 with lowest NCAM1 expression (3%). VR OCI-AML2 cells had higher expression of NCAM1 compared to parental OCI-AML2 cells (80% expression vs 55%; p=0.0003). CRISPR knockout of NCAM1 sensitized parental OCI-AML2 cells to VENcompared to cells containing a non-targeting control guide (Fig 1). To support our pre-clinical findings, we retrospectively identified N=98 ND AML patients treated with HMA+VEN at OHSU from 12/2018 to 12/2022. Median follow-up was 16 months and 60% of patients died. Median age at diagnosis was 73 (range=19-87), with 39% at least 75 years old. While 65% of patients were male, 63% had de novo AML and 23% had an antecedent hematologic disorder (AHD). By European LeukemiaNet (ELN) 2022 prognostic risk classification, 58% had adverse risk (14% unknown). The most common somatic mutations were IDH1/2 (27% of patients), NRAS/KRAS (26%), FLT3 ITD or TKD (19%), NPM1 (13%), and TP53 (13%). According to diagnostic flow, 30% of patients were CD56+, 22% CD11b+, 15% CD64+, and 85% HLA-DR+. Median (range) days between diagnosis and VEN start was 13 (1-285). NCAM1 positivity significantly correlated with shorter OS in the univariable (HR=1.80 [95% CI: 1.04-3.09], p=0.032; Fig 2) and multivariable settings (HR=2.10 [95% CI: 1.17-3.75], p=0.012, N=97), with the latter model controlling for age ≥75, AHD, and CD11b. Conclusion : NCAM1 expression is a marker of poor prognosis in ND AML patients treated with HMA+VEN. Knockout of NCAM1 in the OCI-AML2 cell line sensitized cells to VEN. Our data suggest that NCAM1 expression on AML blasts plays a biological role in promoting cellular resistance to VEN. Given emerging knowledge of VEN targeted downstream pathway associations, experiments are underway to explore the role of MAPK pathway and BCL2 family member dependence.

Non-T-Depleted Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Patients with Relapsed/Refractory Secondary Versus De Novo AML: A Study from the ALWP/EBMT

Background: Secondary acute myeloid leukemia (sAML) is a distinct type of AML. Transplantation, a potentially curative therapy, outcomes are inferior compared to de novo AML. We recently demonstrated (J Hematol Oncol 2023) that results of non-T-cell depleted haploidentical stem cell transplantation (HaploSCT) with post-transplant cyclophosphamide (PTCy) in sAML in complete remission are not significantly different from those in denovo AML. However, the challenge in relapse (Rel)/primary refractory (PR) AML is much higher. Methods:The study aim was to compare the outcomes of HaploSCT with PTCy, performed between 2010 and 2022, in first Rel(Rel1)/PR sAML versus those in Rel1/PR de novo AML. Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. Results: A total of 719 patients (pts) met the inclusion criteria, 129 with sAML and 590 with de novo AML. Median follow-up was 45.6 (IQR] 39.1-57.9) and 43.5 (IQR, 37.5-48.0) months for pts with sAML and de novo AML, respectively (p=0.20). Pts with de novo AML were younger, with a median age of 55.4 (range 18-77.8) versus 61.3 (21-78.8) years, (p<0.0001). The median year of the transplant was 2018 (2010-2011) in pts with sAML and 2017 (2010-2022) in those with de novo AML (p=0.62) and 65.1% and 57.6%, were male (p=0.11). In 81.4% of sAML pts, the antecedent hematological disorder was myelodysplastic syndrome. The cytogenetic risk was categorized as intermediate (58.6% vs 59.4%), adverse (37.4% vs 34.7%), and favorable (4% vs 5.9%) for pts with sAML and de novo AML, respectively (p=0.75) (data missing for 145 pts). A higher percentage of pts with sAML vs de novo AML had PR disease (73.6% vs 58.6%) (p=0.002). HCT-CI was higher in the sAML vs the de novo AML group, with HCT-CI >3 in 40.3% vs 21.9%, respectively (p<0.0001), while the Karnofsky performance status (KPS) did not differ. There was no difference in the frequency of cytomegalovirus (CMV) seropositivity and female donor to male pt combination between the two pt groups. Reduced intensity conditioning was received by 60.2% and 52.2% of the sAML and de novo AML pts, respectively (p=0.1), with thiotepa/busulfan/fludarabine being the most frequent regimen for both groups (38.8% vs 42%, respectively). Graft source was mainly peripheral blood stem cells (PB) in both sAML (69.8.5%) and de novo (66.8%) groups. All pts received PTCy as graft- versus-host disease (GVHD) prophylaxis in combination with immunosuppression, which was cyclosporine A (CSA)/ mycophenolate mofetil in 41.1% vs 52.9% and CSA/tacrolimus in 41.1% vs 33.6% respectively. Cumulative incidence of absolute neutrophil count (ANC) >0.5 x 10 9/L at day 60 was 83.5% vs 88.4% (p=0.13), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was 20% vs 26.9% (p=0.12) and 8.9% vs 10.4%, (p=0.21), respectively. The 2-year (y) total and extensive chronic (c) GVHD were 25.3% vs 20.7% (p=0.27) and 12.5 % vs 10.3% (p=0.46), respectively. In MVA HaploSCT outcomes did not differ significantly between the Rel1 /PR sAML and de novo groups; 2-y non-relapse mortality (NRM) hazard ratio (HR)=1.38 (95% CI 0.96-1.98, p=0.083). Infections and GVHD were the cause of death in 20.8% and 9.3% of pts who died. The HR for 2-y relapse incidence (RI) was 0.68 (95% CI 0.4.7.-1.00, p=0.051) and RI was the main cause of death in 40.9% and 59.3% of pts who died, respectively. The 2-y leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) did not differ between the two groups with HR=0.99 (95% CI 0.76-1.28, p<0.94), HR=0.99 (95% CI 0.77-1.29, p=0.973) and HR=0.99 (95% CI 0.77-1.27, p=0.94), respectively. Adverse-risk cytogenetics was a poor prognostic factor for RI and both higher age (per 10y) and lower KPS were poor prognostic factors for NRM. Adverse-risk cytogenetics and lower KPS were poor prognostic factors for LFS, OS, and GRFS. In addition, pt CMV seropositivity was a poor prognostic factor for OS. Finally, PB grafts were associated with increased risk of all grades and severe aGVHD. Conclusions: In this registry-based retrospective analysis, we observed similar outcomes, of HaploSCT with PTCy for Rel1/PR sAML compared to Rel1/PR de novo AML, with HaploSCT being able to rescue about one-third of the pts. However, relapse is still 43%. The recently approved novel agents for sAML will hopefully further improve sAML outcomes.

Acute Myeloid Leukemia with Inv(3) or t(3;3): A Clinical and Cytogenetic Characterization of 40 Patients

Background: Acute myeloid leukemia (AML) with inv(3) or t(3;3) is an extremely aggressive and rare subtype of AML. Leukemogenesis in inv(3) AML is in part due to juxtaposition of the GATA2 enhancer in close proximity to the MECOM/EVI1 promoter; as the result, the fusion drives EVI1 overexpression and uncontrolled proliferation of myeloid progenitors. Given its rarity, published clinical outcome data are limited. To improve our understanding of the clinical outcomes of inv(3) AML, we conducted a retrospective study to describe the clinical features of a cohort of newly diagnosed inv(3)/t(3;3) AML patients treated at Stanford Cancer Center between 2002 and 2023. Methods: Data were retrospectively collected from databases associated with the Stanford Health Care electronic health record (EHR), and diagnosis dates came from the Stanford Cancer Registry. Inv(3)/t(3;3) AML diagnosis was defined according to WHO criteria as the presence of ≥20% blasts in the bone marrow (BM) or peripheral blood (PB) and the presence of inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) on cytogenetic analysis at initial diagnosis. Response to first induction, salvage, and consolidation therapy as well as allogeneic hematopoietic stem cell transplant (alloHSCT) were captured. CR was defined as the presence of <5% of blasts in the BM evaluation by morphological evaluation after each line of treatment. Overall survival (OS) was defined as time from diagnosis to death from any cause. A descriptive study of the main demographic, clinical, hematologic, and cytogenetic variables of patients who received intensive and non-intensive therapy was performed. The analysis was performed using R 4.3.1. A p value of < 0.05 was defined to be statistically significant. Results: A total of 40 patients met inclusion criteria including 68% (n=27) with de novo AML, 25% (n=10) with secondary AML from an antecedent hematological disorder and 7.5% (n=3) therapy-related AML. Clinical characteristics of the patients are summarized in Figure 1A. The median age at time of diagnosis was 56 (range, 19-78). There was a slight female predominance, with 58% (n=23) female and 42% (n=17) males. Ninety-three percent of patients had an ECOG score ≤1 (n=37). Median leukocyte, hemoglobin, and platelet counts were 4.5 K/uL, [1.3-761], 9.4 g/dL, [3.4-13.6], and 98 K/uL [9-592], respectively. The median blast percentage in BM and PB was 49% [13-98] and 30% [0-95], respectively. Inv(3)/t(3;3) was the only cytogenetic aberration in 10 patients (25%) and chromosome (chr) 7 abnormalities were the most common additional aberration, present in 22 patients (55%). CR after the first induction therapy was achieved in 9 patients (22%); 6 patients (15%) died during or shortly after induction therapy, and the remaining 25 (63%) were resistant. Salvage therapies for patients included re-induction with 7+3, FLAG-Ida, mitoxantrone-containing regimens, clofarabine-based protocols, or combination of hypomethylating agents with venetoclax. Seventeen (43%) patients underwent alloHSCT (10 in CR and 7 with active disease). When comparing intensive vs non-intensive induction regimen, no statistical significance was identified for complete remission (CR) rate (p= 1.00), overall survival (OS) rate (p=0.65) or relapse-free survival (RFS) rate (p=0.86). Similarly, no statistically significant prognostic factors (age, WBC, BM blast %, platelet count, hemoglobin, ANC, or time to transplant) for OS were identified. Interestingly, chr 7 abnormalities in inv(3) patients conferred a worse prognosis in this cohort (OS 41% vs. 59%, p= 0.0064, Figure 1B). This association was confirmed using a multiple Cox proportional hazards regression adjusting for age and blast percentage. Moreover, while chr 7 abnormality was also associated with a lower response rate (CR 14% vs. 40%), it did not reach statistical significance (p=0.12). Conclusions: In summary, de novo AML inv(3)/t(3;3) is a rare and aggressive subtype of AML conferring extremely poor prognosis. There appears to be an increase of incidence in females affecting a slightly younger demographic. Consistent with previous studies, the presence of chr 7 abnormalities was associated with even worse outcomes, which interestingly also drive EVI1 overexpression. The exact link between 3q26 loci rearrangements and chr 7 abnormalities warrants further investigation.

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of >24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.

Real World Outcomes of Patients with Secondary Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation after Induction with Liposomal Daunorubicin-Cytarabine (CPX-351)

Background: Liposomal Daunorubicin-Cytarabine (CPX-351 or Vyxeos), is approved for upfront treatment of adult and pediatric patients with secondary Acute Myeloid Leukemia (sAML) based on results of a randomized phase 3 trial comparing CPX-351 to conventional chemotherapy with 7+3 regimen. The study showed CPX-351 treated patients demonstrated superior complete remission (CR) rates and overall survival (OS) [Lancet et al JCO 2018]. In this study, a higher proportion of CPX-351 treated patients underwent allogeneic hematopoietic cell transplantation (alloHCT), and landmark OS analysis favored CPX-351 treated patients (HR=0.46; 95% CI: 0.24-0.89; p=0.009). Herein, we reviewed City of Hope (COH) and University of California Los Angeles Medical Center (UCLA) database for patients with sAML who underwent allogeneic HCT after CPX-351 induction to investigate OS and disease-free survival (DFS) outcomes of alloHCT in CPX-351 treated patients and to investigate if HCT outcomes are impacted by achievement of pre-HCT measurable residual disease (MRD) negative remission. Methods: We conducted a multi-center retrospective review of 38 consecutive patients who received CPX-351-based induction before allogeneic HCT to treat sAML, at COH (n=10) and UCLA (n=28), between 2017-2021. The primary endpoint was 2-year OS and DFS in all patients. Secondary outcomes included MRD-ve complete remission (CR) after CPX-351 induction. CR was defined as <5% blasts in bone marrow (BM) aspirates. CR with with hematologic recovery (CRh) was defined as absolute neutrophil counts >1000/µL and platelets ≥100,000/µL. Patients without CRh were categorized as CR with incomplete blood recovery (CRi). MRD assessment was done on day-28 BM aspirate using multiparametric flow cytometric (FC) assay with lower limit of sensitivity of 0.01%. OS was defined as the time from the start of therapy to death and patients were censored if alive at the last follow-up, DFS was defined as the time interval from the date of response to relapse or death, whichever occurred first, and patients were censored at the last follow-up if still leukemia free. Descriptive statistics were used to summarize patient demographics, and disease characteristics. Kaplan-Meier curves and log-rank test were used to evaluate OS and LFS. Results: Patients' demographic and disease features are summarized in Table 1. Briefly, the median age at diagnosis was 65 years (range: 14-77) and median blast percentage in BM at diagnosis was 34% (range: 20-69%). Based on ELN criteria, 25 patients (66%) had adverse risk, 12 (32%) had intermediate risk and one (2.6%) had favorable risk AML. sAML was due to antecedent hematologic disorder (AHD) in majority of patients (n=32; 84%), therapy related in four (10%) and MDS-related changes (MRC) in two patients (5.3%). Following Vyxeos treatment, the composite CR rate (CRh+CRi) was 76% (CRh in 25, CRi in 4 patients) and 9 patients (23%) were refractory to upfront therapy. Pre-HCT MRD status was available for majority of patients (n=34; 89%). MRD negative remission by FC was achieved in 58% (20/34) patients (Table 2). The 1- and 2-years OS was 65% (95% CI: 48-78%) and 54% (95% CI: 36-68%), respectively and the 1- and 2-years DFS was 58% (95% CI: 41-71) and 50% (95%CI: 33-64%), respectively (Figure 1). In the 34 patients with available pre-HCT MRD data, no significant difference in OS (50% vs 58%; p=0.4) or DFS (50% vs 48%; p=0.93) was observed based on pre-HCT MRD status. More patients with who were MRD-positive after induction (50%; 7/14) received myeloablative conditioning (MAC) regimen compared to only 15% (3/20) of patients with MRD negative remission. Conclusion: CPX-351 induction in patients with sAML is associated with high MRD negative remission and promising 2-year OS/DFS after allogeneic HCT. In patients with MRD positive remission status after CPX-351 induction, MAC conditioning regimens may be preferred to reduce relapse incidence after alloHCT.

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

Multiparametric analysis of etoposide exposed mesenchymal stem cells and Fanconi anemia cells: implications in development of secondary myeloid malignancy.

Secondary acute myeloid leukemia (sAML) may develop following a prior therapy or may evolve from an antecedent hematological disorder such as Fanconi Anemia (FA). Pathophysiology of leukemic evolution is not clear. Etoposide (Eto) is a chemotherapeutic agent implicated in development of sAML. FA is an inherited bone marrow (BM) failure disease characterized by genomic instability and xenobiotic susceptibility. Here, we hypothesized that alterations in the BM niche may play a critical/driver role in development of sAML in both conditions. Expression of selected genes involved in xenobiotic metabolism, DNA double-strand break response, endoplasmic reticulum (ER) stress, heat shock response and cell cycle regulation were determined in BM mesenchymal stem cells (MSCs) of healthy controls and FA patients at steady state and upon exposure to Eto at different concentrations and in recurrent doses. Expression of CYPA1, p53, CCNB1, Dicer1, CXCL12, FLT3L and TGF-Beta genes were significantly downregulated in FA-MSCs compared with healthy controls. Eto exposure induced significant alterations in healthy BM-MSCs with increased expression of CYP1A1, GAD34, ATF4, NUPR1, CXCL12, KLF4, CCNB1 and nuclear localization of Dicer1. Interestingly, FA-MSCs did not show significant alterations in these genes upon Eto exposure. As opposed to healthy MSCs DICER1 gene expression and intracellular localization was not altered on FA BM-MSCs after Eto treatment. These results showed that Eto is a highly potent molecule and has pleiotropic effects on BM-MSCs, FA cells show altered expression profile compared to healthy controls and Eto exposure on FA cells shows differential profile than healthy controls.

Association between Prior Cytotoxic Therapy, Antecedent Hematologic Disorder, and Outcome after Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia.

(1) Background: Secondary acute myeloid leukemia (AML), i.e., AML arising from prior therapy (therapy-related) and/or an antecedent hematologic disorder (AHD) is generally associated with worse outcomes compared to de novo AML. However, recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary AML is now considered a diagnostic qualifier rather than a separate disease entity. (2) Methods: To assess the association between clinical history and AML outcomes in the context of allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 759 patients with de novo AML, 115 with AHD AML, and 105 with therapy-related AML who received first allografts while in first or second remission. (3) Results: At the time of HCT, these three cohorts differed significantly regarding many patient and disease-specific characteristics, including age (p < 0.001), gender (p < 0.001), disease risk (p = 0.005), HCT-CI score (p < 0.001), blood count recovery (p = 0.003), first vs. second remission (p < 0.001), remission duration (p < 0.001), measurable residual disease (MRD; p < 0.001), and conditioning intensity (p < 0.001). Relative to patients with de novo AML, relapse rates were similar for patients with AHD (hazard ratio [HR] = 1.07, p = 0.7) and therapy-related AML (HR = 0.86, p = 0.4) after multivariable adjustment, as were relapse-free survival (HR = 1.20, p = 0.2, and HR = 0.89, p = 0.5) and overall survival (HR = 1.19, p = 0.2, and HR = 0.93, p = 0.6). Non-relapse mortality was higher for AHD AML (HR = 1.59, p = 0.047). (4) Conclusions: These data suggest that the clinical history by itself contains limited prognostic value for adults with AML undergoing allografting, supporting the most recent approach to use this information as a diagnostic qualifier rather than a disease entity.

Optimizing outcomes in secondary AML

Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.

Time-Dependent Prediction of Relapse in Patients with Acute Myeloid Leukemia

Background: Although most patients with newly diagnosed acute myeloid leukemia (AML) obtain a complete remission (CR) following induction chemotherapy, most subsequently relapse. Previous studies have demonstrated the importance of various prognostic factors for relapse-free survival, including age, cytogenetics, prior antecedent hematologic disorder (AHD), and prior cancer-related therapy. However, assessments of treatment response now include additional factors such as measurable residual disease (MRD) status, time to count recovery, and remission type (CR vs. CR with incomplete count recovery [CRi]). Among patients in complete remission, we set out to examine the impact of additional initial response variables on relapse or death at various time points up to 3 years, a time point after which AML relapses become very uncommon. Methods: Of 972 patients who had a confirmed diagnosis of AML or other high-grade myeloid neoplasm (≥10% blasts) underwent initial induction treatment at University of Washington / Fred Hutchinson Cancer Center between November 2008 and December 2018, 656 achieved a morphologic remission (CR or CRi) and were included in our analysis. The primary outcomes were survival without relapse after 1, 2, or 3 years. Multivariable logistic regression models controlled for the following covariates: age, ELN 2017 risk classification, presence of MRD determined by multiparameter flow cytometry at first remission, gender, WBC count at diagnosis, prior AHD and/or therapy-related disease, performance status, treatment-related mortality (TRM) score, induction intensity (high: CLAG-M, FLAG-ida, or similar; intermediate: 7+3 or similar; low: hypomethylating agent with or without venetoclax), CR vs CRi, and count recovery within 30 days. Time to relapse was estimated using relapse-free survival curves. Results: The median age at diagnosis was 60 years (range 18-91). De novo AML was found in 373 patients (57%) with the remainder a mix of antecedent AHD and therapy-related AML. ELN2017 risk classification was favorable in 181 patients (28%), intermediate in 206 (41%), and adverse in 203 (31%). Performance status was 0-1 in 538 patients (82%). Most patients received high or intermediate-intensity induction (88%). After induction, 540 patients (82%) achieved a CR and 116 patients (18%) CRi. MRD following induction therapy was found in 173 patients (26%). In multivariable analysis, age, remission type (CRi), and MRD status were the strongest predictors of being alive without relapse at years 1, 2, and 3 (year 3 summarized in Table 1). In the year 3 model, CR MRD+ after induction was associated with the largest decrease in odds of being alive without relapse (CR MRD+: odds ratio [OR] 0.15, 95% confidence interval [CI] 0.08-0.27). 3-year relapse-free survival (RFS) of 18.5% (95% CI 13.5-25.5%) for MRD+ patients versus 36.4% (95% CI 31.3-42.4%) for MRD- patients (Figure 1). CRi MRD+/MRD- were both also associated with decreased survival with CRi MRD- (OR 0.33, 95% CI 0.16-0.65) and CRi MRD+ (OR 0.40, 95% CI 0.18-0.87). Increasing age was the second strongest predictor across the models (year 3 OR 0.78, 95% CI 0.67-0.89). Conclusions: Our study identified remission category (CR vs CRi), MRD status, and age as the strongest predictors of being alive without relapse at years 1, 2, or year 3 following induction for patients with AML and other high-grade myeloid neoplasms. Patients with older age or those with evidence of residual detectable disease with MRD or CRi and/or MRD have an increased risk of relapse or death in the first 3 years after initial CR. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Outcomes of Acute Myeloid Leukemia Following Allogeneic Stem-Cell Transplantation after Decitabine and Venetoclax: Subgroup Analysis of a Phase II Trial

Introduction: Venetoclax (VEN)-based lower intensity regimens are the current standard for older/unfit patients with newly diagnosed acute myeloid (AML). Such regimens are increasingly used in the salvage setting as well. Allogeneic stem-cell transplantation (SCT) following VEN-based regimens has been shown to be safe and feasible in pts with AML (Mukherjee et al. J Clin Oncol 2019; Pratz et al. Blood 2019). We herein describe long-term outcomes after SCT following treatment on a prospective clinical trial of 10-day decitabine and venetoclax (DEC10-VEN) for treatment-naïve and previously treated AML (NCT03404193). Methods: In this phase II trial, pts received decitabine 20 mg/m2 for 10 days during induction and 5 days during consolidation. VEN was administered 400 mg daily on D1-28 during cycle 1 but was held on day 21 if bone marrow evaluation showed blasts ≤5%. During subsequent cycles VEN duration could be reduced in pts with myelosuppression. This trial enrolled pts with ECOG PS ≤3 with adequate organ function. Pts with favorable risk cytogenetics were excluded. Pts with newly diagnosed AML were either unfit for intensive therapy, or older than 60 yrs. Pts in relapsed/refractory cohort were ineligible if they had received prior BCL2 inhibitor. Eligible pts with an available donor could proceed to SCT at any time following achievement of response. Response, overall survival (OS) and relapse-free survival were defined per ELN2017. Survival outcomes were not censored at SCT. Data cut-off date was July 26, 2022. Results: Between January 2018 and June 2022 we enrolled 230 pts with AML, high-risk or relapsed/refractory myelodysplastic syndrome or chronic myelomonocytic leukemia, and blastic plasmacytoid dendritic cell neoplasm. Among 201 pts with AML, CR/CRi/MLFS response was achieved in 146 pts (73%) and 40 pts (20%) were able to proceed to SCT; including 21 pts with treatment-naïve AML and 19 pts with either R/R AML or AML following treatment for antecedent hematological disorder (AHD) including MDS-EB (n=2) and CMML (n=1), considered "previously treated AML". The median age of pts undergoing SCT was 66 yrs (range 18-77); 10 pts (25%) were older than 70 yrs, 16 pts (40%) pts had R/R AML, 19 pts (45%) had ELN adverse risk disease and 4 pts had received prior SCT (Table 1). Fourteen pts in each group received additional concomitant therapy with FLT3 inhibitors including gilteritinib and sorafenib (Table 1). All pts proceeding to SCT were in CR/CRi except in the previously treated group where 4 pts had non-CR/CRi responses including MLFS/aplasia. 28 pts (70%) had achieved negative measurable residual disease (MRD) by flow cytometry (sensitivity 0.1-0.01%) prior to proceeding to SCT while 8/40 pts (20%) had persistent MRD. Remaining 4 pts either had inadequate sample or were not evaluated for MRD. Conditioning regimens and donor types are summarized in Table 1. Median no. of cycles of DEC10-VEN administered was 2 (range 1-12) and the median time to SCT was 3.5 mo from start of DEC10-VEN (range 1.1-16.2). The median follow-up duration was 29.1 mo. Among pts with AML who proceeded to SCT, the 100-day post-SCT mortality was 8% (n=3). The median OS for treatment-naïve pts was 35.1 mo and for previously treated pts was 16.7 mo. Median RFS for treatment naïve pts was 23.5 mo and for previously treated pts was 12.9 mo. Landmark analysis of pts achieving CR/CRi/MLFS and alive at 3.5 mo showed that pts with treatment-naïve AML who were eligible to proceed to SCT (n=21) derived significant benefit in OS with median OS 35.1 vs 15.7 mo in pts who did not / were ineligible (n=60) (HR 0.47, 95% CI 0.24, 0.76, p=.01, Fig. 1). Similarly, pts with previously treated AML who proceeded to SCT in CR/CRi/MLFS (n=18) had median OS of 19.3 vs 12.0 mo for pts who could not (n=36) (HR 0.53, 95% CI 0.28, 1.01, p=.07). Both analyses were limited by confounding factors. At data cut-off, 19 pts (48%) are alive, 8 pts (20%) died in remission, and 13 pts (33%) pts died after disease progression (Table 1). Conclusion: In this prospective trial of DEC10-VEN enrolling older/unfit pts with newly diagnosed AML, secondary AML, and younger or older pts with R/R AML, 20% of pts were able to proceed to SCT. DEC10-VEN served as bridge to SCT for responding pts with newly diagnosed as well as previously treated AML, with low 100-day post-SCT mortality. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-279 Molecularly-Defined and Secondary Acute Myeloid Leukemia Are Biologically and Clinically Different Entities

Acute myeloid leukemia (AML) is a heterogeneous disease, which can be clinically classified in de novo AML or secondary AML (sAML) and separate from therapy-related AML. Secondary AML evolves from an antecedent hematological disorder, whereas de novo AML arises in absence of any prior hematological disease or leukemogenic treatment. A broad range of genetic and cytogenetic abnormalities that directly contribute to the development of AML has been identified. Nevertheless, the association of these markers with leukemia ontogeny and clinical response is not completely understood. The primary aim of this study was to discriminate de novo AML from secondary type AML (stAML) based on the occurrence of molecular and cytogenetic markers in a unique large cohort of AML patients (n=2,447) enrolled in the Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) or the Swiss Group for Clinical Cancer Research (SAKK) clinical trials. All patients received intensive treatment. We investigated the clinical and biological differences between de novo AML and sAML with the underlying hypothesis that (molecularly defined) de novo AML and stAML should be considered as two different entities. In our unique AML cohort, we demonstrated that RUNX1, EZH2, SRSF2, STAG2, ZRSR2, SF3B1, ASXL1 and U2AF1 significantly associated with clinically proven sAML (p<0.01). AML cases carrying these mutations were referred to as stAML. Mutations in NPM1, CEBPA (bi-allelic), FLT3-ITD, inv(16), t(8;21) and aberrations involving 11q23 were included as class-defining for de novo AML. AML patients with TP53 mutations were removed from all analyses since this genetically and clinically distinct subtype of AML should be considered as a separate entity. In comparison to de novo AML (n=1705), patients with stAML (n=742) were older (p<0.01), were more likely to be male (p<0.01), carried a higher number of driver mutations (p<0.01), had lower white blood cell counts (p<0.01), more frequently lower bone marrow blast and blood neutrophil counts (p<0.01). Importantly, patients with stAML had a significant inferior event-free (p<0.001) and overall survival (p<0.001). In conclusion, we revealed molecularly defined stAML as an AML subtype with a distinct genetic ontogeny that emphasizes a subgroup of patients with significantly worse clinical outcomes.

PB1820: CD47-BLOCKER TTI-622 COMBINED WITH AZACITIDINE IN PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA (AML) AND WITH AZACITIDINE + VENETOCLAX IN ELDERLY OR UNFIT PATIENTS WITH TP53-WILDTYPE AML

Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a “don’t eat me” signal to suppress macrophage phagocytosis. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Increased expression of CD47 is an adverse prognostic factor in acute myeloid leukemia (AML) due to its association with reduced event-free and overall survival, and blockade of CD47 has shown pre-clinical and clinical activity in AML. In vitro, both azacitidine and venetoclax significantly enhanced the pro-phagocytic effect of TTI-622 on macrophages. Aims: To characterize the safety and preliminary efficacy profile of TTI-622 in combination with azacitidine in newly diagnosed TP53-mutated AML and in combination with azacitidine + venetoclax in elderly or unfit, newly diagnosed TP53-wildtype AML. Pharmacokinetics and immunogenicity of TTI-622 combined with azacitidine ± venetoclax will also be investigated. Primary endpoints include dose-limiting toxicities, incidence of adverse events (AEs) and complete response (CR). Minimal residual disease status will also be evaluated. Methods: As part of an ongoing dose-escalation and expansion trial of TTI-622 (NCT03530683), patients with AML meeting the below key entry criterion are enrolled. Cohort A includes patients with newly diagnosed TP53-mutated AML. Cohort B includes patients with newly diagnosed TP53-wildtype AML who are either elderly (375 years) or unfit. Unfit patients include those < 75 years with one or more of the following comorbidities: Eastern Cooperative Oncology Group (ECOG) performance status of 2, clinically significant heart or lung comorbidities, contraindication to anthracycline therapy, or other comorbidity the investigator regards as incompatible with intensive remission induction chemotherapy. All patients from both cohorts must have documented bone marrow or peripheral blast counts 3 20% and must have received no prior systemic therapy for AML nor hypomethylating agents for any antecedent hematologic disorders prior to transformation to AML. Patients must have no extramedullary disease or leukocytosis >25,000/mL. Renal function must be 330 mL/minute based on Cockcroft-Gault estimate. There are no restrictions based on neutrophil or platelet counts, or hemoglobin level. Patients with AML secondary to antecedent hematologic disorders or therapy induced will not comprise more than 50% of either Cohort. Up to 30 patients will be enrolled into each cohort. In 28-day cycles, patients in both Cohorts will receive TTI-622 8 mg/kg intravenous (IV) infusions weekly combined with azacitidine 75 mg/m2 administered either IV or subcutaneously for 7 consecutive days, repeated approximately every 4 weeks. Patients in Cohort B will also receive venetoclax 100 mg and 200 mg orally on Days 1 and 2, respectively, followed by 400 mg (or equivalent adjusted for azoles) daily thereafter. Safety monitoring includes clinical laboratories and assessments of AEs based on CTCAE v 4.03. Response assessments of both bone marrow and peripheral blood are performed at the end of Cycles 1, 2 and 4; and then every 3 cycles thereafter. Response assessment is per the ELN2017 criteria. Results: Results N/A (trial-in-progress) Summary/Conclusion: Conclusion N/A (trial-in-progress)

Measurable Residual Disease in High-Risk Acute Myeloid Leukemia.

Simple SummaryAssessment of measurable residual disease (MRD) identifies small numbers of acute myeloid leukemia (AML) cells that may remain after initiating treatment. The achievement of MRD negativity (no detectable AML cells remaining) typically predicts better outcomes for patients with AML. Some patients with AML have disease characteristics that put them at a higher risk of treatment failure or relapse; while outcomes for patients with high-risk AML are historically poor with traditional chemotherapy regimens, newer chemotherapy formulations (i.e., CPX-351) and targeted therapies may be more effective in achieving MRD negativity in these patients. Currently, there is no agreement on the best method for determining whether a patient has achieved MRD negativity, and the use of several different methods makes it difficult to compare outcomes across studies. Despite these challenges, regular monitoring of patients for the achievement of MRD negativity will become increasingly important in the routine management of patients with high-risk AML.Mounting evidence suggests measurable residual disease (MRD) assessments are prognostic in acute myeloid leukemia (AML). High-risk AML encompasses a subset of AML with poor response to therapy and prognosis, with features such as therapy-related AML, an antecedent hematologic disorder, extramedullary disease (in adults), and selected mutations and cytogenetic abnormalities. Historically, few patients with high-risk AML achieved deep and durable remission with conventional chemotherapy; however, newer agents might be more effective in achieving MRD-negative remission. CPX-351 (dual-drug liposomal encapsulation of daunorubicin/cytarabine at a synergistic ratio) demonstrated MRD-negativity rates of 36–64% across retrospective studies in adults with newly diagnosed high-risk AML and 84% in pediatric patients with first-relapse AML. Venetoclax (BCL2 inhibitor) demonstrated MRD-negativity rates of 33–53% in combination with hypomethylating agents for high-risk subgroups in studies of older adults with newly diagnosed AML who were ineligible for intensive therapy and 65% in combination with chemotherapy in pediatric patients with relapsed/refractory AML. However, there is no consensus on optimal MRD methodology in AML, and the use of different techniques, sample sources, sensitivity thresholds, and the timing of assessments limit comparisons across studies. Robust MRD analyses are needed in future clinical studies, and MRD monitoring should become a routine aspect of AML management.

Impact of frontline treatment approach on outcomes in patients with secondary AML with prior hypomethylating agent exposure

BackgroundTreated secondary acute myeloid leukemia (ts-AML)—i.e., AML arising from a previously treated antecedent hematologic disorder—is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.MethodsWe retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).ResultsCompared with IC or LIT without venetoclax, HMA plus venetoclax resulted in higher CR/CRi rates (39% and 25%, respectively; P = 0.02) and superior OS (1-year OS 34% and 17%, respectively; P = 0.05). The benefit of HMA plus venetoclax was restricted to patients with non-adverse risk karyotype, where HMA plus venetoclax resulted in a median OS of 13.7 months and 1-year OS rate of 54%; in contrast, for patients with adverse risk karyotype, OS was similarly dismal regardless of treatment approach (median OS 3–5 months). A propensity score analysis accounting for relevant clinical variables confirmed the significant OS benefit of HMA plus venetoclax, as compared with other frontline treatment approaches. In a landmark analysis, patients with ts-AML who underwent subsequent hematopoietic stem cell transplantation (HSCT) had superior 3-year OS compared to non-transplanted patients (33% vs. 8%, respectively; P = 0.003).ConclusionsThe outcomes of ts-AML are poor but may be improved with use of an HMA plus venetoclax-based regimen, followed by HSCT, particularly in those with a non-adverse risk karyotype.

Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives.

Simple SummaryAML is a genetically heterogeneous disease with a median age of diagnosis between 60 and 70 years. Thus, many AML patients are not eligible for intensive chemotherapy. Often, the disease is accompanied by a poor prognosis due to high-risk genetic features or due to antecedent hematologic disorders (e.g., myelodysplastic syndrome). Therefore, AML treatment remains a challenge; even after intensive chemotherapy and allogeneic stem cell transplantation (alloHSCT), AML relapses are regularly observed. Thus, new concepts of AML therapy, considering tailored treatment approaches after comprehensive molecular diagnostic or implementing new immunotherapeutic strategies, are urgently needed. This review provides a detailed overview of recent developments and current promising concepts to improve the treatment and the outcome of AML patients.Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients.

Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation

Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation