Acute Myeloid Leukemia With Myelodysplasia-related Changes Research Articles

[Survival and Prognosis of Patients with Acute Myeloid Leukemia with Myelodysplasia-Related Changes Transformed from Myelodysplastic Syndrome].

To explore the risk factors affecting the survival and efficacy of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) transformed from myelodysplastic syndrome (MDS). The clinical data of 60 patients with AML-MRC transformed from MDS who hospitalized in The Third Affiliated Hospital of Soochow University from January 2010 to December 2021 were retrospectively analyzed. The demographic data and laboratory parameters, cytogenetic karyotypes, target genes of AML detected by next generation sequence, risk stratification, treatment regimen, therapeutic efficacy and survival outcome were documented. Rank sum test and Chi-square test or Fisher exact test were used to compare the survival and efficacy. The effects of clinical parameters, risk stratification and treatment regimens on the survival and efficacy of the AML-MRC patients were analyzed by univariate and multivariate analysis. The median overall survival (OS) of the AML-MRC patients was 4.5 months, the 1-year OS rate was 28.3%, and the complete remission (CR) rate after treatment was 33.3%. The univariate analysis showed that age≥60 years, leukocytosis, severe thrombocytopenia, poor-risk group and only accepted hypomethylating agents(HMAs) or supportive therapy were the risk factors affecting OS. COX multivariate analysis showed that thrombocytopenia ( HR=4.46), HMAs therapy (compared to transplantation, HR=10.47), supportive therapy (compared to transplantation, HR=25.80) and poor-risk group (compared to medium-risk group, HR=13.86) were independent hazard factors for median OS of patients with AML-MRC. The univariate analysis showed that the risk factors affecting 1-year OS in patients with AML-MRC were age≥60 years, thrombocytopenia, time of transformation from MDS to AML (TTA)≥3 months, fibrinogen-albumin ratio index (FARI)≥0.07, CONUT score≥5, poor-risk group and supportive therapy. Binary logistic regression analysis showed that the independent risk factors for 1-year OS in AML-MRC patients were age≥60 years ( HR=11.23), thrombocytopenia ( HR=8.71), FARI≥0.07 ( HR=5.19) and poor-risk group ( HR=14.00). The risk factors affecting CR of AML-MRC patients in univariate analysis were age≥60 years, thrombocytopenia, FARI≥0.1, CONUT score≥5, poor-risk group and supportive therapy, while binary logistic regression analysis showed that age≥60 years( HR=7.35), CONUT score≥5 ( HR=9.60), thrombocytopenia ( HR=12.05) and poor-risk group ( HR=32.5) were independent risk factors affecting CR of the patients. The OS of AML-MRC patients is poor, old age(≥60 years old), supportive therapy, HMA therapy, poor-risk, thrombocytopenia, FARI≥0.07 and CONUT score≥5 may be associated with poor prognosis.

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.

[Clinical and prognostic characteristics of pediatric acute myeloid leukemia with myelodysplasia-related changes under different diagnostic criteria].

Objective: To evaluate the clinical and prognostic differences in acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) children under different diagnostic criteria (World Health Organization (WHO) 2016 and WHO 2022 criteria). Methods: In this retrospective cohort study, clinical characteristics and prognosis information of 260 acute myeloid leukemia (AML) children admitted to Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences from August 2017 to August 2021 were analyzed retrospectively. According to WHO 2016 and WHO 2022 diagnostic criteria, patients were divided into AML-MRC group and non-AML-MRC group, the prognostic and genetic differences between two groups were compared respectively. Meanwhile, the characteristics of children with 8 MRC-related genes defined in WHO 2022 diagnostic criteria were described. Mann-Whitney U test, chi-square test were used for comparison between groups. Survival curve was plotted by Kaplan-Meier method, and comparison between groups was performed by Log-Rank method. Results: Among the 260 children, there were 148 males and 112 females. The follow-up time was 26 (16, 38) months. A total of 28 children (10.8%) were diagnosed with AML-MRC according to the WHO 2016 diagnostic criteria. Compared with non-AML-MRC children, the frequency of PTPN11, RUNX11, SH2B3, MPL and STAG2 mutations was higher in AML-MRC children (25.0% (7/28) vs.4.3% (10/232), 14.3% (4/28) vs.3.9% (9/232), 10.7% (3/28) vs.2.2% (5/232), 10.7% (3/28) vs.2.2% (5/232), 10.7% (3/28) vs.0.9% (2/232), all P<0.05). The 2-year overall survival (OS) and events free survival (EFS) rate of 28 AML-MRC children under WHO 2016 diagnostic criteria were worse than those of 232 non-AML-MRC children ((62.1±10.8)% vs. (94.5±1.6)%, χ2=22.1,P<0.001;(48.0±10.6)% vs. (70.9±3.2)%, χ2=6.33,P=0.012). Twenty-seven children (10.4%) were eventually diagnosed with AML-MRC according to WHO 2022 criteria, their 2-year OS rate were worse than 233 non-AML-MRC children ((60.8±11.1)% vs. (94.5±1.6)%, χ2=24.49,P<0.001), and there was no statistically significant difference in EFS rate between two groups at 2 years ((55.1±10.8)% vs. (70.1±3.2)%, χ2=2.44, P=0.119). Conclusions: Compared with the 2022 WHO diagnostic criteria, the survival rates of children with AML-MRC under the 2016 WHO diagnostic criteria were worse than that of children without MRC.The new version of the AML-MRC diagnostic criteria emphasizes the importance of genes.

Mapping AML heterogeneity - multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses.

Subtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n = 1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA-mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A, NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.

Decitabine-containing conditioning improved outcomes for children with higher-risk myelodysplastic syndrome undergoing allogeneic hematopoietic stem cell transplantation.

Myelodysplastic syndrome (MDS) is a rare clonal hematopoietic disorder in children. The risk stratification system and treatment strategy for adults are unfit for children. The role of hypomethylating agents (HMAs) in higher-risk childhood MDS has not been identified. This study aimed to investigate the outcomes of hematopoietic stem cell transplantation (HSCT) in children with higher-risk MDS at one single center. A retrospective study was conducted in children with higher-risk MDS undergoing HSCT between September 2019 and March 2023 at Blood Diseases Hospital CAMS. The clinical characteristics and transplantation information were reviewed and analyzed. A total of 27 patients were analyzed, including 11 with MDS with excess blasts (MDS-EB), 14 with MDS-EB in transformation (MDS-EBt) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 2 with therapy-related MDS/AML (t-MDS/AML). Eight patients harbored monosomy 7. Before transplantation, induction therapy was administered to 25 patients, and 19 of them achieved bone marrow blasts <5% before HSCT. The stem cell source was unmanipulated-related bone marrow or peripheral blood stem cells for nineteen patients and unrelated cord blood for eight. All patients received decitabine-containing and Bu/Cy-based myeloablative conditioning; 26 patients achieved initial engraftment. The cumulative incidences of grade II-IV and grade III-IV acute graft-versus-host disease (GvHD) at 100 days were 65.4% and 42.3%, respectively. The incidence of cGvHD was 38.5%. The median follow-up was 26 (range 4-49) months after transplantation. By the end of follow-up, two patients died of complications and two died of disease progression. The probability of 3-year overall survival (OS) was 84.8% (95%CI, 71.1 to 98.5%). In summary, decitabine-containing myeloablative conditioning resulted in excellent outcomes for children with higher-risk MDS undergoing allogeneic HSCT.

Transposable Elements Are Differentially Expressed in MDS Stem Cells in a Disease-Stage-Specific Manner

Introduction Transposable elements (TEs) are widely spread across the human genome. Although TEs have been implicated in the pathogenesis of hematological malignancies, their expression in myelodysplastic syndromes (MDS) has not yet received extensive analysis. In the present study, we performed RNA sequence analysis of bone marrow stem and progenitor cells from patients with MDS and secondary acute myeloid leukemia (AML) and profiled differentially expressed TEs. Methods Bone marrow samples were obtained from each patient at the time of diagnosis. Normal bone marrow (NBM) samples from four healthy individuals were purchased from Lonza and processed in the same manner. After separation of CD34 + cells using magnetic beads, we purified lineage marker-negative (Lin -) CD34 + CD38 - stem cells and Lin - CD34 + CD38 + progenitor cells by cell sorting. The sorted cells were subjected to RNA-seq analysis using oligo-dT primers, which can capture poly-adenylated TE transcripts. Each read was aligned to the reference genome, then the annotation of the transcripts was performed using RepeatMasker, a program that screens DNA sequences for interspersed repeats and low-complexity DNA sequences (https://www.repeatmasker.org). Read counts for individual TEs were aggregated to the level of TE class, family, and subfamily according to hierarchies defined by the human RepeatMasker (repClass, repFamily, and repName, respectively). To generate raw counts of individual TE regions in RepeatMasker, the bedtools map function (version 2.27.1) was used with bed files of each sample. Normalization and significant expression differences were detected using DESeq2 (version 2.2.1). Differentially expressed TEs were defined using the cutoff of adjusted P values (q &amp;lt; 0.05). DESeq2 normalized counts were obtained from read counts by considering sequence depth, gene length, and RNA composition. Normalized counts were z-score scaled, and then subjected to uniform manifold approximation and projection (UMAP). Results Thirty-two patients were included in the present study. According to the 2016 revision to the World Health Organization classification (Arber DA, et al. Blood. 2016; 127: 2391-2405), 13 patients (40.6%) were diagnosed with MDS with multilineage dysplasia (MDS-MLD), 15 patients (46.9%) with MDS with excess blasts (MDS-EB), and 4 patients (12.5%) with AML with myelodysplasia-related changes (AML-MRC). We found that 26 and 17 repName TEs were significantly up-regulated in stem and progenitor cells compared with their NBM counterparts, and the majority of them belonged to LTRs, followed by DNA transposons. Since each LTR has multiple individual regions where similar sequences are scattered, LTR expression was further distinguished by the genomic locations of individual LTRs. Comparison of MDS-MLD, MDS-EB, and AML/MRC stem and progenitor cells to NBM counterparts revealed that more LTRs were differentially expressed in stem cells than in progenitor cells. Among them, many of the up-regulated LTRs were shared among different disease types (MDS-MLD, MDS-EB, and AML-MRC) in both stem and progenitor cells. AML-MRC had the largest number of differentially up- and down-regulated LTRs in stem cells. MDS-EB had the largest number of differentially up-regulated LTRs in progenitor cells, while only a small portion of LTRs were down-regulated in progenitor cells. LTRs at individual regions were differentially expressed in a more disease-specific manner, particularly in stem cells. Accordingly, UMAP plots that visualized the expression profiles of LTRs at individual regions showed that AML-MRC stem cells form a unique cluster, discriminating AML-MRC from MDS. To further understand the transcriptional reprogramming of LTRs during the disease progression from MDS to secondary AML, we analyzed the expression of differentially expressed LTRs at individual regions specific to AML-MRC by K-means clustering. They were subdivided into four clusters, of which Clusters 1, 3, and 4 showed gradual upregulation during disease progression, while Cluster 2 showed comparable upregulation at MDS and AML-MRC stages. Conclusions Our results suggest that specific LTRs behave in a disease-status and cell-type-specific manner in MDS and during leukemic transformation, providing fundamental information for understanding the pathogenesis of MDS.

Advances in Acute Myeloid Leukemia Classification: A Comparative Analysis of Who-HAEM4R, Who-HAEM5, and International Consensus Classification

Introduction Two guidelines were recently published to refine the diagnostic criteria of acute myeloid leukemia (AML): the 5th edition of the World Health Organization Classification of Haematolymphoid Tumors (WHO-HAEM5, PMID: 35732831) and the International Consensus Classification (ICC; PMID: 35767897), and both expanded molecularly defined AML subtypes. In this study, we utilized a cohort of 1135 AML cases to examine their performance. Methods From Sep 1, 2018 to Dec 31, 2022, a consecutive cohort of 1135 cases diagnosed with de novo AML according to WHO-HAEM4R (PMID: 27069254) were enrolled, with a median follow-up of 20 months. All underwent high-throughput sequencing (PMID: 34135310, 29932212). Results When classified according to WHO-HAEM4R, 55% of the 1135 cases were diagnosed as AML with recurrent genetic abnormalities, 16% were AML with myelodysplasia-related changes (AML-MRC), 2% were therapy-related AML, 4% were AML with germline predisposition, and 24% fell into AML not otherwise specified (AML, NOS). Major changes in WHO-HAEM5 include the inclusion of AML subtypes of KMT2A rearrangement (KMT2A-r), MECOM-r, and NUP98-r; adding AML with other defined genetic alterations (AML-ODGA) as a basket entity; and annulling the entity of AML with mutated RUNX1 (AML-RUNX1). The entity of AML with CEBPA mutation (AML-CEBPA) has changed to include not only biallelic (biCEBPA) but also single bZIP (smbZIP-CEBPA) mutations. AML-MRC in WHO-HAEM4R is redefined as AML, myelodysplasia-related (AML-MR), with a mutation-based definition based on an 8-gene panel (without RUNX1). When comparing WHO-HAEM4R and WHO-HAEM5 (Fig. 1), AML with KMT2A-r increased from 2% to 10% because WHO-HAEM5 no longer restricts the partner genes of KMT2A. AML with NUP98-r and AML-ODGA in WHO-HAEM5 account for 6% and 4%, respectively. AML-MR increased from 12% AML-MRC to 21% benefited from the 8-gene panel-based definition. AML-RUNX1 has been annulled in WHO-HAEM5 and 63% cases of this subtype were reclassified as AML-MR, and 30 cases with RUNX1 mutations as the only basis for classification were reclassified as AML defined by differentiation. In total, AML without defining genetic abnormalities dropped from 24% to 11%. When comparing WHO-HAEM4R and ICC (Fig. 1), AML with mutated TP53 (AML-TP53) is a new category in ICC and accounted for 4% of AML, 79% of them were previously classified as AML-MRC in WHO-HAEM4R. AML-MR in WHO-HAEM5 is divided into two entities in ICC: AML with MR gene mutations (including RUNX1) and AML with MR cytogenetic abnormalities, comprising 13% and 5% of cases, respectively. ICC only includes in-frame bZIP CEBPA mutations. Thus 6 cases classified as AML-biCEBPA based on WHO-HAEM4R fell into AML, NOS under ICC since their CEBPA mutations were not in bZIP. Conversely, 21 cases with smbZIP-CEBPA and diagnosed as AML, NOS according to WHO-HAEM4R were classified as AML-CEBPA under ICC. Cases classified as AML-CEBPA based on WHO-HAEM5 tended to have a better overall survival (OS) than cases classified as AML-biCEBPA under WHO-HAEM4R because AML-smbZIP-CEBPA was added while cases with MR gene mutations which had a worse prognosis fell into AML-MR under WHO-HAEM5. Despite ICC only included in-frame bZIP-CEBPA mutations, the prognosis of AML-CEBPA diagnosed under ICC was not superior to that under WHO-HAEM5. This might be because cases with both MR cytogenetic abnormalities and CEBPA mutations were reclassified as AML-CEBPA under ICC's hierarchical principle. ICC distinguished AML with KMT2A::MLLT3 from AML with KMT2A-r, while WHO-HAEM5 only included AML with KMT2A-r entity. Survival analysis showed significantly better OS in AML with KMT2A::MLLT3 than AML with KMT2A-r. ICC separated AML-TP53 from AML-MR due to the notorious prognosis of TP53 defects, and cases classified as AML-TP53 showed the worst OS in this cohort. But prognostic analysis showed no difference between AML-TP53 and cases with concurrent TP53 mutation and other AML-defining genetic abnormalities. The rationality of considering AML-TP53 as a distinct entity remains debatable. Conclusions Both new classification systems consider genomic features more extensively and enhance the precise classification of AML. Discrepancies between WHO-HAEM5 and ICC, like classifying AML with RUNX1 mutations and the rationality of defining AML-TP53 as a unique entity, remain open questions that require further research for clearer answers.

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 &amp;lt;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 &amp;lt;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 &amp;lt;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 &amp;lt;60 was 16 mos, and for pts ≥60 was 10 mos (p=0.39). The mOS for pts that achieved CRc in the group &amp;lt;60 was 20.3mos, and for ≥60 was 11.2 mos (p=0.27). Pts that underwent alloSCT in CR1 &amp;lt;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 &amp;lt;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.

Outcomes of Patients with Acute Myeloid Leukemia with Myelodysplasia Related Changes (AML-MRC) Receiving Intensive Vs. Non-Intensive First Line Treatment

Background: Acute myeloid leukemia with myelodysplasia related changes (AML-MRC) a distinct clinico-pathologic subtype of AML recognized in the WHO and ICC 2022 classifications of hematolymphoid neoplasms (AML-MRC and AML-MR respectively). Compared to other subtypes, patients with AML-MRC/AML-MR have a worse prognosis and are less likely to respond to treatment. Traditionally, patients who are eligible for allogenic stem cell transplant (SCT) with AML-MRC/AML-MR are given high intensity chemotherapy (IC), such as daunorubicin and cytarabine (“7+3”), liposomal 7+3 or fludarabine+cytarabine+idarubicin (FLAG-IDA) whereas patients who are not transplant-eligible were treated with hypomethylating agents (i.e. azacitidine). Recently, azacitidine + venetoclax (aza/ven) has emerged as an important option for all AML patients over 75 years of age or with significant comorbidities who are not eligible for IC. However, the efficacy of aza/ven compared to IC for AML-MRC who are candidates for either has not been clearly established. Methodology: We conducted a single centre retrospective review of patients diagnosed with AML-MRC/AML-MR at Sunnybrook Health Science Centre (SHSC). A list of patients with AML-MRC/AML-MR was compiled from records from the Sunnybrook Hematology Biobank, which collects specimens and clinical data from 95% of acute leukemia patients presenting to SHSC. 65 patient charts were reviewed, and 60 patients were included in the study. 3 patients were not treated at SHSC and 2 were more appropriately classified as AML with recurrent genetic abnormalities. Treatment with a “7+3” backbone or FLAG-IDA were considered ‘intensive’ regimens; treatment with azacitidine with or without venetoclax, and low dose cytarabine (LDAC), with or without venetoclax were considered ‘non-intensive.‘ ELN 2022 criteria were used to evaluate responses to therapy. Results: 60 patients with AML-MRC/AML-MR were treated at SHSC from January 2021 to April 2023. The median age was 74 (37-99) y.o. 34 patients were male. The upper age of eligibility for allogeneic stem cell transplant was considered 72 years for this study. 28 patients were SCT eligible (31-72y.o.) and 32 patients were SCT ineligible (73-99y.o.). For SCT eligible patients, 14/28 were treated intensively and 10/28 were treated non intensively. 4 patients did not receive treatment. Of the SCT eligible group, 6/14 intensively treated patients achieved a CR/CRi compared to 5/10 non-intensively treated patients. For SCT ineligible patients, 8/32 did not receive treatment and the remaining 24 were treated non intensively. 12/24 SCT ineligible patients receiving treatment were given azacitidine+ venetoclax (aza/ven) and 9/12 achieved a CR/CRi. 7/24 patients received LDAC + venetoclax and 3/7 achieved a CR. In total, 14/60 patients were treated intensively, 21/60 patients were treated with aza/ven, 7/60 received LDAC+venetoclax, 5/60 azacitidine alone and 1/60 LDAC alone. 12/60 patients did not receive leukemia-directed therapy, either due to concomitant illness precluding treatment or a decision to decline treatment. Notably, 14/21 patients receiving aza/ven achieved a CR/CRi compared to 6/14 intensively treated patients, though more intensively treated patients ultimately proceeded to transplant (Figure 1). 48 patients who underwent therapy had next generation sequencing data for mutations of interest in AML. The most common mutations found in this cohort were ASXL1 (32), SRSF2 (20), RUNX1 (18), TET2 (17), IDH2 (16) and TP53 (12). No differences were found between patients that responded to first line therapy compared to those that did not, or those that responded to intensive chemotherapy compared to those responding to non-intensive treatment (Figure 2). Conclusion: Aza/Ven is an effective treatment regimen for AML-MRC/AML-MR, with 14/21 patients achieving CR/CRi after firstline treatment compared to 6/14 patients after IC. 4/4 patients achieved CR/CRi with salvage aza/ven after failing to respond to IC. Our study suggests that aza/ven should be considered as a firstline treatment option even in patients who are fit for intensive therapy as a means to achieve adequate responses to bridge to allogenic stem cell transplant without attendant toxicities associated with IC. Further studies are required to determine if specific mutations can predict response to either aza/ven or intensive treatment.

Daunorubicin/Cytarabine Liposome +/- Gemtuzumab Ozogamicin for Adult Patients with Newly Diagnosed, Low-Intermediate Risk, FLT3-Wild Type, AML: A Pilot Study

Introduction: Liposomal-encapsulated cytarabine and daunorubicin (CPX-351 or Vyxeos) has been approved by the Food and Drug Administration (FDA) for use in the treatment of newly diagnosed therapy-related AML (tAML) and AML with myelodysplasia-related changes (AML-MRCs). This was based on results of a phase III study conducted in patients with secondary AML (Lancet JE et al. JCO 2018). Despite data that highlighted the advantage of CPX-351 for sAML, it is intuitively likely that this powerful drug is also suitable for non-sAML. The mechanism of action is applicable for every AML. The aim of this study is to evaluate the role of CPX-351 for patients with de novo low/ intermediate risk, FLT3-negative AML. While a definitive phase III study is planned, herein is described the pilot forerunner study. Methods: This pilot multi-center study is planned to recruit 20 patients, ages 18-70 years, with low-intermediate risk FLT3-negative AML. Induction therapy is with CPX-351 on days 1,3,5. One dose of gemtuzumab ozogamicin (GO) can be added on day 1, at the discretion of the treating physician. Re-induction with CPX-351 on day 1,3 is permitted based on the results of day 14 bone marrow examination and at the discretion of the treating physician. Post-induction therapy followed the practice of the participating institutions. The primary endpoint was response rate. A key secondary endpoint was MRD evaluation, after induction, by multi-parameter flow cytometry with a threshold of 0.1%. As the initial genetic evaluation at diagnosis takes time, it was assumed upfront that an adverse risk may only become apparent in some patients with AML after initiation of therapy. Such subjects would ultimately be excluded from the study analysis. Results: Between August 2022 and June 2023, 20 patients were recruited and received the CPX-351 but 4 were finally diagnosed as high-risk and were excluded. The median age of the 15 patients that were included in the analysis was 56 years (range: 21-70), 53.3% were females. Eight of 15 patients (53.3%) were categorized as intermediate risk, according to the 2016 ELN guidelines, and 46.6% as favorable. Four patients (26.6%) received GO in addition to the CPX-351. None of the patients needed to receive re-induction. 100% of the patients achieved CR. Five of 13 evaluable patients (38.4%) achieved MRD-negativity post induction. No unfamiliar or severe adverse events were reported, even among patients who received GO. One patient died from sepsis after hematopoietic stem cell transplant. The median time from day 1 of treatment to neutrophil recovery (ANC≥500/µL) and platelet recovery (≥50,000/µL) was 29 and 24 days, respectively, for the entire cohort and 27 and 24 days, respectively, for those who also received GO. Discussion: The hallmark of this study is reflected by the focus on patients with the low and intermediate-risk AML and not tAML and AML-MRCs, as was approved by the FDA. It includes also young patients (≥18 years), and not only those≥ 60 years. In addition, the CPX-351 was only given as induction therapy (with an option for re-induction) but not after achieving CR. The combination of CPX-351 with GO, although not previously reported, was based on current practice of adding GO to standard induction in some patients, allowing for a realistic future true comparator with standard 7+3 induction. In addition, MRD assessment post induction with CPX-351 has not been previously reported. The CR rate was 100% and the MRD results were a basis for subsequent studies. Finally, this is a pilot study that precedes a definitive planned phase III study that will compare standard induction with 7+3 versus CPX-351, with post-induction MRD monitoring and GO optional in both arms. Such a study may ultimately lead to a paradigm shift in the initial induction therapy of non-adverse risk patients with AML.

CUX1mut Acute Myeloid Leukemia As a Distinct Biological Entity: An Analysis of Clinical Outcomes and Implications

1. Introduction CUX1 is a tumor suppressor gene located on the long arm of chromosome 7. CUX1 mutations induce apoptosis evasion and are more commonly seen in therapy-related myeloid neoplasms. It is frequently mutated in myelodysplastic syndrome and less frequently in acute myeloid leukemia (AML). Preclinical investigations are ongoing to explore therapeutic approaches in CUX1-deficient leukemia cell lines. However, data on the clinical outcomes of patients with AML and mutated CUX1 are sparse. We aimed to characterize the biological and clinical outcomes of CUX1 mut AML. 2. Methods We analyzed next-generation sequencing from 318 patients in the Project ERIS database with newly diagnosed AML treated from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We identified 12 patients with CUX1 mut AML and compared them to a cohort of 306 CUX1 wild-type historical controls. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino &amp; Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results CUX1 mutations are found at a frequency of 3.9% (95% CI, 2.2-6.5) in AML. The median variant allele frequency of CUX1 mutations was 40.3% (range: 3.8-48.7), consistent with a heterozygous presentation. The median age at diagnosis of patients with CUX1 mut who received any anti-leukemic therapy was 57 years (range: 30-78 years), which was not significantly different from CUX1 wt at 65 years (range: 19-88, p = 0.312). Thirty-three (95% CI, 13.8-60.9) percent of patients had AML with myelodysplasia-related changes (AML-MRC) on the initial diagnostic bone marrow biopsy, compared with 29.2% (95% CI, 24.2-34.7, p=0.752) for CUX1 wt. CUX1 mut AML was found in cytogenetically normal specimens at a frequency of 30.0% compared with 49.3% for CUX1 wt (p = 0.337). The most frequent cytogenetic abnormality in CUX1 mut AML was -7 (20.0%), followed by +8 (10.0%) and complex cytogenetics (10.0%). The most frequent cooperating molecular lesions were RUNX1, SRSF2, STAG2, FLT3-ITD, and NRAS (25.0% each). Patients with CUX1 mutations were nonsignificantly more likely to have ELN 2022 adverse-risk disease (odds ratio: 2.013, p = 0.379). In patients treated with intensive cytarabine-based inductions, the median overall survival was 26.3 months in the CUX1 mut group and 17.6 months in the CUX1 wt cohort, which was not significantly different (p = 0.501). Two patients with CUX1 mut AML were treated with first-line venetoclax and a hypomethylating agent. The overall survival was 12.7 months in one patient and not reached at a follow-up time of 20.2 months in the second. 4. Discussion While definitive conclusions are limited by the rarity of the mutation, mutations in CUX1 are heterozygous and appear to be non-significantly more frequently associated with myelodysplastic-related changes and secondary-type mutations. These findings may explain a higher proportion of patients harboring CUX1 mutations that have ELN 2022 adverse-risk disease. While we did not detect any significant survival differences between patients with and without CUX1 mutations, larger cohorts are needed to confirm the prognostic impact of these rare mutations in AML.

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

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

Intrachromosomal amplification 21: A driver of acute myeloid leukemia?

A 68-year-old woman was referred for anemia and circulating peripheral blood blasts. Bone marrow aspirate confirmed the diagnosis of acute myeloid leukemia (AML) with a background of variable dysplasia that was not otherwise sufficient to subclassify as AML with myelodysplasia-related changes (AML-MRC) (panel A; original magnification × 1000; Wright-Giemsa stain). By flow cytometry, the blasts were positive for dim/partial CD7, CD13, CD34, CD117, HLA-DR, partial MPO and TdT, and were negative for other B/T cell associated antigens. G-banding karyotype showed the presence of tandem duplication at the long arm of chromosome 21 (panel B; 46,XX,dup(21)(q21q22)). Single color fluorescence in situ hybridization probes targeting the 21q22.13-q22.2 region showed a homogeneously staining region on chromosome 21 containing >5 copies of RUNX1 (panels C and D; metaphase-interphase FISH), further confirmed by comparative genomic hybridization. Intrachromosomal amplification 21 (iamp21) is a well-recognized event in B lymphoblastic leukemia; however, it is rare in AML with <20 published cases, variably associated with morphologic dysplasia although it uniformly occurred in the setting of complex karyotypes. It was thus postulated to be a late event resulting from genome instability and chromothripsis. In our case, iAMP21 occurred as a sole abnormality, suggesting the possibility of a rather early role in leukemogenesis. N.A wrote the manuscript and compiled the genetics images. Z.C designed the cytology and flow cytometry images. Z.C revised the manuscript. The study received no funding from internal or external sources. The authors disclose no conflict of interests. The Institutional Review Board at the American University of Beirut exempted our single case report from review. Informed consent was explained to and signed by the patient. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Demographic factors affecting patients with AML with myelodysplasia-related changes.

e19027 Background: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a rare and aggressive form of acute myeloid leukemia (AML) that makes up about 25-34% of its annual cases. The subtype includes a varied group of tumors with clinical, genetic, and morphological characteristics that confer poor outcomes. AML-MRC is commonly treated with intensive chemotherapy, but the median survival is only 9-12 months. Given the poor outcomes, gaining a better understanding of epidemiologic factors could reveal opportunities for earlier diagnosis and improved treatment planning. Demographic characteristics of AML-MRC patients were identified and examined using the National Cancer Database (NCDB). Methods: Individuals with a confirmed diagnosis of AML-MRC (N = 14,536) were identified using the NCDB for a retrospective analysis from 2004 to 2020. Patient sex, age at diagnosis, race, household income, insurance status, urban/rural residence, and Charlson-Deyo score were examined by descriptive statistics, and diagnostic trends by year were identified and calculated with regression analysis. Results: A total of 14,536 patients diagnosed with AML-MRC between 2004 – 2020 were identified in the NCDB. Within this timeframe, there was an increasing incidence of diagnosis per year (R2 = 0.9). AML-MRC was more common in males (61.1%) than females (38.9%), and the average age at diagnosis was 68.9 years (SD = 13.0, range = 0 – 90 years). The majority of patients (87.3%) were White. Patients were most likely to be a part of the highest median household income quartile (33.6%) and least likely to be a part of the bottom quartile (13.2%). A higher percentage of patients were insured by Medicare (63.0%) compared to private insurance (25.3%). Most patients lived in counties in metro areas of 1 million population or more (51.4%). Most individuals had Charlson-Deyo comorbidity scores of zero (68.1%). The most common type of treatment facility was academic/research programs (55.1%) followed by comprehensive community cancer programs (23.3%). Conclusions: AML-MRC is a common subtype of AML with a poor prognosis. Previous studies have found that most individuals with AML-MRC are older-aged, White males. Our study corroborated this finding and examined additional demographic factors. We found that these patients were more likely to hold insurance through Medicare, likely reflecting the older average age at diagnosis. Additionally, patients were most commonly in the highest household income quartile and living in a metropolitan area with the highest population density. This could suggest that better access to healthcare improves rates of diagnosis of AML-MRC. Especially given that more people are being diagnosed each year, further research should work to understand the effects of these, and other, socioeconomic factors on the diagnosis, treatment, and prognosis of patients with AML-MRC.

Acute leukemias with complex karyotype show a similarly poor outcome independent of mixed, myeloid or lymphoblastic immunophenotype: A study from the Bone Marrow Pathology Group

Mixed phenotype acute leukemia (MPAL) is a heterogenous group of acute leukemias characterized by leukemic blasts that express markers of multiple lineages. The revised 4th edition WHO classification of MPAL excludes AML with myelodysplasia related changes (AML-MRC), including those with complex karyotype (CK), from a diagnosis of MPAL. Abnormal karyotype is frequent in MPAL with the reported rate of CK in MPAL ranging from 19% to 32%. Due its rarity, the clinical and genetic features of MPAL with CK remain poorly characterized. This study aims to further characterize the genetic features of MPAL with CK in comparison to cases of AML and ALL with CK. Cases of de novo MPAL, AML, and B- and T-ALL patients with CK were collected from 8 member institutions of the Bone Marrow Pathology Group. We found no significant difference in overall survival between MPAL with CK compared to AML and ALL with CK. AML with CK was more strongly associated with TP53 mutations, however the presence of TP53 mutations conferred a worse prognosis regardless of lineage. ALL with CK seems to show increased IKZF1 mutation rates which is known to confer a worse prognosis in ALL. Additionally, MPAL with CK showed similarly poor outcomes regardless of whether a lymphoid or myeloid chemotherapy regimen is chosen. Our results suggest that acute leukemias with complex karyotype show a similarly poor outcome regardless of lineage differentiation and that mutation in TP53 confers a poor prognosis in all lineages. Our results support the exclusion of immunophenotypic MPAL with CK from MPAL and appear to confirm the approach proposed in the revised 4th edition WHO to include them as AML with myelodysplasia-related changes and similar myelodysplasia-related AML categories of newer classifications.

Safety and efficacy of CPX-351 in younger patients (

Letter to Blood| March 23, 2023 Safety and efficacy of CPX-351 in younger patients (<60 years old) with secondary acute myeloid leukemia Clinical Trials & Observations Amanda Przespolewski, Amanda Przespolewski Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY https://orcid.org/0000-0002-8241-8288 Search for other works by this author on: This Site PubMed Google Scholar Aaron D. Goldberg, Aaron D. Goldberg Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY https://orcid.org/0000-0002-2892-2643 Search for other works by this author on: This Site PubMed Google Scholar Chetasi Talati, Chetasi Talati Moffitt Cancer Center, Tampa, FLAbbVie Inc, North Chicago, IL Search for other works by this author on: This Site PubMed Google Scholar Salman Fazal, Salman Fazal Allegheny Health Network, Pittsburgh, PA Search for other works by this author on: This Site PubMed Google Scholar Pankit Vachhani, Pankit Vachhani O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL https://orcid.org/0000-0001-9779-6217 Search for other works by this author on: This Site PubMed Google Scholar Srinivasa R. Sanikommu, Srinivasa R. Sanikommu Levine Cancer Institute, Charlotte, NC Search for other works by this author on: This Site PubMed Google Scholar Swapna Thota, Swapna Thota Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NYThe University of Tennessee Health Science Center, Memphis, TN https://orcid.org/0000-0002-4216-1414 Search for other works by this author on: This Site PubMed Google Scholar Julian Waksal, Julian Waksal Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NYDepartment of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY https://orcid.org/0000-0001-6167-4322 Search for other works by this author on: This Site PubMed Google Scholar Brian Ball, Brian Ball Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NYDepartment of Hematology and Hematopoietic Stem Cell Transplantation, City of Hope Cancer Center, Duarte, CA Search for other works by this author on: This Site PubMed Google Scholar Christopher Famulare, Christopher Famulare Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY Search for other works by this author on: This Site PubMed Google Scholar Maximilian Stahl, Maximilian Stahl Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NYDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Search for other works by this author on: This Site PubMed Google Scholar Jeffrey Baron, Jeffrey Baron Department of Pharmacy, Roswell Park Comprehensive Cancer Center, Buffalo, NY https://orcid.org/0000-0002-9985-3403 Search for other works by this author on: This Site PubMed Google Scholar Elizabeth A. Griffiths, Elizabeth A. Griffiths Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY https://orcid.org/0000-0002-0288-8248 Search for other works by this author on: This Site PubMed Google Scholar James E. Thompson, James E. Thompson Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY https://orcid.org/0000-0003-3030-7559 Search for other works by this author on: This Site PubMed Google Scholar Kendra Sweet, Kendra Sweet Moffitt Cancer Center, Tampa, FL Search for other works by this author on: This Site PubMed Google Scholar Eunice S. Wang Eunice S. Wang Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY Search for other works by this author on: This Site PubMed Google Scholar Blood (2023) 141 (12): 1489–1493. https://doi.org/10.1182/blood.2022016678 Article history Submitted: April 13, 2022 Accepted: November 23, 2022 Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Amanda Przespolewski, Aaron D. Goldberg, Chetasi Talati, Salman Fazal, Pankit Vachhani, Srinivasa R. Sanikommu, Swapna Thota, Julian Waksal, Brian Ball, Christopher Famulare, Maximilian Stahl, Jeffrey Baron, Elizabeth A. Griffiths, James E. Thompson, Kendra Sweet, Eunice S. Wang; Safety and efficacy of CPX-351 in younger patients (<60 years old) with secondary acute myeloid leukemia. Blood 2023; 141 (12): 1489–1493. doi: https://doi.org/10.1182/blood.2022016678 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Subjects: Clinical Trials and Observations, Myeloid Neoplasia TO THE EDITOR: Patients with secondary acute myeloid leukemia (s-AML), a category which includes AML with myelodysplasia-related changes (AML-MRC) and treatment-related AML (t-AML), have poor long-term outcomes following standard induction chemotherapy (“7+3”).1,2 A previous population-based study demonstrated median survival of 6 to 7 months for patients with s-AML and 8 to 14 months for those with t-AML.1 In 2017, a liposomal cytarabine and daunorubicin formulation (CPX-351) was Food and Drug Administration (FDA) approved for upfront treatment of s-AML based on a pivotal phase 3 trial demonstrating improved overall survival (OS) (9.56 vs 5.95 months; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.52-0.9) and remission rates (complete remission [CR]/CR with incomplete count recovery [CRi]) (47.7% vs 33.3%; P = .016) in patients aged 60 to 75 years old than induction chemotherapy with “7+3.”3 The benefits from...

Molecular characterization of AML-MRC reveals TP53 mutation as an adverse prognostic factor irrespective of MRC-defining criteria, TP53 allelic state, or TP53 variant allele frequency.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) generally confers poor prognosis, however, patient outcomes are heterogeneous. The impact of TP53 allelic state and variant allele frequency (VAF) in AML-MRC remains poorly defined. We retrospectively evaluated 266 AML-MRC patients who had NGS testing at our institution from 2014 to 2020 and analyzed their clinical outcomes based on clinicopathological features. TP53 mutations were associated with cytogenetic abnormalities in 5q, 7q, 17p, and complex karyotype. Prognostic evaluation of TP53MUT AML-MRC revealed no difference in outcome between TP53 double/multi-hit state and single-hit state. Patients with high TP53MUT variant allele frequency (VAF) had inferior outcomes compared to patients with low TP53MUT VAF. When compared to TP53WT patients, TP53MUT patients had inferior outcomes regardless of MRC-defining criteria, TP53 allelic state, or VAF. TP53 mutations and elevated serum LDH were independent predictors for inferior OS and EFS, while PHF6 mutations and transplantation were independent predictors for favorable OS and EFS. NRAS mutation was an independent predictor for favorable EFS. Our study suggests that TP53MUT AML-MRC defines a very-high-risk subentity of AML in which novel therapies should be explored.

Outcomes of Newly Diagnosed Therapy-Related AML and AML with Myelodysplasia-Related Changes Treated with 7+3, Hypomethylating Agents with or without Venetoclax and CPX-351: A Retrospective Cohort Study

Introduction Therapy-related acute myeloid leukemia (t-AML) and AML with myelodysplasia-related changes (AML-MRC) are associated with poor outcomes due to older age at diagnosis and adverse-risk cytogenetics and molecular features and, therefore, treatment of these groups of patients remain a challenge. There is a paucity of real-world data on outcomes of t-AML and AML-MRC treated with 7+3, hypomethylating agents (HMA) with or without venetoclax (VEN) or CPX-351 (Vyxeos). Methods We conducted a single-center retrospective cohort study to compare overall survival (OS), event-free survival (EFS), and composite complete response (CCR) of patients with t-AML or AML-MRC treated with first-line 7+3, HMA, HMA+VEN or Vyxeos. Therapy-related myelodysplastic syndrome were not included. OS was defined from day 1 of initial chemotherapy until death from any cause. Patients were not censored at the time of allogeneic transplant. Sixty and 90-day treatment-related mortality were estimated as surrogates for treatment toxicity. Propensity score modeling was used to adjust for baseline characteristics (age, AML subtype, comorbidities, performance status, cardiac ejection fraction, cytogenetics, and mutations). Results Of 488 consecutive AML patients treated at the University of Maryland between 2013-2021, 136 patients had t-AML or AML-MRC and received one of the above therapies. 40% were female. The median age of the cohort was 67.5 [IQR: 60.9-73.2]. The median age of patients who received 7+3 (n=34) was 63.4 years, HMA (n=61) 70.3 years, HMA+VEN (n=27) 72.6 years, and Vyxeos (n=14) 62.2 years (age P-value= 0.1). 42 and 17 patients received decitabine in the HMA and HMA+VEN arms, respectively. None of the patients treated with 7+3 or Vyxeos received HMA prior to AML diagnosis. However, 3 and 6 patients received HMA in the HMA and HMA+VEN arms prior to AML diagnosis, respectively. Both 7+3 and HMA were given mostly before 2019 (7+3: 88%; HMA: 81%) compared to HMA+VEN and Vyxeos, which were given mostly in years 2019 and after (HMA+VEN: 74%; Vyxeos: 71%) (P<0.01). The median follow-up was 73.5 months (mo). Table 1 demonstrates unadjusted outcomes. Figure 1 demonstrates the unadjusted OS of treated groups. Using propensity score for adjustment, there was no difference in median OS or CCR in patients treated with 7+3 vs. HMA (11.2 vs. 10.6 mo, P=0.63; 42% vs. 31%, P=0.38). However, patients treated with HMA+VEN had worse adjusted m-OS than patients treated with 7+3 (5.3 vs. 20.2 mo, P=0.02) or HMA alone (5.3 vs. 10.1 mo, P=0.02). Patients treated with Vyxeos had a statistically similar adjusted-median OS to those treated with 7+3 (5.1 vs. 15.4 mo, P=0.34) and a trend toward a worse outcome than those treated with HMA alone (5.3 vs. 10.1 mo, P=0.07). Conclusion The outcomes of t-AML and AML-MRC remains poor. In t-AML and AML-MRC, using 7+3 and HMA resulted in similar OS; however, improved outcomes compared to HMA+VEN. Almost 50% of patients treated with HMA+VEN died in the first 90 days, possibly related to treatment toxicity. Further studies are needed to determine the role of VEN combination with HMA in t-AML and AML-MRC. Moreover, further real-world, multi-institutional data are needed to evaluate the effectiveness of Vyxeos in t-AML and AML-MRC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CPX-351 Appears Superior to 7+3 in Adverse-Risk AML and AML-MRC

Background: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represents a category of adverse-risk AML with poor overall survival and high rates of relapse. CPX-351 has shown promise in the treatment of therapy-related AML (t-AML) and AML-MRC. A recent phase III trial evaluated CPX-351 versus daunorubicin 60 mg/m2 + cytarabine (7+3) in newly diagnosed t-AML and AML-MRC and demonstrated superior responses and improvement in the median overall survival (OS). However, outcomes with CPX-351 versus 7+3 with daunorubicin 60 mg/m2 in the broader adverse-risk category and in the real-world setting remain unclear. The aim of this study was to characterize response and survival of both regimens in adverse-risk AML. Patients & Methods: We analyzed 47 patients that underwent treatment for ELN 2017 adverse-risk AML from January 2016 to December 2021 at VCU Massey Cancer Center. Patients were divided into two cohorts: patients that received CPX-351 and 7+3 with daunorubicin 60 mg/m2. Baseline demographics were obtained, including age, performance status, and comorbidities, as well as disease characteristics, including molecular profiling either through PCR, NGS, or both at the time of induction, alongside cytogenetic risk, doses of induction regimens, response, and survival. Differences between groups were compared using an unpaired t-test. The event for calculating the OS through the Kaplan-Meier method was the date of death. Survival differences between groups were compared using the Gehan-Breslow-Wilcoxon test. Patients were censored at the date of last contact. Results: There were 15 patients that underwent treatment with first-line CPX-351. The median age at diagnosis was 71 years, the median ECOG score was 1, and the median Charlson Comorbidity Index (CCI) score was 4. The composite response rate (CRR; CR + CRi) was 64.3% and 33.3% of evaluable patients were measurable residual disease (MRD) negative by PCR assays. The median OS was 27.9 months. There were no deaths in the first 60 days. Seven (46.7%) patients in the CPX-351 cohort proceeded to allogeneic stem cell transplant (SCT). In the 7+3 cohort, the median age was 63, median ECOG score was 1, and median CCI score was 5. There were no significant differences in age, ECOG score, or CCI score between the two cohorts. The CRR of the 7+3 cohort was 35.5% and 25% of those evaluable were MRD negative by PCR assays. The median OS was 7.3 months. No patients died within 30 days and 6.7% died within 60 days. Eight (25%) patients proceeded to SCT. The OS was then compared between cohorts, with CPX-351 demonstrating a significant improvement in survival compared to 7+3 (p = 0.047). Conclusions: CPX-351 demonstrated a significant improvement in survival compared to 7+3 with daunorubicin 60 mg/m2 in our cohort of adverse-risk AML. Additionally, composite response rates appeared to be 1.8 times higher in the CPX-351 cohort with fewer patient deaths and an increase in receipt of SCT by 21.7%. These findings support the use of CPX-351 in patients with adverse-risk AML that are candidates for intensive induction. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CREST-UK: CPX-351 Real-World Effectiveness and Safety Study for the Treatment of Newly Diagnosed Therapy-Related AML and AML with Myelodysplasia-Related Changes in the UK

Background: In the UK, CPX-351 (Vyxeos® liposomal) has been licensed since August 2018 for adults with newly diagnosed, therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), primarily based on favorable outcomes for CPX-351 versus 7+3 chemotherapy in a phase 3 trial in adults aged 60 to 75 y with newly diagnosed, high-risk/secondary AML. However, the phase 3 trial population did not reflect the full CPX-351 licensed population. As a complement to the phase 3 trial and to address important data gaps, CREST-UK was performed to assess the effectiveness and safety of CPX-351 in routine clinical practice in the UK and observe the impact of COVID-19 infection in these patients (pts). Methods: CREST-UK is a retrospective, noninterventional, multicenter, single-arm, observational study (NCT05169307) that collected pseudonymized pt data abstracted from the medical records of adults aged ≥18 y with newly diagnosed t-AML or AML-MRC (per WHO 2016 criteria) who received ≥1 infusion of CPX-351 in routine practice; pts who received CPX-351 in a clinical trial were excluded. The primary objective was to describe complete remission (CR or CRi) and overall survival (OS). Key secondary objectives described pt and disease characteristics, frequency of hematopoietic cell transplantation (HCT), OS landmarked from the HCT date, and the CPX-351 safety profile. Median follow-up for OS was 10.6 mo (interquartile range [IQR]: 4.5, 18.4). Results: A total of 147 pts who received their first CPX-351 induction from November 2018 to March 2022 were included from 15 centers. Median age was 64 y (range: 18, 83), with 17 (12%) pts aged <45 y, 39 (27%) aged 45-59 y, 64 (44%) aged 60-69 y, and 27 (18%) aged ≥70 y. Overall, 35 (24%) pts had t-AML and 112 (76%) had AML-MRC (n=43 with prior MDS, n=9 with prior CMML, n=41 with MDS-related cytogenetics, and n=19 with multilineage dysplasia alone); 13 (9%) had received prior azacitidine. The majority (90%) of pts had an ECOG performance status ≤1. Disease risk by European LeukemiaNet 2017 criteria was favorable for 13 (9%) pts, intermediate for 39 (27%), adverse for 66 (45%), and unknown for 29 (20%) due to limited mutational data. Complex karyotype, monosomal karyotype, and/or abn(17p) were reported for 37 (25%) pts. TP53 mutations were reported for 15/66 (23%) pts with evaluable data. A best response of CR+CRi was achieved by 73/138 (53%) evaluable pts, and overall response (CR+CRi+MLFS+PR) was achieved by 88/138 (64%) pts. Post induction, 19/37 (51%) pts in CR or CRi with a known measurable residual disease (MRD) status achieved MRD negativity; 3 additional pts achieved MRD negativity at a later time point. Kaplan-Meier median OS was 12.85 mo (95% CI: 9.2, 15.4; Fig 1), with 2- and 3-y OS estimates of 36% and 34%, respectively. Fifty (34%) pts proceeded to HCT; median OS landmarked from the HCT date was not reached (Fig 2), with a 2-y OS estimate of 71%. Among pts in CR or CRi, median recovery (IQR) to neutrophils ≥500/μL was 33 d (28, 43) and to platelets ≥50,000/μL was 34 d (27, 48) during the first induction. Grade ≥3 treatment-related adverse events (TRAEs) of interest included febrile neutropenia (36%; n=1 grade 5), infections (29%; n=6 grade 5), bleeding (4%; n=1 grade 5), and gastrointestinal events (3%). Cardiac TRAEs of any grade were reported for 5% of pts, with grade ≥3 events in 3% (n=1 grade 5). No extravasation was reported. Estimated all-cause mortality was 7% at 30 d and 14% at 60 d. This study included pts who were diagnosed and treated for AML during the COVID-19 pandemic. A total of 26 COVID-19 infections happened at variable time intervals pre- or post-AML treatment. In this cohort, 2 deaths were directly linked to COVID-19; both were assessed by the site investigator as unrelated to CPX-351 treatment. Conclusion: CREST-UK, a real-world study in the context of the COVID-19 pandemic, confirmed the efficacy and safety of CPX-351 in a broad population that included substantial proportions who were aged <60 y or ≥70 y and/or had adverse-risk disease. CR or CRi with MRD negativity and/or proceeding to HCT was achieved in proportions consistent with clinical trials and other real-world studies. Survival outcomes were also consistent with other real-world studies. No new safety concerns with CPX-351 were identified. These data provide new insights into the use of CPX-351 in routine clinical practice in the UK and support its continued use in adults with newly diagnosed t-AML and AML-MRC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal