Secondary Acute Myeloid Leukemia Research Articles

BRAF mutation in myeloid neoplasm: incidences and clinical outcomes

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

Single-cell transcriptomics dissects the transcriptome alterations of hematopoietic stem cells in myelodysplastic neoplasms

BackgroundMyelodysplastic neoplasms (MDS) are myeloid neoplasms characterized by disordered differentiation of hematopoietic stem cells and a predisposition to acute myeloid leukemia (AML). The underline pathogenesis remains unclear.MethodsIn this study, the trajectory of differentiation and mechanisms of leukemic transformation were explored through bioinformatics analysis of single-cell RNA-Seq data from hematopoietic stem and progenitor cells (HSPCs) in MDS patients.ResultsAmong the HSPC clusters, the proportion of common myeloid progenitor (CMP) was the main cell cluster in the patients with excess blasts (EB)/ secondary AML. Cell cycle analysis indicated the CMP of MDS patients were in an active proliferative state. The genes involved in the cell proliferation, such as MAML3 and PLCB1, were up-regulated in MDS CMP. Further validation analysis indicated that the expression levels of MAML3 and PLCB1 in patients with MDS-EB were significantly higher than those without EB. Patients with high expression of PLCB1 had a higher risk of transformation to AML. PLCB1 inhibitor can suppress proliferation, induce cell cycle arrest, and activate apoptosis of leukemic cells in vitro.ConclusionThis study revealed the transcriptomic change of HSPCs in MDS patients along the pseudotime and indicated that PLCB1 plays a key role in the transformation of MDS into leukemia.

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.

Efficacy and safety of venetoclax plus hypomethylating agents in relapsed/refractory acute myeloid leukemia: a multicenter real-life experience.

Venetoclax (VEN) has been shown to play a synergistic effect in combination with hypomethylating agents (HMAs) in the frontline treatment of acute myeloid leukemia (AML). However, the potential role of this therapy in the relapsed/refractory (R/R) AML setting, still needs to be further unveiled. The aim of the current study was to retrospectively outline the safety profile, response and survival outcomes of R/R AML patients treated with VEN in association with HMAs. Clinical, biological, and molecular data were collected from 57 patients with R/R AML treated with VEN combined with azacitidine or decitabine between 2018 and 2023. The median age of patients was 63 years, 38 (66.7%) received treatment for relapsed disease while 19 (33.3%) for refractory disease, 5 (8.7%) were treated for molecular relapse. A consistent proportion of the cohort was represented by patients with unfavorable prognostic factors such as complex karyotype (36.8%), secondary AML (29.8%), previous exposure to HMAs (38.6%), and relapse after allogeneic stem cell transplant (22.8%). A total of 14 patients achieved CR (24.6%), 3 (5.3%) CRi, 3 (5.3%) MLFS, and 3 (5.3%) PR, accounting for an ORR of 40.4%. The CR/CRi rate was higher in the group treated with azacitidine than in the group treated with decitabine (37.8% vs. 15%). The median OS was 8.2 months, reaching 20.1 months among responding patients. VEN-HMAs treatment allowed to bridge to allogeneic stem cell transplantation 11 (23.9%) of eligible patients, for which a median OS of 19.8 months was shown. On multivariate analysis, ECOG performance status ≥2, complex karyotype and not proceeding to allogeneic stem cell transplantation after therapy with VEN-HMAs were the factors independently associated with shorter OS. Patients treated with the azacitidine rather than the decitabine containing regimen generally displayed a trend toward superior outcomes. The major toxicities were prolonged neutropenia and infections. In conclusion, this study showed how VEN-HMAs could represent an effective salvage therapy in patients with R/R AML, even among some of those patients harboring dismal prognostic features, with a good toxicity profile. Further prospective studies are thus warranted.

Advancements and Challenges in the Treatment of AML.

The therapeutic arsenal for the management of AML has expanded significantly in recent years. Before 2017, newly diagnosed AML was treated with either standard cytarabine- and anthracycline-based induction chemotherapy (for all fit patients) or a single-agent hypomethylating agent (in unfit patients or those 75 years and older). While assessing patient fitness remains important, characterizing the disease biology has become critical to select the optimal initial therapy for each patient with more options available. FLT3 inhibitors, gemtuzumab ozogamicin, and CPX-351 have been shown to improve outcomes for specific subsets of patients. Venetoclax (VEN) with a hypomethylating agent (HMA) is the standard-of-care frontline regimen for most older patients, except perhaps for those with an IDH1 mutation where ivosidenib with azacitidine may also be considered. On the basis of the success seen with HMA/VEN in older patients, there is now increasing interest in incorporating VEN into frontline regimens in younger patients, with promising data from multiple early phase studies. This article focuses on recent updates and ongoing challenges in the management of AML, with a particular focus on the ongoing challenge of secondary AML and considerations regarding the selection of initial therapy in younger patients. An overview of common side effects and toxicities associated with targeted therapies is also presented here, along with recommended strategies to mitigate these risks.

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients.

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

Myeloperoxidase inhibition protects bone marrow mononuclear cells from DNA damage induced by the TOP2 poison anti-cancer drug etoposide.

Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation of reactive oxygen species that are important in anti-microbial action, but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti-cancer drugs, but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations. This leads to the possibility that myeloperoxidase inhibitors could reduce the rate of therapy-related leukaemia by protecting haematopoietic cells from TOP2 poison-mediated genotoxic damage while preserving the anti-cancer efficacy of the treatment. We show here that myeloperoxidase inhibition reduces etoposide-induced TOP2B-DNA covalent complexes and resulting DNA double-strand break formation in primary ex vivo expanded CD34+ progenitor cells and unfractionated bone marrow mononuclear cells. Since MPO inhibitors are currently being developed as anti-inflammatory agents this raises the possibility that repurposing of these potential new drugs could provide a means of suppressing secondary acute myeloid leukaemias associated with therapies containing TOP2 poisons.

FLAG/FLAG-Ida Regimen in Secondary and Relapsed/Refractory Acute Myeloid Leukemia-Even in the Era of New Treatment Modalities Still a Significant Player.

(1) Background: Relapsed/refractory (r/r) and secondary acute myeloid leukemia are highlighted by chemoresistance and poor outcomes. The aim of the study was to assess the efficacy and toxicity of fludarabine, cytarabine, and granulocyte-colony stimulation factor (FLAG) with or without idarubicin (-Ida) and to discuss novel therapies in this setting. (2) Methods: Clinical and cytogenetic data on 130 consecutive patients with r/r and secondary AML treated at our center were retrospectively analyzed. (3) Results: There were 48, 56, and 26 patients with relapsed, refractory, and secondary AML, respectively. The median age was 60 years. The overall response was achieved in 70% of patients. The median overall survival (OS) time for the whole group was 9.4 months. In total, 47% of patients proceeded to allogeneic hematopoietic stem cell transplantation (aHSCT) and these patients had significantly prolonged OS compared to the others (63 months vs. 4.2 months; p < 0.001). Among the variables, including age, FLT3 mutation status, European LeukemiaNet (ELN) 2022 classification risk, FLAG vs. FLAG-Ida, and aHSCT, a multivariate analysis revealed that only aHSCT significantly influenced overall survival. (4) Conclusions: FLAG(-Ida) chemotherapy remains an effective salvage chemotherapy for patients with r/r and secondary AML with a plan of proceeding to aHSCT.

Abstract 564: Therapeutic targeting of JAK/STAT signaling and histone acetyltransferase activity in post-myeloproliferative neoplasm secondary AML

Abstract Post-myeloproliferative neoplasm secondary Acute Myeloid Leukemia (Post-MPN sAML) is an aggressive and lethal hematologic malignancy arising from myeloproliferative neoplasms (MPN). Hyperactivation of JAK/STAT signaling was identified in 50-90% of MPNs - underscoring its role in driving MPN pathogenesis and transformation to post-MPN sAML. Ruxolitinib, a Type-I JAK2 inhibitor approved for the treatment of myelofibrosis, was tested in a Phase II clinical trial in post-MPN sAML. The trial revealed that ruxolitinib improved the quality of life in patients but was not disease-modifying. Thus, there is an urgent need to find synergistic drug combinations capable of complementing the therapeutic activity of JAK2 inhibitors in post-MPN sAML. Here, we demonstrate that combination treatment of ruxolitinib and CBP30, a bromodomain inhibitor of histone acetyltransferases (HAT) CBP and p300, enhances the therapeutic activity of ruxolitinib in post-MPN sAML. Genome-wide CRISPR loss-of-function screens in JAK2-mutated HEL cells determined that knockout of CBP sensitizes leukemic cells to JAK2 inhibitors. Consistently, functional validation through CRISPR/Cas9 demonstrated that genetic deletion of CBP but not of p300 renders HEL cells sensitive to ruxolitinib treatment. Pharmacologic inhibition of JAK/STAT signaling and HAT activity through ruxolitinib and CBP30 treatment in post-MPN sAML lines HEL and SET2 decreases proliferation and induces apoptosis and cell cycle arrest. Mechanistically, the synergism between ruxolitinib and CBP30 elicits a unique transcriptome profile in HEL with significant downregulation of E2F and MYC targets. In addition, epigenetic profiling revealed that the synergism induces global changes in H3K27ac signals with downregulation and upregulation of H3K27ac signals in predicted STAT5/BCL3 and GATA-bounded regions, respectively. Remarkably, combination treatment of ruxolitinib and CBP30 in HEL luciferase NSG mouse xenografts showed significant leukemia regression and decrease in spleen size compared to mice treated with vehicle or single agents. Overall, these results substantiate the potential of targeting JAK/STAT signaling and histone acetyltransferase activity in the treatment of post-MPN sAML. Citation Format: Kalay Bertulfo, Koen Debackere, Hannah Miller, Cindy Ma, Ryan Najac, Adolfo Ferrando, Teresa Palomero. Therapeutic targeting of JAK/STAT signaling and histone acetyltransferase activity in post-myeloproliferative neoplasm secondary AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 564.

White blood cell count nadir to zero following intensive chemotherapy as a predictive factor for patients with acute myeloid leukemia

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.

CXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis.

BCR::ABL1 negative myeloproliferative neoplasms (MPNs) form a distinct group of hematologic malignancies characterized by sustained proliferation of cells from multiple myeloid lineages. With a median survival of 16-35 months in patients with high-risk disease, primary myelofibrosis (PMF) is considered the most aggressive entity amongst all BCR::ABL1 MPNs. Additionally, a significant subset of patients evolves into secondary acute myeloid leukemia (AML) which has an even poorer prognosis compared to de novo AML. As the exact mechanisms of disease development and progression remain to be elucidated, current therapeutic approaches fail to prevent disease progression or transformation into secondary AML. As each MPN entity is characterized by sustained activation of various immune cells and raised cytokine concentrations within bone marrow and peripheral blood, MPNs may be considered as typical inflammation-related malignancies. However, the exact role and consequences of increased cytokine concentrations within bone marrow and peripheral blood plasma are currently incompletely established. Upregulated cytokines can stimulate cellular proliferation or contribute to the development of an inflammation-related bone marrow niche resulting in genotoxicity and thereby supporting mutagenesis. The neutrophil chemoattractant CXCL8 is of specific interest as its concentration is increased within peripheral blood and bone marrow plasma of patients with PMF. Increased concentration of CXCL8 negatively correlates with overall survival. Furthermore, blockage of the CXCR1/2 axis appears to be able to reduce bone marrow fibrosis and megakaryocyte dysmorphia in murine models. Within this review, we summarize available evidence on the role of the CXCL8-CXCR1/2 axis within the pathogenesis of PMF and discuss potential therapeutic modalities targeting either CXCL8 or its cognate receptors CXCR1/2.

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.

Myelodysplasia-related gene mutations are associated with favorable prognosis in patients with TP53-mutant acute myeloid leukemia.

This study aimed to examine the characteristics and treatment outcomes of patients with TP53-mutant acute myeloid leukaemia (AML) and to explore potential prognostic factors. This retrospective analysis included 130 patients diagnosed with TP53-mutant AML at the Fujian Medical University Union Hospital between January 2016 and June 2023. Patients' ages ranged from 17 to 80 years, with a median age of 59 years. The proportions of de novo, therapy-related, and secondary AML cases were 71.5%, 7.7%, and 20.8%, respectively. Complex karyotypes were observed in 60.6% of patients, and the proportions of -5 or del(5q), -7 or del(7q), and - 17 or del(17p) were 41.7%, 27.9% and 14.4%, respectively. DNA methylation- and myelodysplasia-related (MR) gene mutations were observed in 36.9% and 25.4% of patients, respectively. These patients showed poor survival, with a median overall survival (OS) of 4.5 months, a 1-year OS rate of 32.5%, a 3-year OS rate of 18.8%, and a 5-year OS rate of 11.3%. The complete response rates for intensive chemotherapy (IC), hypomethylating agent (HMAs)-based therapies, and azacitidine plus venetoclax were 35.7%, 22.2%, and 37.5%, respectively. Patients who did or did not receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) had similar prognoses (median OS: 6.0 vs. 3.9 months; P = 0.6415). Multivariate analysis indicated that MR gene mutations is an independent favorable prognostic factor of OS (HR = 0.366, 95% CI: 0.181-0.738, P = 0.005). In conclusion, patients with TP53-mutant AML have poor prognoses under current treatment strategies and MR gene mutations are associated with a more favorable survival. Therefore, further studies are needed to improve the survival rates in this population.

Continuous 72-h infusion of zosuquidar with chemotherapy in patients with newly diagnosed acute myeloid leukemia stratified for leukemic blast P-glycoprotein phenotype.

To evaluate the safety, tolerability, pharmacodynamics (PD), and potential efficacy of zosuquidar (Zos) in combination with daunorubicin and cytarabine in elderly patients with newly diagnosed acute myeloid leukemia (AML). Patients with AML (N = 106) were treated with Zos as a 72-h continuous intravenous (CIV) infusion along with chemotherapy. Leukemic blasts from the patients were assessed for P-glycoprotein (P-gp) function using ex vivo bioassays for screening and PD analyses. Patient outcomes were categorized according to primary (N = 56) and secondary (N = 50) AML cohorts (pAML and sAML, respectively) and stratified into P-gp-high and P-gp-low subgroups. Patients with P-gp-high blasts exhibited comparable overall remission rates (ORR) to those with P-gp-low blasts in both the pAML and sAML cohorts. The P-gp-high and P-gp-low subgroups in the pAML cohort exhibited similar overall survival (OS). Patients with sAML and P-gp-high blasts exhibited significantly better OS than those in the P-gp-low subgroup. PD analyses revealed that Zos infusion provided 82h of uninterrupted effective ≥ 90% inhibition of P-gp functional activity in leukemic blasts. These observations provide evidence of Zos efficacy with the 72-h CIV infusion approach. The similarity of ORR in the P-gp-high and P-gp-low subgroups is consistent with Zos-mediated neutralization of P-gp as verified by PD analyses. The bioassay identified sAML patients most likely to respond favorably to Zos co-therapy indicating feasibility as a Zos companion diagnostic. A follow-up placebo-controlled trial is needed to verify these promising results. NCT00129168; First posted on August 11, 2005.

Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease

Incidence of both acute myeloid leukemia (AML) and cardiovascular disease (CVD) increases with age. We evaluated whether pre-existing CVD impacts clinical outcomes in AML. We retrospectively evaluated 291 consecutive adult AML patients treated at our institution, 2014–2020. Pretreatment comorbidities were identified by chart review. Outcomes included complete remission (CR) and CR with incomplete count recovery (CRi) rates, disease-free survival (DFS), overall survival (OS) and incidence of cardiovascular adverse events. CVD was present in 34% of patients at AML diagnosis. CVD patients had worse performance status (p=0.03) and more commonly had secondary AML (p=0.03) and received hypomethylating (HMA) agent-based therapy (72% vs 38%, p< 0.001). CVD (0.45 vs 0.71, p<0.001) and diabetes mellitus (HR= 0.24, 95% CI: 0.08 – 0.8, p= 0.01) were associated with lower probability of achieving CR/CRi. Accounting for age, performance status (PS), complex karyotype, secondary disease and treatment, CVD patients had shorter OS (HR=1.5, 95% CI: 1.1–2.2, p=0.002), with 1- and 3-year OS 44% vs 67% and 25% vs 40%, respectively, but there was no difference in cumulative incidence of relapse between patients with vs without CVD. Thus, CVD is an independent risk factor for lower response rate and shorter survival in AML patients.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNAsplicing factormutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Real-world treatment outcomes from a retrospective cohort of patients with acute myeloid leukemia from an urban safety net hospital.

While continual advancements in acute myeloid leukemia have augmented response rates and survival, outcomes in clinical trials may not correlate with real-world practice as trials may underrepresent individuals with comorbidities, decreased performance status, and older age. Additionally, clinical trials may underrepresent certain ethnicities, and disparities based on ethnicity, socioeconomic status, and insurance have been demonstrated in acute myeloid leukemia. We performed a retrospective chart review of adult patients with acute myeloid leukemia who were treated at Harbor-UCLA from 2014 to 2022 to examine patient characteristics, management patterns, and outcomes in a safety net hospital setting. The median age was 56 years old (range 18-84). In regards to risk stratification, 22%, 33%, and 41% had favorable, intermediate, and adverse risk acute myeloid leukemia, respectively. The most common induction regimens included 7 + 3 (55%), azacitidine (10%), azacitidine + venetoclax (7%), and 7 + 3 + midostaurin (7%). The complete remission rate was 51%. Among patients who received intensive induction chemotherapy, 15% underwent re-induction with a second cycle, 51% received consolidation therapy, and 5% received maintenance therapy with a targeted agent. Overall, 12% of patients received allogeneic stem cell transplant. Median overall survival was 12.2 months, and 5-year overall survival was 18%. Suboptimal response rates and survival in this population may be related to low rates of re-induction and allogeneic transplant in addition to high rates of adverse cytogenetics, secondary acute myeloid leukemia, and supportive care only. Efforts to increase access to clinical trials, novel therapies, and transplants for diverse and underinsured populations are essential.

[The Correlation of Gene Mutation and Clinical Characteristics in Patients with Myelodysplastic Syndrome and Prognostic Analysis].

To explore the correlation between gene mutations and clinical characteristics, prognosis of myelodysplastic syndromes (MDS). Clinical data of 131 patients with MDS were collected from the First Hospital of Lanzhou University from June 2015 to February 2023, which 19 of them developed into secondary acute myeloid leukemia (sAML) during follow-up time. Second generation sequencing technology was used to detect the mutation types of MDS disease-related genes, drawn gene maps, and analyzed their correlation and prognosis based on the clinical data of patients. The median age of 131 MDS patients was 58(17-86) years old. The ratio of male to female was 1.3∶1. A total of 148 gene mutations and 25 types were found in the center. U2AF1 and ASXL1 were often co-mutations with other genes, which were accompanied by 20q- and normal karyotype (NK) respectively. SETBP1 and SRSF2 were more common in patients over 60 years old, while NPM1 and WT1 under 60 years. Older patients had a higher the number of genetic mutations than younger patients. The incidence of SF3B1 and RUNX1 in males was higher than females and DNMT3A in females was higher than males. The number of gene mutations in sAML was higher than MDS (1.8 vs 1.0, P =0.006). The univariate and multivariate analysis showed that IPSS-R prognostic score≥3.5, TP53 were adverse factors for poor prognosis in MDS patients. Patients with monoallelic mutation（ma-TP53）and wild-type（wt-TP53） TP53 had OS better than biallelic mutation（bi-TP53）(P =0.003). The OS of MDS patients was better than sAML(P =0.01) and transplant patients was significantly better than nontransplant patients(P =0.036). Gene mutation is closely related to cytogenetic indexes and clinical features (peripheral blood cell count, sex, age). IPSS-R prognostic score and TP53 were risk factors affecting OS in MDS patients.

A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.

Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.

Survival difference between secondary and de novo acute myeloid leukemia by age, antecedent cancer types, and chemotherapy receipt.

This study compared the survival of persons with secondary acute myeloid leukemia (sAML) to those with de novo AML (dnAML) by age at AML diagnosis, chemotherapy receipt, and cancer type preceding sAML diagnosis. Data from Surveillance, Epidemiology, and End Results 17 Registries were used, which included 47,704 individuals diagnosed with AML between 2001 and 2018. Multivariable Cox proportional hazards regression was used to compare AML-specific survival between sAML and dnAML. Trends in 5-year age-standardized relative survival were examined via the Joinpoint survival model. Overall, individuals with sAML had an 8% higher risk of dying from AML (hazard ratio [HR],1.08; 95% confidence interval [CI],1.05-1.11) compared to those with dnAML. Disparities widened with younger age at diagnosis, particularly in those who received chemotherapy for AML (HR,1.14; 95% CI,1.10-1.19). In persons aged 20-64years and who received chemotherapy, HRs were greatest for those with antecedent myelodysplastic syndrome (HR,2.04; 95% CI,1.83-2.28), ovarian cancer (HR,1.91; 95% CI,1.19-3.08), head and neck cancer (HR,1.55; 95% CI,1.02-2.36), leukemia (HR,1.45; 95% CI,1.12-1.89), and non-Hodgkin lymphoma (HR,1.42; 95% CI,1.20-1.69). Among those aged ≥65 years and who received chemotherapy, HRs were highest for those with antecedent cervical cancer (HR,2.42; 95% CI,1.15-5.10) and myelodysplastic syndrome (HR,1.28; 95% CI,1.19-1.38). The 5-year relative survival improved 0.3% per year for sAML slower than 0.86% per year for dnAML. Consequently, the survival gap widened from 7.2% (95% CI,5.4%-9.0%) during the period 2001-2003 to 14.3% (95% CI,12.8%-15.8%) during the period 2012-2014. Significant survival disparities exist between sAML and dnAML on the basis of age at diagnosis, chemotherapy receipt, and antecedent cancer, which highlights opportunities to improve outcomes among those diagnosed with sAML.