IA Regimen Research Articles

Clinical features and outcomes of patients with acute myeloid leukemia: the single-center experience of 668 patients in China

ABSTRACT Objective To investigate efficacy and prognostic factors in the treatment of adult newly-diagnosed acute myeloid leukemia (AML) with or without allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Methods We retrospectively analyzed 668 patients with newly-diagnosed AML (non-M3 type) in the Department of Hematology at Shanghai Changhai Hospital from January 2012 to December 2021. Based on different induction chemotherapy regimens, patients were categorized into an IA (idarubicin, IDA + cytarabine, Ara-C) (3 + 7, regimen) group (n = 303) and a DA (daunorubicin, DNR + cytarabine, Ara-C) (3 + 7, regimen) group (n = 365) with or without allo-HSCT. Minimal residual disease (MRD), complete response (CR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse effects (AE) were analyzed and compared. Characteristics significantly associated with overall or progression-free survival (OS or PFS) upon univariate analysis were subsequently included in a Cox proportional hazard model. Results This study used data from 668 AML patients. After induction therapy, the CR rate in the IA group was 70.63% and ORR was 79.87%, which were significantly higher than those in the DA group (with a CR rate of 56.99% and an ORR of 70.14%) (P = 0.0002 and P = 0.0035, respectively). There were no significant differences in drug safety between the two chemotherapy regimens used in IA and DA (P > 0.05). The recurrence rate was lower in patients with an MRD < 0.001 than in patients with an MRD ≥ 0.001. A continuous negative MRD during the period is significant because it is associated with prolonged OS and PFS of AML patients. Data from 100 patients in the two groups who underwent allo-HSCT were analyzed using univariate analysis and the Cox proportional hazards model. From the multivariate analysis, MRD was found to be the only independent predictor of OS (P = 0.042; HR 1; 95%CI 0.00–0.76). Conclusion In the treatment of adult AML patients, IA regimen is associated with a high CR rate and ORR rate and does not increase treatment-related toxicity. IA regimen prolongs OS and PFS in AML patients and reduces the likelihood of leukemia cells’ subsequent infiltration into the central nervous system. There is a high correlation between the level of MRD after treatment and the patient's bone marrow recurrence. To obtain superior treatment effects for patients undergoing allo-HSCT, the MRD should be reduced to less than 0.001 before pretreatment. A negative MRD before allo-HSCT can prolong OS in patients with AML. We examined the clinical characteristics and outcomes of AML patients in China, finding novel information on prognostic factors and primary treatment of AML that may be applicable in routine clinical practice.

RETRACTED ARTICLE: The predictive value of BTG1 for the response of newly diagnosed acute myeloid leukemia to decitabine

BackgroundDecitabine has been widely used to treat acute myeloid leukemia (AML); however as AML is a heterogeneous disease, not all patients benefit from decitabine. This study aimed to identify markers for predicting the response to decitabine.MethodsAn intersection of in vitro experiments and bioinformatics was performed using a combination of epigenetic and transcriptomic analysis. A tumor-suppressor gene associated with methylation and the response to decitabine was screened. Then the sensitivity and specificity of this marker in predicting the response to decitabine was confirmed in 54 samples from newly diagnosed AML patients treated with decitabine plus IA regimen in a clinical trial (ChiCTR2000037928).ResultsIn vitro experiments showed that decitabine caused hypomethylation and upregulation of BTG1, while downregulation of BTG1 attenuated the inhibitory effect of decitabine. In newly diagnosed AML patients who received decitabine plus IA regimen, the predictive value of BTG1 to predict complete remission (CR) was assigned with a sensitivity of 86.7% and a specificity of 100.0% when BTG1 expression was < 0.292 (determined using real-time quantitative PCR), with area under the curve (AUC) = 0.933, P = 0.021. The predictive value of BTG1 to predict measurable residual disease (MRD) negativity was assigned with a sensitivity of 100.0% and a specificity of 80.0% when BTG1 expression was < 0.292 (AUC = 0.892, P = 0.012). Patients were divided into low and high BTG1 expression groups according to a cutoff of 0.292, and the CR rate of the low-expression group was significantly higher than that of the high-expression group (97.5% vs. 50%, P < 0.001).ConclusionsLow expression of BTG1 was associated with CR and MRD negativity in newly diagnosed AML patients treated with a decitabine-containing regimen, suggesting that BTG1 is a potential marker for predicting the response to decitabine in newly diagnosed AML.Clinical trial registration: ChiCTR2000037928.

Adding venetoclax or hypomethylating agents to induction chemotherapy as first-line treatment for adults with acute myeloid leukemia: a retrospective case-cohort study

Background: The response rate of traditional first-line induction chemotherapy (IC) for newly diagnosed acute myeloid leukemia needs to be improved, but it is not clear whether adding venetoclax or hypomethylating agents (HMAs) to IC will improve the response rate. Objective: To determine whether venetoclax or HMAs could increase the response rate of IC in patients with newly diagnosed acute myeloid leukemia (AML). Design: A retrospective, propensity score matching analysis. Methods: Newly diagnosed AML patients at Tongji Hospital between 2021 and 2023 were included in this study. By matching cases and controls based on age, gender, baseline bone marrow blast cell proportion, type of AML, and the National Comprehensive Cancer Network (NCCN) risk stratification group, we compared the response rate (CR, CR/CRi, ORR, and MRD negative) and hematological adverse events in newly diagnosed AML treated with IC plus venetoclax or HMAs versus IC alone after one cycle of IC. Results: The addition of venetoclax could improve CR/CRi of IC (83.8% for IC plus venetoclax vs 66.1% for IC alone, p = 0.029). The addition of venetoclax to IA regimen did not improve CR/CRi of IA regimen (76.9% for IA plus venetoclax vs 76.2% for IA alone, p = 0.986). The addition of HMAs could not only improves CR/CRi of IC (85.3%% for IC plus HMAs vs 65.4% for IC alone, p = 0.002) but also improves CR/CRi of IA regimen (91.3% for IA plus HMAs vs 70.0% for IA alone, p = 0.034). The addition of HMAs could improve CR/CRi of patients with adverse mutations (FLT3, IDH1/2, K/NRAS) after IC. The addition of venetoclax and HMAs both extended the duration of agranulocytosis and thrombocytopenia. Conclusion: Adding HMAs might improve CR/CRi of IC including IA. Adding venetoclax might not improve CR/CRi of IA. A well-designed prospective randomized controlled study is now warranted.

Low-Dose IA with Venetoclax Regimen As Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia

Abstract Background: The IA regimen (combination of idarubicin and cytarabine) is used as the most common induction of remission therapy for acute myeloid leukemia, with the complete response (CR) rates of up to 70%. Addition of the BCL-2 inhibitor venetoclax(Ven) to chemotherapy can increase apoptosis priming. In order to further improve the remission rate and prolong survival, our center uses a low-dose IA regimen combined with Venetoclax to treat newly diagnosed primary acute myeloid leukemia under 60 years old. Methods: We retrospectively analyzed 15 patients with newly diagnosed AML, who was under 60 years old. Patients received idarubicin (6mg/m2 IV for 3-days) and cytarabine (60mg/m2 IV for 5-days) with oral venetoclax (400mg daily for 2 weeks) for induction, followed by the same chemo-free regimen for consolidation if patients responded to induction therapy. And then analyze the effects of this regimen on complete remission (CR) rate, minimal residual disease (MRD) negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events. Findings: Between January, 2021 and June, 2023, 15 patients were treated with this regimen. The median age was 43 years (IQR, 36-43) and the median follow-up was 4.25 (IQR, 2.73-15.6) months. Among all patients, the ORR was 86.7% (95% CI 62, 96), the CR rate was 80.0% (95% CI 55, 93), and the MRD negative rate was 66.7% (95% CI 42, 85). According to 2022 ELN risk classification by genetics, the ORR in favorable risk patients were 50.0% (1/2), intermediate risk patients were 100% (7/7), adverse risk patients were 83.3%(5/6). Those who had epigenetic modification mutations (NPM1, FLT3-ITD, CEBPA) were more likely to benefit from this regimen. The most common grade 3 and 4 adverse reactions were neutropenia, thrombocytopenia, and anemia. Conclusion: As induction and consolidation therapy whose adverse reactions were tolerable, the low-dose IA with Venetoclax regimen produces deep remission for the patients with newly diagnosed primary AML.

Picalm::MLLT10 can Identify a New Subgroup of Acute Leukemias of Ambiguous Lineage with Unique Extramedullary Disease and Treatment Response

Background: Mixed-phenotype acute leukemias (MPAL), which is included in acute leukemias of ambiguous lineage (ALAL), can be classified as four different subtypes based on recurring genetic alterations including BCR::ABL, KMT2A and ZNF384 gene rearrangement as well as BCL11B activation. The 2022 WHO classification has already mentioned PICALM::MLLT10 fusions are also enriched in MPAL but need more data. In 2022 ELN classification, PICALM::MLLT10 was identified as acute myeloid leukemia (AML) with other rare recurring translocations but not ALAL. In addition, there is no separate classification for PICALM::MLLT10 in the new ICC classification. Therefore, it is still confused whether PICALM::MLLT10 corresponds to AML or acute lymphoblastic leukemia (ALL) or ALAL. Methods: Fourteen PICALM::MLLT10 positive patients of 390 AL patients (14/390, 3.6%) were identified by RNA sequencing (RNA-seq) in our center from 2020-2022, including 8 female and 6 male, with a median age of 33 years (16-50 years). These patients were newly diagnosed AL according to bone marrow morphology and immunology including 5 ALAL, 5 T-ALL [ 4 early T-cell precursor ALL (ETP-ALL), 1 cortical T-ALL], 2 AML, 1 B-ALL with aberrant expression of myeloid antigen, and 1 B/T MPAL. Results: The mean white blood cell counts of these patients was 8.25×10 9/L (2.34-51×10 9/L) and platelet counts was 168.5×10 12/L (39-429×10 12/L) individually. It should be mentioned that extramedullary disease (EMD) was found in 7 cases (7/14), including mediastinum, tonsil, and skin. In terms of immunotyping, CD7 was identified in all patients (14/14) and CD33 in 71.4% (10/14) patients. The major concurrence mutations were PHF6 mutation (8/14), JAK3 mutation (5/14), and SUZ12 mutation (4/14). Characteristic cytogenetic abnormality t(10;11)(p12.3;q14.2) was only found in three cases (3/14) (Table 1). The PICALM breakpoints are mainly concentrated in exon 17 (n=6) and exon 19 (n=8). Exon 4 (n=8), exon 6 (n=2), exon 9 (n=2) and exon 10 (n=2) are the most commonbreakpointsof MLLT10. To our knowledge, this is the first report about the breakpoints and fusion gene forms of PICALM::MLLT10. For initial treatment, these patients individually received standard ALL induction chemotherapy (VDPCP, vincristine, idarubicin, pegaspargase, cyclophosphamide, prednisone) and AML induction chemotherapy (3+7 IA regimen including idarubicin, cytarabine). The initial complete remission (CR) rate was only 35.7% (5/14), and 9 patients showing no remission (NR). These NR patients subsequently received salvage chemotherapy. It is worth mentioning that 6 of them received combined chemotherapy regimen including low doses of cytarabine (LDAC), granulocyte colony-stimulating factor (G-CSF) and anthracyclines such as aclarubicin or idarubicin or homoharringtonine (CAG or IAG or HAG), and 2 of 6 patients also further received combination therapy with venetoclax (CAG or IAG +VEN). Finally, 5 of them dramatically achieved CR (5/6). In the other 3 patients, 1 patient who was failure to initial Hyper-CVAD A/B regimen also dramatically achieved CR after the more Hyper-CVAD A regimen combined with venetoclax, and 1 patient achieved CR while another still NR with both receiving CLAG (cladribine, cytarabine, G-CSF) regimen. Subsequently 11 patients (9 CR, 2 with refractory disease) received allogenic hematopoietic stem cell transplantation (allo-HSCT), and all the CR patients survived well after HSCT (follow up 3-24 months, median 15 months) without relapse, while 2 NR patients died soon after transplantation because of severe complications (Table 2). Conclusions: Our data suggested PICALM::MLLT10 positive AL should be more appropriately recognized as an independent ALAL entity and may benefit from LDAC, G-CSF and anthracyclines combination chemotherapy as well as venetoclax. Sequential HSCT after chemotherapy combined with venetoclax may further improve long-term survival in AL patients with CR even MRD positive.

Newly Dignosed Early T-Cell Precursor Acute Lymphoblastic Leukemia Successfully Treated with Venetoclax Combined with DA and IA Regime

Abstract Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinctive and extremely aggressive subtype of T-ALL. It is characterized by the aberrant expression of myeloid/stem cell antigens and the lack of Tlymphoid antigens including CD1a, CD4, CD5, and CD8. Currently, standard combination chemotherapy is still the mainstay of ETP-ALL treatment. However, the optimal management remains to be determined. ETP-ALL has low response rates to conventional chemotherapy and high relapse rates with a grim prognosis. Although some ETPALL patients achieved morphologic complete remission (CR), a more signifcant proportion maintained MRD positive. Under the traditional induction and intensifcation treatment strategy, the ETP-ALL group had worse long-term outcomes than the non-ETP-ALL group [1]. A recent preclinical study suggested that inhibition of B-cell lymphoma/leukemia-2 (BCL-2) might be a potential treatment option for patients with ETP-ALL [2]. Here, we present two cases of ETP-ALL clinical reactivity to venetoclax in combination with the IA regimen, providing a better bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Case 1 A 47-year-old female was diagnosed with ETPALL in October 2021. Flow cytometry analysis showed CD7,CD117,CD34,CD13,CD2,CD200,cyCD3 positive,suggestive of ETP ALL. Cytogenetic analysis was normal and molecular panel identified aberrations in TET, EP300 and EZH2. She then recived venetoclax plus DA regime（venetoclax, 100 mg d1, 200 mg d2, 400 mg qd d3-14；daunorubicin 40mg d1-3；cytarabine 100mg d1-5). A bone marrow biopsy after the 1st cycle revealed CR with minimum residual disease (MRD) 1.91% by flow cytometry. She then received 2nd cycle of venetoclax plus CAG treatment and got MRD negative. She received 2cycles of the same combination and remained in MRD-negative CR prior to proceeding with a reduced intensity haploidentical allo-transplantation. She is currently 1 years and 4 months post-transplant and in remission. Case 2 A 53-year-old man was diagnosed with ETP-ALL following bone marrow aspiration in August 2022. He presented with Leukopenia and anemia (WBC 2.53× 109 /L, HB 73 g/L, PLT 148 × 109 /L). Bone marrow biopsy revealed a hypercellular bone marrow with 80% lymphoid blasts, negative for MPO staining. The flow cytometry showed the immunophenotype of the lymphoid blasts (CD7+CD34+CD33+CD13+CD200+cyCD3+nTdT+), which were consistent with the immunophenotype of the ETP-leukemic cells. Cytogenetics revealed der(4)(q35).The molecular panel identified aberrations in CSF3R,DNMT3A,CCND3,CSF3R and WT1. Therefore, ETP-ALL was diagnosed. Initially, he received the first cycles of venetoclax combined with IA regimen (venetoclax, 100 mg d1, 200 mg d2, 400 mg qd d3-14;idarubicin 10mg d1-3,cytarabine 100mg d1-5), and CR was achieved this time. Then, he received a 3rd CAG therapy. Subsequently, he underwent hematopoietic stem cell transplantation (HSCT) successfully in December, and CR was still maintained at now 7 months after HSCT. Conclusion Combination therapy of venetoclax with IA regimen is an effective regimen for treating patients with ETP ALL.

ETV6-ABL1 Fusion Gene Was Associated with a Poor Prognosis in Patients with Acute Myeloid Leukemia

Background:Acute myeloid leukemia (AML) is commonly characterized by chromosomal abnormalities that result in the formation of chimeric genes involved in leukemogenesis. ETV6-ABL1-a fusion gene results from a complex rearrangement involving translocation, inversion, or insertion of ETV6 into chromosomal band 9q34 or ABL1 into 12p13. This rare but recurrent genetic aberration is found in AML patients and is associated with a poor prognosis. Methods:A retrospective review was conducted of three relapsed AML patients with ETV6-ABL1 fusion genes screened by multiplex RT-PCR who were treated at Beijing Lu Daopei Hospital and Hebei Yanda Lu Daopei Hospital between November 2019 and January 2022. Results:At diagnosis, the median age was 32 years (range 32-42 years), and two patients were male(Pt.2,3). AML subtypes included M2 (Pt.2) and M4 (Pt.1,3), and no patient had a prior history of myeloproliferative neoplasms. Clinical and laboratory characteristics at diagnosis included: hepatosplenomegaly (Pt.3), lymphadenopathy (Pt.1), leukocytosis (median 209.71×10 9 /L, range, 60.28-687.2×10 9/L),but no significant eosinophilia(≥1.5×10 9/L). Cytogenetic analyses showed a normal karyotype in all three patients. FLT3-ITD gene mutation was found in two patients(Pt.1,2). All there patients received the same IA regimen(idarubicincytarabine) as induction chemotherapy and achieved complete remission, followed by multi-agent chemotherapy as consolidation treatment.Pt.1 received additional targeted therapy with sorafenib. However, after a median duration of remission (DOR) of 4 months (range 3-8 months), all patients experienced relapse and sought for further therapy at our hospital. Upon re-evaluation by laboratory tests, ETV6-ABL1 fusion gene was detected by multiplex RT-PCR, and additional NUP98-NSD1 fusion was also found in Pt.2. FLT3-ITD gene mutation was confirmed in Pt. 1 and Pt. 2, but the characteristic t(9;12) (q34;p13) chromosomal abnormalities were not present in any of the patients. Pt. 2 presented with an abnormal karyotype of 46, XY, t(3;17)(q12;p11.2),add (10)(q22)[5] / 46,XY[15], while the rest 2 patients had a normal karyotype. Pt.1 died rapidly from serious infection after relapse. Pt. 2 and Pt. 3 received dasatinib-containing combination regimens as salvage therapy and achieved partial remission. Pt. 2 underwent haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT) with an enhanced myeloablative conditioning regimen in March 2021, and has maintained molecular remission until now. Pt. 3 is currently undergoing HSCT preparation. Conclusion: ETV6-ABL1 fusion gene is a rare but recurrent genetic aberration in AML, and its rearrangement is not uniform across eachpatient, typically involving cryptic insertions. Routine chromosome G-banding analysis may not identify this fusion gene, and the combined use of fluorescence in situ hybridization and PCR is recommended for better detection for ETV6-ABL1. Patients with this fusion gene have a high relapse rate and a poor prognosis. Tyrosine kinase inhibitors (eg. Dasatinib)are a reasonable treatment option, and allo-HSCT may be considered for potential cure.

High-Dose Idarubicin Plus Busulfan As Conditioning Regimen to Autologous Stem Cell Transplantation Improves Prognosis in Patients with Favorable and Intermediate-Risk AML

Introduction: The optimal post-remission therapy (PRT) for patients with favorable and intermediate-risk acute myeloid leukemia (AML) remains uncertain. We retrospectively analyzed and compared the efficacy of high-dose idarubicin plus busulfan conditioning regimen combined with autologous stem cell transplantation (ASCT) and intermediate- to high-dose cytarabine consolidation chemotherapy for post-remission treatment (PRT) in patients with favorable- and intermediate-risk AML. Methods: A total of 116 patients with favorable- and intermediate-risk AML according to 2022 ELN risk stratification who were treated with ASCT (n=58) or intermediate- to high-dose cytarabine regimen (n=58) were enrolled in this study. All the patients received IA regimen (idarubicin 10-12 mg/m2 on days 1 to 3 and cytarabine 100 mg/m2/d on days 1 to 7) as induction and complete remission (CR) was obtained in all the patients after one course of induction. Fifty-eight patients were subjected to 2-4 courses of intermediate- to high-dose cytarabine (cytarabine 2-3 g/m2 twice daily on days 1-3). High-dose idarubicin plus busulfan conditioning regimen (I-Bu; idarubicin 20 mg/m2 continuous i.v. from days -13 to -11, busulfan in intravenous formulation: 3.2 mg/m2 or oral formulation: 4.0 mg/m2 from day -5 to -2) combined with ASCT was given to the other 58 patients 2-3 courses of intermediate- to high-dose cytarabine and mobilization and collection of peripheral blood stem cells. Clinical outcomes were retrospectively analyzed for patients belonging to the two treatment arms. Results: The median age was 38 (14-60 years) and 32 years (14-59 years) in ASCT and chemotherapy cohort, respectively. After a median follow-up of 68 months (1-200 months), and the median overall survival (OS) has not been reached in both groups. The 5-year and 10-year OS in the ASCT group was 77.5% and 71.5%, and 5-year and 10-year disease-free survival (DFS) was 73.9% and 71.1%, respectively. The 5-year OS and DFS in the chemotherapy group were 53.5% and 52.4%, respectively. The median OS and DFS of the patients in ASCT group were significantly better than those in chemotherapy group (OS: p=0.009, HR=0.444, CI 0.237 to 0.831; DFS：p=0.018, HR=0.494,CI 0.268 to 0.911). No treatment-related early death (death within 8 weeks after treatment) was observed in the ASCT group. All the patients experienced severe bone marrow suppression and severe (grade 3 or 4) hematological toxicity, and we did not observe severe (grade 3 or 4) cardiotoxic complications during or after ASCT in all the patients. Conclusions: ASCT with I-Bu regimen is possibly a promising PRT for patients with favorable- and intermediate-risk AML in the first CR, improving prognosis of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Efficacy and Survival Analysis of Adult Patients with Acute Myeloid Leukemia after Microtransplantation

To investigate the clinical efficacy and survival factors of microtransplantation (MST) in adult patients with acute myeloid leukemia (AML). For a retrospective analysis of 27 adult patients with AML receiving MST from July 2014 to October 2021, the median age was 59(29-77) years old, 13 cases were ≥60 years old, 14 case were <60 years old, 13 cases were male and 14 cases were female. Classification by FAB: AML-M2 6 cases, AML-M4 6 cases, AML-M5 2 cases, AML-M6 2 cases, AML（Undivided type） 9 cases, AML myeloid sarcoma 2 cases (primary AML 21 cases, AML secondary to MDS 6 cases). Cytogenetic analysis showed 25 patients with a normal karyotype, 2 patients with an abnormal karyotype, and 20 patients with an abnormal molecular biology. Induction chemotherapy regimens mainly include: IA, DA, MA or HA regimen, including CAG or CIG in combination with decitabine, and single-agent decitabine. 17 patients achieved complete remission (CR) after 1 course of induction chemotherapy and 4 patients achieved CR after 2 courses of induction chemotherapy. 3 patients received CR by four courses of decitabine, 2 patients received no remission, and 1 patient underwent no induction chemotherapy and were treated direct MST. There were 16 patients with pretransplant CR and 11 patients were not in remission before transplantation. Follow-up mainly used consult patient's medical records and telephone inquiry to observe the adverse effects and efficacy of MST treatment. Survival analysis was performed by Kaplan-Meier method, with the main observation indicators overall survival(OS) and leukemia-free survival(LFS), and performed with the Log-rank test. Multivariate analysis was performed by the Cox regression model. A total of 79 MST were performed in 27 AML patients with good overall safety and no special serious adverse effects. The median time of leukocyte recovery was 13(4-28) days, and the median time of platelet recovery was 13(4-30) days. There were 50 cases of infection, 5 cases of abnormal liver function and 3 cases of abnormal cardiac function. Except for abnormal cardiac function, all other complications did not affect the treatment and were cure. Acute or chronic GVHD, renal insufficiency, abnormal coagulation function, and severe bleeding were not observed during treatment or during follow-up. As of the follow-up date, the median follow-up time of the 27 patients was 79(14-171) months, the median OS time was 62(1-171) months, and the median LFS time was 15(0-171) months. The 2-year OS rate was 65.7%（17/27）, and the 2-year LFS rate was 47.4%（12/27） . The complete response rate of 27 patients treated with MST was 48.1% (13/27). 8 patients relapsed during MST treatment, including 7 patients after the completion of the first MST course and 1 patient after the completion of the second MST course. 2 patients relapsed after the end of the course of MST. 13 patients died, including 10 patients because of disease progression, two patients from severe infection, and one patient from cardiac damage. MST has the advantages of small toxic side effects, complete compatibility of HLA matching is not required, effective avoidance of GVHD and rapid hematopoietic recovery, which can improve OS and LFS in elderly AML and young AML patients, and is one of the treatment options for patients without HLA matching.

Histone methylation modification patterns and relevant M-RiskScore in acute myeloid leukemia

ObjectiveWe tried to identify novel molecular subtypes of acute myeloid leukemia (AML) associated with histone methylation and established a relevant scoring system to predict treatment response and prognosis of AML. MethodsGene expression data and clinical characteristics of patients with AML were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Molecular subtyping was carried out by consensus clustering analysis, based on the expression of 24 histone methylation modification regulators (HMMRs). The clinical and biological features of each clustered pattern were taken into account. The scoring system was constructed by using differential expression analysis, Cox regression method and lasso regression analysis. Subsequently, the scoring system in the roles of prognostic and chemotherapeutic prediction of AML were explored. Finally, an independent GSE dataset was used for validating the established clustering system. ResultsTwo distinct subtypes of AML were identified based on the expression of the 24 HMMRs, which exhibited remarkable differences in several clinical and biological characteristics, including HMMRs expression, AML-M0 distribution, NPM1 mutation, tumor mutation burden, somatic mutations, pathway activation, immune cell infiltration and patient survival. The scoring system, M-RiskScore, was established. Integrated analysis demonstrated that patients with the low M-RiskScore displayed a prominent survival advantage and a good response to decitabine treatment, while patients with high M-RiskScore have resistance to decitabine, but they could benefit from IA regimen therapy. ConclusionDetection of HMMRs expression would be a potential strategy for AML subtyping. Meanwhile, targeting histone methylation would be a preferred strategy for either AML-M0 or NPM1 mutant patients. M-RiskScore was a useful prognostic biomarker and a guide for the choice of appropriate chemotherapy strategy.

A Prospective Clinical Study of the Efficacy and Adverse Reactions of Azacitidine Combined with IA Regimen As the Induction Treatment of Newly Diagnosed AML

Objective:This single-arm prospective research (ChiCTR2100044731) aimed to evaluate the efficacy and safety of azacitidine combined with IA regimen in the induction treatment of newly diagnosed acute myeloid leukemia (AML), with a view to further improving the efficacy of acute myeloid leukemia with poor prognosis.Methods:Newly diagnosed AML (non-M3) patients who received azacitidine combined with IA regimen induction chemotherapy in the Department of Hematology of the First Affiliated Hospital of Sun Yat-sen University from November 2019 to February 2021 were enrolled, and the efficacy and side effect were analyzed.Results: 1.A total of 33 patients were enrolled. The median age of the enrolled patients was 43.36 years (17-63), including 16 males (48.5%) and 17 females (51.5%). According to NCCN risk stratification, there were 3 patients (9.1%) in the favor group (9.1%) ,13 cases (39.4%) in the intermediate group and 17 cases (51.5%) in the poor group.2.The CR rate of one cycle of azacitidine combined with IA regimen was 66.7%, with a PR rate of 12.1% and a NR rate of 21.2%. After propensity score matching with the newly diagnosed AML patients who received IA regimen as induction chemotherapy in our center, a paired study was carried out. The results showed that there was no significant difference between the 2 groups in the treatment CR rate (66.7% for azacitidine combined with IA vs 54.5% for IA, P=0.592, Fig1). Subgroup analysis (table 1) showed combination of azacitidine with IA significantly improved the CR rate of patients with a ratio of blasts in the bone marrow greater than 67% (83.3% vs 30.8%, P=0.014) and patients in the intermediate NCCN risk group (100.0% vs 37.5%, P=0.001).3.The duration of agranulocytosis in the azacitidine combined with IA chemotherapy group was longer than that in the IA group (21 days vs 19 days, P=0.045). There was no significant difference in the number of platelet transfusions and the number of red blood cell transfusions between the two groups, and there was no significant difference in the incidence of infection between the two groups (table 2).Conclusions:The remission rate of induction chemotherapy for azacitidine combined with IA regimen and IA regimen in newly diagnosed non-M3 AML patients is comparable. Patients with a ratio of immature cells in bone marrow greater than 67% and patients in the intermediate NCCN risk group may benefit from azacitidine combined with the IA regimen. The combination of azacitidine with IA regimen aggravated granular bone marrow suppression. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Decitabine Combined with IA Regimen in the Treatment of Newly Diagnosed Acute Myeloid Leukemia

▪Objective: To evaluate the efficacy and safety of decitabine combined with IA regimen in the treatment of newly diagnosed acute myeloid leukemia.Methods: From September 1, 2013 to October 18, 2019, 164 newly diagnosed acute myeloid leukemia patients who received IA or decitabine combined with IA induction chemotherapy who were hospitalized in the Department of Hematology of the First Affiliated Hospital of Sun Yat-sen University were enrolled. The efficacy and side effects of treatment were analyzed.Results: The complete remission rate of decitabine combined with IA regimen chemotherapy group (n=88) and IA regimen chemotherapy group (n=76) was 83.0% vs. 68.4% (P=0.029, Fig 1). Subgroup analysis (table 1) showed that age ≥40 years old, WBC＜10*10^9/L, Hb＞85g/L, PLT≥50*10^9/L, MCV≥98fL, ratio of bone marrow immature cells ≤45%, NCCN intermediate-risk or high-risk group, patients with FLT3ITD mutation had a higher CR rate in the decitabine combined with IA regimen group. Multivariate analysis showed that combined decitabine was an independent favorable factor affecting the CR rate (OR 3.559, 95% CI: 1.554-8.151, P=0.003). Compared with the IA group, patients in the decitabine combined with IA group took longer to rebuild the granule system (20 days vs 19 days, P=0.026), and the incidence of infection was higher (93.2% vs 78.8%, P=0.028) (table 2).Conclusion: Compared with the IA regimen, the decitabine combined with the IA regimen significantly improves the induction chemotherapy response rate of newly diagnosed non-M3 AML patients, especially for patients with the following characteristics: age ≥ 40 years old, WBC <10*10^ 9/L, Hb＞85g/L, PLT≥50*10^9/L, MCV≥98fL, bone marrow immature cell proportion ≤45%, NCCN risk stratification medium-risk or high-risk group, FLT3ITD mutation. After combining with decitabine, the patient's granular bone marrow suppression increased. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Prognosis of Intermediate- and High-Risk Young AML Patients Who Did Not Receive Allo-HSCT Treated with Intensive Chemotherapy Is Not Superior to That of Elderly AML Patients Treated with the D-CAG Regimen

Introduction: AML is an extremely heterogenous disease which poses fundamental challenges in developing effective treatment regimens, while simultaneously highlighting the critical need for more personalized therapy. This investigation explores AML patients who would benefit the most from the relatively low intensive regimen D-CAG or intensive therapy.Methods: A total of 331 patients with AML who were treated with intensive chemotherapy (young patients, n=179) or D-CAG regimen (older patients, n=152) were enrolled in this study.The young patients received IA regimen (idarubicin 10-12 mg/m 2 on days 1 to 3 and cytarabine 100 mg/m 2/d on days 1 to 7) as induction. A total of 37 patients were recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 27 patients were recipients of autologous HSCT. Patients who were unsuitable for HSCT were subjected to post-remission therapy consisting of 2-4 courses of intermediate to high dose cytarabine (cytarabine 2-3 g/m 2 twice daily on days 1-3). The D-CAG regimen (decitabine 15 mg/m 2 intravenously on days 1-5, cytarabine 10 mg/m 2 subcutaneous injection twice daily on days 3-9, aclarubicin 8-10 mg/m 2/d on days 3-6, and G-CSF 300 μg/d for priming until white blood cell count was >20×10 9/L) was given to the older patients. An additional 4-6 cycles of D-CAG were administered to those who achieved CR. Those who failed to obtain CR after two cycles of D-CAG were given the option of palliative care or alternative treatments. None of the patients in this subgroup received allo- or auto-HSCT.Clinical outcomes were retrospectively analyzed for patients belonging to the two treatment arms.Results: The median age was 67 (range, 60 to 86 years) and 36 years (range, 14 to 59 years) in D-CAG and IA cohort, respectively. In the D-CAG cohort, there were significantly more patients demonstrating an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2-3 in contrast to the IA cohort (17.1% vs. 2.2%, P< 0.0001). Conventional cytogenetic examination was conducted in all patients. However, sufficient metaphase data was not available for 15 of these patients. Based on the 2017 ELN cytogenetic risk classification, patients were risk stratified based on the presence of molecular and cytogenetic aberrances upon diagnosis. A total of 114 patients (34.4%) were determined to possess favorable-risk, 106 patients (32.0%) were intermediate-risk and 96 patients (29.0%) were poor-risk. There were significantly more patients in the favorable-risk category and less in the poor-risk category in the IA cohort as in contrast to the D-CAG cohort (favorable-risk: 47.5% vs. 19.1%, P< 0.0001; poor-risk: 21.2% vs. 38.2%, P=0.001). Older patients harbored significantly more complex, monosomal karyotypes and abnormalities in chromosomes 5 and/or 7 (-5/5q- and/or -7/7q-) in comparison to young patients. Clinical features of gender, white blood cell (WBC), hemoglobin and platelet count at diagnosis as well as percentage of blasts in bone marrow, were similar between the two cohorts.Our data revealed that the young patients had significantly better complete remission (CR) rate (80.4% vs.67.1%, P=0.0051) and median overall survival (OS) (38 vs. 15 months, P<0.0001) compared to older patients. However, the objective response rate (ORR) and median OS of the intermediate- and high-risk groups was comparable between older and young patients who were not recipients of allo-HSCT. The median OS was comparable between D-CAG-treated patients with or without FLT3-ITD, DNMT3A, IDH2, TP53 and as well as DNA methylation associated gene mutations, whereas patients treated with intensive therapy who bore these mutations demonstrated markedly lower median OS in contrast to those bore wild-type genes. Individuals with biallelic CEBPA and NRAS mutations were more likely to benefit from intensive chemotherapy regimens.Conclusions: Intensive chemotherapy had little effect on the prognosis of intermediate- or high-risk young patients who did not undergo allo-HSCT. Patients harboring FLT3-ITD, DNMT3A, IDH2, TP53 and DNA methylation associated mutations were found to benefit more from the D-CAG regimen in comparison to intensive chemotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia

BackgroundIn this study, we retrospectively summarized the differences of molecular gene mutations between MDS and AML patients, as well as the young and older age groups of MDS and AML patients. We also analyzed the response of newly diagnosed AML patients to standard DA or IA induction chemotherapy and the relationship between the chemotherapy outcome and the frequency of different gene mutation abnormalities.MethodsNGS assay covering 43 genes was studied in 93 de novo MDS and 325 non-M3 AML patients. Bone marrow samples from all patients underwent gene mutational analysis by NGS.ResultsAt least one non-synonymous gene mutation was detected in 279 AML patients (85.8%) and 85 MDS patients (91.4%). Contrary to 59 years and younger AML patients, there was a significantly higher incidence of gene mutation in 60 years and older AML patients (2.37 vs 1.94, p = 0.034). Gene mutation incidence in 60 years and older MDS patients increased, but no statistical significance was present (1.95 vs 1.64, p = 0.216). AML patients had a significantly higher gene mutation incidence compared with MDS-MLD patients (2.02 vs 1.63, p = 0.046). Gene mutation incidence was higher in patients with MDS-EB1/EB2 compared with patients with MDS-MLD but there was no statistical significance present (2.14 vs 1.63, p = 0.081). AML patients had significantly higher incidences of CEBPA, FLT3-ITD, DNMT3A, NPM1 and IDH1/2 gene mutations (p = 0.0043, 0.000, 0.030962, 0.002752, and 0.000628, respectively) and a lower incidence of TET2 and U2AF1 gene mutations (p = 0.000004 and 0.000, respectively) compared with MDS patients. Among the individual genes in different age groups, there were significantly higher incidences of RUNX1, IDH2, TP53 and SF3B1 gene mutations (p = 0.0478, 0.0028, 0.0024 and 0.005, respectively) as well as a trend of higher ASXL gene mutation (p = 0.057) in 60 years and older AML patients compared to 59 years and younger patients. There was no statistically significant difference in MDS patients with the different age groups and among the individual genes. Between AML patients and MDS patients among the different gene functional groups, AML patients had a significantly higher incidence of transcriptional deregulation (27.4% vs 15.1%, p = 0.014963), activated signalling (36.3% vs 10.8%, p = 0.000002) related gene mutations as well as a significantly lower incidence of RNA spliceosome (6.15% vs 60.1%, p = 0.000) related gene mutations. Furthermore, among the patients who received either IA or DA regimen for induction chemotherapy, patients with IA regimen had a significantly better CR rate than those with DA regimen (76.6% vs 57.1%, p = 0.0228).ConclusionsDifferent gene mutations had been found in majority of MDS and AML patients. MDS and AML patients had different gene mutation patterns. AML patients with fewer or no gene mutations had a better chance of achieving CR when treated with IA and DA regimen induction chemotherapy.

Impact Of ELN Risk Stratification, Induction Chemotherapy Regimens And Hematopoietic Stem Cell Transplantation On Outcomes In Hyperleukocytic Acute Myeloid Leukemia With Initial White Blood Cell Count More Than 100 × 109/L.

BackgroundHyperleukocytic acute myeloid leukemia (AML) (initial white blood cell count≥100 × 109/L) is a clinical emergency often accompanied by leukostasis syndrome, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC), with a poor clinical prognosis. The aim of this study retrospectively analyzed the clinical features of hyperleukocytic AML, focusing on high-risk factors affecting prognosis, the selection of initial induction therapy, and the impact of hematopoietic stem cell transplantation (HSCT) on prognosis.Patients and methodsA total of 558 AML patients at our center from January 2013 to December 2017 were diagnosed, and 52 (9.32%) patients presented with hyperleukocytosis were retrospectively reviewed.ResultsThe 3-year overall survival (OS) rate in the 15–39 years old and 40–60 years old group was 58.8% and 25.4%, respectively; the longest survival time in patients aged >60 years was only 8 months, and the 8-month OS rate was 8.3% (p=0.002). The 3-year OS rate of the patients in the favorable risk group, intermediate risk group and high risk group, according to the 2017 ELN risk stratification, was 50%, 28.0%, and 29.5%, respectively (p=0.374). The 3-year OS rate of patients carrying CEBPA or NPM1 mutation and those with FLT3-ITD or MLL mutation was 37.5% and 30.0%, respectively (p=0.63). The 3-year OS rate of patients employing an induction regimen of a standard IA regimen was 58.4%, and of those employing a non-standard IA regimen was 22.2% (p=0.065). The 3-year OS rate of the transplantation patients reached 73.8%, while the 9-month OS rate of patients without transplantation was 11.4% (p<0.001).ConclusionThis study suggest that hyperleukocytosis is an independent risk factor for AML patients, regardless of the risk stratification based on cytogenetic or molecular abnormalities. Age is the main factor influencing the prognosis of hyperleukocytic AML. The use of a standard IA regimen and HSCT can significantly improve the patient’s prognosis.

PF278 DECITABINE COMBINED WITH HAAG AS INDUCTION CHEMOTHERAPY FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA

Background:Treatment of newly diagnosed acute myeloid leukemia (AML) remains challenging. Several patients and disease‐related factors contribute to poor outcome in elderly patients or high risk patients with AML, including medical comorbidities, physical frailty, and poor‐risk biologic features. It is confirmed that Decitabine(DAC) has the synergistic reaction with daunomycin or cytarabine. Therefore, we investigated whether DAC combined with HAAG regimen might also be effective for the newly diagnosed of AML patients.Aims:To evaluate the efficacy and toxicity of DAC combined with HAAG regimen as an induction therapy for newly diagnosed AML patients as well as compared with standard IA(IDA 12 mg/m2/d∗3d) regimen.Methods:237 patients with AML who were newly diagnosed in our center between February 2014 and July 2018 were enrolled in this retrospective study. Among them,50 cases received DAC+HAAG regimen(DAC 20 mg/m2/d∗5d combined with low dose of homoharringtonine 1 mg/ m2/ d∗7–14d, cytarabine subcutaneously 10 mg/m2/q12h∗7–14d, aclarubicin 10 mg/d∗4–8d and G‐CSF priming). The other 187 patients received standard IA regimen (idarubicin 12 mg/m2/d∗3d and cytarabine 100 mg/m2/d∗7d).The outcomes of all the patients after one cycle of chemotherapy were evaluated.Results:1.The complete remission(CR) rate of DAC+HAAG group was significantly superior than that of IA group(96.0% vs 75.9%, P = 0.000). And the overall response rate (ORR) of DAC+HAAG group was also superior than that of IA group(100.0% vs 90.7%, P = 0.0.013).2.One‐year OS of DAC+HAAG and IA group were 75.3% and 74.8%.And two‐year OS were 69.0% and 66.1%,respectively. The median OS of the poor‐risk patients receiving DAC+HAAG and IA were 26 months and 32 months, respectively (P = 0.9625). Although the OS of two groups were similar, but the age of patients in DAC+HAAG group were statistically older than the IA group(P = 0.00).Furthermore,there were more patients with PS ECOG&gt;2 in DAC+HAAG group(P = 0.000).3. Treatment related mortality (TRM), duration of neutropenia and thrombopenia were similar in both groups. Patients in DAC+HAAG group had significantly less infection grade 3–4 compared to the patients in IA group(16.0 vs 34.8%,p = 0.011). While the incidence of adverse events including bleeding, cadiotoxicity,liver damage and mucositis were similar(P = 0.424,0.296,0.259,0.060).Summary/Conclusion:DAC+HAAG regimen is a promising induction chemotherapy for newly diagnosed AML patients with mild toxicity, especially for patients who are not suit for standard induction chemotherapy.

Haemophagocytic lymphohistiocytosis occurred during induction chemotherapy in an acute monocytic leukemia patient with FLT3-ITD and DNMT3A mutations

BackgroundHaemophagocytic lymphohistiocytosis (HLH) is considered to be a large challenge for clinicians due to the variable overlaps of symptoms with other severe diseases and a high rate of mortality. Prompt diagnosis and treatment are crucial to avoid a fatal outcome. However, very limited reports have focused on HLH during chemotherapy (Ch-HLH) due to a low incidence and insufficient knowledge.Case presentationA 22-year-old male was diagnosed with acute monocytic leukemia with FLT3-ITD and DNMT3A mutations and pulmonary infection. He received IA regimen (Idarubicin, 8 mg/m2/d for 3 days and cytarabine, 100 mg/m2/d for 7 days) chemotherapy, anti-infection drugs and blood components transfusions. During the stage of bone marrow suppression, he presented with a fever, cytopenia (WBC, 0.43 × 109/L; Hb, 73 g/L and PLT, 1 × 109/L), refractory coagulation dysfunction (APTT, 104.0 s; PT, 30.5 s and Fbg, 0.87 g/L), splenomegaly (3 cm below the costal margin), hyperferritinemia (SF > 3000 μg/L), increased soluble interleukin-II receptors (sIL-2R > 7500 u/mL) and haemophagocytosis in the bone marrow and was diagnosed with HLH. After he was treated with methylprednisolone at 500 mg/d for 3 days, 120 mg/d for 3 days and 80 mg/d for 3 days, followed by a gradually reduced dose combined with powerful anti-infection drugs, his symptoms subsided and his abnormal parameters recovered to normal levels.ConclusionPatients with HLH in acute leukemia have a high rate of mortality. This case report provides helpful clinical experiences relative to the recognition and treatment of Ch-HLH for clinicians.

Clinical observation of standard IA regimen as induction chemotherapy in 242 patients with newly diagnosed acute myeloid leukemia

Clinical observation of standard IA regimen as induction chemotherapy in 242 patients with newly diagnosed acute myeloid leukemia

Evaluating the Impact of the Addition of Cladribine to Standard Acute Myeloid Leukemia Induction Therapy.

Treatment for acute myeloid leukemia (AML) has remained relatively unchanged over the past few decades. Although recent drug approvals have provided an increase in the number of treatment options in AML, further optimization of standard induction therapy is still necessary. The most commonly utilized induction options have been well studied, but there is a paucity of literature comparing the combination of idarubicin with cytarabine and cladribine. To assess the clinical effectiveness of the addition of cladribine to idarubicin and cytarabine (7+3 IA) induction therapy in the treatment of AML. This retrospective, propensity score-matched cohort study evaluated 37 patients with previously untreated AML who received either 7+3 IA or idarubicin, cytarabine, and cladribine (7+3+5 IAC) as induction therapy. The primary end point of this study was complete response (CR), with secondary end points including hospital length of stay (LOS), and adverse event rates. After propensity score matching, odds of reaching CR in the 7+3+5 IAC cohort were increased by 33% (95% CI = 1.09-1.55; P < 0.01) compared with the 7+3 IA cohort. Patients who received cladribine were also found to have a reduction in hospital LOS by 3.5 days (95% CI = 0.07-6.85; P = 0.045) without an increase in adverse event rates. The addition of cladribine to the 7+3 IA regimen may improve clinical outcomes when used as initial induction therapy, without increasing the incidence of adverse event rates.

Efficacy and safety of IA regimen containing different doses of idarubicin in de-novo acute myeloid leukemia for adult patients

目的探讨含不同剂量去甲氧柔红霉素（IDA 8、10、12 mg/m2）的IA方案诱导治疗成人初发急性髓系白血病（AML）（非急性早幼粒细胞白血病）的临床疗效和安全性。方法采用多中心、单盲、非随机、临床对照研究，纳入2011年5月至2015年3月苏州大学附属第一医院及其他36家单位收治的1 215例成人初发AML患者，根据诱导化疗方案中IDA的剂量对患者进行分组，分析不同剂量IDA联合阿糖胞苷（100 mg/m2）组成的IA方案在成人初发AML诱导治疗中的完全缓解（CR）率、血液学及非血液学不良事件。结果可纳入缓解率分析的AML患者共1 207例，IDA 8 mg/m2、10 mg/m2和12 mg/m2组的CR率分别为73.6%（215/292）、84.1%（662/787）和86.7%（111/128），差异有统计学意义（P<0.001）；以IDA 8 mg/m2组为参照组，在调整了年龄、骨髓原始细胞比例、FAB分型、危险度分层后，IDA 10 mg/m2和IDA 12 mg/m2为影响患者CR的有利因素[OR=0.49（95% CI 0.34~0.70），P<0.001；OR=0.36（95%CI 0.18~0.71），P=0.003]。在中、低危组中三组CR率分别为76.5%（163/213）、86.9%（506/582）和86.1%（68/79），差异有统计学意义（P=0.007）；在调整了年龄、骨髓原始细胞比例、FAB分型因素后，IDA 10 mg/m2为影响患者CR的有利因素[OR=0.47（95% CI 0.31~0.71），P<0.001]。在高危组中，三组CR率分别为50.0%（18/36）、60.6%（43/71）和81.8%（18/22），差异无统计学意义（P=0.089），但在调整了年龄、骨髓原始细胞比例、FAB分型因素后，IDA 12 mg/m2为影响患者CR的有利因素[OR=0.22（95% CI 0.06~0.80），P=0.022]。8 mg/m2、10 mg/m2和12 mg/m2组中性粒细胞≤0.5×109/L的中位持续时间分别为14（11~18）、15（11~20）和18（14~22）d，差异有统计学意义（P=0.012）；三组PLT≤20×109/L的中位持续时间分别为14（7~17）、15（11~20）和17（15~21）d，差异有统计学意义（P=0.001）；三组肺部感染发生率分别为9.8%、13.5%和25.2%，差异有统计学意义（P<0.001）。结论在中国成人（18~60岁）初发AML中，建议中、低危组患者采用含IDA 10 mg/m2的IA方案进行诱导治疗；而高危组AML建议选择含IDA 12 mg/m2的IA方案进行诱导治疗。