Secondary Acute Myeloid Leukemia Patients Research Articles

Improved Survival with Venetoclax in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Cohort Study

Background: Venetoclax in combination with azacitidine or low-dose cytarabine has become standard treatment for newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML). Since approval of venetoclax in 2020 in Japan, venetoclax combination therapy have been also used for relapsed or refractory patients although its role in relapsed or refractory disease is not well defined. The survival impact of chemotherapy with venetoclax combination therapy compared with that without venetoclax combination therapy on AML patients in a real-life setting is scarcely reported. Objective: The aim of this retrospective study was to evaluate chemotherapy with or without venetoclax combination therapy in patients with newly diagnosed AML in our institution. Patients and Methods: This study included 234 non-M3 newly diagnosed AML patients who were treated with or without venetoclax combination therapy between February 2008 and July 2023 in our hospital. We evaluated overall survival and composite complete remission (complete remission or complete remission with incomplete hematologic recovery). Overall survival was compared with the use of a cox proportional-hazards regression model adjusted for age (1-year increase) and cytogenetic risk (favorable or intermediate vs. adverse). Composite complete remission was compared between the treatment groups with the use of a logistic regression model adjusted for the same prognostic factors. Subgroup analyses of overall survival was performed according to variables based on disease characteristics at baseline to assess whether the beneficial effect of venetoclax combination therapy varied among specific patient subgroups. Results: We identified 41 patients who were treated with venetoclax as first-line or later treatment and 193 patients who were treated without venetoclax. In the venetoclax group, 26 (63.4%) received venetoclax combination therapy as first-line and 15 (36.6%) as second- or later-line treatement. Twenty (48.8%) were treated with venetoclax combined with azacitidine, 12 (29.3%) with low-dose cytarabine and 9 (22.0%) with both in their course of treatment. Patients in the venetoclax group was older than those in the non-venetoclax group (median age, 76 years vs. 67 years, respectively; P<0.001). FLT3, NPM1, TP53 and IDH1/2 mutational status was comparable between groups. The percentage of patients classified as poor cytogenetic risk category according to the NCCN guidelines for AML, 2021 was higher in the venetoclax group than that in the non-venetoclax group (51.2% vs. 28.0%, respectively; P=0.005). The percentage of patients who umderwent allogeneic hematopoietic stem cell transplantation was lower in the venetoclax group than that in the non-venetoclax group (2.4% vs. 16.6%, respectively; P=0.014). Composite complete remission was achieved in 46.3% (95% CI, 30.7 to 62.6) of the patients in the venetoclax group and 54.4% (95% CI, 47.1 to 61.6) of the patients in the non-venetoclax group (P=0.199). In a Cox model adjusting for age and cytogenetic risk, the 1-year overall survival rate was 79.4% (95% confidence interval [CI], 66.5 to 87.8) in the venetoclax group, as compared with 68.0% (95% CI, 59.6 to 75.0) in the non-venetoclax group (adjusted hazard ratio, 0.64; 95% CI, 0.41 to 1.00; P=0.049). Subgroup analysis of overall survival showed a greater survival benefit in the venetoclax group than in the non-venetoclax group in patients who were 70 years of age or older (P=0.003 for interaction) and in patients with de novo AML (P=0.022 for interaction) after adjustment for age and cytogenetic risk. Conclusions: These real-world data suggested that incorporation of venetoclax combination therapy into existing therapies improved survival in patients with AML. The survival benefit of venetoclax combination therapy was greater in elderly patient and in de novo AML patients than secondary AML patients. Interpretation of the results must be careful because the sample size in the venetoclax group was small. To confirm our findings, further investigation in a larger patient population is required.

Distinct Role of STAT3 and STAT5 Factors in MDS and AML

Introduction: Myelodysplastic Syndrome (MDS) refers to a heterogeneous group of clonal hematologic disorders characterized by hematopoietic dysfunctions and impaired differentiation in the hematopoietic stem and progenitor cells compartment. MDS is commonly referred to as a pre-leukemic stage due to the increased risk of progression to Acute Myeloid Leukemia (AML). AML is an aggressive hematologic malignancy characterized by the accumulation of immature myeloblasts in the bone marrow and the peripheral blood. Signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5) are important regulators of several cellular processes including cell proliferation and survival. Abnormal STAT3 and STAT5 signaling has been implicated in various solid and hematologic malignancies, including MDS and AML, which renders them appealing targets for the development of novel therapeutic strategies. Materials: STAT3, STAT5A or STAT5B knock-downs have been generated in two AML (MOLM-13 and Kasumi-1) and two MDS (MDS92 and MDS-L, gift of Prof. Kaoru Tohyama) cell lines, using shRNAs through lenti-viral delivery. The 4 biological replicates with the highest levels of knock-downs for STAT5A, STAT5B or STAT3 have been selected for each cell line and mRNA sequencing has been performed. To define the genome-wide binding of STAT5A, STAT5B and STAT3 in the two conditions, CUT&Tag has been performed in wild type MOLM-13, Kasumi-1 and MDS-L cells. Additionally, ATAC sequencing has been carried out in the same cell lines to investigate the chromatin conformation changes between the two conditions. Furthermore, STAT3, STAT5A and STAT5B knock-downs have been conducted using shRNAs through lenti-viral delivery in CD34+ enriched cells, isolated from bone marrow mononuclear cells of 14 high-risk MDS patients and 14 secondary (MDS-related) AML patients. The samples have been processed for mRNA-Sequencing to model the leukemic transformation in primary human cells. Results: To elucidate the role of STAT3 and STAT5 in MDS to AML transformation, changes in STAT3 and STAT5 target gene networks have been identified. mRNA sequencing data from STAT3, STAT5A or STAT5B knock-downs in MDS and AML cell lines revealed a distinct role of the three factors in each state. The differential binding of each factor, explored through CUT&Tag, and the gene expression profiles in MDS and AML reciprocally reveal a different function of each factor, including pathways involved in cell cycle and apoptosis. Also, the direct and indirect target genes of STAT3, STAT5A and STAT5B in each condition, as well as a possible interplay between STAT3 and STAT5 activation in AML has been uncovered. The exploration of the chromatin accessibility landscapes between the MDS and AML conditions through ATAC sequencing has provided an insight into the chromatin conformation states, unveiling potential leukemia promoting networks, as well as the involvement of STAT3 and STAT5 pathways in the malignant transformation. Furthermore, a potential cross talk of STAT3 and STAT5 factors with the IKAROS family members, has been linked to AML transformation, as significant differential regulation has been detected between MDS and AML conditions after knock-down of STAT5A and STAT5B. The results are currently validated in primary hematopoietic cells of MDS and AML patients after STAT3, STAT5A or STAT5B knock-downs. Conclusions: Our results show a different role between the two STAT5 factors (STAT5A and STAT5B) in MDS and AML conditions and delineate the role of STAT5A, STAT5B and STAT3 factors and their target gene networks in leukemic transformation, thus providing novel targets for therapeutic management of MSD and AML. Funding: This project is funded by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (ARCH)

Chromosomal aberrations and prognostic analysis of secondary acute myeloid leukemia-a retrospective study.

Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients' transition to AML (i.e., at S-AML diagnosis). The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20-77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P<0.05). S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid.

Abstract A22: Complete mutation concordance with amplicon-based NGS between peripheral blood and bone marrow at 0.5% VAF threshold

Abstract Background: Acute myeloid leukemia (AML) is a hematological malignancy characterized by genomic heterogeneity throughout disease progression and between patients. Traditionally, both multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) samples are collected via bone marrow (BM) aspiration, which is an invasive procedure with risk of infection. Peripheral blood (PB) has been demonstrated as a good substitute for BM but the concordance at different levels of NGS variant allele frequency (VAF) has not been defined. This study aims to demonstrate the relationship of NGS signals between PB and BM. Method: Genomic profiles of 60 matched samples of BM and PB were obtained retrospectively from 24 patients with de novo AML (n=17) or secondary AML (n=7). The samples were subjected to library preparation with a hematologic panel based on AmpliMark, an ultrasensitive amplicon-based NGS platform technology. The hematologic panel covers up to 45 genes common in myeloid and lymphoid neoplasms, with an established limit of detection of 0.1% VAF. Optimized bioinformatics pipeline and in-house sequencing noise removal algorithm were applied for variant selection. One of the secondary AML patients had a concurrent diagnosis of multiple myeloma; for the purposes of this analysis, the myeloma-associated variants were excluded. Results: 50 out of 60 matched BM and PB samples (83.3%) in the cohort were positive for at least one variant in either sample type. Complete or partial concordance of genetic profiles was achieved in 86.7% of the matched BM and PB samples. All samples obtained during diagnosis or relapse showed complete concordance, while all partial concordant and discordant profiles were sampled during post-treatment or remission stages. All BM samples with ≥1.5% abnormal cells detected by MFC demonstrated complete concordance between BM and PB genetic profiles. Analysis at the individual variant level (n=115) showed 78.6% of positive percent agreement (PPA) comparing PB to BM in variant detection. For variants detected at ≥0.5% and ≥0.1% VAF in the BM samples, 100% PPA and 86.4% PPA were achieved from matched PB samples, respectively. A strong correlation of VAF (r=0.98) was also demonstrated between variants detected in BM and PB. Conclusion: PB NGS is particularly sensitive for detection of myeloid specific mutations in de novo and secondary AMLs with complete concordance at VAFs ≥0.5%, when compared to BM. The high concordance and minimally invasive nature of PB sampling makes it a favorable option for diagnostic and monitoring of AML. Citation Format: Benjamin Lim, Chae Yin Cher, Jonathan Poh, Kao Chin Ngeow, Zi Yi Lim, Min-Han Tan. Complete mutation concordance with amplicon-based NGS between peripheral blood and bone marrow at 0.5% VAF threshold [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A22.

Phase II Study of Tagraxofusp in Newly Diagnosed Secondary Acute Myeloid Leukemia (S-AML) after Previous Exposure to Hypomethylating Agents (TAGALONG Study)

Background: S-AML patients with prior exposure to hypomethylating agents (p-HMAs) have dismal clinical outcomes and are unfortunately excluded from many clinical trials. Thus, there is no standard-of-care for this high-risk patient population. Tagraxofusp (TAG; SL-401) is a CD123-directed targeted therapy that carries a truncated diphtheria toxin leading to irreversible inhibition of protein synthesis and apoptosis. TAG is FDA-approved for the treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm. There is high CD123 expression in AML and leukemic stem cells (Jordan, Leukemia 2000); thus, TAG represents a promising investigational therapeutic option. Recent data from the Children's Oncology Group AAML1031 Phase III study revealed that high CD123 expression was associated with high-risk genomic abnormalities and worse clinical outcomes (Lamble, J Clin Oncol 2022). An ongoing study of TAG + azacitidine (AZA) +/- venetoclax demonstrated no dose-limiting toxicities of TAG in newly diagnosed and relapsed/refractory AML/MDS (Lane et al, Blood [Abstract] 2021). Pre-clinical data suggests that down-regulation of DPH1, a gene responsible for synthesizing diphthamide (the target of the diphtheria toxin), is associated with TAG-resistance. Treatment with AZA hypomethylates CpG motifs in the promoter region of DPH1 which can restore sensitivity to TAG. The combination of TAG and AZA led to prolonged time to progression and overall survival than either agent alone in mouse models (Togami et al, J Clin Invest 2019). However, the optimal administration of TAG and AZA is unknown. Objectives: The primary objective of this study is to estimate the rate of complete remission (CR) in patients with newly diagnosed S-AML after p-HMAs receiving TAG +/- AZA. Secondary objectives are to describe toxicity, estimate the overall response rate, overall survival, disease free survival, progression free survival, event free survival, and the rate of allogeneic stem cell transplant. Correlative objectives include identifying genomic and single-cell transcriptomic predictors of response, serial assessment of response and MRD with digital PCR, and assessing CD123 expression in responders versus non-responders. Study Design: Key inclusion criteria are that subjects must be ≥18 years old with newly diagnosed, untreated AML. All subjects must have CD123 expression on leukemia cells by a centralized flow cytometry assay, a documented diagnosis of prior MDS, CMML, MPN, or MDS/MPN overlap syndrome, and have received at least 2 cycles of a HMA. An ECOG performance status of 0-2 and adequate organ function is required (ejection fraction >45%), including an albumin ≥ 3.2 g/dL to mitigate capillary leak syndrome. Key exclusion criteria are subjects who are suitable for and are willing to receive intensive chemotherapy, acute promyelocytic leukemia, and known CNS involvement. Cycles 1 and 2 will consist of TAG administered at 12 mcg/kg IV daily for 5 consecutive days every 21 days. Subjects who achieve a marrow CR (CR, CRi, CRh, MLFS) after Cycle 2 will continue TAG for up to 1 year at 12 mcg/kg IV for 5 days every 28 days. Subjects without a marrow CR after 2 cycles of treatment will be treated with TAG 12 mcg/kg IV for 3 days + AZA 75 mg/m2 SQ or IV on Days 1-7 every 28 days. Patients without an overall response to TAG + AZA after 4 cycles will be discontinued from study treatment. Statistical Design: A Simon's two-stage design will be utilized to test the hypothesis that TAG +/- AZA leads to an improved CR rate compared with historical controls. The null hypothesis that the true CR rate is 15% will be tested against one-sided alternative. In the first stage, 23 patients will be accrued. If there are 3 or fewer patients who achieve CR by cycle 6 of therapy, accrual to the study will be stopped to determine the outcome of the study. Otherwise, the study will move on to Stage 2 and 25 additional patients will be accrued for a total of 48 subjects. The null hypothesis will be rejected if 12 or more CR's are observed in 48 patients. This design yields a type 1 error rate of 0.05 and power of 80% when the true CR rate is 30%. Continuous monitoring for toxicity will be performed and the study will be stopped if there is unacceptable toxicity. The trial will begin recruitment as a multi-center investigator-initiated study in the last quarter of 2022 (NCT05442216). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Prognostic Value of Physical Function in Older Adults with Acute Myeloid Leukemia Treated with Low Intensity Treatment

Several prognostic models have been developed to identify patients at high risk of death, treatment resistance, or poor survival after conventional intensive chemotherapy in older adults with acute myeloid leukemia (AML). There are growing evidence that geriatric assessment can detect unrecognized vulnerabilities in patients with hematological malignancies to help predict treatment tolerance and survival. We prospectively demonstrated the prognostic value of physical function for survival outcomes in intensively treated older adults with AML (Min et al. Blood 2022). However, there are limited evidence for prognostic value of physical function in older adults with AML who were treated with low-intensity therapy, such as hypomethylating agents (HMA) with or without venetoclax (VEN). Thus, we evaluated the prognostic role of physical function scores in older adults with AML treated with low-intensity treatment in a prospective observation cohort (CRIS number; KCT0002261). We have measured physical function by the Short Physical Performance Battery (SPPB) since 2018 in older adults with AML treated with low-intensity treatment. Between 2018 Jan and 2022 May, 71 newly diagnosed AML patients who were aged ≥ 65 years and received low-intensity treatment were examined with SPPB at a median of 3 days prior to the initiation of treatment. The prognostic role of SPPB score on overall survival (OS) was analyzed by the Kaplan-Meier estimates and the log-rank test, and a multivariable Cox hazard model. The median age of 71 patients was 75 years (interquartile range: 70-78). Males were 59.2%, and patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 or higher was 19.7%. Secondary AML patients were 12.7%. Genetic risk stratification by European Leukemia Net (ELN) 2017 classified 23.9%, 36.6%, and 39.4% as favorable, intermediate, and adverse risk, respectively. Patients were treated with HMA alone (azacitidine or decitabine; 59.2%) or HMA and VEN combination (40.8%). Seventy percent of patients were classified as unfavorable group by Wheatley index, which is a validated prognostic model for low-intensity treatment. There were no differences between HMA alone and HMA and VEN combination in terms of Wheatley index. The median SPPB score of patients was 8 (range, 6-11). The SPPB score had a significant association with OS. In univariable analysis, the hazard ratio (HR) for a 3-point decrease in SPPB was 1.11 (95% confidence interval [CI], 1.02-1.20]. The cut-off of SPPB at which the difference in OS was most pronounced was 8. Patients with an SPPB score of 8 or higher had a median OS of 20.2 months (95% CI: 11.3-Not achieved), whereas that of patients with an SPPB less than 8 was 6.9 months (95% CI: 3.3-16.9, p=0.04, Figure A). In a multivariable Cox model of SPPB with other genetic, etiologic variables, the impact of SPPB on OS was still significant (HR for 3-point decrease in SPPB: 1.35 [95% CI: 1.03-1.78], Figure B). Our data show that physical function measured by SPPB is a significant prognostic factor for survival in older adults with AML treated with low-intensity treatment, contrasting limited value of 2017 ELN. This suggests that specified prognostic models including diverse geriatric assessment domains should be studied in these elderly population treated with low-intensity treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Predictors for Relapse Among Patients with AML Who Responded to Venetoclax-Based Treatment - a Real-World Prospective Analysis from the Revive Study Group

Background: Venetoclax (VEN)-based low intensity combinations are approved for the treatment of patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Despite the encouraging composite complete remission rates demonstrated in the VIALE-A trial, disease relapse remains a frequent event with dismal outcome. The aim of the current analysis is to characterize patterns and clinical predictors of relapse in a real-world setting. Methods: The REVIVE study is a prospective, real-life, observational study that assesses patterns of patient selection, efficacy and toxicity. 189 newly diagnosed AML patients from 12 medical centers in Israel were enrolled at initiation of VEN-based low-intensity therapy, between August 12, 2019, and April 15, 2022 (data cut). Demographic, clinical and patient-related baseline characteristics, as well as treatment patterns, safety and efficacy outcomes were collected. For the current analysis, remission was defined as either achieving complete remission (CR), CR with incomplete count recovery (CRi) or morphological leukemia-free state (MLFS). Relapse-free survival (RFS) was calculated from the date of first response to the date of progression of disease or death from any cause, whichever occurs first or lost follow-up in the population of responding patients (CR, CRi, MLFS). A cox proportional hazards model was used to compare relapse-free survival between subgroups of baseline characteristics. Results: Of the 189 patients recruited to the study, 110 (58.2%) achieved a response (CR- 55.5%, CRi- 39.1%, MLFS- 5.5%). The median age of these patients was 75 years, 58.2% were males and 69.1% had ECOG performance status of 0-1. The median time to remission was 35 (0-193) days. As of data cut, with a median follow-up of 278 (31-878) days, 50 patients (45% of responding patients) who achieved response have relapsed. Median RFS was 425 (275-588) days. 1-year after achieving remission 53.3% (42.3%-64.2%) of the patients remained in remission. The estimated OS of the patients who responded was 509 (302-680) days. In univariate analysis, there was a statistically significant association of age (p=0.005) and baseline neutrophil counts (p=0.001) with RFS. The expected hazard of relapse in patients <75 of age was 0.4 times the hazard in patients ≥75 (median RFS of 588 vs. 275 days, respectively). The expected hazard of relapse in patients with baseline neutrophils ≥1,000 cells/µl was 2.7 times the expected hazard in patients <1,000 cells/µl. Patients with a normal BMI (<25) had a hazard of relapse that was higher than those with an overweight BMI (≥25) (p=0.06). There was no statistical association of gender, ECOG performance status, type of AML, cytogenetic risk group, and prior HMA exposure with RFS. On a multivariate analysis, only age and baseline neutrophil counts remained significant in the cox proportional hazards model. A comparison of responding patients with prior myeloproliferative neoplasms (MPNs) (n=14), patients who were excluded from registrational clinical studies, to patients with therapy-related AML/ prior MDS (n=40) demonstrated a significant association with RFS. The median RFS was 154 days (range 76-not reached) in the MPN group compared to not reached in the other group (range 298-not reached, KM estimation for 1 year of 25% vs. 63.8%, respectively p=0.0119). Conclusions: In a real-world, prospective analysis, newly diagnosed AML patients who responded to treatment demonstrated a median relapse free survival of more than 1 year (425 days). Clinical factors significantly associated with shorter RFS were age≥75 and baseline neutrophil counts (≥1,000 cells/µl). AML patients with prior MPN have a shorter RFS compared to other secondary AML patients. Analysis of patterns of post-relapse salvage approaches and survival is planned for future analysis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-440 Prognosis of Molecularly-Defined Secondary Acute Myeloid Leukemia Patients

Mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 were proposed as secondary AML (sAML) defining mutations independent from the patients' history. We evaluated the prognostic impact of molecularly-defined sAML (msAML) patients in the context of the European LeukemiaNet (ELN) risk categories. 459 adult newly-diagnosed AML patients (median age 54) with available genetic and follow-up data were included. Patients received standard induction and consolidation chemotherapy or underwent allogeneic hematopoietic cell transplantation (alloHCT). Patients were classified as de-novo AML (dnAML), msAML carrying ≥ 1 sAML-defining mutations, and clinically-defined secondary AML (csAML) based on previous medical history and cytogenetics. 208 (45%) patients had dnAML, 155 (34%) msAML, and 96 (21%) csAML. 62 msAML patients overlapped with csAML. Of msAML patients, 104 (67%) had 1, 39 (25%) 2, and 12 (8%) 3 or more msAML-defining mutations. The most frequently mutated msAML-defining genes were ASXL1 (n=48, 31%) and SRSF2 (n=44, 28%). The likelihood to reach complete remission (CR) was higher for dnAML compared to msAML patients (92% vs 79%, P =.003), but there was no difference between csAML and msAML patients. The median follow-up of all patients was 5.56 years. The transplantation rate in first CR was similar in dnAML, msAML and csAML patients (33%, 37%, 44%, respectively). Overall survival (OS) was significantly worse in msAML compared to dnAML patients (median OS 3.3 years vs not reached, HR = 1.7, 95%CI 1.2-2.2, P<.001), also when ASXL1 mutated patients were excluded (HR = 1.7, 95%CI 1.2-2.4, P<.001). OS was similar in csAML vs dnAML and in msAML vs csAML patients. In the ELN favorable and intermediate risk groups msAML patients (n=19 and n=52) had a significantly worse OS compared to dnAML patients (n=66 and n=80) (HR=3.1 95%CI 1.5-6.3, P=.001 and HR=2, 95%CI 1.2-3.2, P=.008, respectively). OS was similar in the ELN adverse risk group between msAML (n=79) and dnAML patients (n=31). Accordingly, the ELN risk groups did not stratify OS in msAML patients. msAML-defining mutations identify a subgroup of dnAML patients with poor prognosis and reclassify 10% of all patients in our cohort from favorable/intermediate to the adverse risk group.

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Comparison of Liposomal Daunorubicin and Cytarabine Versus Cladribine and High-Dose Cytarabine-Based Induction Chemotherapy in Secondary Acute Myeloid Leukemia Patients (sAML) or Acute Myeloid Leukemia with Myelodysplastic Related Changes (AML-MRC)

Comparison of Liposomal Daunorubicin and Cytarabine Versus Cladribine and High-Dose Cytarabine-Based Induction Chemotherapy in Secondary Acute Myeloid Leukemia Patients (sAML) or Acute Myeloid Leukemia with Myelodysplastic Related Changes (AML-MRC)

Prognostic Significance of Minimal Residual Disease in Patients with Secondary Acute Myeloid Leukemia

BACKGROUNDSecondary acute myeloid leukemia (AML) is defined as AML that develops from a prior myelodysplastic or myeloproliferative disorder, or from exposure to chemotherapy, radiation, or environmental toxins. Patients with secondary AML have inferior prognosis compared to those with de novo AML,1 and are more likely to be elderly with increased comorbidities and worse performance status.2 The detection of minimal residual disease (MRD) also has independent prognostic value in patients with AML.3-6 In elderly AML patients, MRD predicts worse outcomes independent of the poor treatment risk factors associated with increased age.7Due to the similar disease pathogenesis between elderly AML and secondary AML patients, it is likely that MRD testing will have similar implications. However, there is limited data on the prognostic role of MRD testing in secondary AML. METHODSWe retrospectively analyzed de novo and secondary AML patients at Washington University Medical Center who received post-induction, post-consolidation, pre-transplant, or post-transplant MRD testing during their treatment. MRD testing was performed with multiparameter flow cytometry testing using the “different from normal” method at one reference laboratory,8,9 with positive MRD defined as detection of an abnormal myeloblast population above 0.1%. A total of 180 patients were included. Any patient with at least one positive MRD was considered “MRD positive.” Baseline pretreatment characteristics were compared between groups with Mann-Whitney, Chi-square, or Fisher's exact test, when appropriate. We evaluated overall survival (OS) and relapse rates in de novo and secondary AML patients stratified by MRD status using Kaplan-Meier curves and the log rank test, or cumulative incidence function, as appropriate. Multivariate Cox proportional hazards model was also fitted to determine if MRD testing has similar prognostic value across de novo and secondary AML patients. RESULTSOur analysis included 133 patients with de novo and 47 patients with secondary AML. Secondary AML patients were significantly older at age of diagnosis (mean age 59.85 versus 51.17, p<0.001), however had similar rates of MRD positivity (28% versus 29%, p=0.830). There was a trend toward poorer cytogenetic risk profiles and worse Karnofsky Performance Status in secondary AML (Table 1). In all patients, we confirmed that MRD positivity confers significantly worse OS (45.5% versus 70.8%, p=0.020) and relapse rates at 2 years (53% versus 25.5%, p=0.029) (Figure 1). In de novo AML patients, MRD positivity continued to demonstrate significantly worse 2-year OS (44.1% versus 76.3%, p=0.006) and relapse rates (57.6% versus 20.7%, p=0.008). However, in secondary AML patients, there were no differences in OS (p=0.69) or relapse rates (p=0.98) between MRD positive and negative patients. Multivariate analysis demonstrated significant interaction (p=0.042) between MRD status and AML subtypes. MRD positivity emerged as an independent prognostic indicator of worse OS in de novo patients (HR 2.8, 95% CI 1.524-5.405) but not in secondary patients (HR 1.5, 95% CI 0.188-2.336). DISCUSSIONWe confirm that MRD status is a poor prognostic indicator in all AML patients, and this also holds true in patients with de novo AML. However, we found that MRD status has less prognostic value in secondary AML patients. This may be due to the overall poor prognosis seen in secondary AML patients, suggesting that MRD monitoring in this group of patients may be less useful for risk stratification. However, our study is limited by the small sample size, particularly in the number of secondary AML patients who displayed MRD positivity (N=13). In addition, we defined MRD positivity across all time points of testing, which may decrease patient homogeneity. A larger study with increased follow-up is necessary to confirm our findings, as these results have important implications in risk-stratification and treatment of patients with secondary AML. [Display omitted] DisclosuresDiPersio:BMS, Asterias, Amphivena, Bluebird: Other: Travel, Accomodations, Expenses; Hemedicus, DAVA Oncology: Speakers Bureau; Celgene, Bioline, Vasculox, Cellworks, Rivervest: Consultancy; Magenta Therapeutics: Equity Ownership.

Updated Safety and Efficacy of Venetoclax with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia

Updated Safety and Efficacy of Venetoclax with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia

Screening for myeloid mutations in patients with myelodysplastic syndromes and AML with myelodysplasia-related changes

IntroductionOne of the most critical complications in myelodysplastic syndromes (MDS) is the progression to acute myeloid leukemia (AML). The dynamics of clonal evolution in MDS and how acquired mutations can be used as biomarkers to track disease progression remains under investigation. Objective and methodHerein, we investigated the frequency of common myeloid clonal mutations (FLT3, NPM1, JAK2, IDH1 and IDH2) in 88 patients with MDS and 35 AML patients with myelodysplasia-related changes, followed at a single reference center in northeastern Brazil. ResultsOverall, 9/88 (10%) of the MDS patients and 9/35 (26%) of the secondary AML patients had at least one mutation. While the JAK2 V617F mutation was the most frequent in the MDS patients, the FLT3, NPM1, IDH1 and IDH2 mutations were more frequently found in the secondary AML group. Furthermore, there was a higher frequency of FLT3, NPM1, IDH1 and IDH2 mutations in MDS patients classified as high-risk subtypes than in those of lower risk. ConclusionDespite the limited sample size, our data suggest that mutations in FLT3, NPM1, IDH1 and IDH2 genes could be potential biomarkers to detect early disease progression in MDS.

Durable Remissions and Increased Overall Survival in AML Patients Deemed Unfit for Standard Intensive Chemotherapy Achieved with High-Dose BST-236 (Aspacytarabine) Induction and Consolidation

Durable Remissions and Increased Overall Survival in AML Patients Deemed Unfit for Standard Intensive Chemotherapy Achieved with High-Dose BST-236 (Aspacytarabine) Induction and Consolidation

Leukemic stem cell phenotype is associated with mutational profile in acute myeloid leukemia.

Background/AimsUnderstanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. However, association of LSC with patient prognosis and genetic information in AML patients is unclear.MethodsHere we investigated the associations between genetic information and the various LSC phenotypes, namely multipotent progenitor (MPP)-like, lymphoid primed multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitors (GMP)-like LSC in 52 AML patients.ResultsIn secondary AML patients, MPP-like LSC was significantly higher than de novo AML (p = 0.0037). The proportion of MPP-like LSC was especially high in post-myeloproliferative neoplasm AML (p = 0.0485). There was no correlation between age and LSC phenotype. Mutations of KRAS and NRAS were observed in MPP-like LSC dominant patients, TP53 and ASXL1 mutations in LMPP-like LSC dominant patients, and CEBPA, DNMT3A and IDH1 mutations in GMP-like LSC dominant patients. Furthermore, KRAS mutation was significantly associated with MPP-like LSC expression (p = 0.0540), and TP53 mutation with LMPP-like LSC expression (p = 0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p = 0.0052). This suggests that the dominant phenotype of LSC is one of the important factors in predicting the prognosis and treatment of AML.ConclusionsLSC phenotype in AML is closely associated with the recurrent mutations which has prognostic implication. Further research to confirm the meaning of LSC phenotype in the context of genetic aberration is warranted.

Leukemic Stem Cell Phenotype Is Associated with Mutational Profile in Acute Myeloid Leukemia

Background: Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. As such, understanding the relationship between LSC and genetically defined sub-clones can, in turn, help to understand the heterogeneity of AML. However, to date, there are only a few reports specifically focusing on this topic. To this end, we conducted this study to (1) examine the phenotypic diversity of AML-LSC, (2) explore the association between AML-LSC phenotypes and gene mutations, and (3) investigate the prognostic implications of AML-LSCs. Methods: Mononuclear cells (MNCs) were isolated from the patient's bone marrow aspirates by ficoll gradient centrifugation and cryopreserved in serum-free medium. Stored cells were thawed to Iscove's Modified Dulbecco's Medium (IMDM) and washed with fluorescence-activated cell sorting (FACS) buffer [1% FBS, Dulbecco's Phosphate-Buffered Saline (DPBS)]. Cells were stained with following anti-human monoclonal antibodies: CD45-APC/cy7, CD34-APC, CD38-BV421, CD90-PE, CD123-PE/Cy7, CD45RA-PerCP/Cy5.5. Analyses were performed on a FACSCanto II (HTS) (BD Bioscience) and FlowJo V 10.0 (BD Bioscience) program. For sequencing, the DNA capture probes for 76 target genes were designed using the Agilent SureDesign web-based application. The target regions included protein coding exons with 10 bp intron flanking regions and hot spot regions of the 20 genes involved in recurrent translocations. DNA was extracted on a Chemagic 360 instrument (Perkin Elmer, Baesweiler, Germany). The genomic DNA was sheared using Covaris S220 focused‐ultrasonicator (Covaris, Woburn, MA). We used 50ng of total input genomic DNA. A library preparation was performed according to Agilent's SureSelectQXT Target Enrichment protocol. Paired-end 150-bp sequencing was using NextSeq 550 Dx platform (Illumina, San Diego, CA). Targeted sequencing raw data was obtained in FASTQ format. Results: In secondary AML patients, MPP-like LSC was significantly higher than de-novo AML (p=0.0037), and was higher in MPN-AML than in MDS-AML (p=0.0485). There was no correlation between age and LSC phenotype, though CD34+CD38- subpopulation was enriched in younger patients (&lt;65 yrs). Mutations of KRAS and NRAS were frequently observed in MPP-like LSC dominant patients (3/14 and 4/14), TP53 and ASXL1 mutations in LMPP-like LSC dominant patients (4/12 and 4/12) , and CEBPA, DNMT3A and IDH1 (6/12, 4/12, and 3/12) mutations in GMP-like LSC dominant patients. Furthermore, as shown in Figure, KRAS mutation was significantly associated with the percentage of MPP-like LSC phenotype (p=0.0540), and TP53 mutation with the percentage of LMPP-like LSC phenotype (p=0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p=0.0052). The importance of our study lies in that we showed for a given AML patients there is a dominant LSC phenotype and LSCs are associated with clinical outcomes, supporting the significance of cancer stem cell model for human AML. First of all, based on detailed characterization of the surface immunophenotype of AML LSCs we found that AML show evidence of a hierarchical cellular organization. We also recognized that the composition of LSC phenotypes is associated with AML phenotypes. For example, secondary AML patients showed higher fraction of MPP-like LSCs compared to de novo AML patients. In this regard, the higher expression of MPP-like LSCs could explain the poor response to standard treatments traditionally associated with secondary AML. Furthermore, the higher expression of MPP-like LSCs in post-MPN AML compared to post-MDS AML could explain the dismal prognosis associated with post-MPN AML, despite the relative indolent clinical course in their chronic phase and the presence of druggable target. Conclusion: In conclusion, our findings provide better insights into the characteristics and clinical implications of LSC. Although in a small scale, we provide evidence that specific LSC phenotypes are associated with certain mutations thus should be in the AML risk stratification process. Figure Disclosures Yoon: Janssen: Consultancy; Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Yuhan Pharma: Research Funding; MSD: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

A Descriptive Study on Healthcare Utilization and Costs in Secondary Acute Myeloid Leukemia Patients Treated with CPX-351 Versus Those Treated with 7+3

Introduction: The 7 + 3 regimen, consisting of cytarabine treatment continuously for 7 days, and short infusions of an anthracycline on each of the first 3 days, has been the mainstay for adult acute myeloid leukemia (AML) therapy. However, in older adults and patients with secondary AML, 7+3 is associated with lower remission rates, shorter overall survival, and higher relapse rates than in younger adults and older patients with de novo AML (Kayser et al, Blood 117:2137-2145, 2011; Schoch et al, Leukemia 18: 120-125, 2004). CPX-351 (VYXEOS®) CPX-351 was approved by the FDA in the US in August 2017 and EU in August 2018 for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). It is a fixed combination of daunorubicin and cytarabine at a synergistic 1:5 molar ratio, encapsulated in a liposome to provide optimal delivery of the two drugs. The Phase III pivotal trial demonstrated that CPX-351 significantly improved overall survival (OS; 9.56 vs 5.95 months; hazard ratio [HR] = 0.69; 1-sided P = 0.003) and complete remission rates versus 7+3, and was associated with shorter per patient year (PPY) hospital length of stay (LOS) without an increase in PPY non-drug costs (Chung, et al. AMCP HCRU Abstract JOV-62933; 2018). This study characterized the patients treated with CPX-351 and 7+3 and compared healthcare utilization and costs associated with the treatments using a large U.S.-based hospital administrative database. Methods: A retrospective, observational study was conducted using data from the Premier Healthcare Database. The study included patients aged 18+ years with any inpatient hospitalization or hospital-based outpatient visit with a diagnosis of AML, who received treatment of 7+3 or CPX-351 between 8/1/2017 and 2/28/2019. Variable-length follow-up was used. Patients were excluded if their length of follow-up was shorter than 30 days, or they had received treatment with gemtuzumab, midostaurin, sorafenib, venetoclax, quizartinib, or gilteritinib. Patients were assigned into two cohorts: 1) patients treated with CPX-351; 2) 7+3 treated patients with newly diagnosed t-AML or AML-MRC who were never treated with CPX-351 (CPX-351 eligible 7+3). Outcomes included total inpatient LOS, total costs, drug and non-drug costs. The outcomes were converted to per patient year (PPY) values, which was the original value divided by the length of follow-up and multiplied by 365. Unadjusted descriptive statistics were reported, and bivariate analysis was performed using Wilcoxon rank sum tests to examine the difference in outcomes between 7+3 treated patients and those treated with CPX-351. Results: The study included 195 qualifying patients treated with CPX-351, and 160 CPX-351 eligible 7+3 patients. The median age was 68 years (Q1-Q3: 61-71) in the CPX-351 patients and 61 years (Q1-Q3: 52.5-69) in CPX-351 eligible 7+3 patients. Male patients accounted for 62.6% of the CPX-351 patients and 55.0% of the CPX-351 eligible 7+3 patients. Among the CPX-351 patients, 72.3% were White, while the proportion of White is 75.0% in CPX-351 eligible patients. The median length of follow up was 136 days (Q1-Q3: 68-232) in the CPX-351 patients, and 126 days (Q1-Q3: 54.5-241.5) in the CPX-351 eligible 7+3 patients. The median total inpatient LOS per patient year (PPY) was shorter in CPX-351 patients compared to the CPX-351 eligible 7+3 patients (nominal p=0.068, Table). Although the median total hospital cost PPY of the CPX-351 patients was higher (nominal p&lt;0.001), the non-drug medical cost PPY was not higher than the CPX-351 eligible 7+3 patients (nominal p=0.785, Table). Conclusions: In this inferential analysis, patients treated with CPX-351 appeared to be older than those treated with 7+3. CPX-351 treated patients spent fewer days as inpatients, and the non-drug medical cost incurred was not higher compared to the 7+3 patients eligible for CPX-351, although the drug costs for the CPX-351 treated patients were higher than the 7+3 treated patients. Further adjusted analysis is warranted to control for the differences in baseline characteristics such as age, clinical conditions, and other characteristics in this real-world data. Disclosures Price: Jazz Pharmaceuticals: Employment, Equity Ownership. Cao:Jazz Pharmaceuticals: Other: Zhun Cao is an employee of Premier Inc, which receives payments from Jazz Pharmaceuticals for this research project.; Premier Inc.: Employment, Other: Premier received funding from Jazz Parmaceuticals to perform the study and analysis. Lipkin:Jazz Pharmaceuticals: Other: Craig Lipkin is an employee of Premier Inc, which receives payments from Jazz Pharmaceuticals for this research project.; Premier Inc: Employment. Robinson:Premier Inc.: Employment, Other: Premier received funding from Jazz Pharmaceuticals to perform the study and analysis; Jazz Pharmaceuticals: Other: Scott Robinson is an employee of Premier Inc, which receives payments from Jazz Pharmaceuticals for this research project.. Profant:Jazz Pharmaceuticals: Employment, Equity Ownership.

Genetic alteration patterns and clinical outcomes of elderly and secondary acute myeloid leukemia.

To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e‐AML) and 55 secondary AML (s‐AML) patients with 451 young de novo AML patients. Both e‐AML and s‐AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e‐AML patients. s‐AML patients carried a higher frequency of KMT2A‐AF9. In treatment response and survival, e/s‐AML conferred a lower complete remission (CR) rate and shorter duration of event‐free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s‐AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s‐AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s‐AML, which should be recommended for the treatment of fit patients.

Outcomes and prognostic factors of myelodysplastic syndrome patients with allogeneic hematopoietic stem cell transplantation

目的评价异基因造血干细胞移植（allo-HSCT）治疗骨髓增生异常综合征（MDS）的疗效，并分析预后相关因素。方法回顾性分析2010年1月至2018年3月接受allo-HSCT治疗的165例MDS患者，主要观察患者总体生存（OS）率、无病生存（DFS）率、复发率及非复发死亡率（NRM），并分析影响预后的危险因素。结果全部165例患者中，男105例，女60例，3年OS、DFS率分别为72.5%（95%CI 64.9%~80.1%）、67.4%（95%CI 59.2%~75.6%），3年累积复发率为12.1%（95%CI 7.0%~18.6%），NRM为20.4%（95%CI 14.2%~27.6%）。多因素分析显示，allo-HSCT合并症指数（HCT-CI）是影响OS的独立危险因素（P=0.042，HR=2.094，95%CI 1.026~4.274）。对于难治性贫血伴原始细胞增多（RAEB）及转化为急性髓系白血病（sAML）患者，移植前应用化疗或去甲基化治疗对总体OS无影响[（67.0±7.5）%对（57.7±10.9）%，χ2=0.025，P=0.874]。结论allo-HSCT是治疗MDS的有效手段，非复发死亡是影响生存的主要原因。移植前化疗或去甲基化治疗或许不能使RAEB和sAML患者获益。