Favorable Risk Acute Myeloid Leukemia Patients Research Articles

Hyperleukocytosis Does Not Present a Worse Prognosis in Acute Myeloid Leukemia (Non-APL) with Favorable Risk According to ELN-2022 Criteria: A Retrospective Study

Introduction: Acute myeloid leukemia (AML) with hyperleukocytosis, characterized by a white blood cell count ≥100,000/µL, is usually considered a subtype associated with poor prognosis. For AML patients with hyperleukocytosis, more aggressive treatment approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), are commonly considered. However, when favorable-risk AML accompanies hyperleukocytosis, it is unclear whether the risk level needs to be redefined. There is also no universally accepted treatment strategy for this subtype. We conducted a retrospective, single-center study to investigate the impact of hyperleukocytosis on the response and prognosis of favorable-risk AML according to ELN-2022 risk classification. Method: We retrospectively enrolled 217 favorable-risk AML patients, excluding acute promyelocytic leukemia (APL), treated at Zhejiang University School of Medicine's First Affiliated Hospital from October 1st, 2021, to April 30th, 2023. Some of them have been treated in other hospitals. The diagnosis, risk classification, and response evaluation were determined according to ELN-2022 criteria. Patients were divided into two groups: the hyperleukocytosis group (white blood cell count ≥100,000/µL) and the non-hyperleukocytosis group (white blood cell count <100,000/µL). We compare these two groups on the response rate after the induction chemotherapy, the median overall survival (mOS), and median disease-free survival (mDFS), then evaluate different treatments and other prognostic factors associated with outcomes. Statistical analyses were carried out using SPSS 24.0. The Kaplan-Meier method and log-rank test were used to assess and compare the survival outcomes. Univariate Cox proportional hazards regression was used to determine associated risk factors for overall survival. A two-tailed P value <0.05 was considered statistically significant. Result: Totally 217 patients were enrolled. To balance the impact factors, 12 patients who received high-dose cytarabine were excluded from the non-hyperleukocytosis group. The cohort ready for analysis had 45 patients in the hyperleukocytosis group and 160 patients in the non-hyperleukocytosis group. Two groups had no significant differences in age; gender, FAB classification; platelet counts and hemoglobin level at initial diagnosis; co-existing intermediate/high-risk mutations according to 2022 ELN risk stratification; treated with high-dose cytarabine, or receiving bone marrow transplantation (all P＞0.05). The median follow-up time was 29.5 months, and 154 patients were still alive at the study endpoint. There were no significant differences in the composite complete remission (CRc) rates (73.3% vs. 79.3%, P= 0.389), mOS (65.0m vs. 56.0m, P= 0.574), and mDFS (54.0m vs. 35.0m, P= 0.855) between two groups. With high-dose cytarabine (2.0-3.0 g/m2 q12h X 3 days for at least three courses) as consolidation chemotherapy, the two groups had no significant difference in mOS (Not reached vs. Not reached, P=0.143) and mDFS (21.0m vs. 35.0, P= 0.352). In order to understand the impact of allo-HSCT on the hyperleukocytosis group, we divided this group into the allo-HSCT subgroup and the non-HSCT subgroup. After balancing on age, gender, presence of high-risk mutations, and MRD negativity after the first remission (all P>0.05), the mOS in the allo-HSCT subgroup (n=16) was significantly longer than the non-HSCT subgroup (n=16) (Not reached vs. 46.0m, P= 0.007). However, the mDFS had no significant difference between the two sub-groups (63.0m vs. 43.0m, P= 0.341). The univariate Cox proportional hazards regression analysis revealed that only age had a significant impact ( P= 0.01), all other factors had no significant effects, including hyperleukocytosis, gender, hemoglobin level, platelet count, intermediate/high-risk mutations, or bone marrow transplantation. Conclusion: In favorable-risk AML, hyperleukocytosis does not lead to an adverse prognosis. Received high-dose cytarabine as a consolidation therapy, favorable-risk AML patients with hyperleukocytosis do not have worse OS or DFS than those without hyperleukocytosis. Allo-HSCT may bring longer OS for hyperleukocytosis patients at favorable risk but may not bring longer DFS. Our results suggest favorable-risk AML patients with hyperleukocytosis can be managed equally as non-hyperleukocytosis patients.

Intensified cytarabine dose during consolidation in adult AML patients under 65 years is not associated with survival benefit: real-world data from the German SAL-AML registry

PurposeHigher doses of cytarabine appear to improve long-term outcome in acute myeloid leukemia (AML), in particular for younger patients. To this end, the optimal dosage of single-agent cytarabine in consolidation therapy remains elusive. Here, we assessed the impact of different dosages of cytarabine consolidation after 7 + 3 induction on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry.MethodsPatients between 18 and 64 years of age, registered between April 2005 and September 2020, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high-dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting.ResultsSix-hundred-forty-two patients received HiDAC consolidation with median dosage of 17.6 (IQR (interquartile range), 16.5–18.0) g/m2 for a median number of 3 cycles (IQR, 2–3), whereas 178 patients received IDAC consolidation with 5.9 (IQR, 5.7–8.6) g/m2 for a median of 2 cycles (IQR, 1–3). Both groups differed significantly in some important characteristics (age, sex, cytogenetic risk group, ECOG performance status, disease status, HCT-CI, number of induction cycles). After propensity score weighting for differences in patient and disease characteristics, relapse-free survival after 2 years was comparable between HiDAC-treated (55.3%) and IDAC-treated (55.6%) patients (HR = 0.935, p = 0.69). Moreover, no significant differences in overall survival were observed after 2 years (84.7 vs. 80.6%, HR = 1.101, p = 0.65). Notably, more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p < 0.001). Censoring for allogeneic hematopoietic cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only of European LeukemiaNet (ELN) favorable-risk AML patients, there was no significant difference in outcome. Of note, significantly more patients treated with HiDAC suffered from ≥ 3 CTCAE infectious complications (56.7 [95%-CI 52.8–60.6%] vs. 44.1% [95%-CI 36.6–51.7%]; p = 0,004). The rate of other ≥ 3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups.ConclusionsThis retrospective analysis suggests no significant benefit of high-dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group.Trial registrationNCT03188874.

Intensified Cytarabine Dose during Consolidation Therapy in AML Patients Under 65 Years Is Not Associated with Survival Benefit

▪Background: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive.Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting.Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups.Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. DisclosuresKrause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

AML-225: Outcome with Intensive Chemotherapy vs Hypomethylating Agent-Based Induction Strategies in Patients Older Than 70 Years with Newly Diagnosed, Favorable-Risk Acute Myeloid Leukemia

<h3>Context:</h3> Real-world evidence is lacking regarding the effectiveness of intensive and non-intensive induction strategies in elderly patients with favorable-risk acute myeloid leukemia (AML). <h3>Objectives:</h3> To estimate the rates of complete remission (CR), CR+ CR with incomplete count recovery (CRi), and overall survival (OS) in patients receiving intensive chemotherapy (IC) and hypomethylating agent (HMA)-based induction regimens. <h3>Design:</h3> In this retrospective study, clinical and genomic data were collected by review of records of eligible patients treated at Moffitt Cancer Center. Statistical analyses were performed using SPSS. <h3>Patients:</h3> Elderly (age > 70 years) patients with newly diagnosed, favorable-risk (ELN 2017) AML. <h3>Main Outcomes Measures:</h3> CR, CR+ CRi, OS. <h3>Results:</h3> Out of total 53 patients, 36 (68%) received IC, and 17 (32%) received HMA-based induction regimen. Median age at diagnosis was 74 years (range 70–85). Core binding factor (CBF) abnormalities were detected in 47% patients; 28% had secondary AML. Median blast count was significantly higher in patients receiving IC <i>vs</i> HMA (58% <i>vs</i> 32%, p=0.01). Predominant induction regimen was "7+3" (86%) in the IC group and azacytidine alone (n=11) in HMA cohort. Rate of composite CR (CR+ CRi) was significantly better at 69% (50% CR) in the IC group, compared to 35% (24% CR) with HMA (p=0.01). Six patients on IC and 1 on HMA had early (<30 d) induction-related mortality. Both groups had comparable relapse rates (overall 34%). Median OS was 24.7 months in IC <i>vs</i> 17.5 months in the HMA group, trending toward statistical significance (p=0.058). Overall, 23% patients in the IC group were alive at 5 years, compared to 7% with HMA. In patients with CBF-AML (n=25), median OS was not reached for IC <i>vs</i> 23 months with HMA (p= 0.076); CBF-AML was an independent predictor of survival in the study population. Six patients (3 post-relapse) from the IC group underwent allogeneic stem cell transplant. <h3>Conclusions:</h3> Elderly favorable-risk AML patients had a significantly better composite CR rate on induction treatment with IC than with HMA, with a trend toward improved OS with IC-based induction. A multicenter study with a larger sample size is ongoing to address this question further.

Comparison of Overall Responses after Standard Induction with High Dose Daunorubicin Versus Standard Dose Daunorubicin with Gemtuzumab Ozogamicin in Favorable Risk Acute Myeloid Leukemia

Background: Patients with favorable risk acute myeloid leukemia (AML) by European LeukemiaNet (ELN) criteria are treated with intensive chemotherapy that yields high remission rates and is often curative. Intensive chemotherapy typically includes cytarabine and anthracycline (7+3) with high-dose daunorubicin (dauno 90mg/m2). When compared to 45mg/m2, dauno 90mg/m2 yields superior survival in younger, favorable risk AML patients. Since the re-approval of gemtuzumab ozogamicin (GO), standard practice now incorporates GO in the 7+3 backbone for favorable risk disease, however, it is typically with dauno 60mg/m2 rather than 90mg/m2. We aim to describe responses after 7+3 (dauno 90mg/m2) and 7+3 (dauno 60mg/m2) plus GO (7+3GO) in favorable risk AML. Methods: We retrospectively annotated 56 favorable risk AML patients (pts) who received upfront intensive chemotherapy at Moffitt Cancer Center between 2013 and 2019. They were divided in two cohorts: Cohort A) 7+3 with dauno 90mg/m2; Cohort B) 7+3 with dauno60mg/m2 plus GO at any time during induction or consolidation. Clinical and molecular data were abstracted for each patient in accordance with Institutional Board Review approved protocol. Overall response rates (ORR) included pts achieving complete remission (CR) with minimal residual disease negativity (CRMRD-), CR, CR with incomplete count recovery (CRi). MRD testing included quantitative Real-Time polymerase chain reaction (qRT-PCR) of t(8;21), inv(16) and nucleophosphin 1 (NPM1) tested at least after 2 cycles of intensive chemotherapy. Fisher's Exact method was used to determine significance for categorical variables. All p-values are two-sided. Results: Fifty-six pts were analyzed, including 41 in cohort A and 15 in cohort B. Pt demographics are noted in Table 1. In cohort B, 40.0% received GO on day 1 only (3mg/m2, capped or uncapped), 33.3% received fractionated dosing (3mg/m2 days 1,4,7) and 33.3% received GO during consolidation only. 39.3% of pts had inv(16), 23.2% had t(8;21)(q21.3q22) and 33.9% had mutated NPM1. In all 56 pts, ORR was 94.6%. ORR was 95.1% in cohort A and 93.3% in cohort B (p=0.79). CR rates were 85.4% in cohort A and 73.3% in cohort B (p=0.3) (Table 2). Rate of CRMRD- at any point was higher in cohort B vs cohort A, but did not reach statistical significance (45.8% vs. 20%, p=0.11). CRMRD- was significantly higher in pts with core binding factor (CBF) leukemia in cohort B vs cohort A (81.8% vs. 18.2%, p=0.008). The improvement in CRMRD- was seen in both inv(16) (A vs. B: 22.2% vs. 77.8%, p=0.049) and t(8;21) (0% vs. 100%, p=0.040). In pts with NPM1 mutations, a trend toward higher CRMRD- rates was noted in cohort B but this did not reach statistical significance (A vs. B: 40.0% vs. 100%, p=0.15). Although the median follow up time in cohort B is significantly shorter (12.3 mos in cohort B vs 38.3 mos in cohort A), no difference was observed in the 1-year EFS (68.4% in cohort A and 87.5% in cohort B (p=0.46)) or OS (83.0% in cohort A and 89.0% in cohort B (p=0.96)). No difference was seen in early mortality (30-day) between the two arms (7.3% and 6.7% in cohorts A and B, respectively (p=0.93)). Conclusions: We demonstrate that incorporation of GO to 7+3 with dauno 60mg/m2 yields comparable remission rates to 7+3 with dauno 90mg/m2. Importantly, GO based regimens produce higher rates of MRD negativity compared to 7+3 with dauno 90mg/m2 in CBF leukemia. Longer follow up is needed in order to accurately assess the impact of GO based regimens on overall survival outcomes and whether GO-induced higher MRD negativity rates will translate into superior survival for patients with favorable-risk cohort when compared to 7+3 with high dose daunorubicin. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau. Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. Padron:Incyte: Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.

Genotypic and clinical heterogeneity within NCCN favorable-risk acute myeloid leukemia

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KITwt); and AML with normal cytogenetics and mutations in NPM1 (NPM1mut); or biallelic mutations in CEBPA (CEBPAmut/mut), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPAmut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1mut AML and CEBPAmut/mut AML show significantly reduced overall survival in comparison with CBF-KITwt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management.

Comparison of Autologous Stem Cell Transplantation versus Haploidentical Donor Stem Cell Transplantation for Favorable- and Intermediate-Risk Acute Myeloid Leukemia Patients in First Complete Remission

Stem cell transplantation (SCT) is an attractive postremission treatment option for patients with intermediate-risk acute myeloid leukemia (AML) and for some favorable-risk AML patients with additional nongenetic risk factors. Autologous SCT (auto-SCT) and haploidentical donor SCT (haplo-SCT) are the widely used alternatives in cases of a lack of a HLA-matched donor. However, limited data have been published on the direct comparison between these 2 transplant types. Based on the transplant database in our center, we conducted a retrospective study involving patients with favorable- and intermediate-risk AML in first complete remission (CR1), according to the National Comprehensive Cancer Network guideline. Patients with extramedullary disease or those achieving CR by more than 2 cycles were excluded. In total, 195 patients were included in the study, 88 of whom underwent auto-SCT and 107 haplo-SCT. In the entire cohort analyses the impact of high relapse incidence in the auto-SCT group was compensated by low nonrelapse mortality (NRM), which resulted in a comparable overall survival (OS) (79.0% ± 4.6% versus 80.1% ± 5.0%, P = .769) and relapse-free survival (RFS) (66.1% ± 5.2% versus 77.4% ± 4.8%, P = .079) compared with those observed in the haplo-SCT group. However, for patients with intermediate-risk AML, NRM was similar between the groups, and haplo-SCT exhibited superior survival. In case of post-SCT relapse, patients with intermediate-risk AML showed markedly inferior 3-year OS compared with that shown by patients with favorable-risk AML (23.3% ± 9.8% versus 60.8% ± 14.3%, P = .011). In the multivariate analyses, minimal residual disease (MRD) measured by flow cytometry and gene mutation status before transplantation were independent predictors for both OS and RFS. We concluded that both auto-SCT and haplo-SCT were acceptable options for postremission treatment of patients with favorable- and intermediate-risk AML. Haplo-SCT yielded a better outcome in patients with intermediate-risk AML, but the relapse after SCT still led to a poor outcome. Clearance of MRD before SCT could improve the prognosis after transplantation.

A retrospective analysis of prognosis in favorable-risk acute myeloid leukemia patients with different consolidation regimens

目的探索成人低危组急性髓系白血病（AML）完全缓解（CR）后不同巩固治疗方式对AML预后的影响。方法回顾性分析2010年1月至2015年6月诊治的107例非难治性成人低危组AML患者病例资料，以大剂量阿糖胞苷（HD-Ara-C）为主的巩固化疗方案为对照（化疗组，38例），探索不同巩固治疗方式（微移植16例、自体移植14例及异基因移植39例）对患者预后的影响。结果107例患者中，男59例，女48例，中位年龄33（16~59）岁，中位随访时间为36.5（5.3~79.1）个月，总复发率为20.6%（22/107），总死亡率为18.7%（20/107）。化疗、微移植、自体移植及异基因移植组5年累积复发率（CIR）分别为39.7%、6.2%、14.3%及5.6%，差异有统计学意义（P<0.001），微移植、自体移植及异基因移植组CIR均显著低于化疗组。化疗、微移植、自体移植及异基因移植组5年疾病无进展生存（PFS）率分别为44.7%、93.8%、85.7%及78.1%，差异有统计学意义（P=0.011），其中微移植、自体移植及异基因移植组间PFS率相近，化疗组5年PFS率最低。四组5年总体生存（OS）率分别为54.9%、100%、92.9%及77.4%（P=0.076）。多因素分析显示相对于HD-Ara-C巩固化疗，异基因移植可改善PFS（HR=0.376，P=0.031），但不能改善OS（HR=0.527，P=0.179）；微移植及自体移植均不能改善PFS及OS（P值均>0.05）。结论与HD-Ara-C巩固化疗相比，异基因移植明显降低CIR，改善PFS率，但治疗相关死亡率高。自体移植及微移植疗效与HD-Ara-C巩固化疗相当，可作为低危组AML巩固治疗的一种选择。

Autologous Stem Cell Transplantation in Favorable Acute Myeloid Leukemia Is Associated with a Better Long-Term Prognosis: a Single Center Experience

Introduction: Post-remission therapy in acute myeloid leukemia (AML) is mainly guided by cytogenetic and molecular risks, patient age and performance status. Favorable AML is conventionally treated with induction chemotherapy followed by 3-4 cycles of consolidation. Despite the clear benefit of the graft-versus-leukemia effect, allogeneic stem cell transplantation (alloSCT) is mainly reserved for fit patients with genetic intermediate-poor risk due to its toxicity. Autologous SCT (ASCT) performed at remission allows intensification of the anti-leukemic effect by the administration of high-dose therapy without significant non-relapse mortality (NRM), as compared to chemotherapy. This approach may be particularly appealing in the setting of AML with favorable genetic risk where alloSCT is not the standard of care. The aim of the current study was to retrospectively evaluate the outcome in a large, single-center cohort of favorable-risk AML patients based on post-remission treatment applied.Methods: Consecutive AML patients with the core-binding factor (CBF) translocations or mutations of NPM1 gene/unmutated FLT-ITD treated at the Rambam Medical Center, Haifa, Israel, between the years 2003 and 2015 were included in the analysis. Patients in complete remission (CR) post induction were planned for 2 cycles of consolidation with high-dose ARA-C (HiDAC) followed by ASCT. Patients in whom insurance coverage was denied continued with 3-4 cycles of HiDAC consolidation. Additionally, patients with evidence of post-induction residual disease, as determined by PCR, with a complex karyotype at presentation (in addition to CBF) or diagnosis of secondary AML were referred to alloSCT in CR1 and are also reported here.Results: Seventy nine patients with favorable AML with a median age of 47 [range 18-73] years were identified. Thirty eight (48.1%) patients had mutated NPM1 /unmutated FLT-ITD, 18 (22.8%) patients were with t (8:21) and 23 (29.1%) patients with inv(16). Forty patients (50.6%) received chemotherapy alone, 26 patients (32.9%) received chemotherapy and ASCT and 13 (16.4%) underwent alloSCT. There was no difference between the 3 treatment groups in regard to: response to induction, daunorubicin dose in induction, and need for reinduction. However, age was significantly higher in the chemotherapy group compared with ASCT and allo SCT groups.Two-year relapse-free survival (RFS) was 25%, 81%, and 85% for the chemo, ASCT and alloSCT, respectively (p < 0.00001) (Fig 1). Median RFS was 10.9 months for the chemotherapy group, while it was not reached (NR) either for the ASCT or the allo SCT group.Two-year overall survival (OS) was 49%, 80%, and 67% for the chemo, ASCT and alloSCT groups, respectively (p = 0.00269)(Fig 2). Median OS was 23.6 months for the chemotherapy group, while it was not reached for the ASCT group (NR to NR) and the alloSCT group. NRM at 3 months was 4/40 (10.0%), 0/26 (0%) and 2/13 (15.4%) in the chemo, ASCT and alloSCT groups, respectively. Relapse rate was 70.0% in the chemo group, 15.4% in the ASCT group and 19.2% in the alloSCT group (p < 0.0001). In the ASCT group, among the relapsing patients, 80% were referred to alloSCT. With a median follow-up of 28.6 months (range 4.3-131.4), 45 patients are alive and in CR. In univariate analysis, age and post-induction therapy, which included transplantation (ASCT or alloSCT), were found to be associated with higher OS and RFS.Conclusions: RFS and OS were significantly superior in AML patients with favorable cytogenetics receiving post-induction high-dose therapy with either ASCT or alloSCT. This was achieved with no transplant related mortality or increased toxicity among patients receiving ASCT compared with the chemotherapy group. These data from a single institution support the recent resurgence of interest in ASCT for AML and emphasize the potent anti-leukemic efficacy and minimal toxicity of this modality for patients who are not candidates for an allo SCT. After these decades, it may be time to once again conduct large prospective randomized trials of ASCT versus chemotherapy alone. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mutations Modifying Risk in NPM1+ AML

Introduction:Favorable risk acute myeloid leukemia (AML) is defined by recurrent genetic abnormalities including core binding factor rearrangements such as inv(16) and t(8,21), normal cytogenetics with isolated mutations of NPM1, or bi-allelic mutations of CEBPA. Approximately 60% of patients are cured with standard 7+3 induction and cytarabine consolidation, which is comparable to survival rates of patients who receive allogeneic stem cell transplant (SCT). However, 20-30% of patients treated with chemotherapy still relapse, and relapsed disease remains the leading cause of death in this group. Even if relapsed patients achieve CR2 with salvage chemotherapy, their survival with allogeneic SCT is reduced compared to patients transplanted in CR1. Thus, predicting which favorable risk AML patients are more likely to relapse after chemotherapy would help guide therapy and improve patient outcomes. Recent publications have proposed that additional mutations in genes such as IDH1, IDH2, or DMT3A may impact relapse risk, but reports are conflicting. In addition, studies using minimal residual disease to evaluate disease burden after induction and consolidation has also been shown to predict relapse. We have used high throughput next generation sequencing (NGS) as diagnostic panel for AML at our institution for the past 2 years. This panel looks for mutations in 42 different genes known to be associated with acute leukemias and can quantitatively evaluate genetic MRD at a sensitivity of about 0.1%. We are analyzing favorable risk AML patients in an effort to identify additional mutations that predict relapse and in the process of evaluating the ability of this panel to evaluate MRD.Methods:Clinical samples were obtained with informed consent and with the approval of our institutional IRB. A targeted NGS panel was designed using multiplexed Ion AmpliSeq Designer (Life Technologies) software to amplify and sequence 42 genes relevant to hematopoietic malignancies. 20ng of DNA from bone marrow or blood was used to generate amplicon-based libraries that were sequenced using an Ion Torrent PGM. Bioinformatics analysis was performed using the Torrent Suite v.3.2 pipeline. Open source programs and lab-developed algorithms were used for variant annotation and mutation prediction.Patients with favorable risk AML diagnosed within the past two years had sequencing data available in their medical records. For patients diagnosed >2 years ago, archival samples were obtained and DNA extracted from isolated mononuclear cells or formalin-fixed paraffin-embedded tissue according to standard protocols.Results:We identified 57 patients with favorable risk AML diagnosed at OHSU over the past five years. 48 had enough biopsy material for genetic analysis. Of the 48, 17% had t (8;21), 29% had inv(16), 46% were NPM1+, and 8% had CEBPA mutations. Seven patients received transplant in CR1 for either residual disease or physician discretion. Of the remaining 41 patients, 11 patients relapsed (26%) and 8 of the 11 were NPM1+. Of the 8 relapsed NPM1+ patients, all had additional DNMT3A R882 mutations, IDH1/2 mutations, or both. 13 NPM1+ non-relapsed patients have been evaluated by sequencing to date and only 5 of 13 in the non-relapsed group had additional mutations in DNMT3A and/or IDH1/2(P=0.0185), however only 2 of the 5 had the R882 DNMT3A mutation. No DNMT3A, IDH1 or IDH2 mutations were identified in patients with t(8;21), inv (16) or biallelic CEBPA AML.Conclusions:Although our numbers are small, the presence of the R882 DNMT3A mutation appears to increase the risk of relapse in NPM1+ patients (Figure 1). Other DNMT3A point mutations do not seem to impact the risk of relapse and should be considered separately for relapse risk. Complete analysis and evaluation of MRD is underway. [Display omitted] DisclosuresDunlap:Oregon Health & Sciences University: Employment. Druker:Bristol-Myers Squibb: Research Funding; McGraw Hill: Patents & Royalties; Oncotide Pharmaceuticals: Research Funding; Millipore: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptose Therapeutics Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CTI Biosciences, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fred Hutchinson Cancer Research Center: Research Funding; Henry Stewart Talks: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharamceuticals: Research Funding; Molecular MD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health and Science University: Patents & Royalties; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sage Bionetworks: Research Funding.

Real Life Analysis of the Rete Ematologica Lombarda on ELN Favorable Acute Myeloid Leukemia: The Molecular Remission Is a Necessary Goal for a Good Outcome in All Different Cytogenetic/Molecular Subgroups

Introduction: The European Leukemia Net (ELN) stratification classifies as favorable prognosis four different subgroups of acute myeloid leukemia (AML) with specific cytogenetic/molecular abnormalities. These forms are potentially curable with standard chemotherapy, even though about 30% of patients (pts) still relapse. Overall survival (OS) of 60% at 5 years is reported but it is not clear if all different subgroups show an homogeneous outcome. The purpose of this study was to assess, in a real life setting, the response rate and the outcome of newly diagnosed AML patients with favorable prognosis based on ELN classification. Data were collected from six hematological centers of the regional network REL (Rete Ematologica Lombarda).Methods: Between 2007 and 2014 we analyzed adult AML patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1(group1), inv(16)(p13q22) or t(16;16)(p13q22)/CBFbeta-MIH11(group 2), normal karyotype and mutated NPM1 and negative FLT3-ITD (group 3) or double mutated CEBPA (CEBPA dm) (group 4). All patients received induction, mainly standard 3+7 chemotherapy (or reduced 1+5 in older pts) in 66% of cases, followed by high dose cytarabine based consolidation in 77% of pts. Clinical and molecular data were analyzed at diagnosis and at different time points during treatment and follow up with qualitative and quantitative PCR. The Kaplan-Meier product-limit method was used to estimate survival curves, and the log-rank test was adopted to evaluate differences between groups of pts.Results: We studied 177 AML pts (96 males and 81 females) with a median age of 55 years (range 20-80): 27 of group 1, 35 of group 2, 98 of group 3 and 17 of group 4. Complete hematological response (CHR), assessed in 176 pts, was achieved in 161 pts (92%): 23(85%), 32(91%), 90(93%), 16(94%) respectively in group 1, 2, 3, 4 without significant difference (p=0.26). Molecular complete remission (mCR), evaluated in 152 pts out of 161 in CHR, was documented in 102 pts. Forty pts entered mCR after induction and 62 pts at the end of consolidation or later (1-40 months); therefore, mCR rate was 67%. Considering the type of the method, 48 pts resulted in mCR with qualitative PCR, the remaining 54 (53%) with qualitatitive and quantitative PCR. Median time to mCR was 4 months and was different among groups (p=0.03); in particular, t(8;21) pts obtained mCR later than NPM1 pts (8 versus 2.6 months) (p=0.01). The relapse rate was 41% and the median time to relapse was 10.2 months, without any difference among groups (respectively p=0.5 and p=0.8). Five years overall survival (OS) and disease free survival (DFS) were 65% and 47% with no significant difference among groups (respectively p=0.3 and p=0.9). Age (<60 years) was the only parameter that affected OS (80% versus 41%, p<0.001) and DFS (56% versus 33%, p=0.038). In a time-dependent analysis there is a significant association between mCR and DFS, therefore, if mCR was reached the risk of relapse decreased of 60% (p<0.001). Moreover, if qualitative mCR was confirmed by quantitative analysis, 5 years-DFS was much higher (78%).Conclusion: This study, conducted in a non selected population of favorable risk AML patients, confirms high CR rate and the prognostic value of age, favoring patients younger than 60 years. Our data confirm that the ELN classification identifies a clinically homogeneous group of good risk AML patients sharing comparable outcome even outside clinical trials setting. Molecular complete remission is associated with better outcome, in particular when assessed by quantitative PCR. DisclosuresNo relevant conflicts of interest to declare.

Impact of obesity in favorable-risk AML patients receiving intensive chemotherapy.

We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real-life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically-defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m(2) . Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well-balanced between obese and non-obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event-free (EFS) and disease-free (DFS) survival were not significantly different compared to non-obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non-obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious.

The Role of Anti-CD33 for the Treatment of Acute Myeloid Leukemia – Systematic Review and Meta-Analysis

AbstractAbstract 1521The treatment for acute myeloid leukemia (AML) has not changed dramatically for the last 20 years. Anti-CD33 monoclonal antibody therapy, the most prominent of which is gemtuzumab ozogamicin (GO), has been used over the last decade, in order to improve the results of patients with AML. It has been studied in a variety of contexts; at induction, consolidation and as re-induction after disease relapse. Several randomized controlled trials have evaluated the addition of anti-CD33 to chemotherapy as compared to chemotherapy alone for the treatment of AML.Systematic review and meta-analysis of randomized controlled trials comparing addition of anti-CD33 to chemotherapy with chemotherapy alone in patients with AML, for either induction or post-remission therapy. Patients under 18 years old or those with acute promyelocytic leukemia were excluded. The Cochrane Library, MEDLINE, conference proceedings and references were searched until July 2012. Two reviewers appraised the quality of trials and extracted data. Outcomes assessed were: all-cause mortality at 30 days, all-cause mortality at the end of follow up, complete response and relapse rate. Relative risks (RR) were estimated and pooled.Our search yielded 11 included trials, five of them published as abstracts, including 5239 patients. Most trials assessed GO and two trials assessed lintuzumab as the anti-CD33 agent. Dose and schedule differed between trials. Eight trials examined the effect of anti-CD33 in the induction setting: six assessed the addition of anti-CD33 to intensive induction (daunorubicin and cytarabine based) and two used low dose cytarabine in elderly patients. Three trials examined the addition of anti-CD33 in the post remission setting (one as consolidation, one as maintenance and one after relapse). When analyzing the addition of anti-CD33 in all settings together, there was no difference in all-cause mortality at 30 days or at the end of follow up between chemotherapy with anti-CD33 and chemotherapy alone (RR 1.15 [95% CI, 0.96–1.37, 7 trials], RR 0.96 [95% CI, 0.92–1.00, 8 trials] respectively). In the subgroup of favorable and intermediate risk AML, the addition of anti-CD33 had no effect on all-cause mortality, RR 0.94 (95% CI, 0.87–1.02, 3 trials)], however when analyzing the subgroup of favorable risk patients only, mortality was significantly reduced with the use of anti-CD33 (RR 0.60, 95% CI, 0.42–0.85, 2 trials). Treatment with anti-CD33 had no effect on complete remission rate, RR 1.05 (95% CI 0.96–1.14, 7 trials). Yet, it significantly reduced relapse rate, RR 0.90 (95% CI 0.84–0.96, 4 trials). There was not enough data to evaluate the incidence of veno-occlusive disease.In conclusion, the addition of anti-CD33 to chemotherapy significantly decreased relapse rate, with no effect on all cause mortality. Yet, in the favorable risk subgroup, the use of anti-CD33 significantly reduced mortality. Further research is needed to confirm the beneficial effect in the favorable risk AML patients. Disclosures:No relevant conflicts of interest to declare.