Favorable Risk Karyotype Research Articles

Clinicopathologic characteristics and treatment outcomes of de novo myeloid sarcoma.

e19002 Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p < 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]

Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML)— Transplant Outcomes Post HMA Therapy in a Large International Patient Cohort

Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML)— Transplant Outcomes Post HMA Therapy in a Large International Patient Cohort

Comparison of Frontline Induction Therapy Using Idarubicin in Combination with High-Dose (HDAC3) Versus Intermediate-Dose Cytarabine (IDAC3) in Adult Acute Myeloid Leukemia

BackgroundThe utility of high-dose cytarabine during induction chemotherapy for adult acute myeloid leukemia (AML) remains contentious. Intermediate-dose cytarabine may maintain a high first-cycle complete remission (CR) rate, whilst reducing treatment-related toxicity.AimWe examined the outcomes of adult AML patients treated with idarubicin (12 mg/m2 days 1-3) in combination with high-dose (3 g/m2; HDAC3) or intermediate-dose cytarabine (1.5 g/m2; IDAC3) given twice daily on days 1, 3, 5, and 7.MethodsConsecutive AML patients aged ≤60 years at 2 major tertiary referral centers, the Alfred and Austin Hospitals, were treated with sequential protocols of HDAC3 (n=52; 2010-2014) and then IDAC3 (n=58; 2014-2017). Planned consolidation chemotherapy consisted of up to 2 cycles of idarubicin 9 mg/m2 days 1-2, cytarabine 100 mg/m2 days 1-5, and etoposide 75 mg/m2 days 1-5 (IcE). Favorable-risk karyotype was excluded from this analysis. We assessed treatment responses (2017 European LeukaemiaNet recommendations), 30 and 60-day mortality, ability to deliver consolidation therapy (number of cycles and days from induction to first consolidation chemotherapy), rates of allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission (CR1), rates of total parenteral nutrition (TPN) usage, haematologic toxicities (days to platelet and neutrophil recovery), and relapse-free (RFS) and overall survival (OS) censored for allo-HSCT or loss to follow-up. Statistical analysis was performed using R version 3.3.2.ResultsIDAC3-treated patients were younger than those receiving HDAC3 (median 44 vs 48 years) but had a higher frequency of secondary AML (16% vs 4%); (Table 1). Other baseline characteristics were balanced between both groups. No significant differences were observed for any outcome (Table 2), except the use of TPN which is most likely a result of change in practice over time rather than a true reflection of mucositis. Response rates including CR or CR with incomplete haematologic recovery (CRi) were similar: 79% (HDAC3) vs 83% (IDAC3) after 1 cycle of induction. There was no death at 30 days and only 1 death at 60 days. Allo-HSCT in CR1 was similar; among patients with adverse-risk karyotype, allo-HSCT in CR1 was performed for 9/15 (60%) after IDAC3 and 7/11 (64%) after HDAC3. Days to neutrophil and platelet recovery were also similar.Delivery of consolidation chemotherapy was similar between both groups. After excluding treatment failure and partial remission (PR), 94 patients were eligible for first consolidation chemotherapy (3 patients with PR were considered near CR), of which 14 (15%) did not receive further consolidation therapy with the following reasons: allo-HSCT in CR1 (n=10); prolonged cytopenias (n=3); and maintenance clinical trial (n=1). Twenty-nine patients (31%) received only 1 consolidation therapy due to the following reasons: allo-HSCT in CR1 (n=14); prolonged cytopenias (n=10); non-hematologic toxicities (n=2); relapse (n=2); and unknown (n=1). IcE chemotherapy was administered in all except 2 cases: one received high-dose cytarabine for 1 cycle, and another had reduced idarubicin dose for 1 cycle.Survivors were followed up for a median of 8 (IDAC3) and 37 months (HDAC3), respectively. Median OS were 11.5 and 18.6 months for IDAC3 and HDAC3 (p=0.3), respectively (Figure 1A), and the corresponding median RFS were 8.4 and 9.4 months (p=0.5), respectively (Figure 1B). Overall, the median OS for adverse-risk karyotype remained significantly inferior compared to intermediate-risk (5.6 vs 20.9 months, p=0.009 by log-rank test); among adverse-risk karyotype, this was 5.1 vs 6.5 months for IDAC3 and HDAC3, respectively. Similarly, patients with FLT3 -ITDpos/ NPM1WT had inferior median OS (n=7, 6.1 months) when compared with FLT3 -ITDneg/ NPM1WT (n=55, 15.9 months), FLT3 -ITDpos/ NPM1MUT (n=14, 20.9 months), and FLT3 -ITDneg/ NPM1MUT (n=16, 40.6 months, p=0.06 by log-rank test).ConclusionIDAC3 and HDAC3 were both well tolerated in adult patients with AML with high first-cycle CR/CRi rates observed and low early mortality. No significant differences in hematopoietic recovery or delivery of post-remission therapy was apparent. With the caveat of limited sample size and follow-up duration, survival outcomes appeared equivalent. [Display omitted] DisclosuresGrigg:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees. Wei:AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria.

Systemic Mastocytosis with Associated Acute Myeloid Leukemia (SM-AML): a Poor-Risk Multi-Mutated Disease That Follows a Distinct Diagnostic Algorithm and Requires High-Dose Stem Cell-Targeting Therapy

In systemic mastocytosis (SM), clinical phenotype, response to treatment and prognosis are influenced by the KIT D816V mutation (80-90% of patients positive), additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) and chromosomal aberrations. In core-binding factor acute myeloid leukemias (CBF-AML), KIT mutations are identified in about 30% of cases, conferring an adverse prognostic impact on survival. However, patients with AML are not routinely checked for the contemporaneous presence or absence of SM. We sought to evaluate a) clinical and molecular characteristics, b) responses to treatment and survival, and c) prognostic factors in 44 patients with SM and associated AML (SM-AML). The median age was 64 years (range 28-83), 64% were male. In the majority of patients (30/44, 68%), AML evolved a median of 24 months (range 2-153) after diagnosis of SM without (6/30, 20%) or with (24/30, 80%) an associated hematologic neoplasm (AHN) such as myelodysplastic syndrome (SM-MDS), myeloproliferative neoplasm (SM-MPN) or MDS/MPN (SM-MDS/MPN). Based on histopathology, SM was contemporaneously diagnosed with AML in 14/44 (32%) patients. At diagnosis of SM-AML, the median bone marrow infiltration by mast cells and myeloid blasts was 15% (range 5-65; ≥20% in 45% of patients) and 39% (range 20-95), respectively, and the median serum tryptase level was 92 μg/l (range 2-885; ≥150 in 39% of patients). In the majority of patients, material was available for molecular analyses and revealed the following markers at diagnosis of SM-AML: a) KIT D816V in 36/41 (88%) patients, b) additional mutations by targeted next-generation sequencing (NGS, 28 myeloid gene panel) in 32/33 (97%) patients, the most frequent mutations were: RUNX1 (n=12, 36%), TET2 (n=11, 33%), SRSF2 (n=11, 33%), ASXL1 (n=9, 27%), IDH1 / 2 (n=6, 18%), NPM1 (n=6, 18%), BCOR (n=5, 15%), DNMT3A (n=4, 12%), and, c) an aberrant karyotype in 25/35 (71%) patients (in analogy to related myeloid neoplasms, e.g. MDS or AML, patients were classified according to their karyotype into three groups: favorable-, intermediate- and poor-risk; only 1 patient with a CBF translocation). Patients with a known history of SM were frequently S/A/Rpos (19/22, 86%) and acquisition of additional mutations (NPM1, n=2; IDH1, n=2; BCOR / JAK2 / TP53 / PHF6 / RUNX1, n=1) or karyotype evolution at time of SM-AML was observed in 8/15 (53%) or 9/13 (69%) patients, respectively. NGS on DNA derived from CD34+ myeloid blasts of 6 KIT D816V positive patients revealed the presence of KIT D816V positive blasts in only 1/6 (17%) patients while additional mutations were found in blast cells of all 6 patients. Eight patients received supportive care due to age and/or comorbidity. In 36 patients, disparate combinations of AML-type chemotherapy ± hypomethylating agents (HMA) ± cladribine (n=16) were administered. Cytarabine-based consolidation treatment was administered in 4/36 (11%) patients in complete remission (CR). Allogeneic stem cell transplantation (SCT) was performed in 15/36 (42%) patients, only 6/15 (40%) patients were in CR prior to allogeneic SCT. Overall, 5/10 (50%) patients in CR of AML showed persistence of SM. From diagnosis of SM-AML, the median observation was 10 months (range 0-200); 32/44 (73%) patients died during observation. The median overall survival (OS) was 11 months (95% confidence interval [CI], 4-17) with median OS of 2 (range 0-5), 4 (range 0-12) and 74 (range 0-149) months for patient cohorts who were treated with supportive care, intensive chemotherapy/HMA and intensive chemotherapy followed by allogeneic SCT, respectively (P=0.0002). On multivariate analysis, the only independent prognostic marker for OS was favorable-risk karyotype (n=14) vs. intermediate-/poor-risk karyotype (n=21; median OS 21 vs. 7 months; HR 3.2 [1.3-7.8], P=0.007). We conclude that a) SM-AML seems to be more frequent than commonly believed, b) SM-AML should be regarded as secondary AML evolving from multimutated SM-AHN, c) KIT mutations are not restricted to CBF-AML, d) progression to SM-AML is often triggered by acquisition of new mutations and/or karyotype evolution, e) SM-AML has an aggressive phenotype and a poor prognosis, f) treatment of SM-AML should include a combination of intensive chemotherapy and allogeneic SCT for eligible patients and g) the disease frequency and poor prognosis warrant routine screening of all AML cases for serum tryptase and KIT D816V. DisclosuresNolte:Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Cross:Qiagen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Sperr:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Phadia: Research Funding; Meda: Research Funding; Novartis: Other: Register. Valent:Blueprint: Research Funding; Teva: Honoraria; Deciphera: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria.

Analysis of age-specific cytogenetic changes among 515 patients withacute myeloid leukemia

To characterize cytogenetic changes and prognosis of patients with acute myeloid leukemia (AML) from different age groups. The karyotypes of 515 AML patients were analyzed by using short-term culture of bone marrow cells and R-banding technique. Combined with FAB typing and genetic testing, cytogenetic changes and prognosis of different age groups were analyzed. The abnormal cloning rate was 54.6% among the 515 patients. The abnormal cloning rate and adverse risk karyotype proportion of those with myeloproliferative syndromes (MDS) and secondary AML were higher than those with de novo AML (P = 0.027; P<0.01). A significant difference was found in the number of structural abnormalities and proportion of favorable risk karyotypes among different age groups (P = 0.026; P = 0.004). And there was also a significant difference in the abnormal cloning rate between different FAB types (P<0.01). In those with non-acute promyelocytic leukemia (APL), the expression level of WT1 gene seemed to affect the prognosis. The survival rate of patients with karyotypes of adverse risk was lower than those with karyotypes of favorable risk (P = 0.015). The survival rate of the ≥60-year-old group was lower than the ≤30-year-old and 31 to 59-year-old groups (P<0.01, P<0.01). The karyotypes of AML patients have different age distribution characteristics. The survival rate of ≥60-years-old group and karyotype of poor prognosis is low. Patients with MDS with secondary AML have a poor prognosis.

Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

CASCADE: A phase 3, randomized, double-blind study of vadastuximab talirine (33A) versus placebo in combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia (AML).

TPS7066 Background: AML is associated with poor survival rates in patients (pts) who are not eligible for intensive chemotherapy or allogeneic stem cell transplant (allo-SCT) due to advanced age, comorbidities, and/or disease risk factors. Non-intensive therapies, such as the hypomethylating agents (HMAs) azacitidine and decitabine, are frequently employed in this setting; however, response rates and survival remain suboptimal in this pt population. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Upon binding, 33A is internalized and transported to the lysosomes where PBD is released via proteolytic cleavage of the linker, leading to DNA crosslinking and cell death. In preclinical studies, HMA priming followed by 33A exposure upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. In a phase 1 study, 33A plus HMA was generally well tolerated without a significant pattern of off-target toxicity. Activity of the combination was markedly improved compared to historical data of HMA monotherapy, with a high MRD-negative remission rate and activity maintained in the highest risk subgroups (Fathi et al, ASH 2016). Methods: This phase 3, randomized, double-blind, placebo-controlled global study was designed to compare overall survival between pts treated with 33A plus HMA vs. pts treated with placebo plus HMA (NCT02785900). Secondary endpoints include composite complete remission rate (CR/CRi), event-free survival, and safety. Approximately 500 pts will be randomized in a 1:1 manner to one of the study arms. Investigators may select either HMA (azacitidine or decitabine). Eligible pts are adults with newly diagnosed, previously untreated, de novo or secondary AML, and have intermediate or adverse cytogenetic risk. Pts must not have AML associated with favorable risk karyotype or be a candidate for allo-SCT. Combination treatment may be repeated every 4 weeks until disease progression, leukemic recurrence, or unacceptable toxicity. Study enrollment began in June 2016.

A Series of 116 Therapy-Related Myeloid Neoplasms (t-MN) Patients from 2 French Comprehensive Cancer Centers

Background: Cancer patients (pts) who receive chemotherapy and/or radiation therapy for their primary tumor are at risk for developing therapy-related myeloid neoplasms (t-MN). Estimates of t-MN prevalence are mainly derived from retrospective series from hematology departments: they account for 10 to 20% of all AML cases. However this condition is frequently diagnosed in daily practice in comprehensive cancer centers (CCC). This suspected higher frequency might be due to optimized follow-up protocols and improved survival outcomes after tumor remission. The aim of this study was to assess clinical factors associated with t-MN in 2 French CCC focusing on delay of onset, survival, cytogenetically defined prognosis, treatment received for primary tumor and myeloid disease presentation.Methods: We conducted a retrospective study of cancer pts who developed t-MN seen at Institut Gustave Roussy, Villejuif, France and Institut Curie, Saint-Cloud, France between 2004 and November 2014. As defined in the current 2008 WHO classification, t-MN includes therapy-related acute myeloid leukemia (t-AML), myelodysplastic syndrome (t-MDS) and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). The study inclusion criteria were development of t-MN after chemotherapy and/or radiation therapy for any primary tumor.Results: 116 patients were retrieved from our records. 86 patients were women (74%) and the median age at t-MN diagnosis was 65 years (range, 25-91 years). The distribution of primary malignancies by site was as follows: breast cancer 46 pts, hematologic malignancy (lymphoma and myeloma) 24 pts, gynecologic cancer 14 pts, head and neck cancer 8 pts, urologic cancer 6 pts, gastrointestinal cancer 4 pts, miscellaneous (sarcoma, neurooncology, neuroendocrinology cancer) 14 pts. The median interval between primary cancer and t-MN was 60 months (range, 12-324). At the time of t-MN diagnosis, 69 (59%) had t-AML, 46 (40%) had t-MDS and 1 (1%) had t-MDS/MPN. Of note, among t-AML pts 15 (13%) had AML with recurrent genetic abnormalities and 14 had AML (12%) with MDS-related changes. Median survival from the diagnosis of t-MN was 6.5 months (5y OS was below 20%). Adverse risk karyotypes were prominent (63 pts, 59%) followed by intermediate risk (32 pts, 30%). Of note 12 pts (10%) had favorable risk karyotype. The impact of karyotype on survival was crucial: median survival was 60 months for favorable risk pts, 14 months for intermediate risk pts and only 6 months for adverse risk karyotypes. 26 pts (22%) were treated by radiation therapy alone. Treatment modality (radiation therapy alone, chemotherapy alone or combined treatment) did not affect survival or delay of onset. Of note, when we isolated pts treated by alkylating agents without topoisomerase inhibitors from those treated by topoisomerase inhibitors without alkylating agents we found that the disease presentation did not differ (same proportion of t-AML vs. t-MDS in each group), an observation in contrast with the classical description of post-alkylating agent t-MDS vs. post- topoisomerase inhibitor t-AML.Conclusion: We report a heterogeneous cohort of 116 pts with numerous primary tumors and treatment protocols. Prominent adverse risk karyotypes are in line with a dismal survival yet favorable risk karyotypes are not uncommon and remain associated with a relatively good prognosis. DisclosuresNo relevant conflicts of interest to declare.

Somatic Gene Mutations Serve As Molecular Biomarkers Predictive for Response to Immunosuppressive Therapy (IST) in Myelodysplastic Syndromes (MDS)

IntroductionImmunosuppressive therapy (IST) yields durable hematologic improvement (HI) in a subset of patients (pts) with lower risk MDS. Age, HLA-DR15+, and duration of transfusion dependence are the strongest independent clinical variables predictive for response. We investigated the impact of somatic gene mutations on response to IST in lower risk MDS pts.MethodsMDS pts who received ATG +/- CSA were identified at the Moffitt Cancer Center. The National Institutes of Health (NIH) IST response model was calculated for each pt. Next Generation sequencing (NGS) for somatic gene mutations was conducted using DNA extracted from archived BM prior to therapy. All pts underwent mutation analysis by a 49 myeloid gene panel. The library was generated with the ThunderBolt (RainDance Technologies, Billerica, MA) and sequenced on a MiSeq instrument (Illumina, San Diego, CA). Alignment and variant calling was performed with NextGene (Soft Genetics, State College, PA).ResultsSixty-six pts treated with ATG +/- CSA were identified. Median age was 61 and the majority of pts had IPSS lower risk disease with favorable risk karyotype. Median time to initiation of IST was 1 year. All pts received ATG (60% rabbit (r-ATG); 32% equine (e-ATG)), and CSA was used in 60% of pts. Overall frequency of HI was 42% with a trend favoring e-ATG vs. r-ATG (52% vs. 39%, p=0.09). Erythroid HI was evaluable in 30 pts with 60% responding, neutrophil improvement was evaluable in 15 pts and 39% responded, while platelet improvement was evaluable in 18 pts with 57% responding. Six of 18 (33%) pts with pancytopenia experienced trilineage response. Mean time from ATG to next therapy was 12 mo (median of 7.7 mo). Neither presence of an LGL clone, hypocellular BM or fibrosis, HLA DR15, trisomy 8, nor age influenced response to IST. Pts classified as IPSS-R Very high or high risk were unresponsive (n= 5), whereas 10 of 19 pts (53%) with intermediate risk responded. Poor risk IPSS karyotype was associated with a trend for lower response rate when compared to intermediate and good risk (25% vs. 41% vs. 44%; p=0.6). The response rate based on the NIH IST model was 38% for low response probability category pts and 45% for high probability category (p=0.5). Response rate to IST was higher if administered within 2 years from diagnosis, with an HI rate of 48% vs. 33% when treated after 2 years (p=0.04). Pts who received ATG as first line treatment or after lenalidomide had a trend for higher response rates than those treated after azacitidine (46%,75%, and 25% respectively). Addition of CSA significantly improved HI rate (51% vs. 27% for ATG alone, p=0.02). Transformation to AML occurred in 10 pts, 7% of responders and 24% of non-responders (p=0.08). Median OS was 67.2 mo with no significant difference based on IST response.Among 40 pts evaluated by NGS, 20 (50%) had at least one demonstrable somatic mutation (SM) and 9 pts (22.5%) had two or more SM. SF3B1 was the most common SM detected (n=9, 22.5%), followed by ASXL-1 (n=7, 17.5%), TET-2 (n= 5, 12.5%), and STAG2, EZH-2 and ZRSR2 (2 pts each, 5%), and 1 pt each with IDH-1, KDM6A, SETBP1, RAD2, GNAS or GATA-2. Absence of a SM was associated with a higher response to IST (70% vs. 40%, p=0.16), whereas number of SM (1 vs. 2+) did not influence response. The presence of an SF3B1 mutation was a significantly associated with IST nonresponse (1/9 SF3B1 SM, 11% vs. 21/31 WT, 68%; p=0.01). All pts with SF3B1 SM had ring sideroblasts >15% (RS) by morphology and the corresponding HI rate was 20% among pts with RS vs 50% for those without RS, p=0.09. Median OS in pts with an SF3B1 SM was 111 mo vs. 54 mo in SF3B1 WT (p=0.016). The two pts with EZH-2 and the single pt with WT-1 S achieved HI. Mean duration of response was 12 mo among pts with no SM vs. 9 mo in those harboring a SM (p=0.09). Rate of AML transformation among pts with a SM other than SF3B1 was higher in pts without SM (4/11 pts, 36%vs. 1/20, 5%; p =0.023, with a corresponding reduced median OS (52 mo vs. 96, p=0.24).ConclusionsThese findings support an improved response rate to ATG when administered in combination with CSA, and early in the disease course. The presence of an SF3B1 mutation adversely influences response to IST, suggesting a non-immunologic pathogenesis in this molecularly defined subset. The presence of non-SF3B1 somatic mutations adversely affects response duration and probability of AML transformation. SM should be considered in selection of IST in lower risk MDS patients. DisclosuresKomrokji:Pharmacylics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Incyte: Consultancy. Lancet:Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Padron:Incyte: Research Funding; Novartis: Speakers Bureau.

Prognostic Implication of Therapy-Related Acute Myeloid Leukemia after Comparative Analysis with De Novo acute Myeloid Leukemia

Background: Therapy-related acute myeloid leukemia (t-AML) is regarded as a complication after cytotoxic chemotherapy and/or radiation therapy, and also considered to have a poor survival outcome compared to de novo AML. We still have a question whether t-AML itself indicates a poor prognosis or whether the inferior outcome results from the association with such an adverse characteristics including cytogenetic risk or age or underlying malignancies.Methods: In this single center retrospective study, 1825 patients (median 46 years old [range, 17-92]) with variable karyotypes were enrolled from 2002 to 2013. Fifty-four (3.0%) patients had previous malignancies or autoimmune diseases, and all of them were treated with radiation or toxic chemotherapy before diagnosis of t-AML with a median duration of 36.3 months (range, 2.9-280.5). We analyzed clinical outcomes compared to 1771 de novo AML patients who were not related with any toxic therapies before.Results: Among 54 t-AML patients, 42 (77.8%) was in remission of prior malignant disease and 8 were in stable disease and 4 were in relapsed disease. In t-AML subgroup, median age was older (50 vs. 46 years old, p =0.119), leukocyte and bone marrow blast counts were significantly lower than de novo AML subgroup. There were more female patients in t-AML subgroup (70.3% vs. 45.4%, P =0.003). Among 38 female t-AML patients, 13 (34.2%) patients had breast cancer, 10 patients had hematological malignancies (i.e. APL in 5, lymphoma in 3, multiple myeloma in 2), and 8 (21.1%) had gynecological malignancies (i.e. ovarian and cervical cancer etc.). One or more chromosomal abnormalities (82.6% vs. 68.3%, P =0.015) and more adverse-risk karyotypes (41.2% vs. 20.0%, p<.001) were in t-AML subgroup. Especially, t-AML had more 5 or 7 chromosomal abnormalities (7.8% vs. 2.0%, P =.004) and complex karyotypes (27.5% vs. 7.6%, p<.001) which also included abnormal 5 or 7 chromosomes. Smaller number of t-AML patients received induction chemotherapy (74.1% vs. 87.6%, P =0.006) and early death rate was higher in t-AML group (22.2% vs. 13.7%, P =.083). After median follow-up of 70 months (range: 5.6-165.0), t-AML showed inferior 5-year overall survival (OS) compared to de novo AML (23.8% vs. 39.0%, p <.001). The result was more significant in intermediate to poor-risk group (9.2% vs. 30.0%, p<.001), but it was similar in favorable-risk group (75.0% VS. 62.8%, P =.532). In treated cohort, however, remission rate (70.0% vs. 79.3%, p =.149) and relapse rate (28.8% vs. 35.9%, p =.544) was not different, and multivariate analysis showed t-AML did not affect OS (HR=1.25, P =.185), while age >50 years old (HR=1.48, p<.001), hematopoietic cell transplantation (HCT, HR=0.37, p<.001), favorable-risk karyotype (HR=0.48, p<.001), and post-induction remission status (HR=0.26, p<.001) did. Five-year OS of t-AML patients treated with HCT (n=16) was 50.0%, and for intermediate to poor-risk subgroup treated with HCT, 5-year OS was 33.3%.Conclusion: In this study, t-AML was related with a larger proportion of adverse-risk karyotype, and many patients could not start induction chemotherapy due to old age, and remained prior malignant disease, which might result in poor survival outcome. On the other hand, response to induction chemotherapy of t-AML was similar with de novo AML consistent with a recent report (Kayser et al. Blood 2011). Therefore, if previous malignancy is in remission or in stable disease, aggressive treatment strategy using HCT may overcome poor survival outcome of t-AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Therapy-Related De Novo Acute Myeloid Leukemia on Response and Survival

determined by microarray analysis and validated by qRT-PCR. Future studies will address the mechanism of how PP2A regulates these miRs. Conclusion: Loss of B55 alpha PP2A activity in leukemia can induce diverse survival signaling pathways and allow expression of pro-tumor microRNAs. 207 Impact of Therapy-Related De Novo Acute Myeloid Leukemia on Response and Survival Koji Sasaki, Elias Jabbour, Hagop Kantarjian, Jorge Cortes, Guillermo Garcia-Manero, Gautam Borthakur, Sherry Pierce, Naveen Pemmaraju, Susan O’Brien, Farhad Ravandi Department of Leukemia, The University of Texas MD Anderson Cancer Center Background: The available data on outcome of patients with therapy-related de novo acute myeloid leukemia (t-de novo AML) without antecedent myelodysplastic syndrome (MDS) are limited. Methods: We retrospectively reviewed the records of patients with newly diagnosed AML who presented to MD Anderson Cancer Center between January 2000 and January 2014. T-de novo AML was defined as at least 20% blasts in bone marrow with a history of any previous cytotoxic chemotherapy or radiation therapy and without antecedent MDS. The overall survival (OS) and leukemiaTable 1 Characteristics and Outcomes of Patients with De Novo AM t-de novo AML (n[ 187) de n ( Age at diagnosis, median, years (range) 64 (21-89) 6 Prior radiation therapy, No. (%) 101 (54) Prior chemotherapy, No. (%) 186 (99) WBC count at diagnosis, median, 10/mL (range) 3.2 (0.2-191) 4. Hgb at diagnosis, median, g/dL (range) 9.1 (4.5-12.9) 9. Plt count at diagnosis, median, 10/mL (range) 34 (4-454) 5 LDH at diagnosis, median, IU/L (range) 1359 (210-22090) 118 PB blast percentage at diagnosis, median (range) 8 (0-98) 9. BM blast percentage at diagnosis, median (range) 41 (0-96) 4 Molecular genetic abnormalities at diagnosis, No. (%) FLT3-ITD 17 (9) 9 FLT3-D835 6 (3) 2 NPM1 7 (4) 10 JAK2 3 (2) RAS 17 (9) 5 free survival (LFS) in patients with t-de novo AML were compared to those with de novo AML with normal karyotype (NK) or complex karyotype (CK). Results: Of 1677 patients with newly diagnosed AML, 383 had de novo NK-AML, 218 had de novo CKAML, and 187 had t-de novo AML. The median follow-up was 9.3 months (range, 0.2-161.0). Patient characteristics and outcomes are summarized in Table 1. Of the 187 patients with t-de novo AML, 69 had a history of lymphoma; 63, breast cancer; 10, colon cancer; 10, sarcoma; and 69, another type of cancer. Fifteen of the patients with t-de novo AML (8%) had a favorable-risk karyotype, 53 patients (28%) an intermediate-risk karyotype, and 119 patients (64%) a poor-risk karyotype. The median LFS durations in t-de novo AML, NK-AML, and CK-AML were 7 months (95% confidence interval [CI], 5.1-8.7), 19 months (95%CI, 13.0-25.2), and 6 months (95%CI, 9.0-13.5) (P 100103/mL, platelets <30 0103/mL, nonfavorable cytogenetic abnormalities, positive RAS mutation, and the absence of complete remission or complete remission with incomplete platelet recovery as poor prognostic features related to OS. Conclusion: LFS and OS for patients with t-de novo AML were shorter than those for patients with NK-AML but did not differ significantly from those for patients with CK-AML.

Outcome of Patients (pts) with Therapy-Related De Novo Acute Myeloid Leukemia (t-de novo AML): Single Institution Experience

Background:Therapy-related myeloid neoplasms develop after cytotoxic chemotherapy or radiation therapy. The available data on the outcome of pts with t-de novo AML without antecedent history of myelodysplastic syndrome (MDS) is limited.Methods:We reviewed the records of pts with newly diagnosed AML who presented to our tertiary care center from 1/2000 to 1/2014. t-de novo AML was defined as having at least 20% blasts in bone marrow with a history of any previous cytotoxic chemotherapy or radiation therapy, and without an antecedent history of MDS. Leukemia-free survival (LFS) was defined as time from achieving complete response (CR) to relapse or death. The overall survival (OS) and LFS in pts with t-de novo AML were compared to those of with de novo AML with normal karyotype (NK) and complex karyotype (CK).Results:Among 1677 pts with newly diagnosed AML, 383 had de novo NK-AML, 218 had de novo CK-AML, and 187 had t-de novo AML. The median follow-up was 9.3 months (range; 0.2-161.0). Pt characteristics and outcomes are described in Table 1. Among the 187 pts, 69 had a history of lymphoma; 63 pts breast cancer (Ca); 10 pts colon Ca; 10 pts sarcoma; 8 pts prostate; 7 pts bladder Ca; 6 pts uterine Ca; 5 pts lung Ca; 5 pts head and neck Ca; 30 pts other type of Ca. Among the pts with t-de novo AML, 15 pts (8%) had a favorable-risk karyotype by WHO, 53 pts (28%) intermediate-risk karyotype, and 119 pts (64%) poor-risk karyotype. The median LFS duration in t-de novo AML, NK-AML, and CK-AML were 7 months (95% confidence interval [CI]; 5.1-8.7), 19 months (95% CI; 13.0-25.2), and 6 months (95% CI; 9.0-13.5) (p<.001), respectively. The median OS duration in t-de novo AML, NK-AML, and CK-AML were 7 months (95% CI; 5.9-8.9), 21 months (95% CI; 16.2-25.5), and 12 months (95%CI; 10.6-13.5) (p<.001), respectively. The results of univariate (UVA) and multivariate analysis (MVA) associated with OS were summarize in Table 1. MVA identified age over 60, white blood cell count (WBC) over 10 x103/µL, thrombocytopenia below 30 x103/µL, non-favorable cytogenetic abnormalities, positive RAS mutation, and the absence of CR or CR with incomplete platelet recovery (CRp) as poor prognostic features related to OS.Conclusion:LFS and OS were shorter in patients with t-de novo AML than in those with NK-AML but did not differ significantly from patients with CK-AML.Abstract 2273. Table 1Patient Characteristics and Outcomest-de novo AML [n= 187]de novo AML with NK [n= 383]de novo AML with CK [n= 218]PAge at diagnosis, median (years)64 (21-89]63 (17-90)67 (18-87)Prior radiation therapy, No. (%)101 (54)00Prior chemotherapy, No. (%)186 (99)00White blood cell count at diagnosis, median (x103/µL)3.2 (0.2-191)4.3 (0.2-390.0)2.9 (0.5-278.2)Hemoglobin at diagnosis, median (g/dL)9.1 (4.5-12.9)9.1 (4-14.6)9.0 (2.5-14.2)Platelet count at diagnosis, median (x103/µL)34 (4-454)51 (3-469)42 (2-319)LDH at diagnosis, median (IU/L)1359 (210-22090)1189 (200-42000)1274 (231-20572)Peripheral blood blast percent at diagnosis, median (%)8 (0-98)9.5 (0-98)10 (0-98)Bone marrow blast percent at diagnosis, median (%)41 (0-96)44 (0-96)33 (0-97)Molecular genetic abnormalities at diagnosis, No. (%)FLT3-ITD17 (9)96 (25)5 (2)FLT3-D8356 (3)23 (6)1 (1)NPM17 (4)104 (27)4 (2)JAK23 (2)6 (2)8 (4)RAS17 (9)50 (13)8 (4)RUNX1-RUNX1T14 (2)00CBFb-MYH6 (3)00Response, No. (%)<0.001Complete response89 (48)237 (62)76 (35)Complete response without platelet recovery15 (8)1 (0)15 (7)1-year LFS, (%)336027<0.0012-year LFS, (%)335220<0.0011-year OS, (%)346830<0.0012-year OS, (%)244613<0.001UVA and MVA of OS in t-de novo AMLUVAMVAHazard ratio95% CIAge at diagnosisAge =< 60 years-Age >60 years< .001.0012.2381.417-3.534White blood cell count (WBC) (x103/µL)WBC =< 10.0-WBC > 10.0.002.0371.6171.030-2.540Hemoglobin (Hgb) (g/dL)Hgb >= 8-Hgb < 8.749Platelet count (Plt) (x103/µL)Plt >= 30-Plt < 30.008.0041.8521.224-2.803LDH (IU/L)LDH =<1000-LDH > 1000.640Peripheral blood blast percent (PB blast)(%)PB blast =< 10%-PB blast >10%.178Bone marrow blast percent (BM blast) (%)BM blast =<40%-BM blast >40%.393Cytogenetic abnormalityFavorable-Non-Favorable.002.0195.8361.342-25.370FLT3-ITDNegative-Positive.768RASNegative-Positive.047.0032.5761.367-4.856ResponseCR or CRp-Non-CR or CRp<.001.009.3310.145-0.757CR-Non-CR<.0010.903.9500.418-2.160 [Display omitted] DisclosuresKantarjian:ARIAD, Pfizer, Amgen: Research Funding.

Bone Marrow Aspirates Alone without a Trephine Biopsy May be Insufficient for the Detection of Residual Leukemia Following Intensive Chemotherapy for the Treatment of Acute Myeloid Leukemia

Background: The diagnosis of acute myeloid leukemia (AML), response to treatment and disease recurrence are most commonly assessed with bone marrow studies. Recommendations from leading experts (Bain, 2001) and guidelines of the European LeukemiaNET (Dohner, 2010) and the National Comprehensive Cancer network (O’Donnell, 2012) suggest that only the bone marrow aspirate (BMA) is necessary to assess residual disease while the trephine biopsy (TB) is necessary only when an aparticulate BMA is obtained. In contrast, guidelines of the International Council for Standardization in Hematology (Lee, 2008) suggest that BMA and the TB should be routinely performed together as they provide complementary information. Due to these conflicting recommendations we sought to determine whether the TB provides additional sensitivity for the detection of residual leukemia following intensive chemotherapy for AML.Methods: A single centre retrospective chart review was conducted of bone marrow studies of all AML patients who had received intensive chemotherapy from 2004 – 2013. Those lacking a TB were excluded. Residual disease was assessed by morphological examination of the BMA and TB +/- immunostaining but minimal residual disease (MRD) analysis was not performed.Results: 598 bone marrow studies from 227 patients were evaluated. The median age of the patients was 54.6 (range 18 -77) with 70% age < 60. Forty-four percent were female. Cytogenetics were favorable in 30 (13%), intermediate in 146 (64%), high-risk in 44 (19%) and failed in 7 (3%) of the patients. Of the 598 bone marrow samples 198 (33%) were interim marrows performed 14 days following initiation of induction or re-induction chemotherapy (D14 marrow), 251(42%) were recovery marrows following induction/re-induction chemotherapy (EOI marrow) and 149 (25%) were during follow-up.The BMA was considered to be acellular/hypocellular in 31%, hemodilute in 16.4% and aparticulate/pauciparticulate in 27.3% of samples. As per guidelines > 200 cells were counted in 99.8% of the aspirate samples to ascertain remission status. The median length of the TB segments was 1.85 cm (0.2 – 7.0 cm) and it was considered inadequate in 12.7%, of good or excellent quality in 24.9% and adequate for residual disease assessment in the remainder of cases. Approximately 19 % of TB samples had mild to significant hemorrhagic artifact. The bone marrow cellularity could not be assessed in 1.2% of samples but was patchy in 0.5%, aplastic in 2.8%, hypocellular in 36%, normocellular in 23.6%, hypercellular in 23.2%, packed in 6% and was not described in 6.7% of the cases.Residual leukemia was identified in 33.1% of BMA and in 33.3% of TB samples. The BMA and the TB findings were concordant in 562 of 598 (94%) of cases. In 3.5% (21) of cases residual leukemia was seen in the TB but not the BMA whereas in 2.5% (15) of cases the BMA detected residual disease but the TB failed to do so.The TB led to a change in diagnosis from ‘No Leukemia’ to ‘Residual Disease’ in 5.1% of D14 marrows, 3.6% of EOI marrows and in 1.3% of follow-up marrows with no statistically significant difference between the groups (p=0.178). There was no relationship between a change in diagnosis and whether patients received an anthracycline or a non-anthracycline based chemotherapy regimen (4.4% vs. 3.2%, p=1.0). The TB, however, led to a change in diagnosis more commonly in patients with favorable risk karyotype relative to those with intermediate risk karyotype (20% vs. 6.2%, p= 0.02) but not relative to those with unfavorable risk karyotype (20% vs. 13.6%, p=0.53).Hemodilute bone marrow samples were more likely to have a TB related change in diagnosis relative to undilute samples (8.2% versus 2.6%, p=0.01) as were aparticulate/pauciparticulate samples relative to particulate samples (8% vs. 1.9%, p=0.00046). However, in multivariate analysis, only an aparticulate/pauciparticulate sample was associated with TB related change in diagnosis (p=0.015, OR = 3.6).Conclusions: Our data demonstrate that, following intensive chemotherapy, the BMA alone may fail to identify residual leukemia particularly when the BMA is aparticulate/pauciparticulate. In these situations the TB provides additional sensitivity for the detection of residual disease. Further studies are required to evaluate the need for the TB in particulate samples when combined with MRD analysis. DisclosuresNo relevant conflicts of interest to declare.

Cytogenetics As a Prognostic Factor Of The Overall Survival (OS) Of Mexican Patients With Myelodysplastic Syndrome (MDS)

IntroductionMDS are a heterogeneous group of acquired clonal diseases, characterized by an increase of the apoptosis and several grades of cytopenias. They originate in hematopoietic stem cells with cytogenetic and molecular abnormalities, having the risk of evolving into an acute myeloid leukemia (AML).There are no clinical data of the characteristics of the patients with MDS in Mexico, thus we consider necessary to know the behavior of this disease in our population, also to evaluate the cytogenetic alterations, and to investigate whether they are associated with the OS. MethodsA longitudinal-observational study was performed at the MDS clinic of the Hematology Department of the Specialties Hospital of the Centro Médico Nacional La Raza of the Instituto Mexicano del Seguro Social (IMSS), from January 25, 2005 to January 25, 2013. The primary objective was to evaluate the epidemiological characteristics and the cytogenetic findings of the patients with MDS in our population, establishing its correlation with the OS. We included patients >16 y.o., male and female, with diagnosis of newly diagnosed MDSs with a cytogenetic testing available (GGT-band analysis performed at Quest Diagnostics and Genetica Pre y Post Natal). SPSS version 20 was used for statistical analysis. Survival was evaluated through KM curve. A Multivariate analysis with logistic regression was performed in order to know the OR and 95% CI and a p<0.05 was accepted as statistically significant. ResultsA total of 92 patients were included, 44 (47.8%) men, and 48 (52.2%) women. The cytogenetic study was normal in 72 (78.3%) of the patients and 20% (21.7%) had an abnormal cytogenetic study. The cytogenetic abnormalities were as follows: 5 (25%) had complex karyotype, 3 (15%) had –Y, 2 (10%) hypodiploidy, 2 (10%) del9, 1 (5%) del7, 1 (5%) +9, 1 (5%) t 1;5, 1 (5%) 17p-, 1 (5%) del21, 1 (5%) +19, 1(5%) del5q y 1(5%) +8.77 patients (83.7%) had favorable cytogenetic risk; 8 (8.7%) intermediate cytogenetic risk; and 7 (7.6%) poor risk.The IPSS risk stratification was: low risk in 33 (35.9%) of the patients, intermediate-1 risk in 39 (53.3%), intermediate 2 risk in 5 (5.4%), and high risk in 5 (5.4%).The median OS was 85 months (figure 1), with a median follow-up of 35 months (2-96 months). The median survival for the favorable cytogenetic risk was 82.7 months 95% CI; 74.7-90.6), for the intermediate cytogenetic risk 73.6 months (95% CI; 49.06-98.1), and for the poor cytogenetic risk, 46.8 months (95% CI; 10.6-18.4). The patients with favorable cytogenetic risk had a better survival than those with intermediate or poor cytogenetic risk (P= .001 Log-rank test). (Figure 2)Of the 92 patients, 10 (10.08%) progressed to acute myeloid leukemia the cytogenetic risk of these patients was as follows: 5 had a favorable risk karyotype and 5 had poor risk karyotype. The patients with favorable cytogenetic risk had a lower risk of progression in comparison with those with poor risk karyotype (P= 0.000). The median PFS to AML was 18.7 months (95 CI 4.1-33.2). Survival per cytogenetic risk group: for the favorable cytogenetic risk the median survival was 22.2 months 95% CI (.76-43), and for the poor cytogenetic risk it was 15.2 months, 95% CI (.0-36.8). (P= .362 Log-rank test). (Figure 3). The performance of the cytogenetic study to classify the patients and to estimate the IPSS is statistically associated with mortality (P 0.006). In the multivariate analysis was found that there is an association, independently of the cytogenetic study with favorable risk according to the IPSS, with the protection against mortality, with an OR=0.141, (95% CI 0.042-0.47). This confered a protection factor of 86% for the survival, independently of the treatment and the MDS type. ConclusionCytogenetic alterations in MDS patients differs importantly from other reports, since only a 21.7% of our patients had an abnormal cytogenetic finding. Nevertheless cytogenetic evaluation was very important for this population since it confirmed its prognostic importance for the OS of the Mexican MDS patients. Disclosures:Nacho-Vargas:Novartis Oncologia Mexico: Employment. Romero-Salas:Novartis Oncologia Mexico: Employment.

Age-Stratified Analysis Of The Prognostic Role Of Minimal Residual Disease Detection By Flow Cytometry, In Adult Patients With Acute Myeloid Leukemia

▪Although the therapy of acute myeloid leukemia (AML) has remarkably improved over the last 2-3 decades, two thirds of young adults still die of their disease. In elderly adults, who represent the majority of patients with AML, the results are even more unsatisfactory with less than 10% of patients being long-term survivors. Based on this, age is universally recognized as a critical prognosticator affecting outcome and therefore treatment choice. In consecutive series of adult patients with de novo AML, we have repeatedly demonstrated the prognostic role of minimal residual disease (MRD) as detected by flow cytometry. In particular, we have found that a level of MRD ≥ 3.5x10e-4 residual leukemic cells (RLC) at the end of consolidation is associated with a relapse rate of 70-80%. In the present study we evaluated whether the prognostic impact of MRD assessment after consolidation remained unaltered even in age-stratified (< 60 and > 60 years) populations of adult patients with de novo AML. To this end, we analyzed 149 young (median age 46, range 18-60) and 61 elderly adults (median age 67, range 61-78). All patients under study achieved complete remission after an induction therapy of the EORTC/GIMEMA protocols AML10, LAM99P and AML12 (for patients < 60 years) or AML13, AML15A and AML17 (for patients > 60 years). The two cohorts were well balanced in terms of frequency of FLT3-ITD and NPM1 mutated cases. A lower frequency of favorable-risk karyotypes was observed in elderly versus young patients (4% vs 19%, p=0.024). Of 149 younger patients, 105 (70%) underwent stem cell transplantation (SCT) (45 allogeneic, 60 autologous) as compared to 7 (11%) in the older age group (1 allogeneic, 6 autologous), (p=<0.0001). The frequency of MRD negative measurements was lower among elderly patients as compared to the younger ones [7/61 (11%) vs 42/146 (28%), p=0.009]. The median value of MRD after induction was 2.9x10e-3 RLC (range 0-170) and 3.1x10e-3 RLC (range 0-220) in younger and older patients (p=NS), respectively. Conversely, post-consolidation MRD levels were significantly lower in the younger cohort (1.7x10e-3 RLC, range 0-360) as compared to the older one (3.3 x10e-3 RLC, range 0-72), (p=0.018). In both age groups, disease-free survival (DFS) (Fig. 1) and cumulative incidence of relapse (CIR) were significantly longer and lower for patients who achieved MRD negativity at the post-consolidation time-point (p=0.0003 and <0.0001, respectively). In multivariate analysis, MRD at the post-consolidation time-point (p=0.0013) and karyotype (favorable vs adverse, p=0.0073; intermediate vs adverse, p=0.06) confirmed an independent prognostic role affecting DFS. Even SCT procedure (both autologous or allogeneic), analyzed as a time-dependent covariate, was significantly associated to DFS (p<0.001). Age did not score as a significant variable in any prognostic model. In conclusion, elderly adults with AML infrequently become flow-MRD negative after consolidation therapy (11% vs 29%, p=0.008), likely due to a less intensive approach. However, those who succeed to enter MRD negativity have significantly superior DFS and CIR – comparable to the ones of young patients - that than those who remain positive. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Chemotherapy for Acute Myeloid Leukemia Can Compensate Other Adverse Prognostic Factors in Elderly: A Retrospective Longitudinal Cohort Study in a Local Community, Japan

Abstract 3582 Background:Japan is one of the prominent aging countries, in where incidence and mortality of malignancy in elderly is increasing which is recognized as a concerned national health care issue. Among various types of cancer, incidence and prevalence of elderly acute myeloid leukemia (AML) is increasing as well, and in the most cases those patients have concomitant diseases. Thus far, the treatment for AML in elderly has been generally realized to reduce the dose intensity due to impaired organ function and comorbidity. However, the utility of dose reduction in elderly AML has not been well understood. Thereby, we performed a retrospective population cohort study of AML in a local community in Japan in order to investigate practical risk factor based on general patient population including more than 65 to 75 years old. Patients and method:We reviewed medical charts and medical records of AML patients diagnosed at seven institutions in Kagawa prefecture between January 1, 2006 and December 31, 2010. We collected patients' characteristics, background, and clinical information including laboratory data, adverse events and outcome. Induction therapy regimen was practically decided by each treating physician based on available clinical data and local standards of care, but not on karyotype. We categorized chemotherapy regimens for non-APL patients into 3 groups; intensive chemotherapy, less-intensive chemotherapy, or best supportive care. Results:A total of 213 patients (127 males and 86 females) were diagnosed with AML. With an average population during study periods in Kagawa, the incidence of AML is 4.26 per 100,000 per year. The male to female ratio was 1.48. The median age was 70 years (average 67, range 24∼95). There were 16 APL patients and 197 non-APL patients in this cohort. The 5-year overall survival (OS) rate was 21.1%. In patients who are likely to meet criteria usually applied in clinical studies (i.e., de novo AML with PS 0 to 2 and no renal dysfunction), the 5-year OS rate was 31.5%. Among 197 non-APL patients median age was 70 years (range 24∼95) consists of 119 males and 78 females. The chromosomal karyotype is known to be the strongest prognostic predictor, and each study group advocates the different classification. We classified our cohort according to 5 different karyotype classifications (NCCN, BSCH, MRC-AML10, SWOG and CALGB). On the whole, 4.4∼5.9% of the patients were classified as having favorable risk karyotypes, and 17.7∼29.1% of the patients had unfavorable risk karyotypes. In terms of treatment intensity, 51.8% patients (102/197) received intensive induction chemotherapy. A majority (71.6 %) of patients ≤ 64 years were treated with intensive chemotherapy, while approximately half (46.0%) of patients aged 65 to 74 years, and only 35.6% of patients ≥ 75 years received intensive chemotherapy as induction therapy (P < 0.001). A complete remission (CR) rate in patients treated was 67.6% (69/102) with intensive regimen, 30.4% (17/56) with less-intensive regimen, and 0.0% (0/39) with best supportive care (P < 0.001). Eight week mortality was 6.9% (7/102), 19.6% (11/56), and 41.0% (16/39), respectively (P < 0.001). In non-APL patients, the 5-year OS rate was 10.6%. Subsequent analysis by age group showed that the 5-year OS rate declined with age; the 5-year OS rate and the median survival of non-APL patients ≤ 64 years, 65∼74 years, and ≥ 75 years were 41.5% and 19 months, 14.1% and 10 months, and 8.9% and 7 months, respectively (P = 0.003). Multivariate analysis revealed aging older than 65 year-old, best supportive care, poor PS more than 3, antecedent hematological disease, and unfavorable risk karyotypes were independent adverse prognostic factors associated with OS. Discussion:This analysis provides virtual data from an unselected AML population in a Japanese cohort. Our data can be applied for realistic risk assessment for AML patients including elderly. The present result indicates all prognostic factors has comparable impact on survival, therefore chemotherapy can compensate other adverse prognostic factors even in an elderly patient with poor PS. In aggregates, we conclude it is the best way to adapt as intensive chemotherapy as possible to improve outcomes in the treatment of elderly AML. In further investigation, the external validity of the risk assessment based on identified prognostic predictors from our cohort should be reevaluated for a third party cohort from other countries. Disclosures:No relevant conflicts of interest to declare.

The Expression of LEF1 Gene and its Clinical Significance in Chinese Patients with Acute Myeloid Leukemia

Abstract 4621 Objective:Canonical Wnt signaling controls embryonic development, regulates cell growth, transference and differentiation, it also involves in the self-renewal process of normal tissue and multiplication of stem cell. Recently, the aberrant activation of the Wnt signaling pathway has been implicated in the pathogenesis of human neoplasm including leukemia. LEF1, as a major transcriptional factor of Wnt signaling, plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. High expression of LEF1 has been proposed to be a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia (AML). In this study, we firstly investigated the expression level of LEF1 mRNA and its clinical significance in Chinese AML. Methods:87 samples from 81 Chinese AML patients (81 primary untreated samples and 6 samples after induction therapy) and 14 healthy controls were collected in this study. The LEF1 mRNA expressions were measured by real-time PCR with fluorescent dye SYBR Green I, the GAPDH was used as internal control. The relative quantitative value of LEF1 expression was calculated by means of 2 (−ΔCt). We analyzed the results with established AML prognostic factors such as karyotype, gene mutations, fusion proteins, relapse-free survival (RFS) and overall survival (OS). Results:The expression level of LEF1 mRNA in 81 AML patients was significantly higher than 14 normal controls (p <0.001). LEF1 expression level was further analyzed in the subgroups distinguished by clinical characters. According to national comprehension cancer network (NCCN) guideline, we found that LEF1 was dramatically increased in patients with better risk karyotype group (n=18) than those with the intermediate risk karyotype group (n=51) (P=0.031); patients with PML-RARα positive (n=16) and AML1-ETO positive (n=5) have higher LEF1 level compared with those without PML-RARα or AML1-ETO (n=60). Among 70 patients who have received the induction therapy, we discovered that patients with relative higher LEF1 expression were more likely to achieve CR after first induction therapy (p= 0.031; CR: n=44, no CR: n=26); we further analyzed the samples before and after treatment from 6 patients who achieved CR, the results showed that the LEF1 level were dramatically decreased after first induction therapy (p=0.028). We can not find the differences in RFS and OS between low LEF1 expression group and high LEF1 expression group in total patients. However, among the AML patients with intermediate risk cytogenetic, the lower LEF1 expression was associated with worse RFS (median, 15.0 vs 31.7 months, P=0.044) and OS (median, 16.7 vs 33.7 months, P=0.046) compared with the higher LEF1 expression. Conclusion:These results showed the LEF1 expression in AML patients is markedly higher than normal controls, especially in patients with favorable risk karyotype and PML-RARα or AML1-ETO positive. Patients with higher LEF1 expression seems to more likely to achieve CR after induction therapy. Survival analysis revealed that the higher LEF1 expression patients have a significantly prolonged RFS and OS compared to the lower LEF1 expression patients in intermediate risk karyotype group of AML. Our results in Chinese patients verified that LEF1 can be a potential favorable marker in AML patients. Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) Combined with Leukemic Risk Factors Predict Outcome of AML Patients after Allogeneic Stem Cell Transplantation Following Reduced Intensity Conditioning (RIC).

Purpose: The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is used to assess the impact of comorbidities on the outcome of patients following alloSCT. Nonetheless, in AML patients leukemia-associated risk factors, i.e. cytogenetics, the presence of secondary (sAML) or therapy-related AML (tAML), or disease status prior to alloSCT, are highly relevant with regards to the long-term outcome. We therefore investigated whether the HCT-CI combined with the analysis of a defined set of AML-specific high risk factors may be used to predict the overall outcome of AML patients after alloSCT following RIC.Patients and Methods: 90 patients with high-risk AML (median age 51 (17 – 68) years) who underwent alloHSCT at our institution between 1999 and 2007 were retrospectively analyzed (median follow-up of the surviving patients: 16 (range 2 – 113) months). 50/90 patients (56%) were in CR1, 12/90 (13%) were in CR2, 2/90 (2%) were >CR2, and 26/90 (29%) had refractory or relapsed disease at the time of transplantation. 57/90 patients (63%) had de novo AML and 33/90 patients (37%) had either secondary AML (sAML) or therapy-related AML (tAML). Whereas 4/90 patients (4%) had a favorable risk karyotype, 51/90 patients (57%) or 29/90 patients (32%) had an intermediate risk or a poor risk karyotype as defined by the SWOG/ECOG criteria (Slovak et al., Blood 2000). Notably, 18/90 (20%) patients had an intermediate risk HCT-CI (1–2 points) and 72/90 patients (80%) had an unfavorable score (>2 points). As a preparative regimen all patients received RIC, which consisted of fludarabine 180 mg/m2 + oral busulfane 8 mg/kg + anti-thymocyte globulin 30 mg/kg. As stem cell source peripheral blood stem cells (PBSC) were used in 85/90 patients (94%), whereas 5/90 patients (6%) received bone marrow (BM). 38/90 patients (42%) were transplanted from a matched related donor. A matched unrelated or a mismatched unrelated donor was available in 36/90 patients (40%) or in 16/90 patients (18%). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporin (CSA) + mycophenolate mofetil (MMF).Results: Projected overall survival (OS) or disease-free survival (DFS) of the whole cohort at 1, 3, and 5 years was 60%, 44%, and 44% or 56%, 46%, and 46%. 49/90 patients (54%) are in CCR. Causes of death were relapse (23/90 patients (26%)) or TRM (18/90 patients (20%)). Notably, the HCT-CI alone was not sufficient to predict the overall outcome our cohort of patients after RIC-alloSCT. Therefore, depending on the presence or absence of at least one additional leukemia-specific high-risk factor, i.e. disease status prior to alloSCT >CR1, tAML, or poor risk karyotype, patients were grouped into four subgroups: group I (HCT-CI <4, no high risk), group II (HCT-CI >4, no high risk), group III (HCT-CI <4, high risk), and group IV (HCT-CI >4, high risk). Projected OS in at 1, 2, and 3 years after alloSCT was 73%, 59%, and 59% (group I), 86%, 57%, and 57% (group II), 56%, 46%, and 37% (group III), or 33%, 16%, and 16% (group IV), which differed statistically significant between the 4 subgroups (p = 0.04). In turn, there was no statistically significant difference in TRM between groups I – IV (p = 0.61).Conclusions: These results indicate that the combined analysis of TRM-related factors, as assessed by the HCT-CI, and a limited set of leukemia-specific risk factors, i.e. cytogenetic risk, disease status before alloSCT, and the presence of tAML, may be useful in predicting the overall outcome of patients with AML after alloSCT following RIC.

Therapy-Related Myeloid Leukemia

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are thought to be the direct consequence of mutational events induced by chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities, given for a pre-existing condition. The outcomes for these patients have been poor historically compared to people who develop de novo AML. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-AML. Survival varies according to cytogenetic risk group in t-AML patients, with better outcomes being observed in those with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. A deeper understanding of the factors that predispose patients to the development of therapy-related myeloid leukemia would help clinicians monitor patients more carefully after treatment for a primary condition. Ultimately, this knowledge could influence initial treatment strategies with the goal of decreasing the incidence of this serious complication.

Etiology and Management of Therapy-Related Myeloid Leukemia

The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.