Risk Karyotype Research Articles

IDH1 Mutation Is an Independent Inferior Prognostic Indicator for Patients with Myelodysplastic Syndromes

Background: Genomic sequencing technologies have identified isocitrate dehydrogenase (IDH) mutations in haematological malignancies. The prognostic implications of somatic IDH mutation (mIDH) in myelodysplastic syndromes (MDS) remain controversial. Methods: Mutations in IDH1 and IDH2 were detected using genomic sequencing technologies in 97 patients with MDS. Results: Seven (7.2%) mutations were identified: 3 in IDH1 (all R132C) and 4 in IDH2 (3 R140Q and 1 R140L). The frequency of mutation was 16.6% (2/12) in refractory anaemia with excess blasts (RAEB)-1 and 14.7% (5/34) in RAEB-2. IDH1/2 mutations were closely associated with higher bone marrow blast counts (median 10.0 vs. 2.3%; p = 0.019) and lower absolute neutrophil counts (median 0.44 × 10⁹/L vs. 1.21 × 10⁹/L; p = 0.027). All IDH mutations were mutually exclusive and heterozygous. IDH mutations were not significantly correlated with any specific karyotype. Patients with IDH1 mutations exhibited shorter overall and progression-free survival (OS and PFS; p = 0.039 and p = 0.042, respectively), whereas IDH2 mutations did not affect OS or PFS (p = 0.560 and p = 0.218, respectively). Multivariate analysis indicated that IDH1 mutation (p = 0.018; hazard ratio [HR] 4.735; 95% confidence interval [CI] 1.299-17.264), karyotype risk (p = 0.036; HR 1.619; 95% CI 1.033-2.539) and the revised International Prognostic Scoring System risk category (p < 0.0001; HR 2.122; 95% CI 1.401-3.213) were independent inferior prognostic factors. Conclusions:IDH1 mutation is associated with a poor prognosis.

Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis.

Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. To assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for postsplenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 × 10(9)/L, 25% leukocyte count >25 × 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple-negative 6%. At median follow-up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median postsplenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 × 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR-weighted scoring system with high (3-4 risk factors), intermediate (2 risk factors) and low (0-1 risk factors) risk categories; the corresponding postsplenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2-11.0), 1.3 (HR 2.9, 95% CI 1.8-4.6) and 2.9 years. Postsplenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia-free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF.

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.

The Use of Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity ( 20%), BM blast percentage ( 20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Disclosures Podoltsev:Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Characteristics and Outcomes of Older Patients with Secondary AML According to Treatment Approach

BACKGROUND: Advanced age, AML arising from an antecedent hematologic disorder (AHD), and therapy-related AML (t-AML) are well established risk factors associated with poor outcome in AML. This subgroup of AML has been associated with lower rates of complete remission (CR) and shorter disease-free survival compared with de novo AML in younger patients (pts), when using standard therapy. Developing newer strategies to improve outcomes in this subgroup of pts is therefore a critical unmet need. Establishing baseline metrics from which to evaluate newer approaches is important. We sought to review our own experience with pts treated with different therapies at our institution to establish this baseline.METHODS: We retrospectively reviewed pts aged 60-75 years with newly diagnosed AML treated at our institution from 1990-2015 with one or more of the following characteristics: history of prior MDS, CMML, MPN, or aplastic anemia, the diagnosis of t-AML, or AML with karyotypic abnormalities characteristic of MDS as defined by the WHO. The pts were grouped into 5 study cohorts based on their treatment regimen: 1) High-dose Ara-C based intensive chemotherapy (HiDAC), 2) Hypomethylating agents (HMA)/HMA combinations, 3) Low-dose Ara-C combinations (LDAC), 4) Liposomal Ara-C:Daunorubicin (CPX-351), and 5) Other investigational agents (INV). Pts’ karyotypes were divided into 4 categories: adverse karyotype (complex: defined by >2 chromosomal abnormalities, Del 5/5q, Del 7/7q, 11q, 3q abnormality); diploid karyotype, intermediate karyotype (karyotype other than adverse or diploid); and unknown/not available. Endpoints included complete response (CR) rate/CR with low platelets (CRp) and 8-week mortality rates. Both univariate and multivariate analyses were performed to examine the relationships between disease characteristics and outcomes (CR, Overall survival).RESULTS: We evaluated a total of 931 pts with newly diagnosed AML meeting these criteria of age and secondary AML (s-AML). The baseline characteristics of pts in each group are summarized in table 1. The median age was 68 (60-75) years. Most pt characteristics were well balanced across the 5 treatment groups. Karyotyping was performed in 89% of the pts: 57.5% belonged to adverse risk profile and 31% belonged to intermediate risk profile (excluding diploid). The overall CR/CRp rates for the entire group was 39.5%. CR/CRp rates were lower in the HMA (36%) and INV (16%) groups compared to HiDAC (46%), CPX (45%) and LDAC (43%). Eight week mortality rate for the entire group was 20%: HiDAC (23%), HMA (12%), CPX (10%), LDAC (19%), and INV (27%). The median OS for the entire group was 6 months and by each treatment regimen is shown in Figure 1. There was a significant difference in OS between the 5 treatment groups. Pts receiving less intensive regimens [HMA + LDAC] had a superior median OS compared to those receiving HiDAC-based regimens (6.9 vs. 5.4; P=0.002, Figure 2). There was no difference in median survival in pts treated with CPX compared with conventional lower-intensity approaches (HMA + LDAC) (p=0.75). In the multivariate analysis, age >70yrs, adverse karyotype, and prior treatment for AHD were associated with a decreased OS. Similarly, use of HMA/INV treatment, adverse/intermediate risk karyotype, history of prior treatment for AHD were associated with lower CR rates.CONCLUSIONS: The outcomes of older pts with newly diagnosed s-AML are poor and reflective of their advanced age and poor-risk karyotype. Various treatment approaches have been attempted to improve outcomes. Lower-intensity approaches such as HMA and LDAC-based regimens have response rates similar to HiDAC regimens, but are associated with lower early mortality and improved overall survival. While the investigational liposomal formulation CPX-351was associated with favorable CR rates and low early mortality, the median OS was similar to pts treated with low intensity therapy. The unsatisfactory outcomes using other investigational agents in the INV group underscores the need for more effective therapies for these patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresKantarjian:BMS, Pfizer, Amgen, Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. DiNardo:Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding. Jain:Celgene: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Azacitidin Is Effective in the Therapy Related Myelodysplastic Syndrome.

Introduction:Myelodysplastic syndromes (MDS) are clonal hematopoietic neoplasms characterized by abnormal maturation of precursor cells which often translates into peripheral blood cytopenias and a high rate of transformation to acute myeloid leukemia (AML) due to accumulation of genetic alterations.The AZA-001 trial showed azacitidine (AZA) significantly prolonged median overall survival compared with conventional care regimens (24.5 vs 15.0 months; P=0.0001).AZA is standard first-line treatment for Intermediate-2 and High-risk myelodysplastic syndrome patients who are not immediate candidates for allogeneic stem cell transplantation, but this study included no cases of therapy related MDS (t-MDS).T-MDS is known to have poor prognosis, therefore it is very important to analyze the outcome of patients with t-MDS treated in the front-line with AZA.Methods: We studied newly diagnosed 29 MDS patients who were treated by AZA in our hospital from July, 2010 to April, 2016, retrospectively. AZA was given subcutaneously at 75 mg/m2 per day for 5 or 7 days every 28 days.Results: We analyzed 29 MDS patients. According to the WHO classification, there were 12 RA, 15 RCMD, 10 RAEB-1, 2 RAEB 2 and 1 MDS-U. The median age was 70 year (range 49-88), and men was 12 (41.3%). There were 12 de novoMDS cases (41.3%) and 17 t-MDS cases (58.6%). All of the t-MDS patients had previously received chemotherapy (17 patients, 100%) and 9 patients had also received radiotherapy (9 patients, 53%).Very poor risk group was 47.1% (9/17) in t-MDS group compared to 25.0% (3/12) in de novo MDS group (P=0.26).Median follow up time was 11.4 months (range 1.4-47.8). Twenty five patients (86.3%) were treated by AZA for 5 days. Four patients (13.7%) were treated by AZA for 7 days, but all 4 patients decreased the dosing period to 5 days due to unacceptable toxicity. AZA was given for a median of 4 cycles (range 1-33).In 29 MDS patients, 1-year overall survival (OS) was 60.5% (95% CI, 38.7-76.7%) and 1-year PFS was 40.1% (95% CI, 18.8-60.6%). After a median follow-up of 11.4 months, median OS was 18.7 months (95% CI, 9.4-21).One-year OS was 59.3% in t-MDS group compared to 63.6% in de novo MDS group (P=0.294). 1-year PFS was 38.4% in t-MDS group compared to 40.4% in de novo MDS group (P=0.626).One-year OS was 37.5% in very poor risk karyotype group (R-IPSS) compared to 74.6% in not very poor risk karyotype group (P=0.000748). 1-year PFS was 43.2% in very poor risk karyotype group compared to 39.0% in not very poor risk karyotype group (P=0.594).Focusing on t-MDS group, 1-year OS was 46.9% in very poor risk karyotype group (8/17 47%) compared to 74.1% in not very poor risk karyotype group (9/17 53%) (P=0.054). 1-year PFS was 48.0% in very poor risk karyotype group compared to 26.0% in not very poor risk karyotype group (P=0.339).Conclusions: In our study, 1-year OS in all MDS patients was 60.5%. It was slightly poor prognosis than 1-year OS in AZA-001 trial (about 70%).Our study include t-MDS cases (58.6%). Additionally, AZA was given for a median of 4 cycles in our study but 6 cycles in the AZA-001 trial. It showed severe patient's background of our study. These difference may cause the lower median OS and poorer prognosis.There trended to be more patients who had very poor risk karyotype in t-MDS group, but there was no significant difference between t-MDS and de novoMDS for the 1-year OS and PFS.Azacitidin is effective in the therapy related myelodysplastic syndrome. DisclosuresYokoyama:Chugai: Consultancy. Mishima:Chugai: Consultancy. Nishimura:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Kyowa Kirin: Honoraria, Research Funding; Chugai: Research Funding; Otsuka: Consultancy; Meiji-Seika: Consultancy.

Next-Generation Sequencing in Myelodysplastic Syndromes: Prognostic Interaction Between Adverse Mutations and IPSS-R

▪BackgroundIn a seminal report (NEJM 2011;30:2496), ASXL1, TP53, EZH2, ETV6 and RUNX1 mutations in myelodysplastic syndromes (MDS) were shown to carry an adverse prognostic impact that was independent of the international prognostic scoring system (IPSS) (Blood 1997;89:2079). Two recent studies (Leukemia 20 May 2016; doi: 10.1038/leu.2016.138; Leukemia. 2014;28:241) have proposed mutation-enhanced prognostic models that include the revised IPSS (IPSS-R) (Blood 2012;120:2454 ). In the current study, we applied targeted next generation sequencing (NGS) in order to examine the prognostic interaction between adverse mutations and IPSS-R.MethodsThe study population was recruited from our institutional database of patients with primary MDS, based on availability of archived DNA from the time of diagnosis. The diagnosis of MDS and leukemic transformation (LT) was made according to WHO criteria (Blood. 2009;114:937). Targeted capture assays were carried out, on bone marrow DNA specimens, for the following genes: TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1.Specific variants were deemed as mutations if they are associated with a hematologic malignancy (as identified by COSMIC database), or if they have not been associated with a dbSNP.ResultsPatient characteristics and type and number of mutations:179 patients were evaluated (median age 73 years; 68% males). IPSS-R risk distribution was 11% very high, 18% high, 16% intermediate, 39% low and 16% very low. At least one mutation was seen in 139 (78%) patients including 17% with one mutation, 29% with 2, 20% with 3, 10% with four, 2% with 5 and one patient with 6 mutations. The most frequent mutations were ASXL1 (30%), SF3B1 (20%), TET2 (17%), U2AF1 (16%) and SRSF2 (16%).Mutation clusters and clinical correlates:ASXL1 mutations were associated with the absence of SF3B1 (p=0.007), U2AF1 (p=0.01) and SRSF2 (p=0.003) mutations; SF3B1 with absence of U2AF1 (p=0.004) and SRSF2 (p=0.004) mutations; and U2AF1 with absence of SRSF2 mutations (p=0.01). Clinical correlates of ASXL1 mutations included older age, lower hemoglobin, and lower risk karyotype; SF3B1 with higher leukocyte count, higher platelet count, lower bone marrow blast percentage and lower risk karyotype; TET2 with older age and higher hemoglobin.Univariate overall and leukemia-free survival analysis before and after adjusting for IPSS-R:In univariate analysis, ASXL1, RUNX1 and TP53 mutations adversely and SF3B1 favorably affected survival; only ASXL1 mutations retained significance when analysis was adjusted for IPSS-R (HR 1.5, 95% CI 1.0-2.1; p=0.03). For leukemia-free survival, univariate analysis identified SRSF2, which was near-significant for overall survival (p=0.06), and RUNX1 mutations as adverse and SF3B1 mutations as favorable risk factors; SRSF2 (HR 4.1, 95% CI 1.6-10.2) and SF3B1-unmutated (HR 5.9, 95% CI 1.1-31.5) retained their significance when adjusted for IPSS-R. A borderline significance (p=0.07) indicating inferior survival for patients with three or more mutations was fully accounted for by the significant (P<0.0001) association between the presence of ASXL1 mutations and higher number of mutations.Multivariable analysis with individual IPSS-R variables:When the five IPSS-R variables (hemoglobin, platelets, absolute neutrophil count, bone marrow blast percentage and karyotype) were analyzed (both as continuous and IPSS-R-defined categorical variables) with each one of the aforementioned mutations with significant effect on overall or leukemia-free survival, only ASXL1 retained its significance for overall survival (HR 1.6, 95% CI 1.1-2.3) and SRSF2 (HR 5.2, 95% CI 2.1-13.3) for leukemia-free survival. Other IPSS-R variables that retained their significance for survival, in the presence of ASXL1 mutation status as a covariate, included hemoglobin level, platelet count and karyotype.Conclusions: In our cohort of 179 molecularly-annotated patients with newly-diagnosed primary MDS, ASXL1 and SRSF2 mutations were identified as IPSS-R-independent risk factors for overall and leukemia-free survival, respectively. The current study also suggests the need to re-evaluate currently established risk factors, in the context of prognostically-relevant molecular information. DisclosuresNo relevant conflicts of interest to declare.

CSF3R Mutations Are Predominantly Subclonal Events in Intermediate Risk Karyotype AML and Prevalently Occur with CEBPA Mutations

Background: The colony stimulating factor 3 receptor(CSF3R) plays an important role in granulocyte differentiation and acquired mutations have been described in different myeloid malignancies. Besides chronic neutrophilic leukemia (CNL) and severe congenital neutropenia (SCN), mutations in CSF3R (CSF3Rmut) have also been reported in acute myeloid leukemia (AML) at low frequency and recently have been associated with CEBPA mutations (Lavallèe et al., Blood 2016; Maxson et al., Blood 2016) in adult and pediatric AML. First studies suggest sensitivity of CSF3Rmut CNL against JAK kinase inhibitors suggesting the possibility for targeted therapy for a subset of CSF3Rmut AML patients.Aims: The evaluation of CSF3Rmut in AML with intermediate-risk karyotype for frequency and association with other mutations with special focus on CEBPA mutation status.Methods: We analyzed 274 cases with intermediate risk de novo AML for CSF3Rmut by next generation sequencing (Illumina, San Diego, CA) of exon 14 and 17 (sensitivity: 1%), which contain the mutational hotspot regions of CSF3R. As CSF3R mutations were associated with CEBPA mutations in the above-mentioned studies, we analyzed a selected cohort of 179 CEBPA mutated cases in comparison to 95 cases with CEBPA wild type.202 cases (74%) had normal karyotype (CN-AML) and 72 (26%) had intermediate-risk aberrant cytogenetics according to MRC criteria. Female/male ratio was 127/147 and age ranged from 16- 88 y (median: 64 y). Mutation status of the following genes were available in all cases: ASXL1, CEBPA, FLT3-ITD, FLT3-TKD, GATA2, IDH1/2, KRAS, KMT2A-PTD, NPM1, NRAS, RUNX1 and WT1. All mutations with a variant allele frequency (VAF) < 10% were defined as subclonal. 95 cases had wild type CEBPA (CEBPAwt), 92 cases were CEBPA single mutated (CEBPAsm), 81 cases were CEBPA double mutated (CEBPAdm), 6 cases showed CEBPA mutations withloss of heterozygosity (CEBPA LOH).Results: Overall, in 7/274 patients (3%) CSF3Rmut were detected. This is slightly higher than expected in an unselected AML cohort (Sano et al., Br J Haematol 2015). Cytomorphology revealed AML M0 (n=1), AML M1 (n=2), AML M2 (n=3) and AML M4 (n=1). With regard to immunophenotype CSF3Rmut cases did not differ from CSF3Rwt cases which may be due to limited case numbers. All CSF3Rmut cases had CN-AML. The activating transmembrane mutation p.Thr618Ile, which has been identified as common mutation in CNL was the most frequent mutation (4/7). In addition two mutations leading to a truncated receptor (p.Ser715* and p.Gln749*) and a previously not described frame-shift mutation leading to a defecting splice variant (p.Ser783Glnfs*6) were identified. The median CSF3R VAF was 7% (range 2-45%). In 5/7 cases, CSF3Rmut was subclonal (VAF <10%, see figure). CSF3Rmut cases showed a median of 2 concomitant mutations (range 1-4). The most frequent concomitantly mutated gene was CEBPA (5/7 cases; 2 cases CEBPAsm, 1 case CEBPAdm and 2 cases with CEBPA LOH), followed by NRAS (3/7), ASXL1 (2/7) and RUNX1 (2/7). IDH1, TET2 and WT1 were mutated in one case each (see figure). Mutations in NPM1, FLT3, KMT2A or GATA2 were never detected. Interestingly, in CEBPAdm and CEBPA LOH cases, CSF3R was the only concomitantly mutated gene, whereas CEBPAsm cases harbored mutations in at least 1 gene in addition to CSF3R. In 2/7 CSF3Rmut cases we analyzed changes in the patterns of genetic lesions between diagnosis and relapse. Case 1 harbored CEBPAdm and a subclonal CSF3Rmut (VAF: 7%) at diagnosis. At relapse the CEBPAdm persisted, whereas CSF3Rmut was lost. Case 2 harbored two germline CEBPAmut and one somatic CEBPAmut at diagnosis. In addition, mutations in CSF3R and WT1 were identified. At relapse both the somatic CEBPAmut and WT1mut persisted, whereas CSF3Rmut was lost. These results indicate again that the CSF3Rmut was present only in a subclone of CEBPAmut AML in both cases.Due to the limited number of CSF3Rmut cases, we did not perform survival analysis in this study.Summary: 1) CSF3R mutations are rare and predominantly subclonal events in AML and therefore may not be a suitable target for directed therapy.2) CSF3Rmut prevalently occur with CEBPA mutations but are not limited to CEBPAdm. [Display omitted] DisclosuresFasan:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Perglerová:MLL2 s.r.o: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Other: Part Owner MLL Munich Leukemia Laboratory.

Azacitidine (AZA) Prolongs Overall Survival in Older Patients with Acute Myeloid Leukemia (AML) with Poor Prognostic Karyotypes Compared with Conventional Care Regimens (CCR)

Azacitidine (AZA) Prolongs Overall Survival in Older Patients with Acute Myeloid Leukemia (AML) with Poor Prognostic Karyotypes Compared with Conventional Care Regimens (CCR)

Myelodysplastic Syndromes in Adolescent Young Adults: One Institution's Experience.

There has been little improvement in cancer survival of adolescent and young adult (AYA) patients, aged 18 to 39 years, possibly reflecting different disease biology. Myelodysplastic syndrome (MDS) is mainly a disease of the elderly. The characteristics, outcomes, and response to treatment are not well described in the AYA population. This was a retrospective review of patients from the Moffitt Cancer Center MDS database. We compared baseline characteristics and outcomes of the AYA population to older patients. We identified 51 AYA and 1897 older MDS patients. More female subjects and Hispanics were noted in AYA group. The AYA patients had higher risk disease, more circulating myeloblasts, and more hypoplastic MDS. Autoimmune disorders were more prevalent in older patients. The median overall survival (OS) was 47 months in the AYA group versus 40 months in the older group (P= .26). The median OS was 47 versus 56 months in lower risk AYA group and older group, respectively (P= .46). In the higher risk group, median OS was 82 months in the AYA group compared to 17 months in the older group (P= .001). Thirty individuals (59%) underwent allogeneic stem-cell transplantation in the AYA group versus 241 (13%) in the older group. The median OS for transplanted patients was 55 months in the AYA group and 46 months in the older group (P= .4). In the nontransplanted patients, median survival was 31 months for the AYA group and 39 months for the older group (P=.9). The rate of acute myeloid leukemia transformation was 37% versus 28% in the AYA and older groups, respectively (P=.17). No differences in use or response to hypomethylating agents were observed. Lenalidomide therapy was seldom used in AYA, as none presented with del5q. In AYA, poor karyotype was the only variable strongly associated with worse outcome. Fifteen patients had poor risk karyotypes (29%). The median OS was 47 months, not reached, and 29 months among patients with good, intermediate, and poor risk cytogenetics, respectively (P= .035). MDS is rare and tends to be more aggressive in the AYA population. Karyotype was the most important prognostic factor. Allogeneic stem-cell transplantation offered younger patients the best outcomes.

Abstract 3582: Chromothripsis in AML patients: A new mechanism of cancer initiation and progression

Abstract Introduction: Genomic rearrangements can drive the development of cancer through different mechanisms: chromothripsis, a catastrophic mechanism of genomic instability, could be relevant for hematological disease. Aim: To discover the mechanisms underlying the pathogenesis of Acute Myeloid Leukemia (AML), we studied chromothripsis in our cohort of patients (pts). Methods: We perform SNP Array 6.0 or Cytoscan HD Array (Affymetrix) in a cohort of 104 AML pts at diagnosis. SNP Array data were analyzed by Nexus Copy Number™ v7.5 (BioDiscovery). Results: Seven/104 pts (6.7%) showed chromothripsis events involving different chromosomes (8, 17, 11, 5 and 16). These pts had median age of 68.5 years (range 56-76), complex karyotype and high risk disease according to ELN definition. Among the pts showing chromothripsis, we compared chromosomic abnormalities of pts with de novo (5/7) and secondary (2/7) AML. De novo AML showed a prevalence of trisomy of chromosome 8 in a non-statistical way (4/5 vs 0/2), due to the low number of cases. However, we identified significant differences in the pattern of genes altered in the two groups. De novo AML had copy number gain of PEX1, ANK1, NCOA2, ESRP1, TPD52, ESRP1, ZFPM2 and MITF (p &amp;lt;0.047). In the secondary AML group we detected amplification of APC and deletions of FOXO1 and APP (p &amp;lt;0.047)with enrichment of WNT signaling pathway proteins (p &amp;lt;0.001). The pathways recurrently targeted by chromosomal alteration in de novo AML pts were protein acetylation, transcription factor and histone acetiltrasferase (p &amp;lt;0.001). Moreover, by comparing pts with and without chromothripsis, we identified several genes differentially altered between the 2 groups (p&amp;lt;0.001), including deletion of CYFIP2, TBCA, CRHBP, FNDC9, IQGAP2, TUB3 and GAS8 and amplification of ZFPM2 in pts with chromothripsis, with 5q being the main altered chromosomic region. The most significantly affected pathways in the chromothripsis group were cytoskeleton, microtubules formation, histone acetyltransferase and immune and antigen presentation response pathways (p&amp;lt;0.001). Conclusion: Our data suggest that different pathways and genomic alterations are involved in chromothripsis events in de novo and secondary AML, which could be explained by the repeated rounds of stress underwent by leukemic cells in secondary AML cases. Cytoskeleton and microtubules formation pathways appear to be the main cellular processes implicated in chromothripsis genesis, while alterations of histone acetyltransferase, immune response and antigen presentation pathways could sustain leukemic cells after chromothripsis. Acknowledgement: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12(L. Bolondi), FP7 NGS-PTL project. Citation Format: Maria Chiara Fontana, Viviana Guadagnuolo, Cristina Papayannidis, Giovanni Marconi, Giorgia Simonetti, Antonella Padella, Marco Manfrini, Barbara Santacroce, Margherita Perricone, Silvia Lo Monaco, Emanuela Ottaviani, Simona Soverini, Michele Cavo, Giovanni Martinelli. Chromothripsis in AML patients: A new mechanism of cancer initiation and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3582.

Impact on survival of catastrophic karyotype events in 101 consecutive acute myeloid leukemia (AML) patients: High risk karyotype and chromothripsis.

7044Background: Genomic alterations are proved to initiate cancer and related to prognosis in AML. We tested 101 consecutive AML patients (pts) at diagnosis to find prognostic implications of new g...

Impact of SNP array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for ∼80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (≥1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients.

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.

Mutations of cMYC Exon 2 Are a Rare but Recurrent Abnormality in Adult Patients with Acute Myeloid Leukemia (AML)

Next generation sequencing (NGS) has been extensively used to characterize the molecular background in patients with AML. Several novel recurrent alterations have been discovered, such as the common mutations in the IDH-genes and in DNMT3A. We aimed to use this technology to characterize patients failing induction chemotherapy. To better understand mechanisms of resistance, we applied whole exome based NGS screening in younger AML patients failing conventional induction chemotherapy. In a group of 29 patients, two patients showed mutations in cMYC exon 2. Similar mutations have been reported in diffuse large B-cell lymphoma (DLBCL), Burkitt 's lymphoma and aggressive HIV associated lymphomas. These alterations cluster in the aminoterminal part of the protein and lead to stabilization of the MYC protein, MYC activation and evasion of TP53 mediated tumor surveillance. MYC mutations have only occasionally been described in AML before, but amplification of cMYC or activation of this important oncoprotein via other cellular pathways has been linked to aggressive disease and resistance to treatment. So, in order to better understand the prevalence and the prognostic implications of cMYC mutations in adult AML, we screened a set of more than 1200 patients with AML and advanced MDS for the presence of mutations in the cMYC- gene. Patients and Methods: We retrospectively characterized genomic DNA samples taken at the time of first diagnosis from 1281 patients with AML treated in the AML96 protocol of the Study Alliance Leukemia (SAL). Since all reported mutations cluster in cMYC exon 2, this region was analyzed using conventional Sanger sequencing. In cMYC-mutated patients, a set of 54 genes (Trusight Myeloid Panel) covering commonly mutated genes in myeloid disease was analyzed for alterations using next generation sequencing (NGS) on a MiSEQ instrument. Results: An exon 2 mutation in cMYC was found in 14/1281 (1.1%) of the patients, all mutations clustered in the the MbI-domain between codons 57 and 62, with codon P59 being the most frequently mutated position. Analysis of the allelic burden indicated that the mutations occurred early in the disease. Correlation with clinical, cytogenetic and molecular data showed, that the mutations were predominantly found in patients with normal or intermediate risk karyotype, but they were also seen in good risk and high risk patients. Strikingly, 9 of 14 patients (77%) showed an NPM1-mutation (p=.004) and 7 of 14 (50%) were FLT3-ITD mutated (p=.02). The extended NGS-characterization did not reveal any additional specific secondary alterations associated with this mutation. MYC mutations were found in all FAB-subtypes excluding FAB M0, no significant differences were seen for other clinical variables, including age, sex, white blood cell and bone marrow blast counts. In univariate as well as multivariate analysis, patients with cMYC mutations did not show any significant difference in the rate of complete remission (CR), the event free and the overall survival, even when restricted to subgroups such as patients with normal karyotype or with NPM1 mutations. Conclusions: This study showed that mutations in cMYC exon 2 are a rare but recurrent abnormality in AML. The mutations are significantly enriched in patients with mutant NPM1 and FLT3-ITD, but based on our analysis, they seem not to have any prognostic implications. DisclosuresPlatzbecker:Boehringer: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Thiede:AgenDix GmBH: Equity Ownership; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Grouping of Genetic Risk By the European Leukemia Net Classification Predicts Overall Survival and Relapse Incidence in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction: In acute myeloid leukemia (AML) genetic risk factors are among the strongest predictors for overall outcome. Recently, the European Leukemia Net (ELN) proposed a revised classification based on the presence or absence of specific cytogenetic and/or molecular aberrations. Here, we evaluated the prognostic significance of this system in patients with AML undergoing allogeneic stem cell transplantation (alloSCT).Patients and Methods: A total of 363 patients transplanted at our center between 2004 and 2014 was retrospectively evaluated. According to the ELN classification genetic risk was favorable (N=51), intermediate-1 (N=120), intermediate-2 (N=98), or adverse (N=94). Remission status at the time of alloSCT was first complete remission (CR1) (N=204), CR>1 (N=61), or refractory (N=98). In 107 patients standard myeloablative conditioning (MAC) was used, whereas reduced intensity conditioning (RIC) was applied in 256 patients. Grafts were from either related (N=103) or unrelated (matched: N=191, mismatched: N=69) donors. The median age was 52 (range: 18-75) years.Results: For the surviving patients the median follow-up was 30 (range: 3-129) months. Whereas in the subgroup of patients aged ≥60 years (N=98) no significant differences in disease-free survival (DFS) or cumulative incidence of relapse (CI-R) between the 4 ELN subgroups were found, the ELN classification was highly predictive for in the subgroups aged <60 years. Patients with an adverse risk karyotype had significantly lower DFS as compared to patients with a favorable or an intermediate risk profile, i.e. 30% versus 56% for favorable, 52% for intermediate-1, or 59% for intermediate-2 (p=0.0064). Correspondingly, the CI-R was highest in patients with an adverse risk profile, i.e. 53% at 5 years. In turn, patients with favorable, intermediate-1, or intermediate-2 risk disease had a CI-R of 15%, 40%, or 21% (p<0.001). In the intermediate-1 subgroup, adverse outcome, i.e. relapse, was predominant in the group of FLT3-ITD positive patients, whereas the CI-R in patients lacking a FLT3-ITD was similar to what was observed in the intermediate-2 subgroup.Conclusions: Taken together, our data suggest that the ELN classification of genetic risk is suitable for predicting relapse and overall survival of patients with AML aged <60 years undergoing alloSCT. The adverse outcome of patients in the intermediate-2 subgroup may be related to presence of a FLT3-ITD. Therefore, further efforts are needed to improve the clinical results in this particular group. DisclosuresNo relevant conflicts of interest to declare.

The Prognostic Relevance of Comprehensive Risk Score Is Modulated By Therapy: Analysis of 292 Acute Myeloid Leukemia Patients Registered at the Genova Acute Leukemia Registry (REGAL)

Background, methods and aims of the study.It is widely established that the prognosis of patients with acute myeloid leukemia (AML) is related to clinical (age, denovo or secondary leukemia, presence of comorbidities), cytogenetic and molecular (e.g. FLT3-ITD, NPM1 gene mutation.) factors. We have developed a Comprehensive Risk Score (CRS) identifying three prognostic subgroups with favorable (low risk karyotype or intermediate karyotype + mutations of NPM1 gene without FLT3-ITD), unfavorable (high risk cytogenetics or FLT3-ITD without NPM1 mutation or secondary AML) and intermediate (including all the other patients not belonging to previous groups) prognosis. The clinical utility of CRS was tested on a cohort of 292 AML patients included in the REGAL registry, a regional Italian registry that was established in October 2010 at the University of Genoa.Results.Analysis of age distribution confirmed the increased incidence of AML in patients older than 60 years (n. 182, 62.4%). Patients with de novo or secondary AML were 210 (71.9%) and 82, (28.1%) respectively. Patients with significant and often multiple comorbidities at diagnosis were 131 (44.8%). Seventeen patients (6%) received only supportive therapy, 217 (74.3%) intensive induction regimens (mainly FLAG-Ida and 3+7), including 96% of patients with age below 60 years and 61% of those over the age of 60 years. Therapy with hypomethylating agents (azacitidine and decitabine) was given to 31 patients (10.6%).In the whole cohort of patients 24 months projected survival (OS) was 66% among 62 patients defined as low risk according CRS (median not reached), 37,9% among 118 intermediate risk patients (median 13.8 months) and 12,7% in 112 patients included in the unfavorable risk group (median survival 4.8 months) (p =0.000, Fig. 1).In patients aged younger than 60 years, OS of favorable and intermediate risk groups were similar (77% and 72% in 39 low risk and in 44 intermediate risk patients, respectively), whereas the outcome of 27 high risk patients was worse (OS 28.2%, median survival of 10,3 months, p 0.0001). In the group of elderly patients (> 60 years) the outcome of the intermediate group was rather similar to that observed in the poor risk group (OS 16% and 7% in 74 intermediate and in 85 poor risk patients, respectively, p n.s). On the contrary OS of 23 favorable risk patients was good (49%, p = 0.0015).Twenty-nine patients have actually received an allogeneic bone marrow transplant (BMT) during first CR (66% of 44 with indication) and 14 in second or third CR. The sources of stem cells have been HLA-identical and haploidentical sibling in 45% and 50% of patients, respectively.Discussion and conclusions.Our study suggests that the predictive value of CRS is clearly affected by the therapeutic strategy. Whereas the score allows the stratification of the whole cohort of patients in three groups with different outcome, in younger fit patients a more intensive therapeutic approach, such as the FLAG-IDA regimen and a wider use of allogeneic bone marrow transplantation made possible by the use of haploidentical donors, results in the super-imposable prognosis between favorable risk and intermediate risk patients.However, the same intensive approach cannot overcome the unfavorable features of the majority of high risk patients.In the elderly group median age and comorbidities prevent patients from receiving intensive induction therapy. Therefore, intermediate and unfavorable risk patients show a similar poor outcome. In elderly patients the achievement of a good outcome is related to disease status (denovo AML), favorable cytogenetic and molecular features, good performance status and administration of intensive induction and consolidation treatment, including BMT in selected cases. [Display omitted] DisclosuresCarella:Seattle Genetics Inc.: Research Funding.

Myelodysplastic Syndromes in Adolescent Young Adults (AYA)

Introduction:There has been little improvement in cancer survival of adolescent and young adult (AYA) patients, ages 18-39, possibly reflecting different disease biology in this subgroup. Myelodysplastic syndrome (MDS) is mainly a disease of the elderly. The characteristics, outcomes and response to treatment are not well described among AYA population.Patients and Methods:Retrospective review of patients from the Moffitt Cancer Center MDS database. We compared baseline characteristics and outcomes of AYA population to older patients. Descriptive statistics were used for baseline characteristics. Chi-square test was used for categorical variables, and t-test for continuous variables comparison. Kaplan-Meier estimates were used for overall survival (OS), and cox regression method for multivariable analysis.Results:We identified 51 AYA and 1,897 older MDS patients. Table-1 summarizes baseline characteristics. More females and Hispanics were noted in AYA group. The AYA patients had higher risk disease, more circulating myeloblasts and more hypoplastic MDS. Autoimmune disorders were more prevalent in older patients.The median OS was 47 months (mo) in the AYA group versus 40 mo in the older group (p 0.26). The median OS was 47 mo versus 56 months in lower risk (low and intermediate-1(int-1)) IPSS MDS AYA group and older group respectively (p 0.46). In the higher risk IPSS group (int-2 and high), median OS was 82 mo in AYA group compared to 17 mo in older group (p 0.001). Thirty individuals were transplanted in the AYA versus 241 in the older group. The median OS for transplanted patients was 55 mo in the AYA group and 46 mo in the older (p 0.4). Whereas, in the non-transplanted patients median survival was 31 months for AYA and 39 months for the older group (p 0.9). The rate of AML transformation was 37% versus 28% in AYA and older group respectively (p 0.17). No difference in use or response to hypomethylating agents was observed. Lenalidomide therapy was seldom used in younger patients.In AYAs, poor karyotype was the only variable strongly associated with worse outcome. Fifteen patients had poor risk karyotype. The median OS was 47 months, not reached and 29 months among patients with good, intermediate and poor risk cytogenetics, respectively (p 0.035)Conclusion:MDS is rare and tends to be more aggressive in the AYA population. The karyotype was the most important prognostic factor. The differences in underlying disease biology should be further explored. Allogeneic stem cell transplant offered younger patients best outcomes.Table 1Baseline characteristics of AYA and Older PatientCharacteristicAYA (18-39) (N= 51)Older Patients (> 39 years old) (N=1,897)P valueGenderFemale25 (49%)655 (34.5%)0.025RaceWhite Black Hispanic Other34 (66.7%) 2 (3.9%) 13 (25.5%) 2 (3.9%)1,736 (91.5%) 47 (2.5%) 57 (3%) 41 (2.2%)0.000t-MDSYes10 (19.6%)359 (18.9%)0.902WHO SubtypeRA RARS RCMD Deletion 5q RAEB-1 RAEB-2 AML CML MDS-U MDS/MPN3 (5.9%) 1 (2%) 22 (43.1%) 0 (0%) 11 (21.6%) 10 (19.6%) 0 (0%) 0 (0%) 1 (2%) 2 (3.9%)196 (10.4%) 151 (8%) 583 (30.8%) 51 (2.7%) 372 (19.7%) 336 (17.7%) 1 (0.1%) 60 (3.2%) 44 (2.3%) 94 (5%)0.188IPSSLower risk Higher risk28 (59.6%) 19 (40.4%)1,264 (68.2%) 590 (31.8%)IPSS-RVery low/low Intermediate High/very high13 (30.1%) 14 (32.6%) 16 (37.3%)826 (45.3%) 394 (21.6%) 602 (33%)Hypoplastic BMYes11 (23.4%)178 (9.8%)0.009LGL cloneYes0 (0%)159 (8.4%)0.033Autoimmune diseaseYes8 (15.7%)500 (26.4%)0.055KaryotypeGood Intermediate Poor24 (50%) 9 (18.8%) 15 (31.3%)1120 (60.4%) 300 (16.2%) 434 (23.4%)0.324Peripheral BlastsYes14 (29.8%)246 (13.2%)0.003RBC TransfusionDependent36 (70.6%)1274 (67.3%)0.372 DisclosuresShah:Seattle Genetics: Research Funding; Rosetta Genomics: Other: Grant support; Acetylon: Other: Advisory board; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Other: Advisory board, Speakers Bureau; Bayer: Honoraria; Celgene: Other: Advisory board, Speakers Bureau; DeBartolo Institute for personalized medicine: Other: Grant support. Lancet:Pfizer: Consultancy; Kalo-Bios: Consultancy; Boehringer-Ingelheim: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding.

Minimal Residual Disease (MRD) By Either Flow Cytometry or Cytogenetics Prior to an Allogeneic Hematopoietic Cell Transplant (allo-HCT) Predicts Poor Acute Myeloid Leukemia (AML) Outcomes

Introduction: Persistent AML is a known risk factor for poor outcomes after allo-HCT. The impact of MRD in patients who achieve complete remission (CR) or CR with incomplete count recovery (CRi) has been less well studied.Methods: We retrospectively reviewed the records of AML patients who underwent allo-HCT in morphological remission (<5% myeloblasts and normal marrow cellularity) with or without blood count recovery between January, 2000 and January, 2014. Data was collected for variables known to impact the prognosis of AML patients (Table 1). MRD was defined as evidence of abnormalities associated with AML by either flow cytometry, cytogenetics or Fluorescence in situ hybridization (FISH). The impact of MRD identified at the time of allo-HCT on cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) was assessed in MRD+ and MRD- patients.Results: A total of 166 eligible patients were identified. The median follow-up among living patients is 46 months (range, 13-103).Thirty seven (22%) patients had evidence of MRD (13 by flow cytometry only, 17 by cytogenetics/FISH only and 7 by both). MRD was more common in patients with poor risk karyotype at diagnosis and CRi at the time of allo-HCT (Table 1). PFS (P= 0.0016), OS (P=0.002), and CIR (P=0.02) were all significantly worse in MRD+ patients (Figures 1& 2). In univariate analysis, MRD+ patients, assessed by flow cytometry had worse PFS (P=0.0216) and OS (P=0.0314) compared to MRD- patients. Similarly patients with evidence of MRD+ by cytogenetics/FISH had worse PFS (P=0.007) and OS (P=0.0031). In a multivariate cox proportional hazards model 1) any MRD positivity prior to allo-HCT, 2) poor-risk karyotype at diagnosis, and 3) CRi at allo-HCT independently predicted significantly poor PFS and OS. Only poor-risk karyotype was associated with a significant increase in CIR, while MRD positivity showed a trend towards higher CIR.Conclusion: MRD positivity prior to HCT by either flow cytometry or by cytogenetics/FISH independently predicts adverse AML outcomes.Table 1Comparison of pre-transplant variablesCovariateLabelMRD + (N=37)MRD - (N=129)P-ValueAge(years)< 408 (21%)20 (16%)0.70840 - 5920 (53%)69 (54%)≥ 6010 (26%)39 (30%)Karyotype riskFavorable/ Intermediate19 (53%)95 (74%)0.011Poor18 (47%)33 (26%)Timing of Allo-HCT1st remission (CR1)28 (74%)97 (76%)0.792> CR110 (26%)31 (24%)Allo-HCT after1st relapse(>CR1): duration of CR1> 12 mo31 (82%)113 (88%)0.285≤ 12 mo7 (18%)15 (12%)Secondary AMLNo23 (60%)78 (61%)0.964Yes15 (40%)50 (39%)Complete remission vs CRiCR28 (74%)110 (86%)0.077CRi10 (26%)18 (14%)Conditioning RegimenAblative24 (63%)72 (56%)0.449Other14 (37%)56 (44%)Donor TypeMatched sibling donor12 (32%)42 (33%)0.887Other26 (68%)86 (67%)Female donor: male recipient (FDMR)Other28 (80%)91 (78%)0.844FDMR7 (20%)25 (22%) [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prospective Evaluation of Azacitidine Maintenance Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

▪Introduction and aim. Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is a major cause of treatment failure and is associated with a poor prognosis. Overall survivals are around 50% at 5 years following allogeneic HSCT in intermediate and high risk AML. Survivals remain less than 20% in poor-risk and very poor-risk patients based on the cytogenetic profile. Thus, prevention of relapse following allogeneic HSCT remains an unmet clinical need. Low-dose azacitidine maintenance post-HSCT has been shown to augment graft-versus-leukemia effect and may prolong survivals. We aim to prospectively evaluate the effect of azacitidine maintenance following allogeneic HSCT in high risk AML and MDS.Method. Consecutive patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in remission following first allogeneic HSCT or second allogeneic HSCT (from the original donor) were recruited. High risk AML in this study comprised patients with poor risk karyotype, secondary AML transformed from underlying MDS, presence of fms-like tyrosine kinase 3-internal tandem duplication (FLT3 -ITD) and non-remission before HSCT. Azacitidine was administered at 100mg daily for 3 days per cycle every 28 days until progression or a maximum of 8 cycles. The clinicopathologic and treatment characteristics were determined. The occurrence of graft-versus-host disease (GVHD) was determined. DNA chimerism was determined in the bone marrow before the initiation of azacitidine, after 4th and 8th cycles of azacitidine and at 1 year. DNA chimerism was determined by quantification of polymorphic short tandem repeat sequences. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier analysis.Results. Thirty-four patients with high-risk AML (N=31) and MDS (N=3) were recruited. The median duration of follow-up was 14 months (range: 2 - 44 months). Twenty-two patients received azacitidine maintenance after first allogeneic HSCT, whereas 12 patients received azacitidine maintenance after a second allogeneic HSCT from the same donor following relapse from a first allogeneic HSCT For patients receiving azacitidine after first HSCT, at a median follow-up of 18.5 months (range: 5- 36 months), the median PFS was not reached, and the median OS was 32 months (95% confidence interval [C.I.]: 24.85-39.15). The 24-month PFS and OS were 66.1% and 73.2% respectively. Acute and chronic GVHD occurred in 7 (31.8%) and 17 patients (77%). For patients receiving azacitidine after second HSCT, at a median follow-up of 14 months (range: 9 - 46 months), the median PFS and OS were 9 months (95% C.I.:6.94-11.04) and 14 months (range: 11.77 - 16.23 months). The 24-month PFS and OS were 25% and 14% respectively. Acute and chronic GVHD occurred in 1 (8.3%) and 5 (41.7%) patients respectively. In both groups, 100% donor chimerism was achieved during azacitidine maintenance.Conclusion. Azacitidine maintenance following first allogeneic HSCT resulted in favorable 2-year survivals in selected patients with high-risk AML and MDS. Nevertheless, survivals were poor despite azacitidine maintenance after second allogeneic HSCT from the same donor. Full donor chimerism was maintained during azacitidine maintenance. DisclosuresNo relevant conflicts of interest to declare.