Unfavorable Risk Group Research Articles

AML in Adults - An Update on Diagnosis, Risk Classification and Therapy

There are several changes in the revised WHO classification for acute leukemia. The latest version of the European Leukemia Network (ELN)-risk classification defines AML with mutations in RUNX1, ASXL1 or TP53 to fall in the unfavorable risk group. Consequently, the somatic molecular genetic testing at the time of initial diagnosis should encompass these before mentioned three genes next to the already routine testing of NPM1, CEBPA and FLT3-ITD. Several new innovative substances have been developed and approved for AML therapy. The multikinase inhibitor midostaurin is a new substance in the induction therapy for patients with FLT-3 mutated AML. CPX-351 (cytarabin and daunorubicin in liposomatic formulation in a defined molar relation) is a new option for therapy associated AML and AML with myelodysplastic changes. Enasidenib is a targeting drug for relapsed or refractory AML with IDH2 mutation. Gemtuzumab, a CD33 + antibody-drug-conjugate is approved for CD33 positive cases.

Pathway‐focused gene expression profiles and immunohistochemistry detection identify contrasting association of caspase 3 (CASP3) expression with prognosis in pediatric classical Hodgkin lymphoma

The search for clinically relevant molecular markers in classical Hodgkin lymphoma (cHL) is hampered by the histopathological complexity of the disease, resulting from the admixture of a small number of neoplastic Hodgkin and Reed-Sternberg (H-RS) cells with an abundant and heterogeneous microenvironment. In this study, we evaluated gene expression profiles of 11 selected genes previously proposed as a molecular score for adult cHL, aiming to validate its application in the pediatric setting. Assays were performed by RT-qPCR from formalin-fixed paraffin-embedded (FFPE) lymph nodes in 80 patients with cHL. Selected genes were associated with cell cycle (CENPF, CDK1, CCNA2, CCNE2, and HMMR), apoptosis (BCL2, BCL2L1, and CASP3), and monocytes/macrophages (LYZ and STAT1). Despite using controlled preanalytical and analytical strategies, we were not able to validate the 11-gene score to be applied in pediatric cHL. Principal component analysis (PCA) disclosed 3 components that accounted for 65.7% of the total variability. The second PC included microenvironment and apoptosis genes, from which CASP3 expression was associated with a short time of progression-free survival, which impact was maintained in the unfavorable risk group, Epstein-Barr virus-negative cases, and multivariate analysis (P<.05). Because this is a counterintuitive association, CASP3 active expression was assessed at the protein level in H-RS cells by double immunohistochemistry. In contrast to the association of mRNA levels with a poor therapeutic response, a high number of cleaved CASP3+ cells were associated with longer progression-free survival (P=.03) and overall survival (P=.002). Our results demonstrate the feasibility of using FFPE samples as RNA source for molecular prognostication, but argue against the concept of direct and wide applicability of molecular scores in cHL. We reinforce the potential of CASP3 as an interesting target to be explored in adult and pediatric cHL, and alert for its dual biological role in H-RS cells and tumor microenvironment.

THE EFFICACY OF HIGH-DOSE CONSOLIDATION AND AUTOLOGOUS BONE MARROW TRANSPLANTATION IN FIRST REMISSION OF ACUTE MYELOID LEUKEMIA

Introduction. The question of the most adequate treatment strategy of AML in cases when it is impossible to perform allogeneic HSCT because of any reason still remains open. The aim of this study was to assess the long-term survival of patients with AML who received chemotherapy (CT) or autologous HSCT as consolidation in the first remission of the disease. It was included 135 patients aged 18 to 67 years, with a verified diagnosis of AML (except FAB M3) in the study. Of these, 100 patients received only CT, 35 patients received consolidation with autologous bone marrow transplantation. Patients who achieved remission after completion of induction CT courses received one of three treatment options as consolidation: 1) chemotherapy of standard-intensity (sCT), 2) high-dose chemotherapy (HDCT), 3) autologous HSCT (autoHSCT) conducted after 1–2 courses of high-dose CT. Adverse prognostic factors were identified as: age over 40 years, hyperleucocytosis more than 50,0 × 10 9/L and unfavorable cytogenetic and molecular-biological risk group. Materials and methods. Depending on the number of prognostic factors at the onset of disease relapse-free survival (RFS) was 47 % in their absence, 45 % in the presence of 1 factor, in the presence of 2 factors – 14 % (p = 0,000), regardless of the variant of consolidation therapy (sCT, HDCT, autoHSCT). A high level of white blood cells adversely affects OS (38 % vs. 22 %) and increases the frequency of relapse (52 % vs. 69 %) when performing only CT (sCT and HDCT). At initial white blood cells level more than 50,0 × 10 9/L the 5-year OS was 60 % when performing both autoHSCT and HDCT. Performance of autoHSCT at failure to achieve remission after the 1st induction course CT is associated with the best 2-year OS (62 % vs. 35 %, p = 0,05), EFS (50 % vs. 22 %, p = 0,05) and RFS (50 % vs. 37 %, p = 0,05) in comparison with HDCT and sCT. In favorable cytogenetic risk group 5-year RFS was 80 % when performing autoHSCT and 67 % when performing HDCT; the 5-year OS was 80 % regardless of consolidation therapy option. Conclusion. AutoHSCT is the preferred consolidation option in favorable risk group patients, and after failure to achieve remission after the 1st CT course.

Frontline treatment of AML in adults.

Despite recent progress in diagnosis and leukemogenesis based on genomic landscapes in acute myelogenous leukemia (AML), advances in AML treatment lag behind. Over the past four decades, combination chemotherapy with anthracycline and cytarabine remains the standard induction therapy. Subsequent post-remission consolidation therapy stratifies patients into favorable-risk, intermediate-risk, and unfavorable-risk groups to assign post-remission therapies based on cytogenetic abnormalities and molecular mutations. Allogeneic stem-cell transplant decreases the risk of AML recurrence compared to standard chemotherapy, but it also raises the risk of serious complications. Recent large collections of matched genomic and clinical data may assist in selecting the best individualized therapy for each AML patient. Emerging evidence indicates that molecularly targeted therapies such as FLT3 and IDH inhibitors may be effective in distinct AML subtypes, providing further rationale for a personalized medicine approach. An umbrella trial, such as "BEAT AML Master Trial," designed to offer novel targeted therapy to AML patients based on their genetic characteristics, will be launching worldwide in the near future.

Limited impact of intratumour heterogeneity on molecular risk assignment in endometrial cancer.

IntroductionIndividual prediction of tumour behaviour based on molecular markers may refine adjuvant treatment strategies in endometrial cancer (EC). As these molecular alterations are determined in a small tumour fraction, high intratumour heterogeneity may interfere with correct risk prediction. This study aimed to investigate to which extent intratumour heterogeneity exists for molecular markers and whether it affects the molecular risk assignment in EC.MethodsForty-nine ECs (three tumour blocks/case) were selected with alterations in POLE (n=10), CTNNB1 (n=8), p53 (n=10), mismatch repair (n=11), L1CAM (n=10), and ECs without any of these markers (n=9). Nine ECs carried more than one molecular marker. All 147 blocks were analysed for POLE exonuclease domain and CTNNB1 exon 3 mutations, and for p53, mismatch repair and L1CAM protein expression. All blocks were assigned to a favourable, intermediate or unfavourable risk group, based on a molecular risk assignment.RESULTSConcordance between the three tumour blocks for POLE and CTNNB1 mutational status, and p53, mismatch repair and L1CAM protein expression was found in 100% (48/48), 95.9% (47/49), 93.9% (46/49), 98.0% (48/49), and 91.8% (45/49) of tumours, respectively. These discordances were found in a total of nine cases (18.4%). The intratumour heterogeneity impacted the risk assignment in five cases (10.2%).ConclusionIntratumour heterogeneity of prognostic molecular markers in EC without morphologic heterogeneity is uncommon among three tumour fractions, affecting the molecular risk allocation in a limited number of cases. This low intratumour heterogeneity facilitates the implementation of the molecular risk assignment, advocating its use in clinical decision making.

Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia.

Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making. The recent advances in clinical genomics have led to the recategorization of CN-AML into favorable or unfavorable subgroups. The relapsing nature of AML is thought to be due to clonal heterogeneity that includes founder or driver mutations present in the leukemic stem cell population. In this article, we summarize the clinical outcomes of relevant molecular mutations and their cooccurrences in CN-AML, including NPM1, FLT3ITD, DNMT3A, NRAS, TET2, RUNX1, MLLPTD, ASXL1, BCOR, PHF6, CEBPAbiallelic, IDH1, IDH2R140, and IDH2R170, with an emphasis on their relevance to the leukemic stem cell compartment. We have reviewed the available literature and TCGA AML databases (2013) to highlight the potential role of stem cell regulating factor mutations on outcome within newly defined AML molecular subgroups.

Phase II Results of Ara-C and Idarubicin in Combination with the Selective Inhibitor of Nuclear Export (SINE) Compound Selinexor (KPT-330) in Patients with Relapsed or Refractory AML

Background Acute myeloid leukemia (AML) is one of the most common leukemia’s affecting adults. Although 70-80% of patients achieve a complete remission (CR), patients with AML who fail to achieve a CR after the first cycle of induction therapy and those with relapsed disease have a bleak prognosis. Currently no standard regimen exists for the treatment of patients with relapsed AML and a great clinical need exists for new treatment options. Selinexor, an oral first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 mediated nuclear export to induce cytotoxicity in cells with genomic damage such as tumor cells. In Vivo model with selinexor alone or combination with AraC significantly prolonged the survival of leukemic mice from a median survival of 24 days (APL + vehicle) to 39 days, respectively (P < 0.0001). Combination therapy prolonged survival (P < 0.0001), with some mice being cured of the disease. Phase I clinical study demonstrates encouraging results in AML patient. The role of selinexor as a mono therapy is currently under investigation in phase II. Aims This phase II trial explores the efficacy & tolerability of Ara-C and idarubicin in combination with selinexor in patients with relapsed or refractory AML. Methods Patients with relapsed/refractory AML are treated with Ara-C (100 mg/m2, continuous infusion, day 1-7), idarubicin (10 mg/m2, day 1, 3, 5) every 4 weeks. In the majority of the patients selinexor is administered twice weekly orally starting on day 2 (40 mg/m2). A small cohort of patients received selinexor after registration and before first induction cycle for correlative studies. The primary endpoint is percentage of patients achieving a complete response or complete remission without normalization of peripheral blood counts (CRi). Other endpoints are partial response rate, percentage of patients undergoing subsequent allogeneic stem cell transplant, early death rate, overall survival (OS), event-free survival and toxicity. Results As of 20-April-2015, 18 patients with AML have been enrolled in 3 sites. Informed consent was obtained from all patients. Median age was 56 years. Out of 18 patients, 17 patients received ≥ 1 induction and 15 patients (9 male, 6 female) were evaluable for efficacy at the time of analysis. In average, patients received 2.4 therapies prior to study start. Overall response rate was 53% (13% of patients achieved CR, 40% of patients achieved CRi). Stable disease was observed in 13% of patients. Sixty-seven percent of patients received or were planned for stem cell transplant or donor lymphocyte infusion. Drug related AEs comprised 61% of all CTC Grade 3/4 and 46% of all CTC Grade 1/2 events. Grade 3/4 drug related adverse events (AEs) include febrile neutropenia (71%), diarrhea (71%), anorexia (57%), thrombocytopenia (43%), leukopenia (43%), anemia (29%) and nausea (29%). Grade 1/2 drug related AEs include: diarrhea (86%), vomiting (71%), nausea (71%), anorexia (43%), constipation (43%), fatigue (29%) and oral mucositis (29%). No drug-related deaths occurred. Summary The prognosis of relapsed/refractory AML patients is remarkably poor. Our findings suggest that treatment with Ara-C and idarubicin in combination with selinexor might be a potentially effective strategy for patients with relapsed/refractory AML without unexpected toxicities. Most common AEs were of low CTC grade.

Impact of Duration of Neutropenia and Lymphopenia on AML Patients Undergoing Induction Chemotherapy

Background:Various demographic, clinical and cytogenetic factors have been shown to affect the outcome of patients with acute myeloid leukemia (AML). Some of these risk factors are well-described with performance status and patient age being principal predictors of early death while cytogenetic and molecular factors allow stratification into prognostic categories. However, several critical factors have not been adequately assessed. Typically AML patients treated with standard induction chemotherapy will have cytopenias requiring intervention. Often the neutropenia is prolonged and results in neutropenic fevers and a high risk of infections. We hereby describe a single institution retrospective analysis at the University of Oklahoma Health Sciences Center (OUHSC) in which we evaluate the effect of duration of days with at risk absolute neutrophil (ANC) and absolute lymphocyte counts (ALC) and the occurrence of neutropenic fever on survival and response rates of AML patients.Methods:This is a retrospective chart review of AML adult patients who were diagnosed and treated at OUHSC between 2000 and 2014 and were undergoing initial induction chemotherapy. Outcomes of interest were overall survival (OS), event free survival (EFS: in case of relapse or death) and complete response (CR). Variables of interest wereneutropenic fever, and duration of decreased ANC and ALC counts (ANC<500, ANC<100, ALC<500, ALC<100). Institution policy did not allow granulocytes colony stimulating factors use because of the interference with bone marrow aspirate results. Nonetheless it was rarely used in few cases of septic shock, so this variable was not included in this analysis. Descriptive and bivariate analyses were conducted to evaluate the variables of interest and the outcomes.Models were used to assess the relationship between the variables of neutropenic fever, duration of decreased counts (ANC<500, ANC<100, ALC<500, ALC<100) and the outcome of interest after adjusting for age, race, gender, risk group andwhite blood count (WBC). Multivariable Cox proportional hazard models were used for OS and EFS and multivariable logistic regression models were used for CR. SAS 9.4 was used for all analyses. An alpha of 0.05 was used.Results:A total of 153 patients were analyzed. Mean age was 50 years, 35.7 % female, 64.3% male. Based on cytogenetics 16.9% were in favorable category, 28.6% in intermediate, 25.3% in unfavorable risk group, and 29.2% unknown. Mean number of weeks with ANC <500 was 3.58 (25 days), ANC <100 was 2.81 (20 days), ALC < 500 was 4.47 (31 days), ANC <100 was 3.24 (23 days). Incidence of neutropenic fever was 86.9%. Total number of positive cultures was 55.2%, of which 78.3% were bacterial, 25.3% fungal and 7.7% viral.After adjustment for age, race, gender, WBC and risk group, both neutropenic fever and duration during which ANC < 100 were associated with worse OS (p value <0.05) while duration of ANC< 500 was not significant (p value < 0.0576). When we considered EFS, the duration where ANC<500, ANC <100, and neutropenic fever occurrence were significant (p value <0.05).The hazard ratio of death is 3.15 for those with neutropenic fever compared to those without.With regard to CR, duration of ANC < 100 was significant (p value 0.0272). The duration of ALC <500 or <100 was not significant for OS nor EFS. Examining duration of neutropenia, for every week with ANC <500, there was a 9% higher hazard ratio of death after adjusting for other covariates.Conclusion:In this single-institution, retrospective study, we identified that the duration of neutropenia along with the presence of neutropenic fever during induction therapy adversely affected OS and EFS. Shorter duration of neutropenia significantly correlated with CR. Duration of days with ALC count <500 was not predictive of OS nor EFS. Larger studies are needed to examine the prognostic significance of neutropenia duration and its relationship to OS and CR. Neutropenia duration during induction chemotherapy may be an important risk factor in making decisions regarding future treatments including allogeneic transplant tolerability and aggressiveness of consolidation chemotherapy.It is important to look at this variable in more intensive induction regimens (using higher dose of cytarabine or adding a nucleoside analogue) as prolonged neutropenia may be a marker of poor general health rather than the induction regimen. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk-Adjusted Therapy of Acute Lymphoblastic Leukemia Can Optimize the Indication of Stem Cell Transplantation and Cranial Irradiation: Results of Japan Association Childhood Leukemia Study Group (JACLS) Protocol ALL-02

BACKGROUNDThe trial JACLS ALL-02 for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in unfavorable-risk groups by treatment intensification. These aims were pursued through a refined stratification strategy using white blood cell count, age, immunophenotype, unfavorable genetic aberrations, and treatment response providing an excellent discrimination of risk groups. PATIENTS AND METHODSBetween April 2002 and March 2008, 1252 children with newly diagnosed de novo ALL with 1-18 years of age were enrolled to JACLS ALL-02 trial. Ph+ALL, mature B-ALL, and NK-leukemia were excluded. Patients with BCP-ALL were stratified into 3 groups: standard-risk (SR), high-risk (HR), extremely high-risk (ER), based on initial prednisolone (PSL) response and the modified National Cancer Institute(NCI) workshop criteria. Prednisolone poor response (PPR) was determined after 7 days of monotherapy with prednisone and one intrathecal dose of methotrexate. PSL good responders (PGR; < 1,000 blasts/microL) were divided into SR and HR according to the modified NCI workshop criteria by WBC 10K and age 10, and received conventional therapy. BCP-ALL with PPR (≥ 1,000 blasts/microL) or t(4;11), and acute mixed lineage leukemia/ acute unclassified leukemia were assigned to ER and received intensified post-induction therapy . Patients with T-ALL were treated by a specific protocol that was different from the protocol used for BCP-ALL. Bone marrow response was also evaluated in aspiration smears on day 15 and 33 of induction treatment, and those who had slow early bone marrow response, defined as an M3 marrow on day 15 or M2/3 marrow on day33, shifted to the higher risk and received augmented post-induction therapy. Cranial irradiation was restricted to patients with initial central nerve system involvement or T-ALL with high WBC (≥10K) at diagnosis. Alternatively, protracted TIT was given during induction, intensification and maintenance depending on the risk group (12 doses in SR/T and 15 in HR/ER). Slow early responders who had an M3 marrow on day 15 in ER/T or M2/3 marrow on day33 in any risk, underwent to stem cell transplantation (SCT). PPRs without slow early bone marrow response underwent to SCT only if a matched sibling donor was available. The probability of event-free survival (EFS) and overall survival were constructed using the Kaplan-Meier method. Events in the analysis of EFS included induction failure, death, relapse and secondary malignant neoplasm. All statistical analyses were done according to intent-to treat methods. RESULTSEstimated 4-year EFS and OS for all 1252 patients was 83.7% (SE=1.1) and 90.3% (SE=0.89), slightly better in EFS than the former study (ALL-97; 79.3%, SE=1.7, p=0.054). The SR group (N=457, 37%) achieved excellent 4-year EFS of 90.4% (95%CI: 87.2, 92.7) and 4-year OS 97.3% (95.3, 98.5); in SR without slow early bone marrow response, patients with hyperdiploid and triple trisomy showed excellent 4-year EFS/OS of 100%. In the HR group (N=542, 43%), the estimated 4-year EFS and 4-year OS were 84.9% (81.5, 87.7) and 89.3% (86.3, 91.6), respectively; older age (≥ 6 years) was predictive for inferior OS (hazard ratio=1.14, p<0.0001), and ETV6-RUNX1 was predictive for favorable OS (HR=0.182, p<0.03). In the ER group (N=139, 11%), intensification of consolidation treatment using high-dose dexamethasone and AML-oriented agents led to considerable improvement yielding a 4-year EFS of 74.1% (66.0, 80.6) and a 4-year OS of 87.0 (80.2, 91.6). In T group (N=107, 8%), the dose reduction of L-asparaginase and anthracyclines compared with the ALL-97 resulted in inferior outcome in 4-year EFS 65.1% (54.9, 73.6), but not in 4-year OS 83.2% (74.6, 89.1), although the incidence of pancreatitis decreased. In non-T-ALL, The 5-year cumulative risk of an isolated and total CNS relapse was lower in ALL-02 than in ALL-97 (isolated CNS relapse: 0.8% vs 2.7%, p=0.017, total CNS relapse: 1.4% vs 4.5%, p=0.01). The proportion of CRT and SCT were 2%, 8% in ALL-02 respectively, whereas 31%, 11% in ALL-97 respectively. CONCLUSIONSRefined stratification and risk-adjusted therapy in the JACLS ALL-02 trial can bring about the abolition of prophylactic CRT in non-T ALL and the optimized indication of SCT without compromising the treatment results. DisclosuresNo relevant conflicts of interest to declare.

Prognostic relevance of pretransplant Deauville score on PET-CT and presence of EBV DNA in patients who underwent autologous stem cell transplantation for ENKTL.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) for extranodal natural killer/T-cell lymphoma (ENKTL) is a reasonable option for a subset of patients. The impact of response status, according to positron emission tomography/computed tomography (PET/CT) results and/or presence of circulating EBV DNA prior to ASCT, has not yet been established. We analyzed 27 ENKTL patients with pre-ASCT circulating EBV DNA who had undergone pre-ASCT PET/CT between 2009 and 2014. We classified patients into two groups based on the result of pretransplantation assessment: a favorable risk group (pretransplant five-point Deauville score (DS) of 1-2 based on PET/CT and no detectable EBV DNA) and an unfavorable risk group (DS 1-2 with detectable EBV DNA, DS 3-5 with or without detectable EBV DNA). After a median follow-up of 37 months, overall survival and PFS were significantly different between the two groups (median OS: not reached for favorable risk group vs 7.0 months for unfavorable risk group, P=0.017; median PFS: 16.0 vs 5.0 months, P=0.019). Multivariate analysis revealed that pre-ASCT DS and EBV DNA was the only independent prognostic factor considering stage, IPI and NKPI. Precise assessment of the status of disease before transplantation may provide more benefit from ASCT to ENKTL patients.

Acute myeloid leukaemia: expression of MYC protein and its association with cytogenetic risk profile and overall survival.

Acute myeloid leukaemia (AML) is a clinically aggressive disease with marked genetic heterogeneity. Cytogenetic abnormalities provide the basis for risk stratification into clinically favourable, intermediate, and unfavourable groups. There are additional genetic mutations, which further influence the prognosis of patients with AML. Most of these result in molecular aberrations whose downstream target is MYC. It is therefore logical to study the relationship between MYC protein expression and cytogenetic risk groups. We studied MYC expression by immunohistochemistry in a large cohort (n = 199) of AML patients and correlated these results with cytogenetic risk profile and overall survival (OS). We illustrated differential expression of MYC protein across various cytogenetic risk groups (p = 0.03). Highest expression of MYC was noted in AML patients with favourable cytogenetic risk group. In univariate analysis, MYC expression showed significant negative influence of OS in favourable and intermediate cytogenetic risk group (p = 0.001). Interestingly, MYC expression had a protective effect in the unfavourable cytogenetic risk group. In multivariate analysis, while age and cytogenetic risk group were significant factors influencing survival, MYC expression by immunohistochemistry methods also showed some marginal impact (p = 0.069). In conclusion, we have identified differential expression of MYC protein in relation to cytogenetic risk groups in AML patients and documented its possible impact on OS in favourable and intermediate cytogenetic risk groups. These preliminary observations mandate additional studies to further investigate the routine clinical use of MYC protein expression in AML risk stratification. Copyright © 2016 John Wiley & Sons, Ltd.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias with Hyperdiploid Karyotype

Aim. To evaluate the prognostic impact of the different cytogenetic characteristics, including the modal number, the number of chromosomal aberrations in a complex karyotype, and adverse chromosomal abnormalities (ACA) (-7/7q-, -5/5q-, -17/17p-, t(6; 9)(p22; q34)) on the results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hyperdiploid acute myeloid leukemia (H-AML). Methods. Forty seven H-AML patients (21 women and 26 men, aged from 1 to 58 years, median - 23.9 years) were examined. The analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed. Results. The modal number of chromosomes (MN) of 4748 was the most common one in the karyotype which was observed in 31 (66 %) patients. High hyperdiploidy with the modal number of 49-65 was identified in 13 (28 %) patients, near-triploid and near-tetraploid karyotypes were found in 3 (6 %) patients. Quantitative chromosomal abnormalities were nonrandom. Chromosome 8 (50 %), 21 (32 %), 13 (16 %) and 22 (16 %) trisomy was the most common one. Structural chromosomal abnormalities were detected in 22 (47 %) patients, at that, ACA were found in 7 (19 %) patients. In univariate analysis, the OS and EFS after allo-HSCT differed in patients with different clinical status (remission vs. active disease; p = 0.003 and p = 0.002, respectively), different chromosomal abnormalities in hyperdiploid karyotype (ACA- vs. ACA+; p = 0.001 and p = 0.03, respectively). An additional analysis of selected patients group with a structurally complex karyotype (n = 19) showed, that patients without ACA had a higher OS than patients with ACA (p = 0.03). In multivariate analysis, the disease status (relapse) at allo-HSCT was an independent predictor of decreased OS and EFS (p = 0.004 и p = 0.006, respectively), as well as the presence of the ACA (p = 0.002 only for OS). Conclusion. ACA were high-risk factors in H-AML patients received allo-HSCT. Therefore, the patients with formal criteria of a complex karyotype should not be automatically included in the cytogenetic unfavorable risk group.

Prerequisites to improvement of predictive model of childhood Hodgkin’s lymphoma

Background. Calculation of relative tumor burden in Hodgkin’s lymphoma patients is the simplest and significant parameter which can be used in daily clinical practice as a risk factor. The aim of study was the assessment of influence of relative tumor burden on the late results of a disease. Material and methods. This research included data on 126 patients with Hodgkin’s lymphoma aged from 0 till 18 years (middle age of 11 years), treated risk-adapted treatment according to the DAL-HD and SPBLH-05. Boys was 70, girls - 56 (a ratio 1,25 : 1). Fifty-eight patients (46 %) are stratified in favorable risk group, 50 (39,7 %) - in intermediate risk group, and 50 (39,7 %) are included in unfavorable risk group. Results. Overall survival at 5 years was 93 % (range 91-95 %), event-free survival - 88 % (85-91 %). The average relative tumor burden was 129,4 cm3/m2 (7-609,7 cm3/m2). When carrying out ROC-analysis value of 122,7 cm3/m2 (р ˂ 0,0001) appeared the critical parameter, which worsen the prognosis of a disease. Overall survival in a patients cohort with this volume was 69,6 %, with the volume less than 122,7 cm3/m2 overall survival was 97,2 % (р = 0,00002). Conclusions. The relative tumor burden is the parameter which is significantly reducing survival rates in children with Hodgkin’s lymphoma. Opinion on interrelation of clinical and laboratory parameters with “sarkoma’s saturation” or tumor volume as end result of immunological frustration, it is represented the most perspective direction of studying of Hodgkin’s lymphoma.

Prognostic Significance of Weight Loss and BMI during Induction Chemotherapy of Newly Diagnosed Acute Myeloid Leukemia (AML) Patients

Background: A wide landscape of factors exists to stratify the prognosis of patients with newly diagnosed AML including age, race, cytogenetics, and functional status. However, weight loss and malnutrition have yet to be fully evaluated as possible prognostic indicators for the patient with AML.Aim: This study aims to 1) investigate how weight loss and nutritional markers (BMI and albumin) change over the course of treatment and 2) their prognostic significance in terms of overall survival (OS) and complete remission (CR) in patients with newly diagnosed AML.Methods: We retrospectively analyzed patients from January 2000 to June 2012 diagnosed with AML over 18 years of age, who were treated at OUHSC with induction chemotherapy. 215 AML patients were identified. BMI and albumin levels were examined using mean plots over 3 time points. Patients treated before 2005 were eventually excluded due to the poor documentation of the height and weight. A total of 121 patients had BMI measurements for the first 2 time periods, while 89 had BMI measures at all 3 time periods. Simple descriptive statistics were created for all covariates [mean and SD for continuous covariates; n (%) for categorical variables]. For aim 1, to evaluate changes in BMI and albumin over time, mixed models were used including age (<60 years and ≥ 60 year) and gender.To examine aim 2, a Cox proportional hazards model was used to assess the univariate association of each covariate with survival. A final model was then created using all covariates from the univariate models with p-values <0.25. All two-way interactions with BMI group were explored. Binary logistic regression models were created to examine the association of each covariate with CR. BMI was categorized into two groups according to increase or decrease in BMI over time period.Results: Among the 121 patients mean age was 53 years (range 16 to 89 years). BMI (mean 29.85, 28.75, and 27.9 across the three time points) and albumin (mean 3.30, 3.21, and 2.55 across the three time points) both decrease over time and these changes were not different by age or gender. For OS, a significant interaction between cytogenetic risk group and BMI group was identified; therefore, patients were stratified by these risk groups. Age (p=0.0012) was found to be a more significant prognostic indicator than BMI group in the unfavorable risk group. Among patients in the intermediate cytogenetic risk group, BMI group (p=0.0210) was significantly associated with OS; those with increased BMI have 2.38 times the hazard of death relative to those with a BMI decrease, adjusting for age group. BMI group is not significantly associated with OS in any other model. Albumin was not associated with OS in any model.Conclusion: Age was found to be a more significant prognostic indicator than BMI in the unfavorable risk group, and BMI increase was found to have an increased hazard of death in the intermediate risk group. Further studies are needed to examine the prognostic significance of weight loss during induction chemotherapy. 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.

Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients in First Complete Remission: Significant Impact of the Interval Between Diagnosis and Transplantation on Different Outcomes

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic option for most patients with high risk acute myeloid leukemia (AML). In order to determine whether time between diagnosis and allo-HSCT could have any impact on transplant outcomes, we screened 700 consecutive adult AML patients diagnosed between January 2007 and June 2014 at the Lyon Sud Hospital transplant center. Inclusion criteria were: (1) newly diagnosed AML in patients with age ≤ 65 years, (2) AML classified in the intermediate-2 and unfavorable risk groups according to the Acute Leukemia French Association (3) patients fit for receiving chemotherapy (4) patients candidates for allo-HSCT and in first complete remission (CR1) at transplantation. Two hundred and one patients met the inclusion criteria and were enrolled in the study. Among them, 137 (68%) received allo-HSCT of whom 83 (41%) only received HSCT in CR1 after a median time of 143 days (range: 69-265) from diagnosis. We collected within this interval different delays for donor search, including patients HLA typing and time to unrelated donor identification when a sibling donor was not available. Patients were split into 2 groups based on their time to transplant. An "early transplant group" included 28 (33%) patients transplanted after a median time of 108 days (range: 69-133) after diagnosis. The other 55 (67%) patients transplanted after a median time of 163 days (range: 134-265) were qualified as "late transplant group". Patients and transplantation characteristics according to the timing of transplantation are shown in table 1. After a median follow-up of 16 months (range: 0-60) the 5-year probability of overall survival (OS) and disease-free survival (DFS) for the whole population were respectively, 63.4% and 48.3%. The cumulative incidences of non-relapse mortality (NRM) at 1 and 5 years were constant at 17.5%. The multivariate analysis using proportional hazards modeling showed that conditioning regimen and sex mismatching were independent prognostic factors for DFS, with no significant impact on OS. To evaluate the long term impact of transplantation timing on OS and DFS, we performed a landmark analysis for patients surviving at 1 year post-allo-HSCT. This analysis showed that patients in the early transplant group had a higher probability of OS at 3 and 5 years with 100% survival respectively compared to the late transplantation group with 85.5% and 79.4% respectively (p=0.09); accordingly, we found a significant difference in terms of DFS with 100% probability at 3 and 5 years for the early transplantation group compared to 80% and 56% respectively in the late transplantation group (p=0.02). This difference in terms of OS and PFS was still valid after stratification on the type of conditioning regimen.These results confirm the important impact of allogeneic HSCT timing in high-risk AML patients, early allo-HSCT for patients transplanted in CR1 is associated with a better OS and a very significant benefit in terms of DFS. Further analyses are ongoing including disease monitoring from diagnosis to the last follow-up to identify the potential of transplantation timing on the graft versus leukemia effect. [Display omitted] DisclosuresNicolini:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Clofarabine-Based Consolidation Improves Relapse-Free Survival of Younger Adults with Non-Favorable Acute Myeloid Leukemia (AML) in First Remission: Results of the Randomized ALFA-0702/Clara Study (NCT 00932412)

Background: Clofarabine has been shown as effective as single-agent or in combination with cytarabine in various populations of AML patients. Nevertheless, two randomized studies failed to demonstrate prolonged survival when compared to low-dose cytarabine in older AML patients (Burnett, 2013) or intermediate-dose cytarabine (IDAC) in patients aged 55y or more with relapsed/refractory AML (Faderl, 2012). As this was likely due to excessive toxicity and poor compliance in these difficult-to-treat populations, we made the hypothesis that a more apparent benefit might be observed during post-remission therapy. We thus randomly assessed the role of CLARA combination (clofarabine + IDAC) versus high-dose cytarabine (HiDAC) as consolidation cycles in younger AML patients.Methods: Between 2009 and 2013, 713 patients aged 18-60y old with de novo AML (CBF-AML excluded) were enrolled in the ALFA-0702 trial by 33 French centers. They received a timed-sequential induction with daunorubicin (60 mg/m2, day 1-3; 35 mg/m2, day 8-9), cytarabine (500 mg/m2 CI, day 1-3; 1 g/m2/12h bolus, day 8-10) and G-CSF priming. A first salvage with idarubicin and HiDAC may be proposed to patients not achieving CR/CRp after this first course. Patients in CR/CRp with non-favorable AML (according to ELN classification) or those who needed the salvage (late CR/CRp) were eligible for: 1) allogeneic stem cell transplantation (SCT) if they had a sibling or fully matched unrelated donor; or 2) randomization for consolidation with three HiDAC (3 g/m2/12h cytarabine, day 1/3/5; G-CSF priming) or CLARA (30 mg/m2 clofarabine, day 2-6; 1 g/m2/12h cytarabine, day 1-5; G-CSF priming) cycles if no identified donor. Primary endpoint was relapse-free survival (RFS), patients receiving allogeneic SCT in first CR/CRp after randomization (late donor identification) being censored at SCT time. Secondary endpoints were cumulative incidence of relapse (CIR) and death in first CR/CRp (CID), overall survival (OS), and safety. Anticipating a 35% SCT rate in randomized patients, 230 patients should be randomized to demonstrate a 20% gain in 2-year RFS. A sensitivity analysis without SCT censoring was planned.Results: Among 468 CR/CRp patients of interest (465/552 non-favorable AML + 3/161 favorable AML with late CR/CRp), 221 were randomized between HiDAC (n=114) and CLARA (n=107) consolidation and 247 were not randomized for the following reasons: 181 had an identified donor for SCT; 19 had favorable ELN genotype even if no evidence of normal karyotype; and 47 were negatively selected (13 early relapses, 1 early death, 18 AEs, 15 drop-out). The ITT analysis was conducted in these 221 eligible patients (median age, 48y; 136 intermediate-risk, 85 unfavorable-risk; 18 late CR/CRp; without imbalances between randomization arms), the remaining 9 randomized patients having non-eligibility criteria (6 favorable-risk AML and 3 not in CR/CRp). Among these patients, the rate of SCT in first CR/CRp was higher than anticipated (50%; 55 patients in each arm). With a median follow-up of 37.4 months and SCT censoring, 2-year RFS was 52.1% (40-68) in the CLARA arm versus 30.5% (20-46) in the HiDAC arm (HR, 0.62 [0.39-0.99]; p= 0.042). This was due to a lower CIR in the CLARA arm (44.0 versus 67.7%; p= 0.023) with similar CID (3.9 versus 1.9%, p= 0.60). At 2 years, OS was 68.1% (56-82) in the CLARA arm versus 49.8% (38-66) in the HiDAC arm (p= 0.18). Interestingly, the gain in CIR and RFS was observed in both intermediate- and unfavorable-risk groups and persisted after adjustment on AML risk and age. As expected, these gains were lower when not censoring at SCT (2-year RFS, 57.8 versus 45.6%; p= 0.12). In the 110 randomized patients allografted in first CR/CRp, no differences in post-SCT outcome were observed according to randomization arm. In Mantel-Byar time-dependent analysis, longer RFS was observed after SCT in the HiDAC arm (HR, 0.45; p= 0.004), while not in the CLARA arm (HR, 0.71; p= 0.26). Finally, CLARA cycles were associated with higher hematologic toxicity, more infections and more liver toxicities than HiDAC cycles, especially after cycle 1.Conclusions: As compared to HiDAC, clofarabine-based consolidation improved RFS in younger patients with intermediate- and unfavorable-risk AML in first CR/CRp. CLARA combination might thus become a new standard for post-remission therapy in these patients, especially in those who may not benefit from allogeneic SCT. DisclosuresOff Label Use: CLOFARABINE is not currently approved for this indication.. De Botton:Agios pharmaceuticals: Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The World Health Organization Classification of Skeletal Muscle Tumors in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group

The World Health Organization Classification Since 1995, the International Classification of Rhabdomyosarcoma has provided prognostically relevant classification for rhabdomyosarcoma (RMS) and allowed risk stratification for children with RMS. The International Classification of Rhabdomyosarcoma includes botryoid and spindle cell RMS as superior-risk groups, embryonal RMS as an intermediate-risk group, and alveolar RMS as an unfavorable-risk group. The 2013 World Health Organization (WHO) classification of skeletal muscle tumors modified the histologic classification of RMS to include sclerosing RMS as a type of spindle cell RMS separate from embryonal RMS. The current WHO classification includes embryonal, alveolar, spindle cell/sclerosing, and pleomorphic subtypes of RMS and does not separate the botryoid subtype. To determine if the WHO classification applies to pediatric RMS. To accomplish this goal, we reviewed 9 consecutive Children's Oncology Group clinical trials to compare the WHO and International Classification of Rhabdomyosarcoma classifications with outcome and site of disease. Except for a subset of low-risk RMS, the outcome for botryoid was not significantly different from typical embryonal RMS when analyzed by primary site. Similarly, pediatric spindle cell and sclerosing patterns of RMS did not appear significantly different from typical embryonal RMS, with one exception: spindle cell RMS in the parameningeal region had an inferior outcome with 28% event-free survival. Our data support use of the WHO RMS classification in the pediatric population, with the caveat that histologic diagnosis does not necessarily confer the same prognostic information in children as in adults.

Endoglin (CD 105) as a potential prognostic factor in neuroblastoma.

Endoglin (CD105) is a cytokine that modulates angiogenesis by regulating different cellular functions, including endothelial proliferation, differentiation, migration and formation of microvessels. CD105 is expressed strongly in the tumor vasculature, and intratumoral microvessel density (IMVD), as determined by the use of antibodies to CD105, it has been found to be an important prognostic indicator for outcome in various malignances. This study aims to determine if the clinical outcome of children with neuroblastoma is correlated with IMVD, as determined by CD105 staining and other prognostic factors. Tumor tissue specimens from 38 patients with peripheral neuroblastic tumors who underwent surgical resection or biopsy of their primary tumor without any preoperative therapy were retrospectively reviewed. IMVD was identified immunohistochemically using monoclonal antibodies against CD105. Prognostic factors, such as the MYCN oncogene, disease stage, histopathology and age, were correlated with outcome. Among 38 examined specimens, the median IMVD value was 23.2 (15.1-28.4). The IMVD identified by CD105 was significantly higher in patients with unfavorable histology, metastatic disease, MYCN amplification and COG high risk group. ROC analysis was used to find significant IMVD level regarding EFS. The cut-off >18 was selected according to the greatest sensitivity (100%) and specificity (68.42%). The multivariate Cox proportional hazards analysis demonstrated that MYCN amplification and IMVD were significant prognostic factors in predicting EFS (hazard ratio for MYCN amplification: 3.61; 95% CI: 1.20-10.90; P = 0.023 and for IMVD: 1.05; 95% CI: 1.00-1.09; P = 0.037). IMVD determined by CD105 appeared to be an independent prognostic factor for neuroblastoma.

Development and Validation of a Prognostic Score Involving Disease Status, Patient Age and Donor Type for Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment option for acute myeloid leukemia (AML) when indicated. Numerous pre-transplant risk scores have been developed to predict post-transplant outcome, utilizing a variety of parameters. The purpose of this single-center study was to retrospectively develop and validate a prognostic score based on known significant pre-transplant variables for outcomes of 747 patients that underwent HCT for AML between 1978 and 2013.Median age of all patients at transplant was 44 years (range 17-71 years), 391 patients (52%) were female. HCT was performed in first complete remission (CR1) for 497 patients (67%) and in second complete remission (CR2) or advanced disease for 250 patients (33%). Donors were related for 538 patients (72%) and unrelated for 209 patients (28%). Peripheral blood stem cells (PBSC) were used as a graft source in 367 patients (49%). Myeloablative conditioning (MAC) was administered to 615 (82%) patients, 132 (18%) received reduced-intensity conditioning (RIC) regimens. HCT was performed over the time periods 1978-1990 (n=139), 1991-1999 (n=192), 2000-2006 (n=183) and 2007-2013 (n=233). Median follow-up of survivors was 90 months.Patients were assigned a combined score based on patient age, disease status and donor status. For disease status CR1, age <45 years and related donors, each parameter received a score 0. For disease status CR2 or advanced stage, age ≥45 and unrelated donors, each parameter received a score 1. Patients demonstrated a cumulative score of 0 (n=197), 1 (n=326), 2 (n=179) or 3 (n=45). All 747 patients were randomized into two groups, a test cohort (n=373) and a validation cohort (n=374).Univariate analysis for the test cohort demonstrated a favorable risk group with score 0 (n=92), an intermediate risk group of score 1-2 (n=255) and an unfavorable risk group with score 3 (n=26) with a 5-year overall survival (OS) of 61%, 35% and 20% respectively (p=0.0001)(Figure). Cumulative incidence of relapse (CIR) demonstrated a marginally significant difference between groups (p=0.05) with 5-year CIR 14%, 28% and 23% respectively. Non-relapse mortality (NRM) was marginally different (p=0.07) with 5-year NRM 27%, 39% and 54% respectively.Multivariable analysis of the test cohort for OS demonstrated that the presented scoring system remained significantly prognostic (p<0.0001) accounting for year of transplant as a continuous variable in the analysis (p=0.001, HR for transplant year 0.97, 95%CI 0.96-0.98). For OS, HR was 2.3 and 4.0 for the intermediate and high risk group respectively compared to favorable risk. For CIR, HR was 2.1 and 1.8 for intermediate and high risk patients respectively (p=0.05). For NRM, HR was 1.5 and 2.8 for intermediate and high risk patients respectively (p=0.01).Analysis of the validation cohort confirmed significant stratification for OS on univariate (p<0.0001, 5-year OS 68%, 36% and 30% for the three risk groups respectively) and multivariable analysis (p<0.0001). For CIR, no significant difference was seen on univariate (p=0.3, 5-year CIR 15%, 23% and 17% respectively) or multivariable analysis (p=0.3). For NRM, the validation cohort confirmed significant stratification between the risk groups on univariate (p<0.0001, 5-year NRM 19%, 42% and 48% respectively) and multivariable analysis (p<0.0001).In the presented study we developed and validated this readily calculable pre-transplant scoring system involving age, CR status and donor type which is highly prognostic for OS and NRM of patients undergoing allogeneic HCT for AML. We also demonstrated that the year transplant was performed over the last three decades had no influence on the prognostic significance of the scoring system. [Display omitted] DisclosuresMessner:Otsuka Pharmaceuticals Inc: Research Funding.