Anthracycline-based Induction Chemotherapy Research Articles

Advancements and Challenges in the Treatment of AML.

The therapeutic arsenal for the management of AML has expanded significantly in recent years. Before 2017, newly diagnosed AML was treated with either standard cytarabine- and anthracycline-based induction chemotherapy (for all fit patients) or a single-agent hypomethylating agent (in unfit patients or those 75 years and older). While assessing patient fitness remains important, characterizing the disease biology has become critical to select the optimal initial therapy for each patient with more options available. FLT3 inhibitors, gemtuzumab ozogamicin, and CPX-351 have been shown to improve outcomes for specific subsets of patients. Venetoclax (VEN) with a hypomethylating agent (HMA) is the standard-of-care frontline regimen for most older patients, except perhaps for those with an IDH1 mutation where ivosidenib with azacitidine may also be considered. On the basis of the success seen with HMA/VEN in older patients, there is now increasing interest in incorporating VEN into frontline regimens in younger patients, with promising data from multiple early phase studies. This article focuses on recent updates and ongoing challenges in the management of AML, with a particular focus on the ongoing challenge of secondary AML and considerations regarding the selection of initial therapy in younger patients. An overview of common side effects and toxicities associated with targeted therapies is also presented here, along with recommended strategies to mitigate these risks.

Association between BMI and Survival in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia Treated with Intensive Chemotherapy

Introduction: Obesity is linked to a higher incidence of acute myeloid leukemia (AML) in older adults as well as B-cell acute lymphoblastic leukemia in children and adolescents and young adults (AYA). To date, however, the relationship between weight and clinical outcomes in AYA patients (pts) diagnosed with AML has not been clearly established. We hypothesized that obesity reflected by higher body mass index (BMI) would confer worse prognosis in AYA pts treated with intensive chemotherapy and/or allogeneic stem cell transplant (SCT) for AML. Methods: We conducted a single institute retrospective chart review of AYA patients aged 18 to 39 years diagnosed with AML between Jan 2006 and Oct 2022. All patients received intensive chemotherapy with cytarabine- and anthracycline-based induction and consolidation chemotherapy followed in some cases by SCT. BMI was calculated based on height and weight on the date of AML diagnosis. Additional information including European Leukemia Net (ELN) 2022 risk classification, therapy response (complete remission (CR), CR with incomplete count recovery [CRi]), receipt of SCT, relapsed disease, event-free (EFS), overall survival (OS) and percentage of pts alive at 2- and 5-years after diagnosis were collected. All data was de-identified and procured on an IRB-approved protocol. Results: Seventy-six AYA patients were identified. Median age was 25.2 (range 18-39) years. 39 (51%) were female. The majority (65, 86%) were Caucasian. Per ELN 2022 risk classification, 24 (32%) had favorable, 36 (47%) had intermediate, and 16 (21%) had adverse risk disease. The CR rates based on ELN 2022 risk classification were 86%, 72% and 50%, respectively. Median OS for all pts was 791 days and per risk group was 1379, 569, and 595 days, respectively. Pts were then categorized per initial BMI into 4 categories. The majority of pts (44, 58%) had above average BMI (≥ 25), with 21 (28%) considered overweight with BMI 25-29.9 and 23 (30%) obese defined as BMI >30. Only 3 pts (4%) were underweight with BMI <18.5 (Table 1). Of note, 43% of obese pts had ELN favorable risk vs 33% of overweight pts and 24% of normal weight pts. Overall response rates in each BMI category were similar, ranging from 96-100% except in overweight pts where only 6 of 21 pts (29%) obtained CR. Relapse occurred in approximately one third (29-35%) of pts in the three highest BMI categories. Two thirds of all pts with BMI ≥18.5 underwent SCT. Excluding underweight pts due to small numbers (n=3), there was a trend to decreased survival in pts with BMI ≥18.5. Median overall survival among normal, overweight, and obese pts was 1403, 1295, and 777 days, respectively, with a significant difference between healthy and obese pts (p-value 0.0274 by log rank test). The percentage of pts alive after 5 years was 41%, 29%, and 17%, respectively (Table 2). Conclusion: Our real-world single-institute retrospective analysis suggests that AYA pts aged 18-39 yrs old diagnosed with AML and with higher BMI have decreased overall survival following intensive chemotherapy and/or allogeneic transplant. Obese patients with the highest BMI (>30) had a markedly shorter overall survival (median 777 days) and lower percentage of pts (17%) alive after five years following therapy than AYA AML pts with normal BMI (median 1403 days, 41% 5-year survival). This was despite over 40% of obese pts having favorable ELN risk. Potential reasons for this include biological heterogeneity in BMI cohorts, chemotherapy dosing, weight-related medical co-morbidities (i.e. cardiovascular disease) and/or transplant-related complications leading to shorter survival. Additional analyses to rule out the contribution of these and other factors and to confirm these results in a larger cohort are ongoing.

Mitochondrial apoptosis-related gene polymorphisms are associated with responses to anthracycline-based chemotherapy in acute myeloid leukaemia.

Although anthracyclines are the first-line chemotherapy drugs for treating non-M3 acute myeloid leukaemia (AML), their efficacy remains limited. It is important to identify factors that influence the efficacy of anthracyclines against AML. Mitochondrial apoptosis-related genes play significant roles in the pathogenesis, treatment, and prognosis of AML. We utilized the CRISPR/Cas9 screening system to find AML anthracyclines resistance related genes and several mitochondrial apoptosis-related genes, such as BCL2L11, CASP8, TP63, TP53BP2, PLAUR, SOD2, BNIP3L, and MMP9, were screened out. Then, DNA from 279 patients with AML and 321 healthy individuals were extracted and the contributions of single nucleotide polymorphisms (SNPs) within these genes to the patient's chemotherapy response, susceptibility to AML, and overall survival were investigated. Our findings indicated that SNP rs4251864 in the PLAUR gene was associated with an increase in complete remission after anthracycline-based induction chemotherapy. rs4880 in SOD2 was associated with the response to the second course of chemotherapy, whereas rs3789068 in BCL2L11 was associated with susceptibility to AML. Our results about the association of SNPs in mitochondrial apoptosis-related genes with the response to anthracycline-based chemotherapy in AML provide an important reference for predicting the treatment outcomes in patients with this disease.

Incidence and Risk Factors for Bleeding in Patients with Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy

Background : Bleeding is a major complication of intensive AML induction therapy that has been linked to increased early mortality. Identifying patients with increased bleeding risk could improve outcomes by allowing development of preventative strategies. Prior studies have focused on clinical trial or registry cohorts to identify factors associated with bleeding outcomes, and may not reflect typical clinical practice or have adequately detailed clinical or genetic data. Therefore, we sought to define the incidence and distribution of bleeding in a real-world cohort of AML patients and determine which pretreatment clinical, laboratory and genetic factors were associated with bleeding. Patients and methods: We identified 341 consecutive adult patients with newly diagnosed AML who received anthracycline-based induction chemotherapy. The median age was 61 years (range 19-79). Diagnostic samples from all patients were sequenced for recurrently mutated myeloid genes. We collected pretreatment clinical and laboratory data, and annotated bleeding events during the first 60 days of treatment according to the WHO bleeding assessment scale. Bleeding was classified as clinically significant if WHO grade ≥2, or grade 1 if it prompted a change in platelet transfusion threshold. Disseminated intravascular coagulation (DIC) was assessed using a modified ISTH DIC-score including platelet count, PT-INR, and fibrinogen, where a score ≥3 points indicates high risk of DIC. D-dimer was excluded due to missing data. Results: A total of 87 patients (26%) had clinically significant bleeding events, most commonly involving gastrointestinal (n=35), genitourinary (n=31), and central nervous system [CNS (n=12)] sites. Patients with clinically significant bleeding events had worse survival within the first 60 days of induction treatment compared to patients without clinically significant bleeding (HR 5.24; 95% CI: 2.50-10.96, P < 0.001). The incidence of clinically significant bleeding was higher among patients with a high pretreatment modified DIC score compared to those with a low modified DIC score (44% vs. 24%, P = 0.002, Figure A-B). This difference was most prominent among patients with WHO grade 4 bleeds (22% vs. 3%, P < 0.001, Figure A). Most clinically significant bleeding events (n=57) occurred within the first two weeks of induction treatment (Figure B). Using multivariable logistic regression analysis, we found that pretreatment platelet count <50 x 109/L, PT-INR >1.3, and the presence of a DNMT3A mutation were independently associated with bleeding within the first 60 days of AML induction treatment (Table). Other factors previously linked with bleeding risk, including age, sex, hepatic and renal function, and leukocyte count, were not associated with an increased risk of bleeding in this cohort. Early mortality was particularly high (58%) in patients who experienced a CNS bleed, which events included intraparenchymal and/or subdural hemorrhage (n=9), and hemorrhagic transformation of ischemic stroke (n=3). Two thirds (n=8) of patients with CNS bleeds had high pretreatment modified DIC scores. Using univariate regression analysis, we found that the presence of DNMT3A or TET2 mutations had significantly increased odds ratios for CNS bleeds (3.84; 95% CI: 1.20-12.2 and 4.18; 95% CI: 1.27-13.71, respectively). The frequency of CNS bleeds was significantly higher amongst patients with DNMT3A and/or TET2 mutations compared to patients without these mutations (8% vs. 1%, P = 0.004). Conclusions: The incidence of bleeding in this real-world cohort of AML patients receiving intensive induction chemotherapy was higher than previously reported in selected clinical trial cohorts. Clinically significant bleeding during initial induction was associated with poor short-term survival. Low platelet count, elevated PT-INR and DNMT3A mutations were independently associated with clinically significant bleeding. The incidence of CNS bleeds was highest in patients with DNMT3A or TET2 mutations, and rare in patients without these mutations, raising the possibility that genetic events driving early leukemogenesis may exert pleiotropic effects that impact hemostasis. Together, these results identify a subset of AML patients who may benefit from additional supportive care measures to prevent early bleeding associated with morbidity and mortality of intensive induction treatment. Disclosures Wolach: Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Lindsley:MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors.

Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%). Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.

Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

How to improve quality of life in patients with acute leukemia and comorbid ischemic heart disease treated with anthracycline-based induction chemotherapy.

To evaluate the quality of life (QoL) parameters in patients with acute leukemia (AL) during standard induction chemotherapy, depending on the presence of concomitant ischemic heart disease and to improve them by the prevention of anthracycline cardiotoxicity with L-arginine. A total of 147adult AL patients (72males and 75females with the mean age 54.7 ± 9.3years) were enrolled in the study. QoL assessment was performed at baseline and after induction chemotherapy using SF-36questionnaire. Both physical and mental parameters were evaluated. The QoL analysis of patients with AL at the time of initial diagnosis showed extremely low QoL level in all subgroups compared with healthy individuals. It should be noted that the level of patients' QoL after achieving remission remained significantly lower than those of practically healthy, which is primarily due to the need for further long-term treatment and, probably, the fear of the disease relapse development. It was found that the administration of L-arginine during induction chemotherapy in order to reduce the risk of anthracycline cardiotoxicity development has allowed improving the QoL in patients with concomitant ischemic heart disease. L-arginine decreases the risk of anthracycline-induced myocardial injury and improves QoL in AL patients.

Intensive chemotherapy vs. hypomethylating agents in older adults with newly diagnosed high-risk acute myeloid leukemia: A single center experience

Acute myeloid leukemia (AML) in older patients is often associated with biologic and clinical characteristics that predict poor outcomes to cytarabine and anthracycline based induction chemotherapy (IC). The impact of hypomethylating agents (HMA) in the treatment of these high-risk patients is unknown. Here we retrospectively examined the remission rates and survival outcomes of 201 newly diagnosed patients ≥60 years old with therapy-related (t-AML), secondary (s-AML), or AML with myelodysplasia-related changes (AML-MRC). Ninety-eight patients received IC, and 103 received HMA. Patients in the IC cohort were younger than those who received HMA (68 vs. 74 years; p < 0.01) with lower comorbidity burden. Composite complete remission rates (CR) were 39% in IC and 27% in the HMA cohorts (p = 0.10). Overall survival (OS) was not significantly different between the two cohorts (7.59 mos vs. 5.49 mos; HR 0.75 95% CI 0.55–1.02) despite the fact that more patients in the IC cohort (33% versus 5%, p < 0.01) underwent allogeneic stem cell transplant. Patients with t-AML (HR 0.56; 95% CI 0.33–0.97) and complex karyotype without monosomal karyotype (CK + MK-; HR 0.37; 95% CI 0.19–0.75) had better OS following IC. Patients with CK + MK+ (HR 2.00; 95% CI 1.08–3.70) had improved OS following HMA. Our results support the use of HMA as an alternative upfront regimen in older individuals with newly diagnosed high-risk AML based on similar clinical outcomes to IC.

Abstract 343: Targeting DNA replication as a therapeutic strategy for acute myeloid leukemia with DNMT3A mutations

Abstract Acute Myeloid Leukemia (AML) is an aggressive malignancy of the blood system, wherein somatic mutations in epigenetic modifier and chromatin remodeling genes are common. Recurrent somatic mutations in the DNA methyltransferase 3 alpha (DNMT3A) gene are detected in about 30% of AML cases, and predict poor outcomes in patients treated with anthracycline-based induction chemotherapy, due to suboptimal response to therapy and subsequent early disease relapse. DNA methylation profiling in both primary AML samples and in animal models carrying a DNMT3A mutation detected modest DNA hypomethylation that did not fully explain how mutant DNMT3A contributed to AML pathogenesis. Recent studies have uncovered disordered nucleosome remodeling in response to DNA topological stress in DNMT3A-mutant cells, which was most pronounced during DNA replication. These changes were accompanied by negative enrichment of the cell cycle-associated gene expression signatures and attenuated CHK1 signaling, implicated in DNA damage response and replication fork integrity. Therefore, we hypothesized that targeting the S-phase in leukemic cells with DNMT3A mutations by pharmacologic agents that stall replication may offer enhanced therapeutic benefit. Indeed, our studies show increased sensitivity to replication stalling pharmacological treatments such as nucleoside analogues cytarabine and fludarabine in different cellular systems harboring DNMT3A mutations. This was accompanied by increased apoptosis as measured by PARP cleavage and annexin V binding.Analysis of the DNA damage signaling revealed elevated CHK1 phosphorylation signaling and accumulation of the DNA damage marker gammaH2A.X. A similar drug sensitivity trend was observed in murine Dnmt3a-mutant bone marrow cells treated with cytarabine, using clonogenic survival in MethoCult as readout. In order to examine this, we are developing isogenic cellular systems with differing DNMT3A mutational status via the CRISPR-Cas9 gene-editing approach. Further, these isogenic cell lines will be used as a tool to characterize the effect of mutant DNMT3A on replication progression, arrest, and resolution under pharmacologically induced replication stress. This will include analysis of the chromatin remodeling at the replication forks, proficiency of DNA damage repair, and dynamic localization of wild-type and mutant DNMT3A within the cells throughout the cell cycle. Finally, we will test the efficacy of replication stress inducing therapies in vivo in a genetically accurate mouse model of Dnmt3a-mutant AML. These studies will shed light on the mechanism of a potential vulnerability in DNMT3A-mutant leukemia cells and may lead to a more effective treatment strategy for this common subtype of AML. Citation Format: Kartika Venugopal, Daphné Dupéré-Richer, Jonathan Licht, Olga Guryanova. Targeting DNA replication as a therapeutic strategy for acute myeloid leukemia with DNMT3A mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 343.

GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.

2560 Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consolidation with GMI-1271 plus intermediate dose cytarabine. Dose-limiting toxicity (DLT), defined as myelosuppression in the absence of disease or related Grade 3 (Gr) non-hematologic toxicity beyond day 42, was assessed in the first 3 pts. Results: 24 pts have been enrolled to date and 17 are evaluable for response. The median age was 68 years (range, 60-79) with 58% male pts, 50% secondary AML (sAML) pts and 25% with high-risk cytogenetics (by SWOG). The first 3 pts had no DLT, allowing enrollment to proceed. Common Gr 3/4 AEs included febrile neutropenia (47%), pneumonia (20%), pulmonary edema (13%) and non-fatal respiratory failure (13%). 2 pts died of sepsis within 60 days. The remission rate (CR/CRi) was 12/17 (71%). CR/CRi rate was 75% for pts with de novodisease and 67% for pts with sAML. E-sel ligand was expressed at high levels on blasts in the majority of pts. Conclusions: The addition of GMI-1271 to anthracycline-based induction chemotherapy in untreated elderly pts with AML demonstrates a high remission rate with acceptable side effect profile and low induction mortality. This study compares favorably to previous studies (Lancet, ASCO 2016). A randomized trial is being planned. Clinical trial information: NCT02306291.

Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial.

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741).

Acute Myeloid Leukemia: Past, Present, and Prospects for the Future.

Dose intensification of chemotherapy and the combination of a third cytotoxic agent with standard cytarabine and anthracycline-based induction chemotherapy have led to improved outcomes in select groups of patients with acute myeloid leukemia (AML). However, despite some progress in this area, it appears that we might be reaching the limit of cytotoxic chemotherapy for the treatment of AML, especially in older patients and in those with poor-risk features whose disease tends to be relatively chemoresistant. Recent advances in the molecular classification of AML have identified pathogenic pathways that can be exploited with targeted agents and rational drug combinations. Novel nontransplant immunotherapies also show promise in the treatment of AML, especially when a targetable molecular aberration cannot be identified. Sensitive methods for detecting minimal residual disease in AML have not only improved prognostication of these patients but also provide the framework for risk-adapted strategies in this heterogeneous disease.

GATA-3 Expression in Peripheral T-Cell Lymphomas (PTCL): Identification of a Cut-Off and Prognostic Value in PTCL-NOS Versus Others Hystotypes

Background: Peripheral T-cell lymphomas (PTCL) have an aggressive clinical course with a poor 5-year overall survival with conventional therapy. Autologous stem cell transplantation (autoSCT) and allogeneic stem cell transplantation (alloSCT) can improve long-term disease control in first and second remission, respectively. Prognostic factors are not able to discriminate patients with chemorefractory disease. Preliminary evidence from gene expression profiling (GEP) and immunoistochemical study have suggested that the majority of PTCL-not otherwise specified (PTCL-NOS) can be subdivided in two different groups based on GATA3 and Tbet (transcription regulators of T-helper 2 and T-helper 1 lymphocytes) expression with a poorer prognosis in the former group. Because GEP studies are not feasible in routine clinical practice, we investigated whether expression changes of those proteins could be evaluated by immunohistochemistry (IHC) and used to predict prognosis.Material and Methods: We collected paraffin tissues from 63 consecutive patients (pts) with a diagnosis of PTCL [subtypes: PTCL-NOS (n=32), ALK-negative anaplastic large cell lymphomas (n=15, ALCL ALK-negative), angioimmunoblastic (n=16, AITL)] treated at different Italian Institutions. Sections were analyzed for Ki-67, GATA3, Tbet and CCR4 expression by IHC. Results were expressed as percentages of positive tumor cells. Histology was centrally reviewed. Median age was 58 years (range, 18-76 years); 20 of 63 (32%) pts were characterized by intermediate-high/high IPI; 47 of 63 (74%) pts were candidated to transplantation whereas 16 (25%) were not due to age ≥65 years (n=14) or limited stage/IPI 0 (n=2). Fifty-nine pts (93%) received anthracycline-based induction chemotherapy. Twenty of 47 (43%) pts underwent autoSCT in first (n=11) or subsequent remissions; 23 of 47 (49%) underwent alloSCT in first remission (n=3) or at relapse (n=20). The median follow-up of alive pts was 30 months (range, 8-250).Results: Expression of GATA3 was highly variable, but was significantly higher on average in PTCL-NOS [34% positive tumor cells (range, 1-99%)] than in other subtypes [11% (range,1-97%) in ALK-negative ALCL (p=0.027); 12% (range, 1-82) in AITL (p=0.0025)]; The mean value of Ki67 expression was higher in ALK-negative ALCL [87% (range, 70-95%)] as compared to other subtypes [46% (range,15-90%) in PTCL-NOS (p<0.0001)]; 42% (range, 15-70%) in AITL (p< 0.0001)]; Tbet and CCR4 expression was not significantly different among the subtypes.In PTCL-NOS (n=32), ROC curve analysis identified a cut-off of 27% for GATA3 with 16 pts showing a GATA3 expression higher than the cut-off value. While no significant difference in baseline clinical characteristics was observed among the two groups, pts with GATA3 ≥27% showed a significantly lower CR rate following induction [19% versus 62% (p=0.02)]. Cases with high GATA3 expression were significantly associated with a reduced 5-year PFS and OS as compared to those with low expression [PFS: 6% (95%CI:1%-24%) versus 49% (95%CI:22%-71%), (p=0,004); OS: 39% (95%CI:13%-65%) versus 72% (95%CI:35%-90%) (p=0,04) respectively]. In multivariate analysis including age, IPI score ≥2 and sex, high GATA3 expression retained a strong prognostic value in terms of PFS (p<0.01) and OS (p=0.04). In others hystotypes, high GATA3 expression did not predict the outcome.Conclusions: Our analysis identifies GATA3 ICH expression as a strong prognostic and predictive biomarker among PTCL-NOS. Pts with high GATA3 expression values were characterized by chemorefractory disease and poorer outcome even with transplantation strategies. Validation of this biomarker in a larger series of patients is ongoing. DisclosuresNo relevant conflicts of interest to declare.

VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia

Very late antigen-4 (VLA-4) and CXC chemokine receptor 4 (CXCR4) perform critical roles in the adhesion of hematopoietic and leukemic stem cells to marrow stromal cells. This mechanism is associated with chemoresistance in patients with acute myeloid leukemia (AML). Here, we measured VLA-4 and CXCR4 expressions in leukemic myeloblasts to determine their prognostic implications. Using multicolor flow cytometry, positive VLA-4 and CXCR4 expressions were measured in leukemic myeloblasts in bone marrow aspirates that were obtained from newly diagnosed adult AML patients (n = 98). VLA-4 expression was higher in patients at favorable or intermediate cytogenetic risk than in patients at poor risk (p < 0.001 and p = 0.002, respectively), but CXCR4 expression was not significantly different. Among the 72 non-promyelocytic leukemia patients analyzed who received cytarabine + anthracycline-based induction chemotherapy, high VLA-4 expression was independently associated with a high probability of complete remission (p = 0.019) and superior relapse-free survival (RFS) (p < 0.001). However, high CXCR4 expression independently increased the probability of relapse (p = 0.002) and was associated with a shorter RFS (p = 0.006). When categorizing patients into three groups according to VLA-4 and CXCR4 expression levels, the group of high VLA-4 and low CXCR4 showed longer RFS (p = 0.001) and overall survival (OS) (p = 0.011) than the group of low VLA-4 or high CXCR4.

Assessing the Value of Echocardiograms for Patients with Acute Myeloid Leukemia (AML) Receiving Anthracyclines

BackgroundAML is a life-threatening disease that requires prompt administration of anthracycline-based induction chemotherapy, particularly in younger adults. Prior to treatment initiation, patients (pts) undergo routine echocardiography (echo) screening to assess cardiac ejection fraction (EF) as a measure of induction tolerability, despite American Society of Clinical Oncology and National Comprehensive Cancer Center guidelines which state that only pts with prior cardiac disease or exposure to cardiotoxic drugs or radiation therapy require such evaluation This is costly to the health-care system and may be unnecessary. In this study, we assess whether the use of echo prior to anthracycline-based therapy in AML has a major effect on pt outcomes.MethodsWe reviewed clinical data on AML pts treated with anthracycline-based induction chemotherapy regimens at our institution from 2002-2014. EF was obtained by 2D echo prior to induction chemotherapy initiation. Charlson comorbidity index was used to evaluate comorbidities prior to therapy. A cox proportional hazard model was used to analyze the impact of baseline echo on overall survival, with p-values <.05 denoting significance.Results:Of the 120 pts included, 60 (50%) were female. At diagnosis, median age was 57 years (range, 23-85), white blood cell count (WBC) 8.9 x 109/L (0.3-227), hemoglobin 9.1g/dL (4.7-13.8), platelets 85 x 103 (8-277), bone marrow blasts 48% (14-95%). Cytogenetic risk categories per CALGB 8461 criteria: 12 pts (10%) were favorable, 63 (53%) indeterminate, and 41 (34%) unfavorable. Charlson morbidity index was > 1 in 23 pts (19%) and 50 (38%) were current or former smokers. All pts received induction chemotherapy with either idarubicin (38%), daunorubicin (38%), or mitoxantrone (23%) combined with cytarabine (7+3). In 116 pts (97%), the baseline echo showed a left ventricular ejection fraction (LVEF) >50% (+/- 5). In the 4 remaining pts (3%), the EF was < 40%. In a multivariable analysis controlling for age, WBC, cytogenetic risk group, Charlson comorbidity index, and smoking exposure, LVEF was not associated with overall survival (HR 1.05 with 95% CI 0.99-1.12 and p=.09). Among the 4 pts with EF<40% (age 57-71 years), all received full dose anthracycline and only the 71-year-old patient experienced congestive heart failure during treatment. Six pts (5%) died during induction therapy (4 weeks) and none of these had an EF <40%.ConclusionAmong AML pts who received anthracycline-based induction chemotherapy, results from echocardiography did not impact outcome in >99% in this cohort. It is not clear that echocardiography, particularly in younger pts, provides value, and may delay treatment initiation. DisclosuresNo relevant conflicts of interest to declare.

Impact of Anthracycline-Based Induction Chemotherapy on the Calreticulin, CD47 Exposure and the Percentage of Regulatory T Cells in Patients with Acute Leukemias: Preliminary Study

Background.Pre-apoptotic exposure of calreticulin (CRT) – protein belonging to DAMPs family – on the surface of malignant blasts in response to anthracycline-based chemotherapy is an important activation signal for phagocytosis initiating mechanism of immunogenic cell death. This process is counterbalanced by the negative regulator of phagocytosis – an interaction of CD47-SIRPα. Regulatory T cells (Treg) are supposed to actively counteract antitumor immunity, contributing to the accelerated growth kinetics and cancer promotion.Aims.To investigate correlation of membrane expression of CRT, CD47 on blasts, percentage of CD4+CD25+ Treg cells in the peripheral blood before and 6-12 hours after first administration of anthracyclines with response to first-line induction chemotherapy and median survival time in patients with acute leukemias.Methods.The study was conducted in 29 patients (M/F=15/14) aged 20 to 68 years (median 55), including 25 with a diagnosis of AML, 4 – ALL. All patients received anthracycline-based induction chemotherapy according to protocols with daunorubicin - 20, epirubicin - 8, and idarubicin – 1. CRT, CD47 exposure, Treg percentages were determined by flow cytometry.Results.Of all the patients - 19 achieved complete remission (CR) after the first cycle of first-line induction chemotherapy, 5 - did not achieve any remission (NR), 5 – were not assessed due to death during the treatment. In the group of patients who achieved CR the median CRT expression was 41.5% prior to and 65.7% 6-12 hours after the first dose of anthracycline. The median expression of CD47 presented levels – 5.9% and 29.6%. The median percentage of Treg was characterized by a decreasing tendency – 6.1% and 5.4%, respectively. The median overall survival (OS) in these patients was 5.9 months in median follow-up of 7.2 months. In the group of patients, who did not achieve remission after administration of first-line induction chemotherapy (NR), we observed the lower levels of CRT and CD47 expression in both assays in comparison to the group with CR. The median CRT expression was 9.2% prior to administration and 40.5% 6-12 h after first dose of the chemotherapeutic agent. The median expression of CD47 – 0,5% and 6,3%, respectively. The percentage of T regulatory cells tended to increase following administration of anthracyclines and was higher than in patients with CR – the median - 9.3% and 14.1%. The median OS in that group was 1.3 months in median follow-up of 8.2 months. Furthermore, we showed that a higher percentage of CRT expression before and 6-12 hours after implementing chemotherapy was negatively correlated with OS of the patients (p =0,014, r=-0,46 and p<0,0001, r=-0,50). A similar correlation regarding CD47 expression and Treg percentage was not confirmed in our study.Conclusion/Summary.Labelling of CRT, CD47 exposure, Treg cells percentage might be useful in the assessment and prognosis of response to induction chemotherapy in acute leukemias, but it requires further investigations in a larger group of patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Anthracycline-based induction chemotherapy followed by concurrent cyclophosphamide, methotrexate and 5-fluorouracil and radiation therapy in surgically resected axillary node-positive breast cancer.

The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2-positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS.

Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhage-related death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

Utility of Pre-Induction Cardiac Function Testing in Patients with Newly Diagnosed AML

Abstract 2068 IntroductionCurrent first-line therapy for acute myeloid leukemia (AML) involves a regimen of anthracycline-based induction chemotherapy. Cardiotoxicity is a rare but serious complication of such regimens and although it is a well-established phenomenon there is minimal evidence to inform the optimal frequency or nature of cardiac monitoring in these patients.The Ottawa Hospital measures baseline ejection fraction in all AML patients potentially eligible for induction chemotherapy. In this chart review we evaluated the effectiveness of this practice by weighing the clinically relevant information obtained from this testing against its costs and its potential to delay therapy. MethodsElectronic charts of all patients admitted to the Ottawa Hospital with a primary diagnosis of AML between January 2009 and March 2012 were included for review. Charts were excluded only if initial AML management pre-dated 2009 or occurred at other institutions. We sought to: 1. Determine to what extent cardiac function testing delays chemotherapy administration and 2. Assess the utility of cardiac function testing by a) determining if pre-test risk factor profiles were predictive of abnormal cardiac function, and b) quantifying the instances in which cardiac function testing results altered management. To address these objectives data regarding timing from AML diagnosis to cardiac function testing and induction, individual cardiac risk factor profiles and cardiac function test results, and reasons for deciding against induction chemotherapy were extracted from all included electronic charts and analyzed. ResultsA total of 124 patient charts were included for review. Median patient age was 61 (range 18–97) and patents were more often male (62%). Approximately two thirds (65%) were induced. Patients had a median of two cardiac risk factors (mean 2.3 +/− 1.7), the most common of which were age over 60 (59%), smoking (52%), and obesity (36%). A majority of patients (92, 74%) had cardiac function testing performed, 43 (47%) of which were echocardiograms and 47 (53%) of which were multigated acquisition scans (MUGAs).For patients in whom AML was diagnosed on admission, a bone marrow aspirate was performed within a median of one day. It took a median two days to complete cardiac function testing. Induction proceeded within one day of completion of cardiac function testing in 40 patients (75%) and on the same day in 22 patients (42%). Time courses for patients who were diagnosed with AML prior to admission were shorter than those diagnosed after admission but reflected a similar pattern.Cardiac function tests were available for 92 patients and 4 abnormal results were documented. There were no instances in which results of cardiac function testing lead to changes in dosing or cancellation of planned induction therapy.Patients with abnormal baseline cardiac function tended to have more risk factors than those with normal cardiac function (3.3 +/− 1.3 vs 2.1 +/− 1.7) but this difference was not statistically significant (p = 0.217). Of note 41% of those with normal cardiac function had fewer than two risk factors, while none of those with abnormal cardiac faction met this cutoff. DiscussionThe clinical utility of baseline cardiac function testing in our population of AML patients is questionable. Of 124 patients, abnormal results were rare (3%) and in no instances did these results change management decisions. Cardiac risk factor profiles were not significantly predictive of abnormal cardiac function, but given the rarity of abnormal results in our population it is difficult to draw conclusions from this data. Cardiac function testing ultimately lead to a delay in induction by an estimated median of 2 days. Given the cost and resources used for cardiac function testing (estimated $200–300/test), the additional hospital days spent waiting for its completion (estimated $1,500/day), its potential to delay the administration of emergent induction chemotherapy, and its non-contribution to management decisions, this chart review puts into question the necessity of baseline cardiac function testing in newly diagnosed AML patients. These conclusions merit broader exploration in other centers and patient populations. Disclosures:No relevant conflicts of interest to declare.