Standard Risk Group Research Articles

Expression Level and Clinical Value of PTEN Gene in Patients with Acute T Lymphocytic Leukemia

To study the PTEN gene expression level and its clinical significance in patients with acute T lymphoblastic leukemia. One hundred and twenty-four patients with T-ALL treated in our hospital from January 2014 to May 2018 were selected, and 120 healthy people were selected as control group. The bone marrow of the patients were collected, and mononuclear cells were separated out. PTEN gene expression level was detected by RT-PCR, PTEN protein expression level was detected by Western blot, Kaplan-Meier was used to analyze the survival rate of patients with T-ALL, Cox multivariate regression analyzed was used to analyze the independent influencing factors of patients, and the correlation between PTEN level and clinical characteristics of patients with T-ALL and its prognostic value were analyzed. The relative level of PTEN gene in patients with T-ALL was 0.19±0.06, which was significantly lower than that in control groups (P<0.05). There was significantly positive correlation of the expression level of PTEN gene with white blood cell count （r=0.993）and peripheral blood immature cells （r=0.996） in patients with T-ALL. There was no correlation between PTEN gene expression level and sex, age, LDH level, Hb level, platelet count in patients with T-ALL. And it was found that expression levels PTEN protein in the middle-risk group, the standard-risk group and the high-risk group were significant lower than those in the control group (P<0.05), while those in the high-risk group were significantly lower than those in other groups (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in PTEN gene high expression group were higher than those in PTEN low expression group (P<0.05). Cox multivariate regression analysis showed that white blood cell count and PTEN gene were independent influencing factors of OS (P<0.05); platelet count and PTEN gene were independent influencing factors of DFS (P<0.05). PTEN gene level relates to the prognosis of patients with T-ALL. Patients with better prognosis show a higher PTEN gene level, which provides reference for clinical treatment of patients with T-ALL.

Expression Level and Clinical Value of PTEN Gene in Patients with Acute T Lymphocytic Leukemia

To study the PTEN gene expression level and its clinical significance in patients with acute T lymphoblastic leukemia. One hundred and twenty-four patients with T-ALL treated in our hospital from January 2014 to May 2018 were selected, and 120 healthy people were selected as control group. The bone marrow of the patients were collected, and mononuclear cells were separated out. PTEN gene expression level was detected by RT-PCR, PTEN protein expression level was detected by Western blot, Kaplan-Meier was used to analyze the survival rate of patients with T-ALL, Cox multivariate regression analyzed was used to analyze the independent influencing factors of patients, and the correlation between PTEN level and clinical characteristics of patients with T-ALL and its prognostic value were analyzed. The relative level of PTEN gene in patients with T-ALL was 0.19±0.06, which was significantly lower than that in control groups (P<0.05). There was significantly positive correlation of the expression level of PTEN gene with white blood cell count （r=0.993）and peripheral blood immature cells （r=0.996） in patients with T-ALL. There was no correlation between PTEN gene expression level and sex, age, LDH level, Hb level, platelet count in patients with T-ALL. And it was found that expression levels PTEN protein in the middle-risk group, the standard-risk group and the high-risk group were significant lower than those in the control group (P<0.05), while those in the high-risk group were significantly lower than those in other groups (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in PTEN gene high expression group were higher than those in PTEN low expression group (P<0.05). Cox multivariate regression analysis showed that white blood cell count and PTEN gene were independent influencing factors of OS (P<0.05); platelet count and PTEN gene were independent influencing factors of DFS (P<0.05). PTEN gene level relates to the prognosis of patients with T-ALL. Patients with better prognosis show a higher PTEN gene level, which provides reference for clinical treatment of patients with T-ALL.

Impact of Autologous Transplantation in Patients with Multiple Myeloma with t(11;14): A Propensity-Score Matched Analysis.

Patients with multiple myeloma with t(11;14) have been considered to have standard-risk disease. However, several recent reports have shown contradictory results. We identified 95 patients with multiple myeloma with t(11;14) on FISH studies, who underwent upfront autologous hematopoietic stem cell transplant (auto-HCT) at our center. We compared their outcome with a group of standard-risk patients with multiple myeloma who had diploid cytogenetics by both conventional cytogenetics (CC) and FISH (n = 287). To reduce the bias between the groups, we performed a 1:1 propensity score matching technique for analysis. A total of 160 patients, 80 in each group, were identified. Patients in the 2 groups were matched for age, International staging system stage at diagnosis, serum creatinine at presentation, disease status at auto-HCT, type of preparative regimens, dose of melphalan used for conditioning, and induction and maintenance regimens. Patients in t(11;14) group had a post auto-HCT overall response rate (ORR) of 97.5% (78/80), compared with 100% (80/80) in the standard-risk control group (P = 0.50). Complete response rate in the t(11;14) group was 35% (28/80), compared with 45% (36/80) in the standard-risk control group (P = 0.26). The 4-year PFS rates were 40.8% (95% CI, 29.6%-56.1%) and 51.1% (95% CI, 39.4%-66.3%) in the t(11;14) and standard-risk control groups, respectively (P = 0.14). The 4-year OS rates were 74.9% (95% CI, 63.3%-88.7%) and 88.3% (95% CI, 80.4%-97.0%) in the t(11;14) and standard-risk control groups, respectively (P = 0.17). Also, patients with t(11;14) with concurrent cytogenetics had significantly poor PFS and OS compared with a propensity matched standard-risk control group. Our study confirms that t(11;14) multiple myeloma undergoing upfront autologous transplantation had similar outcomes as patients with multiple myeloma with normal cytogenetic and FISH studies. Existence of additional genomic aberrations by CC or FISH was associated with a worse outcome.

Improved Outcomes of All-Trans-Retinoic Acid and Arsenic Trioxide Plus Idarubicin As a Frontline Treatment in Adult Patients with Acute Promyelocytic Leukemia

Objective To analyze the outcomes of all-trans-retinoic acid (ATRA) and IV arsenic trioxide (ATO) plus idarubicin (IDA) as a frontline induction therapy in 118 acute promyelocytic leukemia (APL) patients with high risk (HR) and standard risk (SR) from January 2008 to December 2017. Methods The medical records of 118 APL patients (HR, n=45; SR, n=73) who received the frontline triple combination regimen at Henan Provincial People's Hospital and Tongji Hospital were retrospectively reviewed. Consolidation therapy comprised 6 cycles of ATO and ATRA plus IDA, and IDA was administered in 1~4 cycles of consolidation therapy based on the comparable clinical efficacy compared with 6 cycles and fewer side effects to myocardium without subsequent maintenance therapy. Results Of 118 patients, there were 3 (2.5%) early deaths and 115 (97.5%) hematologic complete remissions (hCR), and 102 (88.7%) of 115 patients achieved molecular complete remissions (mCR) following induction therapy, and all patients were PCR-negative for PML-RARa after the first cycle of consolidation therapy. The 5-year overall survival (OS) and event-free survival (EFS) were 93.0±2.9% and 92.4±3.0%, respectively. Early death, hCR, mCR and toxicities were comparable between the HR and SR groups. The cumulative incidence of relapse (CIR) in the HR group was 4.7% (n=2), and the CIR in the SR group was 0. The OS and EFS of the SR and HR groups were comparable (92.3±4.5 vs. 92.8±4.0%, X2=0.263, P=0.608; 92.3±4.5 vs. 91.1±4.2%, X2=0.917, P=0.338). The total dosage of IDA was approximately 181~258 mg, and no patient experienced cardiotoxicity. OS and EFS were not influenced by fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation status (P=0.405, 0.528, respectively). Conclusion The triple combination of ATRA and ATO plus IDA as both an induction and consolidation therapy for the HR and SR groups attained excellent outcomes, and this regimen was effective, safe and easy, without maintenance therapy. The triple combination treatment might be a preferred frontline therapy for APL patients, especially for HR patients or patients with the APL FLT3-ITD mutation. Disclosures No relevant conflicts of interest to declare.

Evolving Real-World Treatment Patterns in Patients with Newly-Diagnosed Multiple Myeloma (NDMM) in the United States (U.S.)

Background Multiple myeloma (MM), a malignant neoplasm of plasma cells in the bone marrow, accounts for up to 1.8% of all cancers in the U.S., most frequently affecting people 65-74 years old. A variety of therapies are available to manage MM, including stem cell transplantation (SCT), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), monoclonal antibodies (mAB), and alkylating agents (alk). Given the heterogeneity of MM and the rapidly evolving therapeutic landscape, MM contemporaneous real-world treatment patterns are not well described. We examined the patient characteristics and first-line (LT1) treatment patterns in NDMM patients. Methods MM patients (≥18 years), diagnosed in April 30, 2015 - April 29, 2017 (early cohort) or in April 30, 2017 - April 30, 2019 (recent cohort), were followed retrospectively from MM diagnosis to last patient activity in the Flatiron Health database - a geographically-diverse, longitudinal electronic health record spanning over 280 community and academic cancer clinics in the U.S. LT1 regimens were described as: 1) containing an IMiD (thalidomide, lenalidomide [R], or pomalidomide), PI (bortezomib [V], carfilzomib, or ixazomib), alk (melphalan, cyclophosphamide [C], bendamustine), mAB (daratumumab, elotuzumab), or combinations of these; and 2) doublet/monotherapy (doublets-) vs. triplet or greater agent (triplets+) combinations. Treatment patterns were examined by SCT status and by cytogenetic risk (high: del17p, t(4;14) and/or t(14;16); standard: ≥1 cytogenetic tests without high cytogenetic risk) and age groups (&lt;65, 65-74, ≥75). Duration of therapy (DOT) and time to next therapy (TTNT) were estimated using Kaplan-Meier methods in the early cohort with longer follow-up. Results Of 4,070 NDMM patients, 3,433 were non-SCT (nSCT: early cohort: n=1,736; recent cohort: n=1,697) and 637 had SCT (early cohort: n=407; recent cohort: n=230). In nSCT patients, mean age at diagnosis was 70 years (SD: 10); 46% were female; 36% had stage III (699/1916, among non-missing), and 15% (392/2574, among non-missing) had high risk MM (25% had unknown cytogenetics). SCT patients were younger at diagnosis (mean [SD]: 61 years [9]); 44% were female; 25% (117/470, in non-missing) had stage III, and 19% (102/547, in non-missing) had high risk MM (14% had unknown cytogenetics). Overall, proportions with known cytogenetic risk were similar within SCT status cohorts over time but were lower in the SCT group (nSCT early vs. recent cohort: 26% vs. 24% had unknown cytogenetics; and in SCT: 15% vs. 13%, respectively). In nSCT and SCT patients, respectively, most common regimens were VRd (d: dexamethasone; 44% and 58%), Rd (16% and 7%), Vd (13% and 1%), and VCd (12% and 4%). In nSCT patients, the use of VRd increased over time (37% [early cohort] to 51% [recent cohort]), while frontline therapy with Rd/Vd doublets (19% to 14%/16% to 9%) and with VCd (13% to 11%) decreased. In the nSCT recent cohort, VRd (51%) frontline therapy dominated, with a slightly higher proportion of patients in the high-risk group vs. standard and unknown risk receiving VRd (56% vs. 53% and 46%); use of doublet therapy with Rd/Vd was lower in the high risk (12%/5%) vs. standard risk group (14%/9%). Irrespective of age, VRd was the most common frontline regimen in the nSCT recent cohort, albeit its use was lower among patients 75+ years of age (43%) vs. younger patients (54% [&lt;65 years] and 59% [65-74 years]); 75+ year old patients had a higher use of Rd/Vd doublets (19%/15%) vs. &lt;65 (10%/5%) or 65-74 (10%/6%) years of age. Triplets+ were more commonly used than doublets- across all cohorts: 59% vs. 41% (nSCT early cohort); 74% vs. 26% (nSCT recent cohort); and 89% vs. 11% (SCT early cohort); 95% vs. 5% (SCT recent cohort). mAB use in the recent cohort was low: 1.4% nSCT and 2.2% SCT patients. In the nSCT early cohort, the median (95% CI) LT1 DOT was 10 months (9-11) and for TTNT was 14 months (13-16). Conclusions PI/IMiD treatment combinations were most commonly observed in both nSCT and SCT patients, with an increase in use from early (40%) to recent (56%) cohort in nSCT patients. Use of triplets, generally, is on the rise from early (60%) to recent cohorts (74%). LT1 TTNT was lower than has been shown in clinical trials. These findings indicate a notable change in treatment patterns over time in nSCT NDMM patients, highlighting the changing landscape of MM management. Disclosures Ailawadhi: Celgene: Consultancy; Takeda: Consultancy; Cellectar: Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Romanus:Takeda: Employment. Cherepanov:Takeda: Employment. Yin:Takeda: Employment. Cheng:Takeda: Employment. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

A Multicenter Randomized Non-Inferiority Study of Homoharringtonine Versus Etoposide in Induction Phase for Chinese Childhood Acute Myeloid Leukemia - a Report from China Children's Leukemia Group (CCLG)

Purpose: Classical introduction therapy of etoposide combined with cytarabine and daunorubicin (DAE) is commonly applied in childhood acute myeloid leukemia (AML), but etoposide has an increasing risk of secondary cancer. In this study the non-inferiority effect of homoharringtonine (H) versus Etoposide was compared in induction phase for Chinese childhood AML treated by CCLG-AML 2015 protocol. Patients and Methods: The total of 818 childhood AML patients (median age of 80 months; range from 1 to 193 months) from CCLG-AML 2015 study group (40 centers) were randomly allocated to two induction arms of DAE and DAH. During the course of induction I, 467 patients in DAE group received daunorubicin and cytarabine (DA) plus etoposide (D: 40 mg/m2 per day on days 1, 3 and 5; A: 100 mg/m2 every 12 hours from day 1 to 7; E: 100 mg/m2 per day from days 1 to 5), and 351 patients in DAH group received the same DA does plus homoharringtonine ( H: 3 mg/m2 per day from days 1 to 5). During the course of induction II, Idarubicin (10 mg/m2 per day on days 1, 3 and 5) was used to instead of daunorubicin, and patients accepted corresponding IAE or IAH treatment. All patients were divided into standard, intermediate or high risk group (SR, IR or HR group) according to CCLG-AML 2015 regimen (table 1). They were assessed by bone marrow (BM) aspiration and morphologically defined complete remission (CR: blasts ≤5%), partial remission (PR: blasts between 6~19%), or non-remission (NR: blasts ≥20%) on days 28 of induction. Results: DAH/IAH group showed non-inferiority for remission rates both in induction Ⅰ (DAE 70.2% vs DAH 76.6%, P = 0.041) and induction Ⅱ (IAE 79.4% vs IAH 87.7%, P = 0.016). Total CR rate at end of induction Ⅰ reached 73.0% and it didn't differ between DAE and DAH group for IR or HR group (IR group: DAE, 73.9% vs. DAH, 77.3%, P = 0.529; HR group: DAE, 53.9% vs. DAH, 62.6%, P = 0.128). But for SR group, CR rate of DAH group is significantly higher than DAE group (DAE, 85.1% vs. DAH, 95.1%, P = 0.013). It has similar results after induction Ⅱ. Total CR rate reached 83.1% and all patients has almost gained CR/PR for SR or IR group, only 2 patients still couldn't obtain remission. There was no significant difference in SR or IR group between two arms, but for HR group, CR rate significantly increased in those who accepted IAH chemotherapy (SR group: IAE, 91.2% vs. IAH, 95.0%, P = 0.398; IR group: IAE, 87.1% vs. IAH, 92.5%, P = 0.275; HR group: IAE, 66.1% vs. IAH, 78.8%, P = 0.050). Conclusion: Homoharringtonine is an effective cytotoxic drug and DAH regimen showed non-inferiority induction effect compared with classical DAE regimen in childhood AML, especially for patients of standard risk group. Disclosures No relevant conflicts of interest to declare.

Impact of Adding Melphalan to Fludarabine and a Myeloablative Dose of Intravenous Busulfan for Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Fludarabine and a myeloablative dose of intravenous busulfan with or without total body irradiation (Flu/Bu4) is a widely accepted myeloablative conditioning regimen with reduced toxicity for allogeneic hematopoietic stem cell transplantation (HSCT) that has been able to expand the indications for allogeneic HSCT while maintaining the intensity. However, relapse is a major concern especially in patients with high-risk hematological malignancies. Accordingly, a novel conditioning regimen that included Flu/Bu4 plus melphalan (Flu/Bu4/Mel) was used, with excellent outcomes, i.e., the 2-year overall survival (OS) was 54.9% in patients with non-remission acute myeloid leukemia. However, no study has compared Flu/Bu4/Mel and other conditioning regimens. Therefore, this multicenter retrospective observational study aimed to investigate the impact of adding melphalan to Flu/Bu4 by comparing patients who received Flu/Bu4/Mel and those who received Flu/Bu4. Methods The present study included 2394 adult patients who received Flu/Bu4/Mel (n=581) or Flu/Bu4 (n=1813) between January 2010 and December 2016 at the Japan Society of Hematopoietic Cell Transplantation. High-risk disease was defined as incomplete remission in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well as refractory anemia with excess blast transformation in patients with myelodysplastic syndrome; standard risk disease was defined as stable disease or disease progression in patients with malignant lymphoma before HSCT. We set the primary endpoint as the 5-year OS, evaluated by using the log-rank test. To compare the impact of the conditioning regimen on the primary endpoint, we used a multivariable Cox proportional hazards model. The following adjusted covariates were selected clinically based on previous studies: age, sex, disease, disease status at HSCT, hematopoietic cell transplant comorbidity index (HCT-CI), donor source, acute graft versus host disease prophylaxis, and years of HSCT. In addition, we performed propensity score matched analysis to minimize the potential treatment selection bias because the baseline characteristics of patients and disease could have influenced the selection of the conditioning regimen. Propensity score matching with a 1:1 ratio was performed by using the nearest neighbor-matching method with a caliper width fixed at 0.01. In addition, detailed analysis was performed by dividing patients into the high-risk and standard risk groups because the initial single-center retrospective studies mainly enrolled patients with high-risk disease. Results A total of 2394 patients were enrolled and analyzed: 581 patients received Flu/Bu4/Mel and 1813 patients received Flu/Bu4. The median age was 60 years (interquartile range, 53-63 years) and 1489 patients (62.2%) were men. The clinical characteristics of patients treated with Flu/Bu4/Mel and those treated with Flu/Bu4 were different. The Flu/Bu4/Mel group included more patients who were young, had acute myeloid leukemia and malignant lymphoma, had high-risk disease, had higher HCT-CI, received cord blood transplantation, received tacrolimus-based acute graft versus host disease prophylaxis, and had undergone transplantation recently. Regarding the primary endpoint, the 5-year OS after allogeneic HSCT was 33.7% (95% confidence interval [CI]: 27.5-40.1%) in the Flu/Bu4/Mel group vs 35.4% (95% CI: 32.7-38.1%) in the Flu/Bu4 group (p=0.794). The adjusted hazard ratio was 0.73 (95% CI: 0.62-0.85) for the Flu/Bu4/Mel group compared to the Flu/Bu4 group (p&amp;lt;0.001). After propensity score matching, the 5-year OS after allogeneic HSCT was 35.1% (95% CI: 28.0-42.2%) in the Flu/Bu4/Mel group vs 28.1% (95% CI: 22.4-34.0%) in the Flu/Bu4 group (p=0.008; Figure). On detailed subgroup analysis, among patients with high-risk disease, the 5-year OS was 29.5% (95% CI: 23.0-36.4%) in the Flu/Bu4/Mel group vs 20.8% (95% CI: 17.3-24.6%) in the Flu/Bu4 group (p&amp;lt;0.001), while among standard-risk patients, it was 46.3% (95% CI: 35.6-56.2%) in the Flu/Bu4/Mel group vs 43.8% (95% CI: 40.3-47.4%) in the Flu/Bu4 group (p=0.745; P for interaction: 0.010). Conclusion The results showed that Flu/Bu4/Mel resulted in superior 5-year OS compared to Flu/Bu4, with an adjusted hazard ratio of 0.73. In addition, patients with high-risk disease showed better survival benefit with Flu/Bu4/Mel treatment. Figure Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

Transient Elevations in Markers of Hepatic Function during Pediatric Acute Lymphoblastic Leukemia Treatment Are Common but Do Not Influence Outcomes: A Study of 805 Patients from the Learn Consortium

Introduction: Hepatotoxicity is a frequent and challenging adverse event in children with acute lymphoblastic leukemia (ALL), but patient factors that are predictive of hepatotoxicity are not well understood. We leveraged a data repository jointly developed by two pediatric oncology centers within the Leukemia Electronic Abstraction of Records [LEARN] Consortium to assess the landscape and determinants of liver dysfunction throughout ALL therapy in patients who were risk-stratified to receive either standard- or high-intensity treatment blocks. Methods: The subjects were children ages 1-21 years who were treated for ALL between 2006-2014 at either Children's Hospital of Philadelphia or Texas Children's Hospital. Demographics, disease-related data, and every laboratory value collected during treatment were obtained by targeted manual abstraction and extensive semi-automated extraction of patient electronic medical record (EMR) data. To reduce cohort heterogeneity, we excluded patients who received non-standard ALL therapies. Patients were categorized as receiving either standard-intensity or high-intensity treatment for their first three blocks of therapy (Induction, Consolidation, Interim Maintenance 1 [IM1]) based on chemotherapeutic agents delivered in those blocks. Differences in laboratory value-determined hepatoxicity were then analyzed based on this categorization for all remaining phases of therapy. Hepatic lab values (AST [SGOT], ALT [SGPT], total bilirubin [t. bili], and conjugated bilirubin [c. bili]) were first normalized to the age-based upper limit of normal (ULN), and the median value was then determined. A multivariate mixed-effects linear regression model with random effects was used to identify differences in the treatment group medians and the following covariates: age, race/ethnicity, sex, BMI, and ALL immunophenotype. Laboratory values were classified by the CTCAE v5.0 grading system, with grade ≥ 3 considered 'elevated.' Results: 805 pediatric ALL patients were included in the analysis, representing 114,095 hepatic lab values (Table 1). Less than 10% of patients had elevated lab values at diagnosis. Throughout treatment, the majority of lab values fell within 1-2x ULN for age for both standard- and high-intensity treatment groups (Fig. 1a-d). The median hepatic lab values for the high-intensity group were slightly higher than the standard risk group across all treatment phases, and this difference was most consistently significant in Consolidation and Delayed Intensification. Among the four hepatic labs that were assessed, ALT had the most significant deviation above normal (up to 30x ULN, Fig 1a). Patients were more likely to have elevated transaminases during maintenance than prior to maintenance (Fig. 1e). Similarly, but to a lesser degree, patients were more likely to have elevated t. or c. bili during maintenance than prior to maintenance. Age, race, and BMI were correlated with elevated hepatic labs, with Hispanic and/or overweight patients more likely to have elevations in 3 or more phases of therapy (Table 2). However, no hepatic lab abnormalities were correlated with either overall or relapse-free survival. Conclusions: This is the first comprehensive study of measures of hepatotoxicity in a large and uniformly-treated cohort of pediatric ALL. While significantly elevated hepatic labs are rare at diagnosis, they are common during ALL treatment and are seen more commonly in maintenance than in prior phases. Patients who are overweight and/or Hispanic are more likely to experience grade 3 or higher hepatoxicity. We observed no relationship between hepatotoxicity and relapse or survival. Further studies are ongoing to delineate the temporal correlation of liver function and chemotherapy dosing and administration. Disclosures No relevant conflicts of interest to declare.

High Risk Genomic Alterations Identified at the Time of Diagnosis Are Strongly Associated with MRD and Subsequent Poor Outcomes in AYA ALL Patients Treated on a Pediatric Inspired Chemotherapy Regimen

High Risk Genomic Alterations Identified at the Time of Diagnosis Are Strongly Associated with MRD and Subsequent Poor Outcomes in AYA ALL Patients Treated on a Pediatric Inspired Chemotherapy Regimen

Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (&gt;3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p&gt; .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

Real-World Outcomes of Ixazomib in the Treatment of Multiple Myeloma from a Single Center in China

OBJECTIVE:To review the role of ixazomib in the treatment of MM from a single center in China, focusing on the efficacy and safety of this oral PI at all stages of disease since ixazomib was approved by CFDA in 2018.METHODS:The data of real-world outcomes were collected from of the patients with high-risk multiple myeloma diagnosed in the blood diseases hospital,CAMS&amp;PUMC from July 2018 to June 2019 when the patients received the first Ixazomib cycle. The patients were divided into three groups, which were salvage therapy of R/RMM, maintenance and frontline therapy of NDMM respectively.RESULTS:The first group was Ixa-based salvage treatment in R/RMM.31 patients were included and median age was 62years(47-71).The proportion of patients with cytogenetic high risk was 50%(One patient was unable to stratify risk). Extramedullary invasion was very high 40% in early relapse. Half of them received more than 2 lines of treatment, and about 10% received 4 or more lines of prior treatment. ORR was 51.6%; ≥ PR 35.5%; VGPR+CR9.7%.The median ixazomib therapy cycles were 3(1-12). 5 patients entered maintenance therapy for more than eight cycles.In all 8 patients who interruptedIxazomib treatment,six were due to disease progression,one was SD,and the remaining one will receive CART therapy.The median follow-up was 6.8 months, and the median PFS was not yet achieved.The survival curves of high-risk group and standard-risk group were obviously separated, but there was no statistical difference.However, the prognosis of extramedullary invasion group was very poor. PFS was significantly shorter than that of control group after treatment with Ixazomib(2.86m vs NA).The second group was Ixa-based maintenance therapy of NDMM. Seven patients received maintenance therapy after ASCT, and 20 transplant-ineligible(TIE) patients entered maintenance therapy.Maitenance with Ixazomib appears to have efficacy with deepen responses,the transplantation group(57.1%CR before vs 85.7%after) similar to the non-transplantation group(35.3%before vs 58.8%after).All the patients did not interrupt Ixazomib treatment.Only 1 patient(3.7%) had grade 4 adverse events, which was thrombocytopenia.The median ixazomib therapy cycles were 4(1-11).The third group was Ixa-based frontline therapy. The median age of 24 patients was 66y (42-79), CA High Risk was 25% (6/24), R-ISS III Stage was 12.5%(3/24), and no patients with EMD.The total of 9 patients were suitable for transplantation. Among them, 5 patients completed stem cell collection, 3 patients completed autotransplantation, 1 patient waited for transplantation, and 1 patient entered the continuous treatment group because of poor mobilization.The other 4 patients were still in induction stage. There were 15 patients in the TIE group and one patient dropped out of the group because of disease progression.The remaining 23 patients achieved a overall response rate of 78.3%. Nearly half of the patients achieved deep remission(VGPR+CR 43.5%).Posttransplantation patients could achieve 100% deep remission rate.As the number of treatment cycles increased, the proportion of complete remission increased in TIE patients.CONCLUSION:Ixazomib as induction/consolidation after ASCT, followed by maintenance, is well tolerated, convenient, and effective. Ixazomib is an important option for high-risk patients with real-world experience.KEYWORDS:Real-world, Ixazomib, multiple myeloma Figure Disclosures No relevant conflicts of interest to declare.

Aberrations Detected By FISH in Brazilian Multiple Myeloma Patients

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy with genetic abnormalities that comprise the most important prognostic factors. Chromosomal aberrations also influence the evolution and treatment refractoriness. Abnormalities progress in a stepwise way, from the pre-malignant stage of monoclonal gammopathy of undetermined significance, through smoldering until symptomatic MM. While marrow karyotype reveals only &lt;30% of aberrations, FISH may show in up 90% of cases. FISH has become an essential tool in diagnosis, risk-classification and personalized therapy. There are two main groups of abnormalities: primary (trisomies and 14q or IGH gene translocations) which occur in plasma cells evolving into clonal stage, and secondary (-13/13q-, del(17p), +1q21/del1p), occurring during disease progression. As there are few reports of genetic aberrations in Brazilian MM patients, the objective of this study was to enlarge the casuistic and compare results. Objective: To dissect FISH aberrations detected in a larger set of Brazilian MM patients. Material and Methods: From Jan 2012 to Nov 2017, 417 MM patients were selected for the study. FISH was performed on isolated CD138 immunomagnetic beads plasma cells, using probes for 6q23.3 (MYB), 11q12.1 (D11S3347), 11q22.3 (ATM), 13q14.3 (D13S319-D13S25-RB1), 13q34 (D13S1825-LAMP1), 14q32 (IGH, break-a-part), 17p13.1 (TP53) IGH/FGFR3, IGH/CCND1 and IGH/MAF, according to the manufacturer´s instructions. At least 100 interphase cells were counted, and results described according to ISCN 2016. The cut off level was in-house established by mean +2 standard deviation from normal bone marrow controls. Results: Patients mean and median ages were 63.9 and 64y, respectively. M:F rate was 1.5:1. FISH showed abnormalities in 80% (333) of cases. Considering primary abnormalities: IGH-FGFR3 rearrangements were detected in 22.5% (30 patients), IGH-CCND1 in 57.2% (76), IGH-MAF in 3.7% (5 patiens), and 16.6% (22) IGH-unidentified gene. The most frequent trisomies were: 6 (62 patients), 11 (93 patients) and 17 (33 patients), some co-occurring and others isolated. 89 (31.6%) cases presented &gt;3 aberrations, from which 25% had del(17p) (TP53) as well; 65 cases had three aberrations and 127 less than three abnormalities. Referring to secondary aberrations, 67(20.1%) cases presented del(13q) (RB1 and LAMP) and 32 (9.6%) del(17p) (TP53). Stratifying to prognosis (mSmart 2.0) 37 (10%) patients were considered as high-risk; 92 (27.6%) intermediate; 160 (48%) standard and 44 were not classified. Discussion: Comparing these results to literature reports, at diagnosis, Brazilian MM patients have mean and medium ages younger than European and North American populations. This type of difference has been detected in other hematopoietic neoplasias as well. FISH results were thoroughly similar referring to the total percentage and type of aberrations, but some variations in the frequency of aberrations were observed. Most patients were classified in the standard-risk group, presenting hyperdiploidy (30%) and t(11;14)(19%). The percentage of high-risk patients was reasonable (10%). Most of those with more than three aberrations also presented del(17p), a marker of adverse cytogenetics, as expected. The frequency of del(17p) was not unexpected, most being heterozigous deletion. Cases described as IGH-unidentified gene rearrangements may have been due to the unavailability of probes for chromosomes 6 and 20, at the time of the study. The same happened to 1q gain and del(1p). In summary, the spectrum of aberrations detected allowed identifying high-risk patients, choosing adapted therapy and improving outcomes. Disclosures No relevant conflicts of interest to declare.

Encouraging Results with ALL IC-BFM 2009 Protocol Therapy in Pediatric Acute Lymphoblastic Leukemia/Lymphoma in Resource-Limited Setting: A Single-Center Study from India

Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. The survival rates in pediatric ALL have improved to 80-90% in high-income countries, where the goal of current risk-adapted treatment protocols is to minimize treatment-related mortality. In contrast, cure/survival rates are still lower in low-income countries, due to combined effect of disease-related factors, high incidence of treatment abandonment, higher rates of relapse, &amp; higher treatment-related mortality. The Berlin-Frankfurt-Münster (BFM) protocol versions are commonly used for treatment of pediatric ALL in many centers. There is no published data on treatment outcomes with ALL IC-BFM 2009 protocol in pediatric ALL in India. Objective: The study aims to evaluate the treatment outcomes in Indian pediatric ALL/LBL patients treated with ALL IC-BFM 2009 protocol under severe resource-limited settings, in terms of morphological complete remission (CR), minimal residual disease (MRD) status, and disease-free survival. Methods: Our study enrolled 25 newly diagnosed pediatric ALL/LBL patients (age ≤18 years) between February 2018 &amp; June 2019. Induction chemotherapy was initiated as per ALL IC-BFM 2009 protocol after obtaining informed consent. Risk stratification was done as per protocol into standard risk (SR), intermediate risk (IR), and high risk (HR) groups, based on age, baseline leukocyte count, cytogenetics &amp; molecular study findings, day 8 steroid response (peripheral blood absolute blast count), bone marrow MRD by flowcytometry on day 15, and bone marrow morphological response on days 15 &amp; 33 of induction phase. Additional imaging was done to assess response in LBL patients. Central nervous system (CNS)-directed therapy with intrathecal chemotherapy was administered as per protocol. Post-induction therapy consisted of an augmented early intensification phase, risk-adapted consolidation therapy phase, a delayed intensification (reinduction) phase, &amp; maintenance phase. Therapeutic cranial radiation (18 Gy) was administered only to patients with documented CNS leukemia. Results: Of the total 25 patients, 17 had B-ALL, six had T-ALL &amp; two had T-LBL. Median age of patients was 9 years (2-18 years), with 11 boys &amp; 14 girls. All the patients had BCR-ABL negative disease; three patients had t(12;21)(p13;q22)/ETV6-RUNX1. Seven patients (28%) had hyperleukocytosis (leukocyte count &gt;1,00,000/µL) and two patients had CNS leukemia at presentation. Nine out of the 25 patients (36%) were in high risk group as per criteria. Eight patients (32%) had poor steroid response on day 8 of induction (PB blasts ≥ 1000/µL). Six patients had M3 marrow on day 15 (&gt;25% blasts in marrow). Day 15 bone marrow MRD was &lt;0.1% in 13 patients (52%), &gt;0.1% in 7 patients (28%) and could not be done in 5 patients (including the two T-LBL patients). Twenty-three out of 25 patients (92%) achieved morphological CR (marrow blasts &lt;5%) on day 33. There were two deaths in induction; both patients were not in CR as per day 33 bone marrow morphology criteria. One B-ALL patient in HR group died of early medullary relapse. The remaining 22 patients are in CR &amp; doing well on follow up, and four of them have started maintenance phase therapy. The results are summarized in Table 1. Conclusion: Our preliminary results with ALL IC-BFM 2009 treatment protocol in Indian pediatric ALL/LBL patients are encouraging, with 92% complete remission rate, 88% disease-free survival and manageable treatment-related toxicity in spite of severe resource constraints. Long-term follow up &amp; enrollment of higher number of patients is planned. Disclosures No relevant conflicts of interest to declare.

Improved Treatment of Childhood ALL in Malaysia

The survival rate of childhood acute lymphoblastic leukemia (ALL) has reached &gt;80-90% in developed countries, which is a triumph of modern medicine. This success is due to implementation of contemporary treatment protocols, optimal application of risk stratification, risk-directed multi-agent chemotherapy regimens, and improved supportive care. Unfortunately, such improvements have not translated to Low Middle Income Countries (LMICs), where 90% of the world's children live. The estimated 5 year survival rates in Asia range widely between 44.3% and 80%. The Intercontinental-BFM2002 study, conducted in 15 upper-middle and high-income countries reported a 5 year event-free survival (EFS) and overall survival (OS) rates of 74% and 82%, respectively. Factors that may contribute to the lower survival in LMICs are highly complex, including delays in presentation, diagnostic inaccuracy, restricted budget for risk-stratification and appropriate treatment, treatment abandonment and socio economic status. In Malaysia, different protocols are used by different leukemia treatment centers for treating children with ALL. In UKM Medical Centre (UKMMC), the UKALL protocols (modified UK X, XI, XII, 97(99) and 2003) have been used in the Pediatric Hemato-Oncology Unit since the 1990s. Herein, we report the adopted protocol, the stratification profile and outcome of children with ALL, treated with modified UKALL 97(99) and UKALL 2003 in our institution from 2006 to 2014. Clinical data from children with ALL, who received these modified therapies, were retrospectively reviewed. Prednisolone was used in modified UKALL97(99) and Dexamethasone in modified UKALL 2003, while 6-mercaptopurine was used in both modified protocols. Otherwise, chemotherapy and duration of treatment were identical to the original protocols of Regimens A, B and C. ALL was diagnosed based on standard morphology and immunophenotyping criteria. At diagnosis, patients were stratified according to the National Cancer Institute (NCI) risk criteria and using FISH for detection of cytogenetic abnormalities. EFS and OS were determined using the Kaplan-Meier methods. Newly diagnosed ALL in 156 children were included in the study; 103 (66.0%) were standard risk, 49 (31.4%) were high risk and 4 (2.5%) were infants. There were 2 children with Down syndrome. The success rate of FISH was 76.4% (94/123). Patients were stratified as standard risk, based on ETV6-RUNX1, and high risk based on unfavorable cytogenetics, BCR-ABL and MLL rearrangements. Half of the patients with unfavorable cytogenetics were classified in the NCI high risk group, with WCC &gt;100x109/L. A total of 151 patients were treated as per risk stratification, 2 patients transferred care, while 3 patients refused treatment. Mortality from sepsis during treatment was approximately 10%, including 2 deaths during induction remission and induction at relapse. The majority of disease progression was relapse-related, however, treatment abandonment also contributed to relapse. Approximately 5% of patients abandoned their treatment (3 patients abandoned and 3 patients refused treatment). The 5-year OS for the standard risk group was 86.6%, with 3-year and 5-year EFS of 88.1% and 83.4%, respectively. The 5-year OS for the high risk group was 65.7%, while 3-year and 5-year EFS were 64.7% and 58.2%, respectively (Figure 1). The MRC UKALL97 stratification by NCI risk reported a 5-year EFS of 83.1% for the standard risk group and 66.9% for the high risk group, while the UKALL2003 interim analysis reported a 5-year EFS of 87.7%. The MRC UKALL97/99 reported a 5-year OS of 88%. The cure rate of children with standard risk ALL at UKMMC, using modified UKALL 97(99) and UKALL 2003 protocols, was comparable to MRC UKALL97. However, the cure rate for high risk ALL was comparatively lower. This single center study from UKMMC has highlighted some critical factors that improved the outcome of children with ALL and suggests further improvements that are necessary to reduce the relapse rate, especially in the high risk ALL patients. Disclosures No relevant conflicts of interest to declare.

Preliminary Lasso Regression Analysis Identifies DNA-Damage Gene Expression Signature Predictive of Clinical Outcomes in Patients Using Gemtuzumab Ozogamicin

Background: In September 2017, the FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate, for treatment of newly diagnosed and relapsed/refractory AML setting the pace for a new era of personalized therapeutic options for AML. While the future of GO as a therapy in AML is bright, studies have shown that clinical response to GO is subject to interpatient variability (Gbadamosi 2018). Hitherto, efforts to understand the interpatient variation have focused on profiling CD33 expression levels (Pollard et al. 2016) and more recently on genetic variation in CD33 and ABCB1 predicative of GO response (Chauhan et al. 2019, Rafiee et al. 2019). However, efforts to understand interpatient variability in regards to calicheamicin, the DNA-damaging cytoxin linked to the antibody portion of GO, have been limited. Thus, we hypothesized that interpatient differences in expression levels of genes involved in pharmacodynamic effects of calicheamicin may impact GO response/resistance. Methods: Herein, our group has used the least absolute shrinkage and selection operator (LASSO) regression analysis method to identify critical genes with expression levels predictive of clinical outcomes in response to GO. Using data from the TARGET database, the expression levels of 18 genes, selected for their role in calicheamicin induced DNA-damage response, were extracted for AML patients treated with GO in the AAML03P1 and AAML0531 clinical trials (N=128; Table 1). Using a penalized LASSO regression algorithm (glmnet R-package), a Cox regression model was fit on to the expression levels of the selected gene. A thousand bootstraps of LASSO regression were performed and genes included in greater than 95% of the models were further selected. Average coefficients from the LASSO model were used to generate a gene signature equation designated as the DNA-damage response score (DDRS) given the nature of the genes included. Patients were classified into high (DDRS High) or low (DDRS Low) values for DDRS according to the median value and evaluated using Cox-proportional hazard model for survival data analysis, while the Chi-square test was used to examine the differences between categories, and the Wilcoxon rank-sum test was used to assess the differences in averages where appropriate. Results: The DDRS equation was defined as DDRS = (AKT1*-0.070) + (CASP9*-0.091) + (H2AFX*-0.160) + (XRCC4*0.373) where gene expression levels are multiplied by the coefficients obtained from the LASSO regression (Figure 1). Patients in the DDRS High group had significantly worse event free survival (EFS; HR = 2.22, P &amp;lt; 0.001; Figure 2A), lower complete remission rates (67.7% vs 94.6%, P &amp;lt; 0.001; Figure 3A), and a trend towards worse overall survival (OS; HR = 1.70, P = 0.058) as compared to patients within DDRS Low group. DDRS score was also significantly different amongst patients that were MRD+ve vs. MRD-ve after induction 1 therapy (21% difference, P = 0.038; Figure 3B). Consistent results were seen within standard risk group patients where patients in the DDRS High group had significantly worse EFS (HR = 2.29, P = 0.01; Figure 2B) as compared to those in the DDRS Low group. In preliminary multivariate Cox regression analysis, the DDRS remained a significant predictor of EFS amongst age, risk group, FLT3 status, and WBC (HR 2.42, P &amp;lt; 0.001; Table 2). Conclusion: Our preliminary investigation using LASSO regression model defined DDRS, a gene signature predictive of clinical response in patients treated with GO. The model included four genes well known for their involvement in DNA-damage response: AKT1, a kinase that regulates cell growth and division; CASP9, The initiator caspase involved in apoptosis; H2AFX, a DNA-damage marker that recruits other DNA-damage response proteins to damaged loci; and XRCC4, a ligase for DNA damage repair. Our future work focuses on expanding this investigation in bigger cohorts of patients representing different risk groups of AML as well as in vitro mechanistic studies. Once validated for its sensitivity and specificity to calicheamicin response, our results hold promise towards developing strategies for understanding interpatient variability in GO response and personalizing GO therapy based on diagnostic gene expression signatures. Disclosures No relevant conflicts of interest to declare.

Risk Factors of Acute Pancreatitis in Pediatric Acute Lymphoblastic Leukemia Patients: A Single-Center Experience

Background: Acute pancreatitis during chemotherapy of acute lymphoblastic leukemia (ALL) is an often fatal complication which is mainly associated with asparaginase. Despite of the improvement of supportive care during treatment of ALL, the prediction of acute pancreatitis has not been feasible. The aim of this study was to identify the risk factors of acute pancreatitis in pediatric ALL patients. Patients and methods: This study included total 421 patients under 18 years old of age who were newly diagnosed with ALL and treated at Asan Medical Center Children's Hospital between January 2000 and December 2018. Patients in standard-risk group received a modified COG AALL0331 based treatment, and those in high-risk group received Korean multicenter high-risk ALL treatment. For national insurance coverage, native L-asparaginase was used as a first choice in all patients except patients who accepted the expanses of Pegylated-asparaginase (PEG). Patients who developed hypersensitivities to native asparaginase or PEGs, Erwinia-asparaginase was administered. Fibrinogen, triglyceride, amylase, lipase, and coagulation battery were checked before every asparaginases in all patients. The diagnosis and grading of acute pancreatitis were based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The cases of acute pancreatitis after relapse or allogenic hematopoietic stem cell transplantation were excluded. All the laboratory data were collected and analyzed retrospectively. Results: The incidence of acute pancreatitis in pediatric ALL was 3.3% (14 patients) and asparaginase associated acute pancreatitis was 2.8% (12 patients). Acute pancreatitis occurred in mainly in induction chemotherapy (n=8, 67%). Two patients were developed acute pancreatitis in consolidation chemotherapy, 1 in interim maintenance chemotherapy. Among 8 patients who developed acute pancreatitis in their induction chemotherapy, 1 patient was not associated with asparaginase. Among 14 patients, 2 patients were expired of disease progression and none of patient died of acute pancreatitis. Grade 2, 3 of acute pancreatitis patients were 6 and 8 respectively. There was no grade 5 acute pancreatitis. Eleven out of twelve patients who developed acute pancreatitis associated with asparaginase medication re-challenged asparaginase medication after experiencing acute pancreatitis. Among re-challenged patients, only 1 had second acute pancreatitis and discontinued asparaginase medication. There was no significant difference in incidence of acute pancreatitis with initial BSA, protein C, protein S, and age at diagnosis. Multivariate analysis identified prolonged activated partial thromboplastin time (aPTT) before acute pancreatitis in 1 week was significantly involved with risk factor of acute pancreatitis (p=0.013) Eight patients (67%) received a fresh frozen blood transfusion(FFP) before acute pancreatitis in a week. Conclusions: Prolonged aPTT and FFP transfusion are particularly at risk for acute pancreatitis in pediatric ALL patients. Cautious re-challenging asparaginase medication after experiencing grade 2 and grade 3 acute pancreatitis is needed. Early diagnosis and manage asparaginase-associated acute pancreatitis will contribute patients with sufficient effect of asparaginase medication. Disclosures No relevant conflicts of interest to declare.

The influence of different intensity of treatment on hormonal markers of gonadal function in acute lymphoblastic leukemia survivors.

Anti-cancer treatment in children can deteriorate gonadal function and affect future fertility. We analyzed the hormonal markers of gonadal function in adolescent leukemia survivors, treated in childhood with different levels of aggressiveness. We analyzed hormone levels in 69 adolescents and young adults, leukemia survivors stratified into standard (SR), intermediate (IR), and high (HR) risk groups, and in 80 healthy controls (38 men) at a similar age. We assessed follicular stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B in the whole group, testosterone in males, and E2 and anti-Müllerian hormone (AMH) in females. Males classified into HR group presented, in comparison to control, higher levels of FSH, LH, lower inhibin B, and normal testosterone, whereas in SR and IR group, the hormonal values were comparable to the control. In females, in all risk groups, the levels of FSH, LH, E2, and inhibin B were comparable with the control, but the mean AMH levels were slightly lowered. We did not observe the effect of prophylactic cranial irradiation (12 or 18 Gy) or the time of treatment (before vs. during puberty) on hormone levels. In females, a positive correlation was found between the time interval after the end of treatment and AMH levels. Male leukemia survivors having undergone more intensive chemotherapy show the symptoms of disturbed spermatogenesis and need to be followed-up in the future. Women, irrespective of the risk group, can develop the signs of preterm ovarian insufficiency. They should be informed about the impact of the treatment on gonadal function.

Improved Outcomes of All-trans-retinoic Acid and Arsenic Trioxide Plus Idarubicin as a Frontline Treatment in Adult Patients With Acute Promyelocytic Leukemia

IntroductionThe purpose of this study was to explore the outcomes of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) plus idarubicin (IDA) as a frontline treatment in adult patients with acute promyelocytic leukemia (APL). Patients and MethodsWe analyzed the outcomes of ATRA and intravenous ATO plus IDA as a frontline induction therapy in 118 patients with APL with high-risk (HR) and standard-risk (SR) disease from January 2008 to December 2017. The medical records of 118 patients with APL (HR, n = 45; SR, n = 73) who received the frontline triple combination regimen at Henan Provincial People’s Hospital and Tongji Hospital were retrospectively reviewed. Consolidation therapy comprised 6 cycles of ATO and ATRA plus IDA, and IDA was administered in 1 to 4 cycles of consolidation therapy based on the comparable clinical efficacy compared with 6 cycles and fewer side effects to myocardium without subsequent maintenance therapy. ResultsOf 118 patients, there were 3 (2.5%) early deaths and 115 (97.5%) hematologic complete remissions; 102 (88.7%) of 115 patients achieved molecular complete remission following induction therapy, and all patients were polymerase chain reaction-negative for promyelocytic leukemia-retinoic acid receptor alpha after the first cycle of consolidation therapy. The 5-year overall survival (OS) and event-free survival (EFS) were 93.0% ± 2.9% and 92.4% ± 3.0%, respectively. Early death, hematologic complete remissions, molecular complete remissions, and toxicities were comparable between the HR and SR groups. The cumulative incidence of relapse in the HR group was 4.7% (n = 2), and the cumulative incidence of relapse in the SR group was 0. The OS and EFS of the SR and HR groups were comparable (92.3% ± 4.5% vs. 92.8% ± 4.0%; X2 = 0.263; P = .608; 92.3% ± 4.5% vs. 91.1% ± 4.2%, X2 = 0.917; P = .338). The total dosage of IDA was approximately 181 to 258 mg, and no patient experienced cardiotoxicity. OS and EFS were not influenced by fms-related tyrosine kinase 3 internal tandem duplication mutation status (P = .405 and P = .528, respectively). ConclusionThe triple combination of ATRA and ATO plus IDA as both an induction and consolidation therapy for the HR and SR groups attained excellent outcomes, and this regimen was effective, safe, and easy, without maintenance therapy. The triple combination treatment might be a preferred frontline therapy for patients with APL, especially for those with HR or the APL fms-related tyrosine kinase 3 internal tandem duplication mutation.

416P - Meta of classical chemotherapy compared with high-dose chemotherapy combined with autologous stem cell transplantation in newly diagnosed medulloblastoma patients after radiotherapy

BackgroundHigh-dose chemotherapy combined with autologous stem cell rescue (HDCT+ASCR) has been used to treat newly diagnosed medulloblastoma (MB), but there was no high-level evidence to support its efficacy. MethodsDatabases were retrieved, and patients were divided into two groups: group A was radiotherapy combined with HCDT+ASCR, and group B was classical radiotherapy and chemotherapy. The clinical benefit rate, progression-free survival (PFS), total survival (OS) and toxicities data were extracted. Results22 clinical trials met the inclusion criteria, 416 in group A and 2331 in group B. There was no difference in CBR between two groups (80.0% vs. 71.5%, P=0.262). The 3-year PFS (3-y PFS) of group A was significantly better than group B (79.0% vs. 69.5%, P=0.004). The analysis found that there was no difference between the two groups of the standard risk group or the high-risk group. In the standard risk group, the 5-y PFS of group A was significantly better than group B (83.6% vs.75.6%, P=0.004). Comparison of 3-y OS and 5-y OS between two groups of all MB patients showed no difference (P=0.086; P=0.507), stratified analysis was the same result. The gastrointestinal toxicity in group A was significantly higher than that in group B (P=0.016), and the level 3/4 ototoxicity in high-risk group A was higher than that in group B (P<0.001). ConclusionsHDCT+ASCR was not recommended for newly diagnosed high-risk MB patients. The clinical significance of HDCT+ASCR at the time of initiation in the standard risk group remains to be further explored. Legal entity responsible for the studyThe Second Hospital of Hebei Medical University. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Long-term follow-up of children with acute promyelocytic leukemia treated with Beijing Children’s Hospital APL 2005 protocol (BCH-APL 2005)

We studied the outcomes of children with APL treated by the Beijing Children’s Hospital’s (BCH) acute promyelocytic leukemia (APL) 2005 protocol (BCH-APL2005). The clinical data of 77 patients enrolled from January 2005 to June 2015 were analyzed retrospectively. The hematologic complete remission (CR) rate and overall survival (OS) rate were evaluated between standard-risk (SR) and high-risk (HR) groups. Prognostic factors and complications were investigated in these two groups. CR in the SR and HR groups was 96.4% (54/56) and 85.7% (18/21), respectively, while the 10-year OS was 94.6% (53/56) and 76.2% (16/21), respectively. The cumulative incidence of early death was 6.5% (5/77), and the SR and HR groups were 1.8% (1/56) and 19.0% (4/21), respectively. Only two patients relapsed, and the relapse rate was 2.6% (2/77). According to Kaplan–Meier analysis, the SR group had a significantly better long-term survival than HR counterparts (p= .016). Initial leukocyte count was the only prognostic factor (p= .016) by univariate analysis, while other factors, such as FLT3-ITD and platelet count, had no correlation with prognosis. In addition, early deaths were mainly due to intracranial hemorrhage. Although the combination of all-trans retinoic acid (ATRA) and chemotherapy can improve the outcome of APL patients, the early deaths and anthracycline-related cardiac toxicity were relatively higher in our study. Current efforts focus on reducing or even avoiding chemotherapy in APL children and rest on the frontline regimen of intravenous arsenic trioxide or oral realgar-indigo naturalis formula plus ATRA, which is the direction for APL treatment.