Dose Of L-asparaginase Research Articles

Modified SMILE (mSMILE) is active in the treatment of pediatric Epstein-Barr virus-associated natural killer/T-cell lymphoma: a single center experience, case series.

The Epstein-Barr virus-associated natural killer (NK) and T-cell lymphoma (EBV + NK/T cell lymphoma) is a severe illness mainly affecting children and young adults, often resulting in a poor prognosis. To date, there is no consensus on an established treatment strategy. This study aims to evaluate the efficacy and safety of the mSMILE (modified steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen in treating EBV+ NK/T-cell lymphoma and to provide insights into potential treatment outcomes. In this study, we conducted a retrospective analysis of the clinical data and treatment outcomes for patients with EBV + NK/T cell lymphoma treated at Children's Hospital of Nanjing Medical University between July 2017 and January 2022. These patients received at least two cycles of the mSMILE chemotherapy, in which a single dose of pegaspargase was substituted for 7 doses of L-asparaginase per cycle. Eight patients were included in the study: one with extranodal NK/T-cell lymphoma, one with primary nodal NK/T-cell lymphoma, and six with Systemic EBV+ NK/T cell lymphoma of childhood. The results showed that five patients achieved complete remission, two achieved partial remission, and one showed progressive disease, resulting in a complete remission rate of 62.5% and an overall response rate of 87.5%. The 3-year overall survival (OS) and event-free survival (EFS) rates were 87.5% and 75%, respectively. The most common adverse reactions associated with chemotherapy were hematologic toxicities of stages III to IV. Nonhematologic adverse reactions mainly included impaired liver function, infections, and oral mucositis, which were resolved with aggressive anti-infective therapy. Based on our clinical experience, the mSMILE appears to be a safe and effective treatment option for EBV + NK/T-cell lymphoma, meriting further investigation in late-phase clinical trials.

Implementation of plate reader-based indooxine and Nessler protocols for monitoring L-asparaginase serum activity in childhood acute lymphoblastic leukaemia.

Monitoring the blood serum activity of L-asparaginase in children with acute lymphoblastic leukaemia (ALL) has been highly recommended to detect enzyme inactivation that can cause relapse and to avoid unwanted toxicity. Nevertheless, perhaps at least partially due to the lack of clinically approved commercially available kits or standardized and independently reproduced and validated in-house protocols, laboratory assay-based determination of the optimal doses of L-asparaginase is not carried out routinely. In this study, we adapted previously published protocols for two plate reader-based colorimetric methods, indooxine and Nessler, to measure asparaginase activity. Mock samples with dilutions of the enzyme for initial optimization steps, and patient samples were used as a proof of principle and to compare the two protocols. For the first time the indooxine and the Nessler methods are adapted for a plate reader and L-asparaginase serum activity levels are compared by both protocols. Passing-Bablok and Bland-Altman's statistical analyses found very little difference, strong correlation (r = 0.852), and bias of only 6% between the data from the two methods when used for fresh patient samples. Furthermore, we demonstrate that the Nessler method could also be applied for frozen sera as the results, compared to fresh samples, showed little difference, strong correlation (r = 0.817), and small bias (9%). We successfully adapted and validated two methods for measuring L-asparaginase activity in cALL and provided the most detailed description to date on how to reproduce and implement them in other clinical laboratories.

Thromboprophylaxis with Intermediate Dose Low Molecular Weight Heparin in Adults Undergoing Induction with L-Asparaginase for Acute Lymphoblastic Leukemia

Introduction Adolescents and young adults (AYA, defined as age 15-39 years) with acute lymphoblastic leukemia (ALL) have a poorer prognosis than their pediatric counterparts. To replicate the success of ALL treatment in children, pediatric-inspired regimens have been incorporated into the treatment of AYA and often include the use of L-asparaginase. Rates of thrombosis in adults receiving L-asparaginase for treatment of ALL have been reported to be as high as 34%, compared to only about 5% in pediatric patients. The risk of thrombosis is elevated primarily during the induction phase of treatment. Several strategies have been studied in adults, including antithrombin III replacement, fresh frozen plasma replacement, and prophylactic dosing of anticoagulation, however no clear guidelines exist on how to prevent thrombosis in these high-risk patients. To prevent L-asparaginase-induced thrombotic events, our institution implemented a standard practice of 1mg/kg/day of low molecular weight heparin (LMWH), a dose in-between prophylactic and therapeutic dosing, administered to all adults with ALL who were treated with L-asparaginase during induction chemotherapy. In this current study, we report data from patients who have been treated with this strategy from 2012 to present, focusing on the antithrombotic efficacy and safety of 1mg/kg/day LMWH in this population. Methods This retrospective chart review included 62 patients who received prophylactic anticoagulation with the LMWH enoxaparin (1mg/kg/day) while undergoing induction chemotherapy with L-asparaginase for ALL at the Oregon Health & Science University from 2012 to present. Anticoagulation with enoxaparin was initiated with the first dose of L-asparaginase and continued until the day of discharge or day 30 of induction. The primary outcome was the incidence of thrombosis within the first 30 days of L-asparaginase administration. Minor and major bleeding events, as defined by the International Society of Thrombosis and Haemostasis (ISTH), were recorded. Statistical analysis with univariate regression models was performed to evaluate the association of thrombotic events with demographic, disease and treatment variables. Results Sixty-two patients received 1mg/kg/day LMWH prophylaxis during ALL induction between January 2012 and June 2023 (43 with B-ALL and 19 with T-ALL). Median age at induction was 25.7 years (range 18-39 years). A majority of patients (83.9%) received the maximum dose of 2500mg/m 2 of L-asparaginase. Four patients (6.5%; 95% CI 1.8%-15.7%) experienced a thrombotic event within the first 30 days of induction with L-asparaginase; 3 of the events were catheter-associated and were treated supportively or with catheter removal, and 1 patient developed a distal lower extremity deep vein thrombosis related to myositis. Median time to thrombosis was 13.5 days (range 11-22 days). There were no significant associations between development of thrombotic events with age, gender, B- or T-cell precursor, or dose of L-asparaginase. No thrombosis-related deaths or major bleeding events occurred. Conclusions Prophylactic anticoagulation with intermediate dose 1mg/kg/day LMWH in adults with ALL undergoing induction chemotherapy with L-asparaginase is a safe and an effective strategy to prevent serious thrombotic events. Our institutional rate of 6.5% of patients experiencing thrombotic events during induction with L-asparaginase, with all of the events being clinically low risk, compares favorably to historically reported rates in adults and approaches the low rates reported in children. Further prospective research is warranted.

Toxicity of L-asparaginase drugs in acute lymphoblastic leukemia treatment

Currently no therapy of acute lymphoblastic leukemia is conceivable without L-asparaginase drugs, with its antileukemic effect by extracellular asparagine depletion, thus preventing its admission to leukemic cell. Besides high antitumor effect, L-asparaginase drugs have side and toxic effects, such as hypersensitivity reactions, thrombosis, pancreatitis / pancreatic necrosis, and hepatotoxicity. For L-asparaginase safety profile improvement a technology of pegylation was lay down and PEG-aspargase drug produced. This drug has less toxic effects and recommended as first-line therapy of acute lymphoblastic leukemia. Drug monitoring for assessment the effectiveness and toxicity of L-asparaginase is optimal. Such therapy individualization helps for L-asparaginase dose finding and decrease frequency and severity of side effects.

Frequency and Risk Factors for Hyperglycemia in Children with Acute Lymphoblastic Leukemia During Induction Chemotherapy

Background: Hyperglycemia is a common side effect and it has long been recognized as a consequence of corticosteroids and L-asparaginase, chemotherapeutic agents key to ALL treatment. This study was done to determine the frequency and identify the risk factors for hyperglycemia in paediatric ALL during induction chemotherapy.
 Material & Methods: This prospective observational study was done among 87 newly diagnosed ALL cases of 1-18 years of age. After initial work up patient got induction chemotherapy according to UK ALL 2003 (modified) protocol in BSMMU. Anthropometric measurements and CBC, RBS/ 2 hours after glucose/ FBS and corresponding urine sugar was assessed after 2nd, 4th, 6th and 9th dose of Lasparaginase and after completion of induction. Data were analyzed by SPSS 17.0.
 Results: Eight patients (9.75%) of the study cohort developed hyperglycemia. Among ³10 years of age 36.8% had hyperglycemia compared to 1.6% of younger children (p<0.001). No gender difference was found. Obese and overweight (p <0.001 in both cases), positive family history of diabetes mellitus using 4 drugs during induction remission phase of chemotherapy were found significant risk factors for hyperglycemia.
 Conclusion: In this study frequency of hyperglycemia was 9.75% and frequency of transient hyperglycemia (TH) was 7.3%. Older age, obese or overweight children, positive family history of diabetes mellitus, patient getting regimen B according to UK-ALL 2003 (modified) protocol had shown increase the risk of hyperglycemia.
 BANGLADESH J CHILD HEALTH 2021; VOL 45 (3) : 155-161

Feasibility and Improvement in Survival with a Risk-Adapted Treatment Regimen for Childhood Acute Lymphoblastic Leukemia in a Limited Resource Setting

Introduction: High-intensity therapeutic regimens results in ALL have not been reproduced in limited resource settings, due to the lack of appropriate support therapy, diagnostic methods, limited access to drugs, and high treatment related mortality. For low and middle-income countries, treatment of these patients represents a challenge. In Mexico acute leukemia represents 49% of all pediatric cancers, with a 5-year overall survival between 50 and 60%, a relapse rate of 26%, induction related mortality of 3-10%, and a mortality in remission of 14%. We report the results of an adjusted treatment regimen based on an adapted risk stratification for a limited-resource setting. Objective: To implement a risk stratified treatment protocol for a limited resource setting, with the aim of reducing induction related mortality, and improving EFS and OS. Materials and Methods: From January 2017 to March 2020, all patients diagnosed with ALL between 0 and 15 years of age in a single center in northeast México were captured in a prospectively maintained database. Depending on risk stratification, patients received an adjusted treatment protocol with variations on intensity and duration for the different phases. The main differences were the amount of anthracycline doses during induction (2 for low, 3 for intermediate/high patients), the requirement of at least 20 doses of L-asparaginase for intermediate/high risk patients, and the use of Capizzi-style methotrexate for intermediate risk and high-dose methotrexate only for high-risk patients (Table1). Demographic data was reported using distribution analysis, and the Kaplan-Meier method was used to analyze and predict OS and EFS. Results: There were 59 male and 41 female patients; the median age at diagnosis was 5.5 years. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 94% and 6% patients, respectively, with a follow-up of 41 (0.33-65) months. Regarding risk stratification, 42%, 34%, and 24% children were classified as high, intermediate, and low-risk, respectively. After one week of corticosteroids 80% of patients had a good response, and 84% of patients achieved a negative measurable residual disease (MRD) after induction chemotherapy. Estimated EFS and OS at 5 years were 70% and 77.5% respectively. Of the 93 patients evaluable for response, MRD positivity (16%), induction related mortality (6%), and relapse (16%) rates were lower in this cohort when contrasted with previous protocols. EFS for low, intermediate, and high-risk groups was 73%, 85%, and 56% and OS 88%, 90% and 61% (Figure 1) Conclusions: The implementation of a risk-adjusted chemotherapy regimen adapted for our limited-resource center, improved treatment continuity and was associated with better OS, and EFS. Early relapse rates were also reduced, without increasing induction mortality associated with toxicity. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and standardize therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Acute pancreatitis in children with acute lymphoblastic leukemia correlates with L-asparaginase dose intensity.

L-Asparaginase (L-Asp) is an important therapeutic for childhood acute lymphoblastic leukemia (ALL). Asparaginase-associated pancreatitis (AAP) is a severe complication of L-Asp related to the dosage. We investigated the incidence of, and risk factors for, AAP in pediatric patients with ALL. From January 2002 to December 2018, pediatric patients with ALL treated at National Taiwan University Hospital were enrolled in this study. The diagnosis of AAP was based on the criteria of the Ponte di Legno Toxicity Working Group. Of the 353 patients enrolled in this study, 14 (4.0%) developed AAP. The incidence of AAP in ALL patients was significantly higher after treatment with the 2013 protocol compared with the 2002 protocol of the Taiwan Pediatric Oncology Group (9.5% vs. 1.3%). Multivariate analysis showed that a high peak L-Asp dose intensity (>45,000 U/m2/month) and older age at diagnosis (>6.8 years) were independently predictive of AAP development. The incidence of acute pancreatitis in childhood ALL was correlated more strongly with the peak dose intensity than with the cumulative dose of L-Asp. These results could be used to reduce the treatment-related complications of ALL. L-Asparaginase is an important therapeutic for childhood acute lymphoblastic leukemia, and the accumulated dosage of L-asparaginase is considered as a major risk factor of asparaginase-associated pancreatitis. This article demonstrated that the incidence of pancreatitis correlates with the dose-intensity of L-asparaginase, but not the accumulated dosage. Identification of patient group with high risk of pancreatitis could lead to early diagnosis and reduce the complication. This finding could aid in developing further new protocol or therapeutic strategy design to reduce treatment-related complications and improve clinical outcomes of childhood acute lymphoblastic leukemia.

Pediatric-inspired regimen with late intensification and increased dose of L-asparaginase for adult acute lymphoblastic leukemia: the KALLA 1406/1407 study.

Background/AimsThe objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology.MethodsData of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib.ResultsA total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events.ConclusionsThe KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.

The Outcome of Children With Acute Lymphoblastic Leukemia Without Receiving Sufficient Dose of L-Asparaginase

In acute lymphoblastic leukemia (ALL) patients treated with L-asparaginase, discontinuation of the drug occasionally occur due to severe drug complications or resistance, however, due to the high efficacy of this drug in the recovery of patients and the prevention of disease recurrence, resuming the drug regimen is preferred in most patients. What we did in this study was to evaluate and compare the effects of clinical outcomes in the two modes of continuing and discontinuing drug use. In this retrospective cohort study, all children with ALL who had been treated with L-asparaginase during the years 2005 to 2015 were included in the study and categorized into two groups receiving complete treatment regimen (n=160) and those who had to discontinue the drug due to appearing complications (n=9). The rate of relapse and mortality rate was determined and compared across the two groups with a median follow-up time of more than 5 years. 5-yrs Overall survival of all enrolled patients in the groups continued and discontinued was 91.4±2.5% and 71.4±17.1%, respectively (P=0.792). Also, 5-yrs event-free survival of the two groups was 75.8±3.5% and 71.4±17.1%, respectively (P=0.557. Relapse was revealed in 17.5% and 33.3% respectively and mortality in 16.9% and 0.0% (P=0.261). However, the overall prevalence of hypersensitivity reaction to the drug was significantly higher in those patients who discontinued their drug regimen (100% versus 24.4%, P<0.001). Hypersensitivity reaction to drugs may be an important factor in discontinuing L-asparaginase in patients with ALL. The discontinuation of L-asparaginase supplementation due to various complications such as hypersensitivity reactions may be effective in the survival of these patients. However, accurate determination of the effect of discontinuation of this drug on the outcome of children with ALL requires a more comprehensive study with more complicated cases.

Successful Toxicity Reduction in Ma-Spore ALL 2010 in Standard/Intermediate Risk Childhood ALL: Replacing Cytarabine/Doxorubicin with More Vincristine and L-Asparaginase during Consolidation and Delayed Intensification

As ~90% children with Acute Lymphoblastic Leukemia (ALL) are now cured, the next challenge of contemporary ALL therapy is curing with less toxicity. To reduce toxicity, the Malaysia-Singapore ALL 2003 (MS2003) study lowered the intensity of induction in Standard(SR)/Intermediate Risk(IR) patients by removing Daunorubicin. However, toxicities causing prolonged delays during Consolidation and Delayed-Intensification(DI) remained major problems. To address these delays, the MS2010 study: (1) Replaced half of all cytarabine blocks with 2 doses of Vincristine(VCR) per block (2) Implemented Doxorubicin-free DI Protocol V (3) Added 1 dose of L-Asparaginase(L-Asp) to each DI block. Here, we report the significant improvements in MS2010 compared to MS2003 in terms of treatment-related toxicities. Methods MS2003 (Yeoh AEJ et al. J Clin Oncol 2012) started with a 3 drug induction for non-HR patients in a BFM ALL-IC 2002 backbone where SR consisted of 2x Protocol III and IR consisted of 3x Protocol III. In MS2010 (Yeoh AEJ et al. J Clin Oncol 2018), SR consisted of 2x Protocol V and IR consisted of 2x Protocol III + 1x Protocol V (Table 1). We performed a per-protocol analysis of 315 children with de novo SR/IR ALL, treated on MS2003 (n=183) and MS2010 (n=132) in 2 centers in Singapore, with a median follow up of 10.7 and 6.4years respectively. We analyzed clinical toxicity data, focusing on hospitalizations for fever (regardless of neutrophil count). Mean differences were adjusted for baseline characteristics including sex, race, age and Down syndrome. Results Overall decreased hospitalization stay and phase delays. In MS2010, the total duration of hospitalization for fever are fewer and shorter; this is most apparent for DI phases. For SR group, total length of stay during DI decreased from 13.7 to 6.1 days with adjusted(adj.) δ=7.0 days (95% CI 3.5-10.5, p<0.001). For IR group, this was from 19.1 to 11.5days with adj.δ=5.2 days (95% CI 0.2-10.3, p=0.042). In MS2010, overall delays in treatment are significantly reduced -- SR: From 65.9 to 16.4days, adj.δ=48.8 days(95% CI 39.8-57.8, p<0.001); IR: From 106.9 to 23.6days, adj.δ=80.9days (95% CI 68.4-93.5, p<0.001). The reduction in delays are mainly seen during Consolidation and DI. Overall, patients also completed intensive chemotherapy in a much shorter duration of time in MS2010 (see Table.1). Total ICU admissions were decreased (SR: 9.0% to 4.7% p=0.346 ; IR: 13.5% to 5.9% p=0.57). Total episodes of bacteremia were also decreased (SR: 31.2% to 18.75% p=0.708 ; IR 31.4% to 26.5% p=0.23). MS2010 Protocol III had 5 doses of L-Asp compared to 4 doses of L-Asp in MS2003 Protocol III. Although L-Asp is generally considered less myelosuppressive, there was a significant increase in the number of hospitalizations during MS2010 Protocol III blocks. This translated to longer hospitalizations per patient in MS2010 during those specific phases (III#1: adj.δ=-1.6 days 95% CI -2.8 to -0.3 p=0.017; III#2: adj.δ=-1.9 days 95% CI -3.2 to -0.6 p=0.006). These increases in hospitalizations in MS2010 Protocol IIIa were most likely due to an additional single dose of L-Asp. Equivalent survival outcomes Based on a per-protocol analysis, 5 year Event-Free survival(EFS) outcomes between the cohorts were equivalent. In the SR cohort, 5yr EFS was 93.6% (MS2003) vs. 95.5% (MS2010) p=0.685. In the IR cohorts, 5yr EFS improved from 89.4% (MS2003) to 95.6% (MS2010) p=0.151, although statistical significance was not reached. Overall, significant improvements: reduction in hospitalisation stays and reduction in treatment delays were observed in MS2010. This was achieved through a combination of (1) Replacing half of all cytarabine blocks with 2 doses of VCR per block; and (2) New DI Protocol V with no Anthracyclines. Despite the AIEOP-BFM 2000 experience of increased toxicity with Protocol III, our modifications to consolidation Ib and Protocol III have led to less phase delays, tolerable toxicities with comparable outcomes. Disclosures No relevant conflicts of interest to declare.

Effect of Dose and Schedule of L-Asparaginase Administration on Early Minimal Residual Disease in Acute Lymphoblastic Leukemia

AbstractBackground and Objectives: L-asparaginase has become the backbone of acute lymphoblastic leukemia induction. In Berlin–Frankfurt–Munster (BFM) 95/2000 protocols, L-asparaginase was given twice weekly for initial 4 weeks. While sufficient L-asparaginase levels are important, there is no apparent correlation between high L-asparaginase levels and minimal residual disease (MRD). In view of toxicities of L-asparaginase, we planned to study the effect of dose and schedule of Escherichia coli-derived L-asparaginase on early MRD by phasing the same total dose, once a week over 8 weeks. Methods: This prospective, observational study enrolled 45 children and young adults ≤40 years. Modified BFM 95 protocol was followed. Weekly 5000 IU/m2 L-asparaginase was given intravenously, and MRD was analyzed at the end of 4 weeks (MRD1) and at 8 weeks (MRD2), using multicolor flow cytometry. MRD positive was defined as residual blasts ≥0.01%. Results: Thirty-one patients were eligible for final analysis. Nine could receive scheduled eight doses of L-asparaginase and 22 patients received less than eight doses. We analyzed age, gender, diagnosis, prednisone response, cytogenetics, central nervous system status, BFM risk group, MRD2, and relapse. L-asparaginase dose association was not statistically significant with respect to MRD2 (P = 0.237). There were no cases of pancreatitis, hypersensitivity, bleeding, or thrombosis. Reasons for patients receiving less than the scheduled eight doses were low serum fibrinogen levels and liver dysfunction. This study revealed 8 MRD1-negative and 13 MRD2-negative patients. Conclusion: L-asparaginase dose intensity does not affect early MRD. Phasing L-asparaginase over 8 weeks could lead to the achievement of more MRD2-negative status and thereby improve long-term outcome. This strategy may also reduce the incidence of adverse drug events.

Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL.

Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3+) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1+ and TLX3+ T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes. We compared TLX1+ and TLX3+ adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (ASNS) and in vitro l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples. We show that TLX1+ patients expressed low levels of ASNS when compared with TLX3+ and TLX-negative patients, due to epigenetic silencing of ASNS by both DNA methylation and a decrease of active histone marks. Promoter methylation of the ASNS gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, ASNS promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24-0.71; P = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23-0.70; P = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (P = 0.012). We conclude that ASNS methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.

Extranodal Natural Killer/T-Cell Lymphoma Nasal Type in 87 Cases from Spain: Clinical Presentation, Treatment and Prognostic Factors. Study from the Geltamo Group

Introduction and Objective: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL-NT) is associated with Epstein-Barr virus (EBV) and is much more common in Asia and Latin America than in western countries. Data on disease presentation and outcome from European series are very limited. The objective of the study is to analyze the clinical characteristics at diagnosis, treatment received and outcome of a series of patients from Spain.Patients and Methods: Eigthy-seven patients with ENKTL-NT diagnosed from 2000 to 2017 were identified in 24 academic centers in Spain. Clinical data were collected retrospectively. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Variables included in the univariate analysis were: race, gender, age, previous sinusitis, nasal localization, Ann Arbor stage, ECOG performance status (PS), B symptoms, LDH, beta2-microglobulin, albumin and C-reactive protein. Multivariate analyses were performed by Cox proportional hazard regression model.Results: Clinical characteristics at diagnosis are shown in Table 1. Seventy-seven patients received active treatment, 31 (40%) with chemotherapy (CT) alone, 39 (51%) with CT and radiotherapy (RT), 7 (9%) with RT alone (median dose 50 Gy). First line therapies were: CHOP/CHOP-like in 30 (42%) patients, high-dose L-Asparaginase-containing regimens in 27 (38%), and other regimens in 14 (20%); 12 patients proceeded to stem-cell transplant in first line (10 auto / 2 allo). Response rate was evaluable in 70 patients (by PET/TC in 55%): CR 35 (50%), PR 9 (13%), SD/progression 26 (37%). Median number of CT lines was 2 (1-6). With a median follow-up of 38 months, 3 yr OS was 38% (95% CI 27-49), and 3 yr PFS 25% (95% CI 14-35). Causes of death were: progression 35 (67%), toxicity 12 (23%), second neoplasms 5 (10%). The variables at diagnosis significantly associated with poor OS were: age ≥ 60 yr, extranasal disease, Ann Arbor III-IV, ECOG PS 2-4, increased LDH, and decreased albumin. In the multivariate analysis including all the previous variables, ECOG 2-4 PS (HR 3.3, 95% CI 1.4-7.0) and low albumin (HR 3.6, 95% CI 1.4-9.3) maintained the negative influence in OS. Patients treated with regimens that included high dose L-Asparaginase had 3 yr OS of 61% (95%CI 40-82), compared with patients treated with CHOP/CHOP-like 3 yr OS of 19% (95%CI 5-32) (p=0.009). These differences were statistically significant both in patients with nasal involvement (3 yr OS 82% with L-Asparaginase vs 21% with CHOP, p=0.01) or with localized disease (3 yr OS 71% with L-Asparaginase vs 24% with CHOP, p=0.03). Differences were not statistically significant in patients with extranasal involvement (3 yr OS 48% with L-Asparaginase vs 14% with RCHOP, p=0.2), or advance disease (3 yr OS 48% with L-Asparaginase vs 14% with CHOP, p=0.2), probably because the low number of patients.Conclusion: This is the largest series reported of Caucasian patients with ENKTL-NT. Patients are young at diagnosis and one fourth had a previous history of chronic sinusitis. This population has a poor outcome, being progression the main cause of death. Poor clinical condition at diagnosis (high ECOG PS and low albumin level) is the main factor related with poor survival. Therapies with high dose L-Asparaginase improve the survival in this western population compared with the classical CHOP regimen. [Display omitted] DisclosuresGonzález-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Martín:Celgene: Consultancy, Honoraria, Other: Travel expenses; Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Panizo:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Sanchez Blanco:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria. Marin Niebla:Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Amgen: Other: Medical education of Staff, Speakers Bureau. Queizan:Janssen: Consultancy. Lopez:Roche: Research Funding.

Effectiveness of Premedication and Rapid Desensitization in Hypersensitivity to L-Asparaginase

Purpose: L-asparaginase is a crucial chemotherapeutic agent for the treatment of acute lymphoblastic leukemia. However, hypersensitivity to L-asparaginase is common which limits its clinical use. Methods: We performed 44 cases of premedication and 3 cases of desensitization in 16 patients with hypersensitivity to L-asparaginase. Results: With premedication, 33 cases completed L-asparaginase injection with no hypersensitivity reactions. Eleven cases showed mild hypersensitivity reactions, such as urticaria. Desensitization was performed in 3 cases: in 2 cases, desensitization was successful, and in 1 case the medication was switched to Erwinia asparaginase. Conclusion: Premedication and desensitization appear to be useful in helping patients receive desired doses of L-asparaginase in pediatric patients with acute lymphoblastic leukemia. (Allergy Asthma Respir Dis 2015;3:288-293)

Meta-analysis and meta-regression analysis to compare the outcomes of chemotherapy for T- and B-lineage acute lymphoblastic leukemia (ALL): the use of dexamethasone, l-asparaginase, and/or methotrexate may improve the outcome of T-lineage ALL

The effects of intensive regimens and the roles of drugs used might differ between T- and B-lineage acute lymphoblastic leukemia (ALL). We performed a literature search for clinical studies published from January 1998 to March 2013. Studies were eligible for inclusion in the analyses if they included more than 80 patients with adult ALL who were treated with a uniform regimen and compared T- and B-lineage ALL. Studies that included only adolescent or elderly patients were excluded. We identified 11 clinical studies, which included a total of 381 and 1366 patients with T- and B-lineage ALL, respectively, and performed meta-analyses using the selected studies. Nine studies included patients with Philadelphia chromosome-positive (Ph+) ALL. A meta-analysis using the random-effect model demonstrated superior survival in patients with T-lineage ALL compared to those with B-lineage ALL (hazard ratio 1.78, 95% confidence interval 1.50-2.11), though the inclusion of patients with Ph+ ALL in B-lineage ALL must have influenced this result strongly. We performed meta-regression analyses, adjusted according to whether or not patients with Ph+ ALL were included in each study. Use of dexamethasone (Dex), higher dose of methotrexate (MTX), and higher dose of L-asparaginase (L-asp) were associated with a significant trend toward a better outcome in T-lineage ALL. A meta-regression analysis including Dex and the dose of L-asp or MTX together as covariates showed that these factors were independently significant. In conclusion, the use of Dex and high-dose L-asp or MTX may improve the outcome of T-lineage ALL. This hypothesis should be tested in a prospective study including only patients with Ph-negative ALL.

High Dose Cytarabine, Mitoxantrone and L-Asparaginase (HAMA) Salvage For Relapsed Or Refractory Acute Myeloid Leukemia (AML) In The Elderly

AML is a disease of older adults with the median age at diagnosis of 68. Elderly AML, generally defined as patients ≥60 years of age, is a clinically distinct disease highlighted by worse overall survival (OS), lower complete remission (CR) rates, and higher treatment related toxicity. Most elderly AML patients who achieve a CR will eventually relapse and require further chemotherapy. Despite the central role of relapsed disease in elderly patients few studies have reported on outcomes using salvage chemotherapy in patients over 60 years of age and no standard regimen has been established.We retrospectively examined data for 108 consecutive relapsed or refractory AML patients treated with the HAMA regimen at Wake Forest between May, 1999 and December, 2010. This regimen consists of high dose cytarabine (3gm/m2 in patients <60, 1 to 3gm/m2 in patients ≥60) given Q12 hours for 5 doses, mitoxantrone at 6mg/m2 once daily for 3 days immediately following the cytarabine and a single dose of L-asparaginase at 6000 units/m2 following the last dose of mitoxantrone. We collected data on age, gender, race, comorbidities, baseline lab values, cytogenetics at relapse, length of first remission (CR1), attainment of second complete remission (CR2), further therapy received and survival. Statistical analysis was performed using Kaplan-Meier estimates and Cox proportional hazards models.Of the 108 patients analyzed, 75 were ≥60 years old and 33 were younger than 60 at the time of HAMA treatment. The median age for the younger cohort was 51 (range 20-59) and for the elderly cohort was 68 (range 60-84). Older patients were more likely to have refractory disease (25% vs 6%), one or more comorbidities (47% vs 12%) and poor risk cytogenetics (23% vs 16%). Early all cause mortality (30 and 60 day) was 13% and 22% respectively for all patients and 17% and 28% for those ≥60. The percentage of patients that died during hospitalization or were discharged to hospice was 25% for all patients (12% <60, 31% ≥60). CR2 was achieved in 41% of patients (49% <60, 37% ≥60). Median OS was 7 (2.1-14.3), 13.6 (4.9-68) and 5.8 (1.3-11.9) months for all patients, <60 and ≥60 cohorts respectively. For those patients ≥60 who achieved a CR median OS was 11.9 months. At 12 months 56% of patients <60 were alive compared with 24% for patients ≥60. By 24 months these numbers fell to 40% and 3% respectively. In the <60 cohort 27% (9/33) went on to allogeneic hematopoietic stem cell transplant (HCT) compared to 12% (9/75) in the ≥60 cohort. The only significant predictors for OS were cytogenetic risk score (p=0.0050) and length of first CR >1 year (p=0.0005). Of the 16 patients in the cytogenetic poor risk group only 12% (2/16) achieved CR2 and none were alive more than 14 months from relapse. Median survival for patients with CR1 >1 year was 13.6 (5.9-19.7) months compared to 5.8 (3.3-7.2) months for patients with CR1 <1 year.In conclusion, the HAMA salvage regimen when given to older patients results in a 37% complete remission rate with a median survival of almost one year in this subgroup, however only 12% went on to allogeneic HCT and only 3% were alive 24 months after relapse. Patients with poor risk cytogenetics regardless of age were not effectively salvaged with this regimen and should be offered experimental therapy when possible. Disclosures:No relevant conflicts of interest to declare.

L-Asparaginase

We conducted a randomized trial to compare the influence of 3 additional doses of L-asparaginase on clinical outcome of newly diagnosed childhood acute lymphoblastic leukemia (ALL). Patients were treated using Indonesian WK-ALL-2000 protocol between 1999 and 2005 and randomized to receive (3A arm, n=61) or not to receive (0A arm, n=56) an additional 3 weekly doses of 6000 IU/m(2)/dose of Escherichia coli L-asparaginase during consolidation treatment on top of 2 doses (standard-risk patients) or 5 doses (high-risk patients). Events after remission included relapse (37.6%), death (16.2%), and abandonment of therapy (15.4%). There was no significant difference in relapses between the 2 arms. Patients in arm 3A versus 0A tended to have a lower 5 years disease-free survival (47.4±7.9% vs. 51.7±7.9%, P=0.72) and lower 5 years event-free survival (29.5±5.8% vs. 35.7±6.4%, P=0.61). We conclude that in our setting the use of 3 additional doses of L-asparaginase during consolidation therapy did not result in survival advantage. Contrariwise, adverse effects from this drug included higher treatment cost and systemic toxicity.

Transient diabetes mellitus secondary to L-asparaginase

Secondary Diabetes Mellitus (DM) has been associated in about 1-14% of patients with hematologic malignancy treated with L-asparaginase. An 11-year old Filipino female, diagnosed with Acute Lymphoblastic Leukemia, developed hyperglycemia associated with polyuria and polydipsia while on-going induction chemotherapy. There was no family history of diabetes mellitus. Chemotherapy drugs included L-Asparaginase, Prednisone, Vincristine and intrathecal methotrexate using the LIC protocol. Among these agents, Prednisone and L-Asparaginase are known to cause hyperglycemia. Given the risk, the patient was monitored by checking for glucosuria at least once a week. The L-asparaginase was started on Day 8 of chemotherapy after one week of Prednisone given at 60mg/kg/m2. No glucosuria was noted prior to the start, as well as during the first week of chemotherapy. On Day 16 of chemotherapy, after 4 doses of L-Asparaginase at 6000u/m2 3x a week, she developed epigastric pain, vomiting, polyuria, excessive thirst, hyperglycemia and glucosuria (+4). Arterial blood gas was normal and negative for urine ketones. Serum amylase and lipase were likewise normal. The Random blood sugar was 680 mg/dL (37.4mmol/L). Upon repeat the next day, it was 619 mg/dl and HbA1c at 7.4%. Regular insulin started at a dose of 0.8unit/kg/day given every six hours which was later increased to 1unit/kg/day. The patient was maintained on pre-mix Insulin (70% isophane/ 30% regular) at 1.2 unit per/kg/day with good control of blood sugar between 100-200mg/dl. L-Asparaginase was completed for 9 doses. The patient required tapering doses of insulin therapy for one month after the last dose of L-Asparaginase. After discontinuation of insulin, blood monitoring for two more weeks showed no recurrence of hyperglycemia and the associated symptoms. Inhibition of insulin and insulin receptor synthesis, leading to a combined insulin deficiency and resistance syndrome, is the supposed mechanism of the L-asparaginase effect. The temporal relationship of the appearance and resolution of hyperglycemia with the L-Asparaginase administration and discontinuation respectively, is the strong basis for attributing the transient DM to the said agent rather than to steroids. However, the risk and severity of DM increases when L-asparaginase and steroids are used concomitantly. Close monitoring of the blood sugar levels of such patients is emphasized.

Diabetes ketoacidosis in L-asparaginase therapy

Case E.C, 10 years old female brought to the ER due abdominal pain. Patient is a diagnosed case of B-Cell Acute Lymphoblastic Leukemia (ALL) thru clinical symptoms, laboratory work-ups and flow cytometry since 2 months prior to her present admission. She has been receiving 8 doses of L-asparaginase (leunase) and Prednisone (60mg/day for a week then 40mg/day for 3 weeks) for almost one month before this recent admission. One week prior to hospitalization, the patient had nocturia (2-3x/night), polyuria and polydipsia. On the day of admission, she had sudden onset difficulty of breathing associated with severe abdominal pain and vomiting. She came in non-ambulatory, in cardiorespiratory distress with BP: 100/70mmHg, HR: 150/min, RR: 60/min, Temp: 37.3°C. Pertinent physical exam showed signs of dehydration with abdominal tenderness, and signs of circulatory compromise. Fluid resuscitation was immediately instituted. The initial assessment at the ER was pancreatitis but the serum amylase and lipase were normal. Other lab work-ups showed blood glucose of 26.8 mmol/L (NV:3.08-7.92), sodium at 115 mmol/L(NV:132143), potassium of 3.3, Chloride at 88mmol/L (NV: 98116). Blood gas showed ph of 7.1, a pCO2: 50, HCO3 at 3.7, and a base deficit of -22.5mmol/L. Urinalysis showed +4 of glucose and +3 of ketones. The patient was then managed as a case of DKA and fluid resuscitation was continued and insulin drip was started. The haemoglobin A1c level at diagnosis was 11.4% but the C-peptide was normal. Patient condition improved and was discharged with insulin injection. The insulin was discontinued after completion of her induction phase and with normalization of blood glucose.

Modified SMILE in the Treatment of Natural Killer T-Cell Lymphoma, Nasal and Nasal Type: A Single Center US Experience

Abstract 2688 Introduction:Extranodal NK/T cell lymphoma (ENKL) is a rare subtype of peripheral T cell lymphoma. The treatment of ENKL is largely dependent upon the extent of disease at the time of presentation. Historically these tumors have shown poor responsiveness to chemotherapy and patients with localized disease are often treated primarily with radiotherapy. Overall survival is poor for those with advanced disease. Recent studies exploring the use of L-asparaginase alone or in combination with other cytotoxic chemotherapy has led to significant response rates in the up-front and relapsed/refractory setting. The novel regimen SMILE (steroid=dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) appears particularly active in ENKL (Yamaguchi M Cancer Sci 2008; 99: 1016–1020). We report our experience in consecutive untreated patients using a modification of SMILE (mSMILE) in which a single dose of pegylated-L-asparaginase is substituted for 6 doses of L-asparaginase per cycle and the cycle length shortened to 3 weeks. Methods:Starting in 9/09 the MSKCC lymphoma service began adopting mSMILE (Steroid=dexamethasone 40 mg IVPB days 2–4, methotrexate 2000 mg/m2 day 1, ifosfamide 1500 mg/m2 days 2–4, pegylated-L-asparaginase 2500 IU/m2 IVPB day 8, and etoposide 100 mg/m2 days 2–4) for treatment of our patients with newly diagnosed ENKL. Cycles of chemotherapy were repeated approximately every 3 weeks and all patients received growth factor support. Each patient’s disease status was established by ENT direct examination, PET/CT, and bone marrow biopsy. Patients with localized (L) disease (I, IE) were intended to receive mSMILE for two cycles prior to consolidative radiotherapy. Patients with locally advanced (LA) or disseminated (D) disease were intended to receive 2 to 3 cycles of mSMILE along with radiotherapy to bulky original sites with high dose chemotherapy and stem cell transplantation as consolidation. Primary response evaluations were PET/CT for all patients after 1–2 cycles of mSMILE. Results:Eight patients with newly diagnosed ENKL were seen between 09/09 and 07/11. Seven had nasal ENKL and 1 had ENKL-nasal type. Extent of disease was: L=5, LA=1, D=2. Patient characteristics were: age median 43.5 (24–64); male:female=5:3; Caucasian-5 (Latino-2) and Asian-3. Treatment was as follows: two cycles of mSMILE followed by involved field radiation therapy to 45 cGy (n=5), mSMILE for 3 cycles in locally advanced (n=1) and disseminated disease (n=2) along with radiotherapy to prior bulky sites followed by either autologous (n=1) or allogeneic (n=2) stem cell transplantation. Responses to mSMILE after at 1–2 cycles by PET/CT were: overall response rate 100% (8/8), complete response (CR) 88% (7/8), and partial response (PR) 12% (1/8). Toxicities were grade 3–4 neutropenia (n=6), grade 3–4 anemia (n=2), grade 3–4 thrombocytopenia (n=2), grade 3 nausea and vomiting (n=3), upper respiratory infection (n=2), syncope (n=1), and febrile neutropenia (n=1). All patients had increased LFTs during treatment (grade 3–4 n=1), all resolved to safe pre-treatment levels prior to the next cycle and did not affect dosing or drug administration. At median follow-up of 5.5 months (range 2–23) 7 patients are alive. Five are alive in remission post therapy for a median of 14 months (range 4–23) and 2 patients (1CR; 1PR) are currently undergoing radiotherapy after responding to mSMILE. One patient with disseminated disease died in remission at day +83 post allogeneic stem cell transplant of tacrolimus induced TTP. Discussion:We report our experience in 8 consecutive patients treated with mSMILE for newly diagnosed ENKL. This is the first series of patients treated with this approach outside of Asia. In this data set 88% of patients achieved a CR rate after 1–2 cycles of mSMILE. This intensive chemotherapy regimen carries significant hematologic toxicity. Our modification of substituting pegylated L-asparaginase on day 8 and using growth factors in order to treat on an every three-week basis allowed patients to maintain intended dose intensity. Ultimately, a larger study is needed to validate our observation. However, the activity shown to date suggests this is a more active regimen than those previously used such as CHOP and carries the potential to improve outcomes in these patients. Disclosures:Horwitz:Sigma Tau: Consultancy.