Pegaspargase Research Articles

Universal premedication and therapeutic drug monitoring for asparaginase-based therapy prevents infusion-associated acute adverse events and drug substitutions.

Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions. Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost. We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P=0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P=0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125779 drug savings alone per substitution prevented ($12402/premedicated patient). Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.

Venous Thromboembolism Following Pegaspargase in Adults Receiving Antithrombin Supplementation: A Single Center Characterization of Risk Factors and an Assessment of Supplementation Practice

Introduction: Venous thromboembolism (VTE) is a significant adverse event in adults receiving pegaspargase (PEG) for acute lymphoblastic leukemia (ALL). PEG increases VTE risk by depletion of antithrombin III (AT). Heparin requires adequate AT for anticoagulation. Younger adults with T-cell ALL receiving prednisone may be particularly at risk. Retrospective series (most with L-asparaginase) suggest AT supplementation may decrease VTE, however prospective data in adults beyond induction is limited while the optimal dose of AT remains undefined and varies across series. We reviewed adults at our institution who received PEG for ALL to assess the incidence of VTE within our AT supplementation practice. Laboratory and cost data for AT repletion were also analyzed.Methods: Adults who received PEG for ALL between 11/2015 and 7/2018 were retrospectively identified. Institutional recommendations were to supplement AT if serum AT < 60% following PEG for at least the first 2 courses (induction/consolidation). AT levels were assessed twice weekly until normalized. AT supplementation following additional cycles was recommended for all patients receiving therapeutic anticoagulation. Pharmacists calculated the AT dose using a repletion factor of 80-120%, rounded to the nearest vial. After VTE, patients received therapeutic enoxaparin throughout all remaining PEG doses, with enoxaparin held only if platelets < 50,000/mcL or for procedures. After 3/2018, all patients receiving PEG also received enoxaparin prophylaxis when platelets >30,000/mcL. A retrospective analysis was done to assess the incidence of VTE. Secondary endpoints included an assessment of VTE risk factors, ability to achieve therapeutic AT levels with supplementation and to characterize drug therapy costs with AT supplementation.Results: Thirty-one patients (30 newly diagnosed, 1 in relapse) with ALL received ≥ 1 dose of PEG followed by AT supplementation. Seventeen of 31 patients were adolescent/young adults (AYA) and 13/31 had T cell ALL. Additional patient characteristics are summarized in table 1. The incidence of VTE was 19%, with 7 VTEs identified in 6 patients. Two patients developed CNS thrombosis (1 fatal), 1 had a pulmonary embolism, and the remainder were upper extremity VTE. Six of 7 VTE occurred during the first two courses at a mean of 66 days (range 6-225) following the first PEG dose. Patients with VTE had a median platelet count of 118/mcL (range 34-377) and a mean AT nadir of 53% (36-98) within 72 hours of VTE. Two of 7 events occurred despite enoxaparin prophylaxis. Five of 6 (83%) patients with VTE had T-ALL; which was more common in the VTE vs. no-VTE group (p = 0.01). The incidence of VTE within the T-ALL group was 38%. Patients with VTE were all AYA and were younger than those without VTE (median 31 vs. 42 years, p = 0.06). Patients with VTE received a higher mean PEG dose than patients without VTE (4589 vs. 3504 units, p < 0.0001), reflective of the more aggressive dosing in the AYA regimen. Six of 7 VTEs occurred during a course containing prednisone (p = 0.08 vs. dexamethasone). AT nadirs during cycles with VTE were similar to cycles without VTE. No clinically significant bleeding occurred. Characteristics of patients with VTE are summarized in table 2.Overall the mean time to AT nadir was 11 days. Therapeutic AT (> 60%) following supplementation occurred 56% of the time. Most AT doses (89%) were calculated with a correction factor of 80-89%. The probability of obtaining a therapeutic AT increased when a higher repletion factor (> 90%) was used (76% vs. 52%, p = 0.06). Patients received a mean of 1.9 (0-6) doses of AT per PEG dose, and a mean of 5.9 (1-21) AT doses throughout treatment. The mean AT supplementation cost per PEG dose was $11,663 with 186 doses administered ($3.22/unit).Conclusions: VTE occurred in 19% of patients receiving AT supplementation following PEG, with 2/7 events involving the CNS. The risk of VTE was greatest in younger adults with T-ALL receiving concurrent prednisone and higher doses of PEG. AT levels were low at the time of VTE in most patients, however nadirs were similar compared to courses not complicated by VTE. Routine or augmented VTE prophylaxis and a higher AT repletion goal (> 90%) may further limit VTE risk but given the cost and patient inconvenience, prospective evaluation is needed to confirm the benefit. [Display omitted] DisclosuresFrey:Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board.

Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents.Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0.Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60.Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1).Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2.Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse.At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%).Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. [Display omitted] DisclosuresGeyer:Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

Evaluation of pegaspargase (PEG-ASP) adverse events among adolescents and young adults (AYAs) and younger patients with lymphoid malignancies (LM) at the Children’s Hospital of Eastern Ontario (CHEO).

10531Background: PEG-ASP is a common component of the chemotherapy regime for LM, but with significant side effects. The aim of this study was to determine the prevalence of major adverse events: a...

A retrospective analysis of the impact of antithrombin III supplementation on the incidence of pegaspargase-induced venous thromboembolism.

e19006Background: Pegaspargase (PEG), a key component in the treatment of acute lymphoblastic leukemia (ALL), can cause venous thromboembolism (VTE). Limited studies have explored the benefit of an...

Adverse effects of pegaspargase in pediatric patients receiving doses greater than 3,750IU.

Increased toxicities have been identified with higher doses of pegaspargase (PEG-ASP) in adults. This has led to routine use of a dose cap of 3,750IU for adult acute lymphoblastic leukemia (ALL) patients in most institutions. In pediatric ALL patients, PEG-ASP is not capped. There is concern at our institution that larger doses may result in increased rates of adverse effects and that increased monitoring may be warranted in pediatric patients receiving doses greater than 3,750IU. The objective of this study is to quantify the difference in the rates of PEG-ASP-associated adverse events between pediatric patients who received doses greater than 3,750IU and less than or equal to 3,750IU. Retrospective chart review of patients 1-21 years old with pre-B-cell ALL who received PEG-ASP between 2007 and 2014 at an academic medical center. Of 183 patients included in the analysis, 24 received PEG-ASP doses higher than 3,750IU and 159 received doses less than or equal to 3,750IU. The incidence of venous thromboembolism (VTE) was significantly higher for patients in the group that received more than 3,750IU compared with those who received 3,750IU or less (20.8 vs. 1.89%, respectively; P = 0.0011). The incidence of pancreatitis (P = 0.0306) and hyperglycemia (P = 0.0089) were also higher in the group that received more than 3,750IU. PEG-ASP doses higher than 3,750IU are associated with higher rates of VTE, pancreatitis, and hyperglycemia in pediatric patients with pre-B-cell ALL. Patients receiving more than 3,750IU should have increased monitoring, and larger, multicenter trials are needed to determine if monitoring, VTE prophylaxis, and potential dose capping recommendations should be added to clinical trial protocols.

Efficacy and safety of pegaspargase and L-asparaginase in the treatment of NK/T-cell lymphoma

Objective To compare the clinical efficacy and adverse effects of pegaspargase (PEG-ASP) and L-asparaginase (L-ASP) in the treatment of NK/T-cell lymphoma. Methods A retrospective ana-lysis was conducted on the clinical data of 46 patients with NK/T-cell lymphoma in Department of Oncology of Hospital of Qingdao Commercial Staff from September 2009 to July 2015. There were 24 patients treated by PEG-ASP combined with GDP (gemcitabine+ cisplatin+ dexamethasone) as PEG-ASP group, and 22 patients treated by L-ASP combined with GDP as L-ASP group. The efficacy and adverse reactions were compared between the two groups. Results In the PEG-ASP group, there were 11 patients with complete remission, 7 patients with partial remission, and the complete remission rate and objective response rate were 45.83% and 75.00%. In the L-ASP group, there were 9 patients with complete remission, 6 patients with partial remission, and the complete remission rate and objective response rate were 40.91% and 68.18%. There was no significant difference between the two groups in objective response rate (χ2=0.263, P=0.608). Adverse effects such as myelosuppression (25.00% vs. 22.73%, χ2=0.033, P=0.857), coagulopathy (8.33% vs. 9.10%, χ2=0.008, P=0.927), liver and renal dysfunction (8.33% vs. 18.18%, χ2=0.982, P=0.322), gastrointestinal reaction (41.67% vs. 40.91%, χ2=0.003, P=0.958) were similar in the PEG-ASP group and L-ASP group. But the risk of allergic reaction incurred by PEG-ASP was much lower than L-ASP (4.17% vs. 36.36%), with a significant difference (χ2=7.561, P=0.006). Moreover, the PEG-ASP group had a shorter duration of hospitalization [(10.04±1.63)d] than the L-ASP group [(13.09±2.76)d], with a significant difference (t=-4.612, P=0.000). Conclusion The efficacy of PEG-ASP and L-ASP in the treatment of NK/T-cell lymphoma is similar, but the rate of allergic reaction of patients treated with PEG-ASP is significantly lower, and the hospitalization time is significantly shorter, which is worthy of further clinical application. Key words: Lymphoma, extranodal NK-T-cell; Asparaginase; Treatment outcome; Drug toxicity; Pegaspargase

CAG regimen plus pegaspargase in treatment of adult refractory acute lymphocytic leukemia: report of one case and review of literature

目的 观察CAG方案联合培门冬酶治疗成年人难治性急性淋巴细胞白血病（ALL）的疗效及患者不良反应。 方法 应用CAG方案联合培门冬酶治疗1例化疗5个周期未达完全缓解（CR）的难治性成年人ALL，对其临床资料进行分析并复习相关文献。 结果 该患者经CAG联合培门冬酶方案治疗1个周期获得CR，再行巩固治疗1个周期后行同胞全相合异基因造血干细胞移植，期间4度粒细胞缺乏期及血小板减少时间均较短，未出现严重感染，主要不良反应为胆红素、氨基转移酶升高。 结论 CAG方案联合培门冬酶治疗难治性成年人ALL效果良好，安全性高，但需扩大病例数进一步论证。

Clinical analysis of 60 relapsed pediatric patients with acute lymphoblastic leukemia

Objective To explore the factors for the relapse, prognosis and the treatment strategy for relapsed pediatric patients with acute lymphoblastic leukemia(ALL). Methods From January 2007 to January 2015, 60 pedia-tric relapsed ALL patients were recruited in Beijing Children's Hospital, Capital Medical University.The association between prognosis and different sites of relapse, and the duration of first complete remission and the treatment strategy were analyzed. Results The median age of the 60 patients was 70.5 months, 51 patients out of 60 cases were B-cell immunophenotype, with the median diagnosis-relapse interval 30.5 months.Forty-five patients belonged to marrow relapse and 15 had isolated extramedullary relapsed.Fifty-six patients received treatment after relapse.Thirty-two out of 56 patients survived without disease, the median follow-up was 19 months (3-78 months). The remission rates induced by Cyclophosphamide, Prednisone, Doxorubicin, L-Asparaginase, Vindecine (CODLP) induction, and Dexa-methasone, Doxorubicin, Pegaspargase, Vindecine (VDLD) regimens were 85.7%(12/14 cases) and 92.9%(39/42 cases), respectively.The overall survival (OS) of bone marrow relapsed patients and the isolate extramedullary relapsed patients were 57.14%(24/42 cases) and 78.57%(11/14 cases), respectively.However, there was no statistical difference(χ2=0.073, P=0.787; χ2=2.979, P=0.084). The OS of the early, intermediate and late relapsed patients were 43.75%(7/16 cases), 46.67%(7/15 cases) and 80.00%(20/25 cases). The differences between early, and late relapsed patients, intermediate and late relapsed patients were statistically significant, respectively(χ2=10.122, P=0.001; χ2=6.179, P=0.013). The OS of chemotherapy group versus hematopoietic stem cell transplantation group(HSCT) in bone marrow relapsed patients were 26.92% (7/26 cases) and 100.00%(16/16 cases). Statistically, the difference between the 2 groups was significant(χ2=18.481, P<0.001). Conclusions The accurate gradation treatment regimen on the original diagnosis could reduce relapse rate effectively, VDLD protocol was still an useful induction regimen for relapsed ALL patients, and allo-genetic HSCT was the good choice for relapsed patients at high risk, che-motherapy with local irradiation treatment strategy could assist longer survival for the relapsed patients with isolated testicular leukemia. Key words: Acute lymphoblastic leukemia; Relapse; Child

Efficacy of pegaspargase combined with GEMOX regimen on extranodal natural killer/T-cell lymphoma and its influence on coagulation function

Objective To evaluate the efficacy of pegaspargase (PEG-ASP) combined with GEMOX regimen for the treatment of extranodal natural killer (NK) /T-cell lymphoma (ENKL), and to observe the changes of coagulation function. Methods 35 patients with histologically confirmed ENKL were enrolled from January 2010 to December 2014. All patients received 180 cycles of PEG-ASP combined with GEMOX chemotherapy and the efficacies were observed. The coagulation items such as prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fbg) and international normalized ratio (INR) were tested respectively on day 1st, day 8th and day 14th of every treatment cycle. Results Among 35 patients, 11 patients (31.43 %) were in stage Ⅰ-Ⅱ, and 24 patients (68.57 %) were in stage Ⅲ-Ⅳ. All patients were subjected to 180 cycles of PEG-ASP combined with GEMOX chemotherapy, and each case was estimated to receive 6 cycles. The overall response (CR+PR) rate (ORR) was 71.43 % (25/35), the ORR was 81.82 % (9/11) in stage Ⅰ-Ⅱ group, and 66.67 % (16/24) in stage Ⅲ-Ⅳ group. The increased PT and APTT and decreased Fbg were observed on day 8th of the chemotherapy. The increased APTT and decreased Fbg were still observed on day 14th of the chemotherapy. Compared the data of patients one day before chemotherapy with healthy persons, the changes had statistical significance (P < 0.05). Conclusions PEG-ASP combined with GEMOX regimen in the treatment of ENKL is safer and more effective compared with traditional chemotherapy, but the abnormal alternations of coagulation might be common during therapy. Dealing with the bleeding risk and supplement with plasma, PPSB or Fbg in time should be necessary. Key words: Extranodal NK/T cell lymphoma; Pegaspargase; Treatment outcome; Routine coagulation function

Efficacy observation of pegaspargase combined with intensity modulated conformal radiotherapy in the treatment of 20 patients with early-stage nasal NK/T cell lymphoma

目的 观察培门冬酶联合调强适形放疗(IMRT)治疗Ⅰ~Ⅱ期鼻腔NK/T细 应。 方法 回顾性分析2011年1月至2013年9月20例原发鼻腔NK/T细胞淋巴瘤患者的临床资料，其中，男性14例，女性6例；中位年龄41岁(16~66岁)。采用以培门冬酶为主的POD方案化疗联合IMRT。 结果 20例患者完全缓解10例，部分缓解7例，稳定1例，进展2例。不良反应多为Ⅰ~Ⅱ度，可耐受。 结论 培门冬酶联合IMRT同步治疗Ⅰ~Ⅱ期鼻腔NK/T细胞淋巴瘤疗效好，不良反应轻。

Allergic reactions associated with pegaspargase in adults

One of the severe toxicities of pegaspargase (PEG) is the development of allergic reactions. This study retrospectively assessed 311 PEG doses administered to 139 acute lymphoblastic leukemia patients from May 1, 2008 to July 30, 2014 for allergic reactions based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Fourteen reactions were recorded in 13 patients (9.4%). The rate of reaction did not differ between patients who received pre-medications and those who did not (p = 0.939). Patients who received only IV PEG doses had a higher rate of reaction compared to only IM PEG (14.0% vs 1.6%; p = 0.010). Six of the seven patients with CTCAE grade 4 reactions received a majority of IV doses, suggesting that severity of reactions may increase with IV administration. Capped doses at 3750 units only had a reaction rate of 2.3%, while uncapped doses over 3750 units were found to have a 6.0% reaction rate (p = 0.194).

Incidence of Allergic Reactions to Pegaspargase (PEG) Administered Intramuscularly Versus Intravenously (IM vs. IV) in Children and Young Adults with High Risk B-Lymphoblastic Leukemia (HR B-ALL): Results of Children's Oncology Group (COG) Studies AALL0232/AALL1131

Introduction: Asparaginase is a vital component of multi-agent chemotherapy for patients with HR B-ALL, but rates of allergic reactions following administration of PEG range from 3-24%. Similar or increased rates of allergic reactions have been reported following IV vs. IM PEG when administered on varying chemotherapy backbones. The COG trials recently changed from IM to IV administration of PEG. We report the rate of allergic reactions/anaphylaxis (Grade 3-4) following IM vs. IV PEG on sequential trials for newly diagnosed patients with HR B-ALL.Methods: Patients 1-30 years of age with newly diagnosed HR B-ALL were eligible for the sequential COG studies, AALL0232 and AALL1131. We limited this analysis to non-Down Syndrome patients who received highly similar chemotherapy regimens prior to maintenance therapy, including a 4-drug Induction with 14 days of dexamethasone or 28 days of prednisone, the COG augmented Berlin-Frankfurt-Munster (BFM) Consolidation, High Dose Methotrexate during Interim Maintenance, and Delayed Intensification (DI). Patients received a total of 5 doses of PEG (2,500 units/m2/dose) administered IM (AALL0232) or IV (AALL1131) during these phases of therapy: Induction (n=1), Consolidation (n=2), DI (n=2). Chi square analysis of the rates of Grade 3-4 allergic reactions/anaphylaxis (Common Terminology Criteria for Adverse Events v4.0) following IM vs. IV PEG was performed.Results: Grade 3-4 allergic reactions/anaphylaxis rates in patients receiving IM vs. IV PEG (Table) were 0.54% vs. 0.22% during Induction (p=0.10), 14.4% vs. 12.64% during Consolidation (p=0.18), and 2.1% vs. 0.97% during DI (p=0.07).Conclusion: Rates of Grade 3-4 allergic reactions/anaphylaxis were similar following IM vs. IV administration of PEG in patients with newly diagnosed HR B-ALL when treated on sequential COG studies, further establishing the safety of delivering IV PEG.Table 1Allergic Reactions Following IM vs IV PEGAllergic reaction/Anaphylaxis (Grade 3-4)AALL0232(IM PEG)AALL1131(IV PEG)p-value(Chi square test)Induction15/2771 (0.54%)4/1797 (0.22%)0.10Consolidation342/2369 (14.4%)114/902 (12.64%)0.18DI22/1060 (2.1%)7/715 (0.97%)0.07 DisclosuresHunger:Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Merck: Equity Ownership.

Coagulation Disorder after Treatment of Pegaspargase and L-Asparaginase

Introduction:Pegaspargase(PEG-ASP) and L-asparaginase(L-ASP) has been widely used in the treatment of acute lymphatic leukemia, changes of coagulation function after treatment are not actually the same. So we performed the present study to analyze coagulation disorder after PEG-ASP and L-ASP treatment of adults with acute lymphatic leukemia.Methods and materials:Totally 153 hospitalized patients with acute lymphatic leukemia treated with L-ASP or PEG-ASP were studied from January, 2010 to January, 2015. Of all 153 patients analyzed, they received L-ASP treatment 158 dose times and PEG-ASP treatment 60 dose times respectively.Results:There is no difference of the distribution of age, sex, white blood cell count at diagnosis and risk factors of the disease. Agranulocytosis combining with intestinal infection, bleeding or thrombosis and the inducing remission rate between the two groups has no significant difference (P =0.11,0.61,0.33). The total infusion of fresh frozen plasma or cryoprecipitate or fibrinogen after treatment shows no significant difference between the two groups (P =0.11,0.75,0.21).Fibrinogen level decreases slower in the treatment of PEG-ASP(9.37 day vs 7.40 day, P =0.02) than that of L-ASP. What's more, fibrinogen decreases slower when L-ASP used at interval compared with continuous use, however, the incidence rate of bleeding and related complications is higher when used at interval early (p =0.028).Conslusion:Because of the preponderance to monitor the changes of fibrinogen and the equal rate of complications and inducing remission rate, it is recommended to use PEG-ASP. L-ASP used at interval can monitor the coagulation function easily than continuous use, but the early use of L-ASP may overlay the drug side effects and related hematology toxicity caused by chemotherapy, then cause an increased incidence of complications. DisclosuresNo relevant conflicts of interest to declare.

Clinical efficacy of pegaspargase plus GEMOX regimen for initial treatment of nasal NK/T-cell lymphoma

Objective: To evaluate the efficacy and safety of pegaspargase plus GEMOX (pegaspargase, gemcitabine, oxaliplatin) regimen in the initial treatment of nasal NK/T-cell lymphoma. Methods: Twelve preliminarily diagnosed nasal NK/T-cell lymphoma patients in Tianjin Medical University Cancer Institute and Hospital from June 2011 to March 2012 were analyzed. All patients took the pegaspargase plus GEMOX regimen (gemcitabine 800-1 000 mg/m on days 1 and 8, oxaliplatin 130 mg/m on day 1, and pegaspargase 2 500 IU/m on day 2), every three weeks for one cycle. The efficacy and toxicity of the regimen were evaluated in the follow-up treatment. Results: After two cycle treatments, 1 patient dropped out of treatment because of acute pancreatitis; the remaining 11 patients had response, in which 1 achieved complete response , 7 had partial response, 2 had stable disease, and 1 had progressive disease. The objective response rate was 72.7%, and the disease control rate was 90.9%. The 2-year overall survival rate was 90.9%. With median 6-cycle P-GEMOX regimen treatment, 81.8% of 11 patients presented side effects, primarily myelosuppression and hepatic dysfunction. Conclusion: Pegaspargase plus GEMOX regimen showed high efficacy on the initial treatment of nasal NK/T-cell lymphoma patients, but the incidence of adverse effect was still high.

Clinical study on pegaspargase combined with EPOCH regimen in the treatment of relapse and refractory non-Hodgkin's T-cell lymphoma

Objective To observe the effect and toxicity of pegaspargase combined with EPOCH(P-EPOCH)regimen for patients with relapse and refractory non-Hodgkin's' T-cell lymphoma(T-NHL). Methods A total of 15 patients with pathologically diagnosed T-NHL from January 2010 to January 2014 of the Beijing Military Region General Hospital who had been treated with CHOP or CHOP-like regimens were relapse or refractory. They were treated by P-EPOCH regimen [VP16 50 mg/m2, E-ADM 12 mg/m2, VCR 0.4 mg/m2, dissolved in 500 ml saline sustained static drops 24 h on day 1 to 4; CTX 750 mg/m2, intravenous injection on day 5; pegaspargase 2 500 U·m-2·d-1 given as intramuscular injection on day 6; oral prednisone 60 mg/m2 on day l to 6; 21 days of a cycle]. Results All the 15 patients were treated by P-EPOCH regimen. The response rate of the whole group was 66.7 %, including CR 4 cases(26.7 %)and PR 6 cases(40.0 %). The median survival time was 20 months(5-30 months), and(2-year)overall survival rate was 46.6 %. Main side effects were myelosuppression, liver dysfunction and disturbance of blood coagulation. Conclusion P-EPOCH regimen is effective for patients with relapse and refractory T-NHL and has better tolerance, and wovthy of clinical study. Key words: Pegaspargase; EPOCH regimen; Non-Hodgkin's T-cell lymphoma; Treatment outcome

A Multicenter, Open-Label, Phase 1 Study Evaluating the Safety and Tolerability of Pegaspargase in Combination with Gemcitabine in Advanced Metastatic Solid Tumors and Lymphoma

Purpose: To evaluate the maximum tolerated dose, safety profile, pharmacokinetics, and pharmacodynamics of pegaspargase (PEG-ASP) in combination with gemcitabine in patients with advanced metastatic solid tumors and lymphoma. Methods: We conducted a multicenter, open label, nonrandomized, Phase 1 dose escalation study designed to evaluate up to 10 cohorts of patients with advanced or metastatic solid tumors and lymphoma. Seventeen patients were treated with of PEG-ASP in combination with gemcitabine. Results: The study was terminated early because the doses for PEG-ASP suggested for de-escalation were predicted not to provide desired sustained asparaginase concentrations based on the analysis of treated patients.

Pulse indicator continuous cardiac output measurement-guided treatment aids two pediatric patients with severe acute pancreatitis complicated with acute respiratory distress syndrome

To evaluate the clinical value of the pulse indicator continuous cardiac output (PiCCO) system in patients with severe acute pancreatitis (SAP) complicated with acute respiratory distress syndrome (ARDS). Two cases of SAP with ARDS were monitored using PiCCO during comprehensive management in the Pediatric Intensive Care Unit (PICU) of Shengjing Hospital, China Medical University. To guide fluid management, the cardiac index (CI) was measured to assess cardiac function, the global end-diastolic volume index (GEDVI) was used to evaluate cardiac preload, and the extravascular lung water index (EVLWI) was used to evaluate the pulmonary edema. Case 1 was diagnosed with type L2 acute lymphoblastic leukemia (intermediate risk) and received the sixth maintenance phases of chemotherapy this time. After a 1-week dosage of chemotherapeutic drugs (pegaspargase and mitoxantrone), he suffered SAP combined with ARDS. Except comprehensive treatment (life supporting, antibiotic, etc.) and applying continuous veno-venous hemodiafiltration (CVVHDF) to remove inflammatory mediators. PiCCO monitor was utilized to guide fluid management. During the early stage of PiCCO monitoring, the patient showed no significant manifestations of pulmonary edema in the bedside chest X-ray (bedside ultrasound showed left pleural effusion), and had an oxygenation index 223 mmHg (1 mmHg = 0.133 kPa), GEDVI 450 ml/m², and ELVWI 7 ml/kg. We increased cardiac output to increase tissue perfusion and dehydration speed of CVVHDF was set at 70 ml/h. Two hours later, GEDVI significantly increased to 600 ml/m² and ELVWI significantly increased to 10 ml/kg, the oxygenation index declined to 155 mmHg, the bedside chest X-ray showed a significant decrease of permeability (right lung) and PEEP was adjusted to 5 cmH₂O (1 cmH₂O = 0.098 kPa), indicating circulating overload. ARDS subsequently occurred, upon which the fluid infusion was halted, the dehydration rate of CVVHDF raised (adjusted to 100-200 ml/h). On day 3 in the PICU, EVLWI dropped to 6 ml/kg, GEDVI dropped to 370 ml/m², and the oxygenation index increased to 180 mmHg. On day 8, the patient was successfully weaned from the ventilator. However, on day 9, the patient reverted to mechanical ventilation due to secondary infection. On day 30, the patient was discharged for voluntarily giving up treatment. Late follow-up results showed that the patient was dead one day after giving up treatment. Case 2 was admitted due to SAP induced by overeating one day before admission. On day 2, the patient showed dyspnea and oxygen saturation decreased to 80%. We applied mechanical ventilation, CVVHDF to remove inflammatory mediators and PiCCO to guide fluid management. According to the initial data of PiCCO, EVLWI was 9 ml/kg, GEDVI was 519 ml/m², the oxygenation index was 298 mmHg, the bedside chest X-ray showed decreased permeability and PEEP was adjusted to 5 cmH₂O, suggesting the existence of ARDS. During treatment, the dehydration speed of CVVHDF was set at 50 ml/h to maintain the balance of fluid input and output. Two hours after PiCCO monitoring, the oxygenation index decreased to 140 mmHg, GEDVI 481 ml/m², EVLWI 9 ml/kg, thus the dehydration speed of CVVHDF was increased (up to 100 ml/h). On day 4 in the PICU, EVLWI was 9 ml/kg, GEDVI was 430 ml/m², oxygenation index was 394 mmHg, and the bedside chest X-ray showed that permeability was higher. On day 5, the patient was transferred from PiCCO. On day 30, the patient recovered and was discharged. PiCCO monitoring can provide real-time surveillance of cardiac function, cardiac preload and afterload, and extravascular lung water in pediatric patients with SAP combined with ARDS. These results are clinically significant for the rescue of critically ill patients with ARDS or shock.

Efficacy and tolerance of pegaspargase-based chemotherapy in patients with nasal-type extranodal NK/T-cell lymphoma: a pilot study.

Nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKL) is a highly invasive cancer with a poor prognosis. More effective and safer treatment regimens for ENKL are needed. Pegaspargase (PEG-Asp) has a similar mechanism of action to L-asparaginase (L-Asp), but presents lower antigenicity. The aim of the present research was to evaluate the safety profile and the latent efficacy of a PEG-Asp-based treatment regimen in patients with ENKL. Data collected from 20 patients with histologically confirmed ENKL, admitted to the Third Affiliated Hospital of Sun Yat-Sen University from January 2009 to August 2013, were included in the study. All patients received 2500 IU/m2/IM PEG-Asp on day 1 of every 21-day treatment cycle. Patients received combination chemotherapy with CHOP (n=5), EPOCH (n=7), GEMOX (n=7) or CHOP with bleomycin (n=1). After 2-5 treatment cycles (median, 4 cycles) of PEG-Asp-based chemotherapy, five patients (25%) showed a complete response (CR), and the overall response rate (ORR) was 60%. Grade 3/4 neutropenia occurred in fourteen patients (70%). Grade 3 alanine aminotransferase (ALT) elevation was observed in two. Grade 1-2 non-hematological toxicity consisted of activated partial thromboplastin time (APTT) elongation (n=9), hypofibrinogenemia (n=6), hypoproteinemia (n=17), hyperglycemia (n=3), and nausea (n=6). No allergic reactions were detected. No treatment related death was reported. Our results suggested that PEG-Asp-based chemotherapy presented an acceptable tolerance and a potential short-term outcome in patients with nasal-type ENKL.

Asparagine synthetase expression and its potential prognostic value in patients with NK/T cell lymphoma.

Natural killer (NK)/T cell lymphoma usually shows a highly aggressive clinical course and the overall prognosis is poor. At present, there are no standard therapeutic regimens for this disease. Although chemotherapeutic protocols containing L-asparaginase (L-Asp) or pegaspargase (PEG‑Asp) have improved the efficacy of treatment, some patients are resistant to L-Asp or PEG-Asp. Previous studies demonstrated that the elevated expression of asparagine synthetase (ASNS) is correlated with the resistance to L-Asp or PEG-Asp and may also affect the prognosis in some types of tumors, but the expression level and clinical significance of ASNS in NK/T cell lymphoma remain unknown. Therefore, we investigated the expression and clinical significance of ASNS in lymphoma cell lines and patients with NK/T cell lymphoma. Firstly, we detected PEG-Asp and L-Asp activity using MTT assay and expression of ASNS using real-time PCR in the 7 lymphoma cell lines. Secondly, we used branched DNA-liquidchip technology (bDNA-LCT) for detecting ASNS mRNA in formalin-fixed, paraffin-embedded tissue sections in 50 cases of NK/T cell lymphoma and in 12 cases of nasal polyps and chronic rhinitis. Moreover, we analyzed the correlations between the expression of ASNS and the sensitivity to L-Asp and PEG-Asp in 7 lymphoma cell lines and with clinicopathological features and prognosis of NK/T cell lymphoma patients who used chemotherapy containing L-Asp and PEG-Asp. There was a marked difference in the sensitivity to L-Asp and PEG-Asp of the 7 lymphoma cell lines. YTS and SNK-6 cells were highly sensitive to PEG-Asp and had relatively low levels of ASNS mRNA expression. Hut-78, Jurkat and Karpas 299 cells were naturally resistant to PEG-Asp, and the ASNS expression levels were extremely high. The expression level of ASNS was relatively low in the NK/T cell lymphoma tissue compared to levels in the nasal polyps and chronic rhinitis (0.480±0.307 vs. 0.739±0.267; P=0.009). ASNS expression level was associated with III-IV tumor stage (P=0.041) and a high International Prognostic Index (P=0.018) in patients with NK/T cell lymphoma. The NK/T cell lymphoma patients with higher ASNS expression had a reduced median survival time when compared with the survival of patients with low ASNS expression (P=0.033). Cox regression test showed that the ASNS expression level is an independent prognostic factor for NK/T cell lymphoma patients. In conclusion, the expression of ASNS was closely related with the sensitivity of lymphoma cell lines to L-Asp and PEG-Asp in vitro and also had a certain effect on the survival of NK/T cell lymphoma patients. In conclusion, high ASNS expression in NK/T cell lymphoma is correlated with worse clinicopathological features.