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With regard to secondary end points, at a median follow-up of 15 months IQR, 6. Moreover, a lower rate of adverse effects AEs has been reported with blinatumomab vs historical controls who received chemotherapy in the same period. Of the 22 controls treated with 2 cycles of chemotherapy consolidation, However, a trend for a higher rate of seizures was observed in patients over 10 years of age, at Another study,4 conducted more recently, showed that outcomes remain suboptimal, even with enhanced supportive care and reduced chemotherapy intensity. Investigators hypothesized that replacing chemotherapy consolidation with blinatumomab could lead to increased efficacy with greater MRD clearance and increased safety with reduced treatment-related mortality. To be eligible, patients needed to be treated and registered according to the trial protocol. Therefore, one of the key inclusion criteria was, you had to be MRD positive at the end of induction. Because these patients had Down syndrome and had detectable MRD at the end of induction, they were classified as intermediate or high risk. Those included in the standard-of-care arm received induction treatment, followed by 2 cycles of chemotherapy consolidation. They then received delayed intensification and subsequent maintenance treatment. Those in the experimental arm received induction treatment, followed by 2 cycles of blinatumomab consolidation, and then delayed intensification and maintenance. MRD assessments were done at the end of induction, day 15 of cycle 1 of consolidation, end of cycle 1 of consolidation, and end of cycle 2 of consolidation, among other time points. The primary end point was the proportion of MRD undetectable patients at the end of 1 cycle of blinatumomab. The induction backbone was based on what was used in UKALL , Samarasinghe said, which was dexamethasone, asparaginase, and vincristine or daunorubicin, which was added for slow early responders on day However, after induction deaths, daunorubicin was omitted in May After blinatumomab, patients received delayed intensification and maintenance with monthly pulses. There was also a high induction death rate of 9. The remaining 33 patients were included in the analysis. All 33 patients received 1 cycle of treatment, with 2 patients stopping because of neurotoxicity; both of these patients achieved undetectable MRD off study. All remaining 31 patients had undetectable MRD and went on to receive cycle 2 of treatment. Additional data indicated that the rate of seizures in those above 10 years was Notably, Four of 6 patients experienced their first seizure event in cycle 1, 5 of 6 patients were rechallenged, and 3 of 5 experienced a second event and stopped. After the updated data, investigators changed their supportive care for seizure prophylaxis. The new recommendation is to begin levetiracetam 1 week before to achieve therapeutic levels prior to initiating blinatumomab. Samarasinghe concluded by saying further follow-up is needed for additional assessment. Disclosures: Dr Samarasinghe disclosed that blinatumomab was supplied by Amgen and educational honoraria was received by Amgen. Conferences Conference Coverage Conference Listing. Choose Specialty Biosimilars. Brain Cancer. Breast Cancer Breast Cancer. CAR T-cell Therapy. Disparities in Cancer Care. Global Oncology. Gynecologic Oncology Gynecologic Oncology. Lung Cancer. Oncology Business Management. Pediatric Oncology. Supportive Care. Spotlight - In-person and virtual events just for HCPs. Author s : Kristi Rosa. Conference European Hematology Association Congress. Higher seizure rates were noted in patients over 10 years old, prompting changes in seizure prophylaxis. Related Videos. Related Content. Latest Conference Coverage. View More Latest Conference Coverage. About OncLive. Editorial Board. Contact Us. Do Not Sell My Information. Contact Info. About Us.

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Official websites use. Share sensitive information only on official, secure websites. Asparaginase ASNase is an important component of acute lymphoblastic leukemia ALL treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase Erwinia substitution was approved in for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown. Patients aged Maintenance therapy did not contain ASNase. Patients with Erwinia substitution who completed subsequent courses were not at increased risk HR, 1. Our results illustrate the severe consequences of Erwinia shortages. Asparaginase ASNase is an important part of acute lymphoblastic leukemia ALL treatment in children, adolescents, and young adults. What is the impact of omitting asparaginase doses on outcome in childhood acute lymphoblastic leukemia ALL? Substituting Erwinia asparaginase for pegylated asparaginase did not affect outcomes. Asparaginase should only be discontinued in higher-risk patients with ALL when the risk of additional toxicity outweighs the increased risk of relapse. The continued global shortage of Erwinia asparaginase places children with ALL at risk for compromised outcomes. Even in patients who receive Erwinia , subsequent toxicities may necessitate discontinuation. The impact of Erwinia substitution on outcome is also unknown. All patients enrolled in either of these 2 studies were included in this analysis. All trials were approved by the NCI and by the institutional review board of each participating center. Details of each trial, including chemotherapy regimens and randomized treatment interventions, have been published AALL03B1: ClinicalTrials. SR-average patients were randomly assigned to standard therapy 2 total doses of PEG-ASNase versus standard therapy with intensified consolidation 4 total doses. Slow early responders and patients with other high-risk features CNS3 status, testicular involvement, steroid pretreatment received additional postinduction therapy with 2 delayed intensification and interim maintenance phases. Additional details can be found in Appendix Tables A1 and A2 online only. During the study period, Erwinia was only intermittently available to patients, through either clinical trials or 8 compassionate or commercial use. ASNase activity monitoring was not routinely performed. For AALL, data were also collected on whether patients receiving Erwinia subsequently discontinued Erwinia for any reason. In addition, although data on the treatment phase in which discontinuation occurred was collected, data on the precise timing and hence the exact number of missed doses was not. The key prognostic variable examined was receipt of ASNase doses. The latter category included both patients who discontinued PEG-ASNase without Erwinia substitution and those in whom Erwinia was substituted but subsequently discontinued. Among patients in AALL, additional potential prognosticators included presenting WBC, methotrexate randomization Capizzi v high dose , and rapid versus slow early response. The latter was also a proxy for the length of premaintenance therapy. The cumulative incidence of PEG-ASNase discontinuation was calculated among the total study population, with induction failure, relapse, second cancers, and death considered competing events. To determine the impact of ASNase receipt on outcome, landmark survival analyses were conducted starting at the beginning of maintenance therapy, because no additional ASNase doses were prescribed past this point in therapy. These landmark analyses thus included only patients who began maintenance therapy. Disease-free survival DFS was defined as time from maintenance initiation to relapse, death, development of a second malignant neoplasm, or last follow-up. Overall survival OS was defined as the time from maintenance initiation to death from any cause or date of last follow-up if alive. Survival curves were compared using log-rank tests. Cox proportional hazards models were used for multivariable analysis of outcomes. All analyses were performed using SAS software, version 9. All graphics were generated using R, version 2. Table 2 shows demographic and disease-related characteristics. Allergic reactions were also responsible for more than half of the instances of PEG-ASNase discontinuation without Erwinia substitution; other reasons included pancreatitis and stroke. Erwinia , Erwinia chrysanthemi asparaginase. Appendix Table A4 online only shows characteristics of the patients included in the landmark analysis those starting maintenance , with reasons for coming off of protocol therapy prior to starting maintenance given in Appendix Table A5 online only. Among such patients, 99 had an event, including 95 Disease-free survival of National Cancer Institute high-risk patients stratified by asparaginase received. DFCI treatment regimens rely on a prolonged phase of postremission asparagine depletion lasting 30 weeks. In a subsequent DFCI study, Erwinia substitution after allergic reactions did not affect outcomes, although only 42 such patients were reported. In stark contrast, we found that failure to receive all ASNase doses was associated with a marked deterioration of DFS for higher-risk patients, even when patients with pancreatitis or thrombosis, who may have been sicker and experienced treatment delays, were excluded from analyses. This finding supports previous studies demonstrating therapeutic nadir serum ASNase activity levels with Erwinia 8 and should reassure both clinicians and caregivers. However, it also lends critical urgency to efforts to solve the current global Erwinia shortage or to develop alternative recombinant ASNase products that may be used in patients with PEG-ASNase allergy. Although access to Erwinia has been intermittent both before and after regulatory approval in , the current shortage due to ongoing manufacturing issues dates to October Clinicians have had to defer or omit doses as a result. Our findings support that the Erwinia shortage will result in additional relapses among children with ALL and provide evidence of the serious consequences that increasingly frequent chemotherapy shortages can have on patient outcomes. The differential impact of ASNase discontinuation in high-risk versus SR patients may reflect differences in the intensity of treatment necessary for cure in these 2 populations. Almost all such patients experiencing discontinuation would therefore have missed only 1 dose. Our results also imply that other strategies to avoid unnecessary ASNase discontinuation are warranted. Nonallergic reactions to PEG-ASNase, especially when given intravenously, may be related to acute hyperammonemia, are difficult to distinguish from allergic hypersensitivity, and frequently prompt clinicians to unnecessarily discontinue ASNase. Importantly, they also used universal ASNase activity monitoring to ensure that any neutralizing antibodies masked by premedication would nonetheless be detected, although such instances were rare. In addition, investigations of dose capping and of agents such as levocarnitine that may mitigate the risk of hepatotoxicity are justified. Several study limitations merit note. First, we could not determine the exact number of missed ASNase doses and therefore could not establish a threshold above which decrements in outcome occurred. In addition, the standard treatment arms for patients with rapid early response comprised only 2 doses of PEG-ASNase, thereby limiting the opportunity for subsequent Erwinia discontinuation. Fourth, a substantial number of patients came off protocol therapy before reaching maintenance for a variety of reasons. Risk estimates from our landmark analyses should therefore only be cautiously applied to patients at the beginning of therapy. Fifth, among NCI high-risk patients, not receiving all prescribed ASNase doses was associated with OS only in univariable analysis and not in multivariable analysis. However, because the magnitudes of association were similar, we cannot say with certainty whether we were underpowered to detect a difference in OS or whether such patients would benefit from salvage therapy on relapse. However, even in the latter case, relapse therapy is extremely intensive, with high cumulative doses of chemotherapy and potential stem cell transplantation, with the consequent risks of late effects. Finally, our study cannot guide clinicians on whether treatment should be modified for patients in whom additional ASNase therapy is contraindicated. In conclusion, patients in whom Erwinia was administered because of hypersensitivity to PEG-ASNase maintained outcomes as long as all subsequent Erwinia courses were received. In contrast, not receiving all prescribed doses of ASNase, in whatever form, was associated with substantially inferior outcomes. ASNase should only be discontinued when the risk of continuing ASNase therapy outweighs the increased risk of relapse, particularly in higher-risk patients. Efforts to restore the global Erwinia supply and prevent future disruptions are critical to maintain patient outcomes. Conception and design: Sumit Gupta, Elizabeth A. Raetz, Reuven Schore, Wanda L. Salzer, William L. Carroll, Naomi J. Winick, Stephen P. Hunger, Mignon L. Loh, Meenakshi Devidas. Collection and assembly of data: Sumit Gupta, Wanda L. Salzer, Len A. Mattano Jr, William L. Carroll, Stephen P. Hunger, Meenakshi Devidas. Maloney, Len A. The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians Open Payments. As a library, NLM provides access to scientific literature. J Clin Oncol. Find articles by Sumit Gupta. Find articles by Cindy Wang. Find articles by Elizabeth A Raetz. Find articles by Reuven Schore. Find articles by Wanda L Salzer. Find articles by Eric C Larsen. Find articles by Kelly W Maloney. Find articles by Len A Mattano Jr. Find articles by William L Carroll. Find articles by Naomi J Winick. Find articles by Stephen P Hunger. Find articles by Mignon L Loh. Find articles by Meenakshi Devidas. Accepted Feb 27; Issue date Jun Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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