PEG Asparaginase Research Articles

Achievement of therapeutic levels using dose-reduced peg-asparaginase in adult patients with acute lymphoblastic leukemia.

6530 Background: Peg-asparaginase (PEG) doses range from 2000-2500 IU/m2 in pediatric-inspired regimens for acute lymphoblastic leukemia (ALL). Pediatric PEG dosing in adolescents and young adults (AYAs) has resulted in improved outcomes, but PEG-associated toxicities increase with age and often limit its use. Therapeutic dosing is determined by asparagine (ASP) depletion for 14 days after dose; L-asparaginase levels can act as a surrogate marker of ASP depletion. We previously showed dose reduced PEG (defined as <2000 IU/m2) results in high rates of therapeutic L-asparaginase 7 days post PEG (Derman et al, Leuk Lymphoma 2020). Here we describe prolonged duration of ASP depletion and comparable toxicities after dose reduced PEG in adults with ALL. Methods: Patients ≥18 years with ALL or lymphoblastic lymphoma (LBL) who received PEG from 1/1/2008 to 9/28/2023 were identified for retrospective chart review. Those with ≥1 PEG trough level (defined as 10-20 days after dose) were included. The primary endpoint was therapeutic PEG levels (≥0.1IU/mL L-asparaginase) at 7 and 14 days post administration, with secondary endpoint being induction grade 3+ toxicities (CTCAE v.5.0). Results: 49 patients met inclusion criteria, of which 48 received PEG during induction. Median age was 34.7 (range 18-66), 67% were male and 53% had B-cell ALL. 17 (35%) received an induction dose ≤ 500 IU/m2, 22 (46%) received 501 to ≤1000 IU/m2 and 9 (19%) received >1000 IU/m2. Induction median dose was 1000 IU/m2. Among those with PEG trough levels, 79% were therapeutic after induction; of note, 4 patients were transitioned from PEG to Erwinia asparaginase due to silent inactivation. During induction, 23 (48%) patients had ≥1 grade 3+toxicity, including 5 (10%) with hepatotoxicity, 1 (2%) with pancreatitis, and 2 (4%) with a thrombotic event. There was no statistical relationship between dose level and toxicities (p=.8). Conclusions: This study demonstrates durability of therapeutic L-asparaginase levels and ASP depletion that persists 14 days despite dose reduction. There were decreased rates of hepatotoxicity and comparable rates of pancreatitis and thrombotic events compared to rates reported in CALBG 10403 (C10403) (Stock et al, Blood 2019), which utilized standard pediatric dosing. In addition, our cohort’s median age was significantly older than those treated on C10403. This suggests PEG dose reduction may offer similar therapeutic ASP depletion with comparable or reduced toxicities. Dose reduction should be studied prospectively in AYAs with ALL. [Table: see text]

High Efficacy and Feasibility of a Full Pediatric Induction in Adults Aged up to 55 Years with Philadelphia-Negative Acute Lymphoblastic Leukemia

Background: Treatment of acute lymphoblastic leukemia (ALL) in adults has historically shown unsatisfactory outcomes when compared to the outstanding results obtained in pediatric patients. Pediatric protocols rely on increased drug intensity and on a tighter evaluation of minimal residual disease (MRD) for early intensification. Nowadays, pediatric-inspired protocols have been established as the standard of care for adolescents and young adult patients (AYA) leading to improved results. In the setting of older patients, probably due to the limited data available, the feasibility of such intensive therapies, and in particular the administration of high doses PEG-asparaginase (PEGASP), is still a matter of debate. In this context, the NOPHO group reported that a full-pediatric protocol was feasible and highly effective in adult patients, up to 45 years of age. Aim: The aim of our study was to evaluate the feasibility and efficacy of the entire full pediatric AIEOP-BFM LAL 2009 protocol in an older cohort of adult patients up to 55 years. Methods: Since May 2013, 28 consecutive adults diagnosed with Ph-neg ALL received first line therapy according to AIEOP- BFM-ALL 2009 protocol, which includes high PEG-asparaginase (PEGASP) doses, with an accurate MRD-driven therapeutic strategy. The protocol consists of 2 induction blocks: IA (Vincristine, Daunorubicin, PEGASP, IT methotrexate) and IB (Cytarabine, 6-mercaptopurine, cyclophosphamide, IT methotrexate), I consolidation block (high-dose methotrexate, 6-mercaptopurine, IT methotrexate), maintenance therapy (6-mercaptopurine, weekly MTX, IT Methotrexate). Median age in our study was 45 years (range 17-55), equal to the maximum age allowed in the NOPHO study. Fifteen patients had B-ALL, 13 T-ALL/T including 5 Early-T phenotype. Dose intensification and stem cell transplantation (SCT) were scheduled according to baseline and MRD-driven risk assessment. MRD was evaluated by multicolor-flow cytometry (MFC), with a threshold for positivity of 0.025%, and molecular PCR for JH rearrangement (MOL), with a sensitivity greater or equal to 10-4 in all patients. Patients with MOL MRD >10-4 but <10-3 were defined as low-level positive. MRD time points were day 33 and day 78 (MFC and MOL). Results: All patients achieved complete hematological remission following the first Induction course (100%). One patient died during induction due to infection by multidrug resistant P. aeruginosa. In general, therapy was well tolerated. Remarkably, patients in this study received high dose of PEGASP (median 10000 UI/sqm, equal to 4 administrations at 2500 UI/sqm each) without experimenting life threatening toxicities, which mostly consisted in asymptomatic elevation of transaminase (7 patients G3, 1 G4) and/or bilirubin (9 patients G3, 1 G4) only requiring supportive therapy. No major bleeding or thrombotic events o other >G2 toxicities were observed. All except one patient achieved CR at day 33 and all patients achieved CR at day 78. MFC MRD evaluation at day 33 resulted negative in 24/25 evaluable patients (95%). Day 33 MOL-MRD was evaluated in 22 patients, and resulted negative, low level positive or positive in 14, 5 and 3 patients, respectively. MRD assessment at day 78 showed both MFC and MOL negativity achieved in all 25 and 22 evaluated patients, respectively (Fig. 1). Four very high-risk patients underwent SCT in negative MRD status. After a median follow-up of 59 months (CI 95% 38.45-78.63), median survival was not reached, 5-years OS was 88.7% (Fig. 2). One patient died due to progressive transverse myelitis after isolated CNS relapse and one patient died due to sudden cardiac arrest while in complete MRD negative remission, 6 months after completion of therapy. All other 25 patients are alive and in complete MRD negative remission. Conclusion: The application of a full pediatric induction regimen in a cohort of adult ALL patients with a median age of 45 years proved to be feasible, with tolerable toxicities. In particular, we didn't observe major toxicities during the intensified PEGASP administration and all patients were able to receive the planned PEGASP doses. The possibility to maintain the correct timing translated in a very high MRD negativity rate and promising OS survival.

Central Retinal Vein Occlusion (CRVO) in Acute Lymphoblastic Leukaemia (ALL) Adult Patient Treated with Peg Asparaginase

ntroduction Asparaginase, available as native asparaginase or polyethylene glycol (Peg-aspa), is an essential component of multi-agent treatment protocols for Acute Lymphoblastic Leukaemia (ALL). It works by deaminating L-asparagine, leading to apoptosis and cell cycle arrest in leukemic cells. However, peg-asp is associated with various toxicities, including thrombotic complications mainly cavernous sinuses thrombosis and venous thrombosis. Methods and Results: We report a 48-year-old Indian gentleman, known to be hypertensive, diagnosed to have Precursor T-Lymphoblastic leukaemia/ lymphoma (NOS), when he presented with bicytopenia and a mediastinal mass. He was treated as per ALL protocol for adult at National centre for cancer care and research (NCCCR)Doha, which is adopted from UKALL-14 protocol. He received induction treatment (1A& 1B) and has achieved a morphological remission. He received prophylactic anticoagulation with low molecular weight heparin (LMWH) which was stopped only in the cytopenic nadir. During the ascending phase of induction 1B, He presented with acute onset of floaters and blurred vision in the left eye. Urgent CT head scan revealed vitreous haemorrhage. Full blood count was normal except Platelets of 20*10 9ul. Coagulation screen, fibrinogen level and anti-thrombin level was within normal limit. Ophthalmological evaluation revealed vitreous and retinal haemorrhages, indicating Central Retinal Vein Occlusion (CRV). MRI/MRV brain ruled out intracranial venous thrombosis. CSF analysis excluded CNS disease. He received supportive transfusion; however, he has progressed to permanent loss of vision in the left eye. Therapeutic anticoagulation is not indicated in his case. Thrombotic events can occur during induction therapy for ALL mainly cavernous sinuses thrombosis and venous thrombosis, yet CRVO is an unusual site for thrombotic events and associated predominately with age-associated vasculopathies. In the reported case, several factors contribute to thrombosis, including acute leukaemia, prolonged hospitalization, age, presentation with a mediastinal mass, steroid use as well as Peg-aspa and the patient was managed with prophylactic anticoagulation while on therapy. Asparaginase induces a hypercoagulable state by decreasing antithrombin III, protein C, and protein S levels, leading to hypofibrinogenemia and augmenting the risk of thrombotic events. Thrombosis can negatively impact disease-free survival and long-term outcomes, resulting in complications such as therapy delays, post-thrombotic syndrome, and central nervous system-related issues (seizures, neurocognitive deficits, blindness). While these complications may lead to hesitancy or discontinuation of peg-asp use, early recognition and vigilant monitoring of antithrombin III and fibrinogen levels can help to guide management. In cases where the treatment course is complicated by thrombotic events, a high index of suspicion should arise considering strongly the causative agent to be Asparaginase. Thromboprophylaxis with low-molecular-weight heparin (LMWH) is widely accepted as supportive therapy in ALL management. Conclusion: ALL patients receiving Asparaginase therapy are at risk of developing thrombotic events. Early identification of symptoms and risk stratification are essential for improved disease outcomes. Awareness and understanding of peg-asp-induced thrombosis, including unusual site thrombosis can help guide treatment decisions and improve patient outcomes in ALL therapy.

Incidence and Characteristics of Hypersensitivity Reactions to PEG-asparaginase Observed in 6136 Children With Acute Lymphoblastic Leukemia Enrolled in the AIEOP-BFM ALL 2009 Study Protocol.

The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

Updated Outcomes of the University of Southern California (USC) ALL Frontline Regimen (based on CCG-1882) after Protocol Modification in the Era of Novel Agents in Ph-Negative ALL Patients

INTRODUCTION: Pediatric inspired regimens in adolescent young adults and adults have improved outcomes in acute lymphoblastic leukemia (ALL). CALGB 10403 was prospectively tested in patients 17-39 years and achieved a 3-year event free survival of 59%. In 2007, we reported outcomes after incorporating peg-asparaginase (PEG) dosed at 2000mg/m in induction for patients aged 17- 55 years. This was well tolerated and achieved a complete remission (CR) rate of 96%. In 2014, we reported experience with the use of multiple doses of PEG (CCG-1882) for newly diagnosed ALL adult patients achieving a 7-year overall survival (OS) of 51%. Since then, the USC ALL regimen consisting of 2 induction phases, was further modified with a goal of maintaining good outcomes and improving compliance and toxicities. Fractionated doses of cytarabine were changed to a single dose, the methotrexate dose of 1g/ m2 (2.5 g/m2 if T cell) given D1,15 in intensification phases was changed to 3g/ m2 (B and T cell) given in single doses, and consolidation was increased to six cycles allowing for PEG holidays. Moreover, the approval and incorporation of novel agents such as blinatumomab and inotuzumab also changed outcomes in ALL. Therefore, this study reports an update of outcomes since further modification of the USC ALL pediatric-based regimen in the era of novel agents. METHODS: This is a retrospective review which included adults aged 18 years with newly diagnosed Philadelphia negative ALL (2016-2020) treated at the USC/Norris Comprehensive Cancer Center and the Los Angeles County Hospital (LAC). Primary objectives were over-all survival (OS), event-free survival (EFS), disease-free survival (DFS) at 3 years. Secondary outcomes were complete remission/complete remission with incomplete recovery (CR/CRi) and minimal residual disease (MRD) by flow cytometry rates. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant. RESULTS: 121 patients with Ph-negative ALL were reviewed (49.6% Ph-negative B-ALL, 23.9% Ph-like B-ALL, 0.8% B cell lymphoblastic leukemia (LBL), 9.1% T cell ALL, 4.1% T cell LBL, 4.1% early T-cell, 5.8% mixed phenotype acute leukemia (MPAL). Median age at diagnosis was 39.3 years. There were 71.9% Hispanic, 15.7% White, 9.9% Asian, 2.5% African Americans. 57.9% males, 42.1% females. In terms of risk stratification, the majority were unfavorable at 54.6% and 37.8% unknown. Median BMI was 29.6 kg/ m2. 52.5% had hepatic steatosis and 5% had CNS disease pre-induction. 68.7% received PEG during induction 1, and 67.9% during induction 2. Post-induction 1, 83.5% patients achieved CR/Cri with 49% MRD negativity by flow. Post-induction 2, 75% achieved CR/Cri with 57.1% MRD negativity by flow. 26.4% received blinatumomab but not allo-HSCT. 20% received blinatumomab and underwent allo-HSCT. 34.7% received blinatumomab for MRD flow positivity, median 2 cycles, only 5.8% received inotuzumab, 35.5% underwent allogenic stem cell transplant. 28.9% and 9.1% had any relapse and refractory disease, respectively. Mortality rate was at 14.9%. 3y OS was at 80.7%, 3y EFS at 54.3% and 3y DFS 61.3%. When stratified by MRD flow negativity after induction 1 and 2, 3y OS was 83.7% vs 91.1% (p=0.55), 3y DFS was 68% vs 64.1%(p=0.98) and 3y EFS was 68% vs 59.5% (p=0.84). When stratified by blinatumomab use, 3y OS 72.5% vs 85.1% (p=0.15), 3y EFS was 31.6% vs 67.5% (p=0.001), 3y DFS was 40.1% vs 73.1% (p=0.001) (Fig 1-2). Use of PEG resulted in grade 3/4 toxicities including hypersensitivity (4.1%), transaminitis (21.5%), pancreatitis (5.4%), hypertriglyceridemia (49.5%), hypofibrinogenemia (45.5%), hyperbilirubinemia (21.5%) and thrombosis (16.5%). CONCLUSIONS: The modified pediatric-based USC ALL induction regimen using PEG maintained a high 3y OS at 85.3% and appreciable 3y EFS at 54.3% and 3y DFS at 61.3%, with tolerable toxicities in an era of novel agents like blinatumomab. This compares favorably with the original USC ALL regimen, CALGB 10407 and GRAALL 2005. Of note, 3y EFS and 3y DFS were significantly lower in those who underwent blinatumomab since these patients were MRD flow positive and lacked deeper remissions, but 3y OS (72.5%) remained high regardless, even though 26.4% who received blinatumomab were not able to go for allo-HSCT. This suggests the beneficial effect of blinatumomab. Further follow-up is necessary to provide a more robust and mature survival data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ODP155 Successful Treatment of PEG-Asparaginase Related Hypertriglyceridemia with Omega-3 Acid Ethyl Esters

Abstract Introduction Young adults diagnosed with acute lymphoblastic leukemia (ALL) have been increasingly treated with a pediatric-inspired regimen including asparaginase, to improve both quality and quantity of survival. Peg-asparaginase (PEG-ASP) is a long-acting formulation of L-asparaginase (L-ASP), an enzyme that selectively kills leukemic cells by depleting plasma asparagine. Treatment with PEG-ASP provides multiple benefits including increased complete remission rates and overall survival, however, numerous toxicities can occur including fatigue, nausea, vomiting, hypersensitivity, thrombosis, pancreatitis, hepatotoxicity, and, less commonly, hypertriglyceridemia (HTG). Several treatment approaches have been reported for patients with PEG-ASP induced HTG but strong evidence supporting any specific option is lacking. Clinical case: A 24-year-old woman presented with sacral joint septic arthritis that led to the discovery of underlying B-cell acute lymphoblastic leukemia (B-ALL). Soon after diagnosis the CALGB 10403 protocol, which contains PEG-ASP, was initiated. Sixteen days after the initial PEG-ASP dose of 3,750 units it was noted her plasma serum was lipemic with TG of 669 mg/dL, which peaked the next day to 1,314 mg/dL while the patient remained asymptomatic and without signs or symptoms of pancreatitis. She was started on a brief course of insulin drip (lasting 6 hours) and a low-fat diet. Four days later fish oil (omega-3 acid ethyl esters) 2 gm twice daily was added, and two days later micronized fenofibrate 67 mg as well. She was tolerating this regimen for three days when fenofibrate had to be discontinued due to elevated liver enzymes while fish oil was continued. Triglycerides continued to successfully trend down over the course of two weeks, and after reaching a level of 111 mg/dL she was re-challenged with another dose of PEG-ASP 3,750 units. After the second dose of PEG-ASP, her TGs became elevated again but peaked at 542 mg/dL. She received a third dose of PEG-ASP 3,750 units two months later when TG remained below 200 mg/dL. A month later she received a fourth/final dose of PEG-ASP 3,750 units which led to transient elevation of TGs peaking at 437 mg/dL but returning to levels below 200 mg/dl within two months. Throughout the course of her treatment with PEG-ASP, she continued to take fish oil. Conclusion Multiple studies showed that the benefit to toxicity ratio of asparaginase in young adults with ALL is favorable. Our conclusion is that in patients who develop HTG, fish oil can be utilized as a treatment and continued as long as they are receiving PEG-ASP, especially in patients unable to tolerate fenofibrate. We would like to bring attention to this case with the current positive outcome given the fact there is currently limited evidence on the safety of re-challenging patients with PEG-ASP after experiencing HTG. Presentation: No date and time listed

Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG–asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

The association of age and adverse events of PEG-asparaginase in a pediatric tertiary care hospital; a retrospective review.

Pediatric patients have a better survival rate for lymphoid malignancies than adolescents and young adult patients (AYA) and current evidence suggests that asparaginase plays a role in improved response to treatment. This study aimed to evaluate if increasing age as a continuous variable demonstrated increasing toxicities to PEG-asparaginase (PEG-ASP) for those patients treated at a tertiary care pediatric hospital. A retrospective chart review from 2007 to 2017 was conducted in the pediatric population at the Children's Hospital of Eastern Ontario (CHEO). Patients having received PEG-ASP were included. Event incidence and risk related to age at diagnosis were assessed through parameter estimates and Wald chi-square analysis. In total, 75 adverse events were observed: 34/186 (18.3%) experienced allergic reactions, 8/186 (4.3%) pancreatitis, 31/186 (16.7%) thrombosis, and 2/186 (1.1%) hemorrhage. One hundred and eighty two patients had complete information for inclusion in our model. A correlation between age at diagnosis and higher risk of allergic reaction (p < .001) and pancreatitis (p < .035) was observed. Allergic reaction and pancreatitis following administration of PEG-ASP have a higher risk of occurrence as age of diagnosis increases up to 18 years of age. This includes the lower limit of traditionally defined AYA population of 15-39 and warrants precaution as PEG-ASP is included in older populations treatment regimens at pediatric centers.

Recurrent Septic Arthritis and Osteomyelitis with Enterococcus gallinarum in a Child with Acute Lymphoblastic Leukaemia

The patient was diagnosed with ALL at the age of 13 years and was commenced on the UK ALL 2011 treatment regimen including intrathecal methotrexate, daunorubicin, PEG asparaginase and vincristine. She presented eight months after her initial diagnosis.

COVID-19 mRNA Vaccination Appears Safe in Pediatric Patients With A Hypersensitivity Reaction To PEGylated Escherichia Coli L-Asparaginase

L-Asparaginase is an established component of acute leukemia therapy. PEG-asparaginase (PEGAsp), Escheria coli L-asparaginase linked to polyethylene glycol (PEG), is a common first-line formulation. However, PEGAsp hypersensitivity occurs in 10-15% of patients, with the PEG component most commonly suggested [PCA1] antigenic culprit. Because mRNA COVID-19 vaccines contain PEG, albeit of a different molecular weight, administration safety in patients with prior PEGAsp hypersensitivity has been questioned.

Influence of Bisphosphonates or Recombinant Human Parathyroid Hormone on in Vitro Chemotherapy Sensitivity in Acute Lymphoblastic Leukemia Cells

BACKGROUNDOsteonecrosis and low bone mineral density (BMD) are serious osteogenic side effects of acute lymphoblastic leukemia (ALL) treatment. Bisphosphonates and recombinant human parathyroid hormone (rPTH) tend to be used to ameliorate osteonecrosis-related symptoms as well as to enhance bone mineral density in children with ALL and severe bone fragility. Only one preclinical study on the safety of bisphosphonates during ALL treatment is available, which raises concerns about their impact on leukemic drug sensitivity. Here, we assessed the influence of various bone-modifying agents (zoledronate, pamidronate and rPTH) on in vitro cytotoxicity of chemotherapeutic agents (vincristine (VCR), daunorubicin (DNR), dexamethasone (DEXA), 6-mercaptopurine (6-MP), PEG-asparaginase (PEG-ASP)) and prednisone (PRED) that are commonly used in ALL treatment.METHODSPotential cytotoxic effects of the bone-modifying agents on leukemia cell viability and on in vitro cytotoxic responses of chemotherapeutic agents were tested in various T-cell and B-cell leukemia cell lines using methyl-thiazol-tetrazolium (MTT) assays. Bone-modifying agents were added at concentrations up to a five-fold of their physiological peak plasma concentration. For each assay, 50th percentile of maximal inhibitory concentration was determined. To quantify the combined effects of the bone-modifying agents on chemotherapeutic agent-induced cytotoxicity, median (interquartile range) combination indexes (CI) were calculated. We considered a median CI of < 0.8 as synergism and > 1.2 as antagonism (based on the method of Chou).RESULTSZoledronate, pamidronate or rPTH in combination with DNR, 6-MP and PEG-ASP showed median CI values between 0.8 and 1.2. Variable inconclusive results were obtained in combination with VCR. Only the combination of a five-fold peak plasma concentration of zoledronate or pamidronate with DEXA resulted in median CI values of 1.15 (range, 1.08-1.48), and 1.34 (range, 1.07-1.62), respectively. Additional experiments using DEXA as well as PRED in combination with one-, three- or five-fold physiological peak plasma concentrations of zoledronate or pamidronate revealed that median CI values stay within 0.8 and 1.2, except for DEXA exposed leukemia cells in combination with a five-fold physiological peak plasma concentration of pamidronate which repeatedly showed a median CI value above 1.2 (1.34, range 1.04-1.86).CONCLUSIONSZoledronate, pamidronate or rPTH do not seem to influence drug sensitivity of DNR, 6-MP or PEG-ASP, even at a five-fold physiological peak plasma concentration. Nevertheless, our findings suggest a minimal effect of pamidronate on DEXA-induced leukemia cell death. This suggests that even though zoledronate or pamidronate do not seem to negatively influence DEXA- or PRED- induced toxicity in expected physiological concentrations (one- to three-fold physiological peak plasma concentrations), these bone-modifying agents may only be considered with caution in individual cases, and preferably in clinical trial settings before being applied on a large scale in children with ALL. DisclosuresNo relevant conflicts of interest to declare.

An Update on Outcomes Using the USC ALL Frontline Regimen (based on CCG-1882) after Further Modification of Protocol in the Era of Novel Agents in Ph-Negative ALL Patients; A Retrospective Study

▪INTRODUCTION: The use of pediatric inspired regimens in adolescent young adults and adults has improved outcomes in acute lymphoblastic leukemia (ALL). CALGB 10403 was prospectively tested in patients 17-39 years, showing a 3-year event free survival of 59%.In 2007, our institution reported outcomes after incorporating peg-asparaginase (PEG) dosed at 2000mg/m 2 in induction for patients aged 17- 55 years. This regimen was well tolerated and resulted in a complete remission (CR) rate of 96%. In 2014, we reported experience with the use of multiple doses of PEG (CCG-1882) for newly diagnosed ALL adult patients, with a 7-year overall survival (OS) of 51%. Since our last report, the USC ALL regimen consisting of 2 induction phases, has been further modified with a goal of maintaining good outcomes, and improving compliance and toxicities. Fractionated doses of cytarabine were changed to a single dose, the methotrexate dose of 1g/m 2 (2.5 g/m 2 if T-cell) given D1,15 of intensification phases was changed to 3g/m 2 (B and T cell) given in single doses, and consolidation was increased to six cycles allowing for PEG holidays (Table 1).Moreover, the approval and incorporation of novel agents such as blinatumomab and inotuzumab also changed outcomes in ALL. Therefore, this study reports an update of outcomes since further modification of the USC ALL pediatric-based regimen in the era of novel agents. METHODSThis is a retrospective review which included adults aged >18 with newly diagnosed Philadelphia negative ALL between 2016 and 2020 treated at USC/Norris Cancer Center and Los Angeles County Hospital (LAC). Primary objectives were over-all survival (OS), event-free survival (EFS), disease-free survival (DFS) at 3 years, and secondary outcomes were complete remission/complete remission with incomplete recovery (CR/CRi) rates and minimal residual disease (MRD) by flow cytometry. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant.RESULTS: 121 patients with Ph-negative ALL were identified (49.6% Ph-negative B-ALL, 24% Ph-like B-ALL, 0.8% B cell lymphoblastic leukemia (LBL), 9.1% T cell ALL, 4.1% T cell LBL, 4.1% early T-cell, 5.8% mixed phenotype acute leukemia (MPAL). Median age at diagnosis was 38.5 years and maximum age of patient to receive pegasparagase during induction 1 was 63 years. 71.9% Hispanic, 15.7% white, 9.9% Asian, 2.5% African American. 57.9% males, 42.1% females. 3.4% were favorable, 4.2% intermediate, 54.6% unfavorable and 37.8% unknown by karyotypic risk stratification. Median BMI was 28.9 kg/m 2.54.6% had hepatic steatosis either on history or imaging and 5.1% had CNS disease pre-induction.Post-induction 1, 81.4% of patients achieved CR/CRi and 50% MRD negative. Post induction 2, 82.2% achieved CR/CRi, 67.7% MRD flow negative. Post-consolidation 1, 90.9% were MRD flow negative. 33.1% subsequently received blinatumomab for MRD positive disease, 5% given inotuzumab for relapsed disease, 32.2% underwent allogenic hematopoietic stem cell transplant (allo-HSCT). Median number of pegasparagase doses received during treatment was 2, rate of relapse and mortality was 27.3% and 13% respectively.Median OS and DFS were not reached but median EFS was 35 months. 3-year OS was 85.3%, when stratified according to MRD post induction 2; 3-year OS was 91.7% for MRD positive patients and 91.2% for MRD negative patients (p=0.55). 3-year DFS was 83.2%; 88.2% for MRD positive patients and 97.4% for MRD negative patients (p=0.22). 3-year EFS was 47.3%; 51.3% for MRD positive patients and 50.6% for MRD negative patients (p=0.49) (Tables 2-3).Use of pegasparagase resulted in grade 3/4 toxicities including hypersensitivity (4.1%), transaminitis (21.5%), pancreatitis (5.4%), hypertriglyceridemia (49.5%), hypofibrinogenemia (45.5%), hyperbilirubinemia (21.5%) and thrombosis (16.5%). CONCLUSIONSPediatric-based modified USC ALL induction regimen led to a high 3-year OS (85.3%), DFS (83.2%) and EFS (47.3%) with predictable toxicity and compares favorably with original USC ALL regimen, CALGB 10407, GRAALL 2005 and USC/MSKCC regimen.Interestingly, MRD positivity after induction 2 did not adversely affect OS, DFS or EFS, which is likely due to incorporation of blinatumomab and inotuzumab. These agents could have allowed for deeper remissions allowing Ph-negative patients with residual disease to receive allo-HSCT. [Display omitted] DisclosuresChaudhary: Oncotartis: Consultancy; Pancella: Consultancy; Moderna: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy . Douer: Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy. Yaghmour: Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau.

Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase.

Vaccinationis a critical tool in the prevention of COVID‐19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer‐BioNTech) mRNA vaccine is approved for individuals aged 12–17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG‐asparaginase (PEG‐ASNase) and 10%–30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG‐ASNase allergy.

Peg-Asparaginase Administration on Day 3 of Remission Induction Accelerates MRD Response in Children with B-Cell Precursor Acute Lymphoblastic Leukemia

To improve the outcome of children with standard and intermediate risk acute lymphoblastic leukemia (ALL) by the addition of PEG-asparaginase (PEG) on day 3 of remission induction was one of the key aims of trial ALL MB-2008 (J. Roumjantseva et al, Pediatriya, 2009). Therapy was designed based on previous MB-group studies (A. Karachunsky et al, Leukemia, 2008). Aim of the present study was to evaluate the influence of day 3 PEG on the end-induction MRD-status which is one of the significant predictors of outcome in children with B-cell precursor ALL (BCP-ALL).Patients and methods. In total, 474 patients (242 boys and 232 girls aged 1 to 17 years (median 5 years 8 months) were studied. Inclusion criteria were: BCP-ALL, treatment according to protocol ALL MB-2008, compliance with standard risk group (SRG, n=266) and intermediate risk group (ImRG, n=208) criteria according to the protocol stratification system, and availability of end-induction (day 36) bone marrow (BM) samples. Remission induction of ALL MB-2008 consisted of oral dexamethasone (6mg/m2 daily), 5 injections of vincristine (1,5 mg/m2), 0-2 injections of daunorubicin (DNR, 45 mg/m2) and 6 triple intrathecal injections. Patients were randomized in respect to PEG administration on day 3. SRG patients were divided into three groups (PEG+DNR+, PEG+DNR- and PEG-DNR+); ImRG patients were split into two (PEG+DNR+ and PEG-DNR+). MRD detection was performed by multicolor flow cytometry (MFC) in three reference laboratories. Samples with a tumor cell level above 0.01% were considered MRD-positive. Outcome parameters were event-free survival (EFS) and cumulative incidence of relapse (CIR). Median of follow up was 5 years.Results. Outcome in 474 study group patients was not significantly different from outcome of 2310 children with BCP-ALL enrolled in SRG and ImRG of ALL MB-2008 trial in whom MRD was not studied: EFS was 0.86±0.02 and 0.84±0.01, respectively, p=0.14, and CIR was 0.12±0.02 and 0.09±0.01, p=0.38.MFC MRD data obtained at day 36 had a significant impact on prognosis in SRG patients. EFS as well as CIR were worse for patients with MRD >0.1% (n=26; EFS 0.47±0.15, CIR 0.49±0.17) compared with 248 patients with low/negative MRD (EFS 0.94±0.2, CIR 0.05±0.02, p<0.001). Nevertheless, the distribution of MRD levels was completely different dependent on randomization arms: in arm PEG-DNR+ (n=92) 18.5% of patients belonged to the group with unfavorable MRD compared with only 6.2% in arm PEG+DNR- (n=80, p=0.017) and 4.3% in arm PEG+DNR+ (n=94, p=0.002). Interestingly, in two PEG+ arms the number of patients with high MRD was not significantly different (p=0.558). Despite the lower proportion of high MRD levels in PEG+ arms MRD maintained its prognostic significance also in these patients. EFS was 0.65±0.16 and CIR 0.35±0.18 in 9 children with MRD ≥0.1 compared with EFS 0.94±0.02 and CIR 0.05±0.02 in 165 patients of the low MRD group (p<0.001 for both EFS and CIR).In ImRG, MFC MRD data disclosed a prognostic value, as well. EFS was 0.92±0.03 and CIR 0.06±0.02 for 143 patients with MRD-negativity on day 36; in contrast, outcome of 78 MRD-positive patients was significantly inferior (EFS 0.73±0.06, CIR 0.25±0.06, p<0.001 for both comparisons). Like in SRG, in ImRG the distribution of MRD levels was different between two randomization arms. In PEG-DNR+ group (n=93) only 54.8% of patients were MRD-negative at the end of remission induction. In contrast, in PEG+DNR+ group (n=115) the proportion of patients with favorable MRD results was significantly higher (76.5%, p=0.001). Again even with low number of MRD-positive cases in PEG+ arm, day 36 MRD disclosed a significant influence on outcome: In 88 MRD-negative patients EFS was 0.93±0.03 and CIR 0.05+0.03, significantly better than in 27 MRD-positive patients (EFS 0.80+0.08 and CIR 0.17+0.08, p=0.025 and p=0.019, respectively).Conclusions. Administration of PEG at day 3 of remission induction leads to a more rapid MRD response in children both with standard-risk and intermediate-risk BCP-ALL. In SRG, rapidity of MRD clearance in PEG+ arms was independent of the additional administration of daunorubicin. We conclude that end-induction MRD data are independent predictors of outcome despite the small proportion of MRD-positive patients after the implementation PEG during induction. DisclosuresNo relevant conflicts of interest to declare.

Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Levocarnitine for pegasparaginase-induced hepatotoxicity in acute lymphoblastic leukemia

Pegasparaginase (PEG-Asp), commonly used in acute lymphoblastic leukemia (ALL), is associated with hyperbilirubinemia and elevated transaminases. Treatment of acute hepatotoxicity is limited to case studies reporting success with levocarnitine (LC). In a retrospective analysis, 25 ALL patients experienced Grade ≥3 hyperbilirubinemia and/or elevated transaminases following a single dose of PEG-Asp where 12 patients received LC compared to 13 patients with no intervention. Median LC dose was 50 mg/kg/day for a median of 11 days. Median values were greater in the LC group: total bilirubin 5.2 mg/dL vs 4.5 mg/dL (p = 0.19), AST 75.5 units/L vs. 30 units/L (p = 0.05), and ALT 263.5 units/L vs 47 units/L (p = 0.003). Time to resolution (TTR) did not significantly differ between LC and control (p = 0.08), however, patients on LC did resume therapy sooner (p = 0.17). Although significant limitations exist in the study, LC did not result in a clinically significant impact when used to treat PEG-Asp-induced hepatotoxicity.

2417 PEG-Asparaginase (PEG-ASP) Induced Liver Injury: Case Report and Systematic Review of the Literature

INTRODUCTION: Drug induced liver injury (DILI) is the most common cause of acute liver failure (ALF) in the USA. L-asparaginase (L-ASP) and its pegylated form (PEG-ASP) are antineoplastic agents used in acute leukemias. Here we present a case of severe DILI secondary to PEG-ASP and a systematic review of published cases. CASE DESCRIPTION/METHODS: Methods: PubMed search detected 343 abstracts related to ASP, of which 18 were relevant to our case. We used descriptive statistics to compare the published experience with our patient. Case: A 45 yo female with acute lymphoblastic leukemia (ALL) was admitted with a cholestatic liver injury and jaundice 14 days after starting PEG-ASP. She had normal liver enzymes prior to onset of treatment. Tests for viral and autoimmune hepatitis were unremarkable. Diagnostic ultrasound suggested only a fatty liver parenchyma. Liver biopsy revealed severe steatosis and mild cholestasis without fibrosis. Naranjo scale was 6 consistent with probable adverse drug reaction. PEG-ASP was stopped, steroids and L-carnitine infusion were started, however DILI continued to worsen. At their peak Total/direct bilirubin were 21/17 mg/dL, ALP 1,504 U/L, GGT 2,329 U/L and AST/ALT 153/50 U/L. Patient never developed ALF. Liver enzyme panel normalized over the next 8 weeks. Results: In our review of 18 reported cases, most were females (72%), adults (72%), with 32% being adults &lt;50 years. The patterns of liver enzyme abnormality were cholestatic (26%), hepatocellular (21%), or mixed (21%) (unknown in 32%). Median time from starting ASP to DILI was 17 days. When biopsy was performed (11 patients) macrovesicular steatosis was uniformly present. Overall 6 patients died (one died of ALF) and 12 recovered with normalization of liver enzymes over the course of 2-26 weeks. DISCUSSION: Our patient is a classic case of DILI given onset of injury within 2-3 weeks of initiation of treatment, exclusion of alternate etiologies, histopathology showing severe steatosis, and complete normalization of liver enzymes following drug discontinuation. It is important to recognize ASP-DILI as 30% of cases end in ALF or death; nearly all cases will delay important treatment of acute leukemia. L-carnitine was reported as a potential rescue therapy, though its efficacy is uncertain. CONCLUSION: ASP related DILI is marked by severe steatosis and significant liver enzyme abnormalities occurring within weeks of starting treatment and resolving over many weeks after. Prompt recognition and drug discontinuation are imperative.

Dose-Adjusted Intensive Chemotherapy Is Safe and Tolerable in Older Patients with Ph-Negative ACUTE Lymphoblastic Leukemia

Topic Significance & Study Purpose/Background/Rationale Outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor [PMID 19897583, 28419558, 22409379, 10653870]. PEG-Asparaginase (PEG-Asp) is a key component of the chemotherapeutic regimens for treatment of pediatric and younger adult ALL [PMID 29450465]. Older patients with Ph-negative ALL are often not offered PEG-Asp containing regimen due to concerns related to tolerability and safety [PMID 28355969]. Methods, Intervention, & Analysis The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted pediatric chemotherapy regimen for adults (≥40 years) with diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced to 40 mg/m2/day, and PEG-Asp to 1000 units/m2. For patients aged ≥61 years, PRD was further reduced to 25 mg/m2/day. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects (AE) based on Antithrombin III (ATIII) and fibrinogen levels. Findings & Interpretation Fourteen patients with median age 60 years (45 – 76) were evaluable, and three patients were ≥ 70 years. Eleven patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Eleven patients (79%) attained a complete remission (CR) at the end of induction (EOI), four of them with detectable minimal residual disease (MRD). Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 – 60), four remain in CR at last follow up (median 563 days, range 259 – 883), and one died of relapsed disease 67 days post-HCT. The other eight patients who are receiving chemotherapy are in remission at last follow up (median 317 days, range 63 – 714). Observed PEG-Asp related AE were asymptomatic hypofibrinogenemia and low ATIII levels (n=10), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). No patient experienced early death, severe allergic reaction or clinical pancreatitis. Discussion & Implications This dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and with tolerable and manageable AE in this patient population with significant co-morbidities. Treatment related mortality was 0%. Twelve of the 14 patients are currently in sustained remission (median follow-up 399 days, range 63-883). Further prospective evaluation is under way.

Feasibility of High Doses Peg-Asparaginase Administration in a Cohort of Adult Acute Lymphoblastic Leukemia Patients

Background: The application of pediatric-inspired regimens for the treatment of adult acute lymphoblastic leukemia (ALL) patients has led to a significant improvement in clinical outcome. The increased use of non-myelosuppressive agents such as peg-asparaginase (PEG-ASP) in modern adult protocols greatly contributed to improve treatment outcome. However, concerns about the safety of PEG-ASP administration in adults have emerged. Patient-related factors as high body mass index (BMI) or pre-exhistinghepatic steatosis have already been identified as risk factors contributing to PEG-ASP related toxicity. However, few data are available on the role of specific concomitant medications potentially contributing to PEG-ASP toxicity.Aims: To identify patients and therapy-related factors contributing to the development of PEG-ASP associated toxicity in a cohort of adult ALL patients who received intensive induction treatment according to a full pediatric or an alternative intensive regimen.Methods: Since 2013, 26 adult ALL patients received PEG-ASP in our Center. Median age was 47 years (range 19-76). Nineteen patients were treated in front-line setting: 11 according to the full pediatric protocol AIEOP-BFM 2009 (median age 36, range 19-56), 4 patients according to a national pediatric-like protocol for adult patients (median age: 47,5, range 39-59) and 1 patient aged 76 received PEG-ASP plus reduced-intensity chemo. Ten patients received PEG-ASP as part of salvage therapy for relapsed/refractory disease.Methods: PEG-ASP- related toxicities were recorded and classified according to the guidelines published by Stock et al (Leukemia and Lymphoma, 2011). The incidence of PEG-ASP-related toxicity was analyzed considering as a separate episode each course of therapy including PEG-ASP administration (with a median duration per episode of 1 month, range 0,5-2 months). Patient features, timing and doses of chemotherapic agents and concomitant medications were recorded. A total of 49 episodes were analyzedResults: No grade III-IV pancreatic, thrombotic or hemorrhagic adverse event were observed. Isolated hyperbilirubinemia was the most frequent adverse event observed (n. 24 grade II, N. 5 grade III, N. 2 grade IV). Grade III hepatotoxicity was observed in 5 patients; 3 patients had grade IV hepatotoxicity. In all of them, ultrasonography showed the onset of acute liver steatosis. All 3 patients had received concomitant therapy with Idarubicin (IDA), vincristine (VCR) and vancomycin. In all the 3 cases patients died due to superimposed infections.In univariate analysis age > 45 yrs, administration of PEG-ASP therapy with active leukemia or BMI >25 were not related with an increased incidence of grade III-IV hepatotoxicity which was instead significantly higher when a cumulative dose of IDA of at least 20 mg/sqm over a single episode (p 0.047, HR 1.48) was administered. Cumulative dose of VCR of at least 2 mg/sqm determined a borderline increase in toxicity risk (p 0.055, HR 4.75). Administration of estroprogestinic hormones were significantly associated with the risk of developing hepatic-toxicity (p 0.024, HR 1.33). No increase was observed with any dose of prednisone/dexametasone, daunorubicin, cyclophosphamide, cytarabine, methotrexate, and 6-mercaptopurine. Among antimicrobial therapies, vancomycin, synthetic penicillines + B-lactamases inhibitors and Carbapenems administration increased the risk of grade III-IV hepatotoxicity (p 0.009, HR 1.85, p 0.010 HR 3.02, p 0.047 HR 2.02). No significant increase in the risk of toxicity was observed with azoles. Notably, none of the patients undergoing full pediatric induction, which contains higher cumulative doses of PEG-ASP, experienced grade IV hepatotoxicity.A multivariate logistic regression analysis disclosed that administration of IDA, sexual hormones and synthetic penicillines + B-lactamases inhibitors were independent predictors of grade III/IV hepatotoxicity (p 0.014, 0.024, 0.041; Tab. I).Conclusion: In our experience the toxicity profile of PEG-ASP in adult patients is overall manageable even when high doses were administered according to a full pediatric schedule. Our data suggest that the development of severe hepatic toxicity is significantly influenced by chemotherapy schedule and specific concomitant medications. DisclosuresGobbi:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

Dose-Adjusted Intensive Chemotherapy Is Safe and Tolerable in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia

BackgroundThe outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor when compared to younger ALL patients [PMID 19897583, 28419558, 22409379, 10653870]. Asparaginase (Asp) induces death of human lymphoblasts, and effective asparagine depletion is associated with improved outcomes in ALL. PEG-Asparaginase (PEG-Asp), which has a longer half-life than Asp, is a key component of the intensive chemotherapeutic regimens utilized for treatment of pediatric and younger adult ALL [PMID 29450465]. Frequently, older patients with Ph-negative ALL are not offered PEG-Asp containing pediatric chemotherapy regimen because of concerns related to tolerability and safety in this population [PMID 28355969].MethodsThe Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted, CALGB 10403 based intensive chemotherapy regimen for adults (≥40 years) with a diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced from 60 to 40 mg/m2/day from D1 to D28, and PEG-Asp reduced from 2500 to 1000 units/m2 (D4). For patients aged 61 years and above, PRD was further reduced to 25 mg/m2/day, and PEG-Asp to 1000 units/m2 on D4. In CD20+ ALL, rituximab x 8 doses were added to the regimen. CNS-prophylaxis consisted of intrathecal methotrexate at D1, D8 and D29 during induction, and during subsequent courses of chemotherapy based on the CALGB 10403 protocol. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects. After the administration of PEG-Asp, Antithrombin III (ATIII) and fibrinogen levels were monitored on the same day, twice a week, for at least two weeks. If ATIII levels were < 70% and/or fibrinogen levels < 120 mg/dL, levels were corrected with the administration of ATIII concentrate and/or cryoprecipitate, respectively.ResultsTwelve patients with a median age of 58 years (45 - 76) were evaluable, and three patients were ≥ 70 years. Nine patients had B-cell ALL and three T-cell ALL. Three patients had a white blood cell count > 30 x103/µL at diagnosis. An ECOG status ≤ 2 at diagnosis was described in all patients, and all of them had multiple complex cytogenetic and molecular abnormalities. Ten patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Nine out of the twelve patients (75%) attained a bone marrow morphological complete remission (CR) at the end of induction (EOI), three of them with detectable minimal residual disease (MRD) that became undetectable after completing course II. Of the three patients who had ≥5% bone marrow blasts at EOI, one attained a CR with undetectable MRD at the end of course IA and another when switched to blinatumomab, and the third one died of progressive disease. No patient experienced early death. Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 to 60 years) and four remain in CR at last follow up (median 489 days, range 181 - 841), and one died of relapsed disease 67 days post-HCT. The other six patients who are receiving chemotherapy are alive and in remission at last follow up (median 272 days, range 52 - 639).The common adverse effects associated with PEG-Asp administration in this older group of patients were asymptomatic hypofibrinogenemia and depleted ATIII levels requiring supplementation (n=8), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). Severe allergic reaction, clinical pancreatitis and cognitive impairment were not observed.ConclusionThis age-based dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and a tolerable and manageable adverse event profile in this older patient population with significant co-morbidities. Treatment related mortality was 0%. Ten of 12 patients are currently in sustained remission, either with chemotherapy alone or following allogeneic HCT (median follow up 422 days, range 52 to 841 days). Treatment optimization for older patients with ALL utilizing an intensified, age-adjusted PEG-Asp containing induction and consolidation therapy regimen is associated with favorable outcomes and provides an effective bridge to potentially curative therapies such as HCT. Further prospective evaluation is under way. DisclosuresKremyanskaya:Incyte: Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.