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Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial

Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity... OPEN Leukemia (2017) 31, 58–64 www.nature.com/leu ORIGINAL ARTICLE Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial 1 2 3 4 5 6 2 2 2 7 B Patel , AA Kirkwood , A Dey , DI Marks , AK McMillan , TF Menne , L Micklewright , P Patrick , S Purnell , CJ Rowntree , 2 3 P Smith and AK Fielding Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/ m PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25–65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death 440 versus ⩽ 40 years, odds ratio (OR) 18.5 (2.02–169.0), P=0.01; Ph − versus Ph+ disease, OR 13.60 (3.52–52.36), Po0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG- ASP-related adverse event, most commonly hepatotoxicity (36.5%, n = 27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged 440 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib. Leukemia (2017) 31, 58–64; doi:10.1038/leu.2016.219 INTRODUCTION remission (CR), overall survival, minimal residual disease (MRD) quantitation at the end of the first phase of induction and Depletion of extracellular asparagine by parenteral administration antiasparaginase antibody formation. Here we report on of the enzyme L-asparaginase is a key component of most current the outcome of PEG-ASP administered during induction in the therapeutic strategies in acute lymphoblastic leukaemia (ALL). In first consecutive 91 trial subjects. At this point, it was judged children, intensive L-asparaginase treatment, typically delivered by by the trial management group that a toxicity end point pegylated Escherichia coli-derived L-asparaginase (PEG-ASP), 1–6 7 had been reached and a change was made to the PEG-ASP improves clinical outcome, offering a longer half-life and a trial therapy. lower risk of antiasparaginase antibody formation. Safety and 8,9 efficacy is less well established in older adults, and toxicity can be substantial —in a phase 2 trial, failure to deliver the intended doses was closely correlated with advancing age. MATERIALS AND METHODS UKALL14 (NCT01085617) is an on-going, multicentre, phase 3 UKALL14 induction phase 1 treatment study that addresses several questions in the treatment of Eligible patients were aged ⩾ 25 and ⩽ 65 years with newly diagnosed ALL, newly diagnosed adult ALL. A major study aim is to evaluate irrespective of Philadelphia (Ph) chromosome status. There was no the addition of two doses of 1000 IU/m PEG-ASP to the standard exclusion for poor organ function or performance status at diagnosis. induction regimen that had been evaluated in our previous study, Ethical approval was obtained from the UK National Research Ethics UKALL12, in which non-pegylated E. coli L-asparaginase was Committee. All patients gave written, informed consent, according to the given at 10 000 IU daily on days 17–28 of phase 1 induction. Declaration of Helsinki. Patients received a 5–7-day prephase of dexamethasone 6 mg/m /day followed by two sequential courses of The only other change to the ‘backbone’ induction regimen induction therapy, termed induction phase 1 and induction phase 2, between the two consecutive national trials was the addition of a respectively. Patients with precursor B lineage ALL were randomised steroid prephase and the substitution of pulsed dexamethasone to receive chemotherapy alone or chemotherapy plus four doses of for prednisolone. The aim of these changes was to make our rituximab given on day (D) 3, D10, D17 and D24, PEG-ASP 1000 IU/m regimen more compatible with a 'paediatric-inspired' intensive 2 2 on D4 and D18, daunorubicin 60 mg/m and vincristine 1.4 mg/m approach. (2 mg max.) on D1, D8, D15 and D21, dexamethasone 10 mg/m D1, The overall end point of the trial is event-free survival. However, − D4, D8–D11 and D15–D18 and a single 12.5 mg intrathecal methotrexate a specific end point of the PEG-ASP evaluation is toxicity related dose on D14. Patients with Ph chromosome-positive (Ph+) disease to PEG-ASP. Secondary end points include rate of complete received continuous oral imatinib from D1, starting at 400 mg and 1 2 3 Barts Cancer Institute, The London School of Medicine, Queen Mary University of London, London, UK; CR UK and UCL Cancer Trials Centre, London, UK; Cancer Institute, 4 5 6 University College London, London, UK; Centre for Clinical Haematology, Nottingham City Hospital, Nottingham, UK; United Bristol Healthcare Trust, Bristol, UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK and Cardiff and Vale UHB, London, UK. Correspondence: Professor AK Fielding, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. E-mail a.fielding@ucl.ac.uk Received 22 April 2016; revised 6 July 2016; accepted 8 July 2016; accepted article preview online 2 August 2016; advance online publication, 9 September 2016 Toxicity during UKALL14 induction therapy for ALL B Patel et al Figure 1. Schematic of UKALL14 treatment protocol. High risk features: karyotypes: t(9;22) t(4;11), low hypodiploidy near triploidy or complex, 9 9 − 4 age440 years, WBC ⩾ 30 × 10 /l (precursor B lineage ALL), ⩾ 100 × 10 /l (T-cell-ALL), molecular minimal residual disease positivity (41×10 ) after induction phase 2. escalating to 600 mg given daily throughout induction. Antibacterial, used to examine risk potential factors for induction death and grade 3/4 antiviral and antifungal prophylaxis was mandated, but centres used adverse events (AEs). Factors with a conservative Po0.2 in the univariate local policy for choice of agents. Granulocyte colony-stimulating analysis were included in the multivariable analyses. All analyses were factor support was strongly recommended. Routine antithrombotic conducted using Stata 14.0 (Stata Corporation, College Station, TX, USA). prophylaxis was suggested but not mandated for all patients with Non-fatal grade III–IV AEs causally related to PEG-ASP were those classified platelet counts 450 × 10 /l. Anticoagulation with antithrombin replace- as probably or definitely related. All AEs were graded according to CTCAE ment was recommended in the case of thrombosis. Routine coagulation version 4.0. factor replacement for laboratory-detected coagulopathy was specifi- cally discouraged. All patients had an initial assessment of response—including MRD RESULTS response by BCR-ABL transcript monitoring or clonal immunoglobulin Patient characteristics (Ig)/T-cell receptor gene rearrangement quantification—at the end of Ninety-one eligible patients (from 37 centres) were enrolled induction phase 1, which did not affect treatment decision. Formal assessment of response to induction therapy (outside the scope of this onto UKALL14 between 30 December 2010 and 19 April 2012. report) was documented after phase 2 induction. One patient died before starting any treatment and has been A simplified schema of the remainder of UKALL14 treatment is provided excluded from all analyses. Patient characteristics at diagnosis in Figure 1. are summarised in Table 1. The majority (59 of 90, 66%) of patients were aged 440 years and nearly a third (26/90, 29%) Causality assessment for toxicity and death had Ph+ ALL. Most patients (92%) had performance scores of The standard Common Terminology Criteria for Adverse Events (CTCAE) 0–1 at diagnosis. Median follow-up was 36.0 months (12 days– reporting system (http://ctep.cancer.gov/protocolDevelopment/electronic_ 50.4 months). applications/ctc.htm) was used. Causality of events was attributed, as is standard practice, by both the local site Principal Investigator and the Induction deaths central study clinical team. Additional detailed questionnaires and Principal Investigator's narratives were received for all induction deaths allowing a Progress through the induction therapy blocks is shown in more detailed analysis of individual events. Figure 2. Among those commencing phase 1 induction therapy (n = 90), there were 18 early deaths. Two patients died of progressive ALL and the other 16 (16/90, 18%) deaths were PEG-ASP antibody assays related to induction treatment, occurring at a median time from Antibodies against PEG-ASP (IgG and IgE) were measured by two indirect start to induction of 23 days (range 10–53). enzyme-linked immunosorbent assays, which detected anti-PEG-ASP and non-pegylated anti-E. coli (non-pegylated asparaginase). Seroconversion The causes of induction deaths are summarised in Table 2. In 12 was reported with positivity in at least one assay with a clearly negative of the 16 (75%), the causes of death were most often multi- predose sample. Anti-asparaginase antibody ratio over negative control factorial; sepsis together with hepatotoxicity occurred in 8 of 16, 41.1 was used to define positivity. 50.0%. Neutropenic sepsis alone occurred in 3 of the 16 patients, (18.8%). A causative organism was identified in 11 of the cases of Serum asparaginase activity by MAAT testing sepsis, with a Gram-negative bacterial infection being responsible PEG-ASP enzyme activity was quantified in sera using the MAAT assay. in 8 of those. Additional causes of death were: hepatotoxicity plus Therapeutic enzyme levels were defined as 4100 IU/l. bowel ischaemia (n = 2), acute coronary syndrome plus neutro- penic sepsis (n = 1), hepatotoxicity plus pancreatitis (n = 1), and pulmonary haemorrhage (n = 1). Nine of the 11 hepatotoxicity- Statistical analysis related induction deaths were associated with grade 3–4 Induction phase 1 treatment-related death was defined as any death hyperbilirubinaemia. In total, half of the induction deaths were occurring before the start of phase 2 induction where the cause of death was not primarily attributable to progressive ALL. Logistic regression was accompanied by recognised PEG-ASP toxicities (namely, those Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al dose on D18. For patients who died during induction, the Table 1. Patient characteristics at diagnosis median time from last dose of PEG-ASP to death was 13 days (range 6–50). Characteristic N (%) Lineage Risk factors for induction death B-precursor 77 (86) Table 3 shows a univariate analysis of factors predictive of T-cell 13 (14) induction death. Age, Ph positivity and high-risk cytogenetics were all risk factors. Patients aged over 40 years had a more than Sex Male 48 (53) 10-fold increase in risk of death during induction with Ph+ disease Female 42 (47) conferring a more than 8-fold increase compared with Ph − disease (odds ratio (OR): 8.65 (2.61–28.71), Po0.001). There Age at entry (years) was no relationship to baseline albumin levels or body mass index Median (range) 46.50 (25–65) (BMI). The data monitoring committee also confirmed that there ⩾ 55 29 (32) was no relationship to rituximab randomisation arm. The multi- ⩾ 41 59 (66) variable analysis is also shown in Table 3. Although high-risk cytogenetics appeared to be associated with induction death, this Presenting WBC (×10 /l) Median (range) 9.26 (0.52–297.4) was driven by the presence of t(9;22), so this factor alone was o30 62 (69) included in the multivariable analysis. Age and Ph status remained 30–99.9 15 (17) significantly associated with induction death; in patients who were 100+ 13 (14) Ph − , there were no deaths in the 21 patients aged ⩽ 40 years and 5 in the 43 patients aged440 years. In patients with Ph+ ALL, 1 of Cytogenetic risk status a the 10 patients aged ⩽ 40 years died compared with 10 of the 16 High risk 28 (31) who were aged 440 years. Low risk 42 (47) Unknown 20 (22) AEs during phase 1 induction therapy t(9;22) Including the patients discussed above who subsequently Absent 64 (71) died, 87 of the 91 patients (97%) experienced a grade 3–5AE Present 26 (29) during induction phase 1; among these 46 (51%) suffered one or Low hypodiploidy/near triploidy more recognised PEG-ASP toxicities; 34 had grade 3–5AEs Absent 65 (72) indicating liver dysfunction, including 22 with raised bilirubin. Present 4 (4) Other PEG-ASP toxicities included pancreatitis (n = 3), intracra- Failed/missing 21 (23) nial haemorrhage (n = 1), allergic reaction (n = 3), coagulation disorder (n = 4) and vascular events (n = 6). Thirty-seven of the 74 t(4;11) surviving patients (50.0%) experienced at least one recognised Absent 75 (83) grade 3–4 PEG-ASP-related, non-fatal toxicity summarised in Present 7 ( 8) Table 4. Hepatotoxicity—including biochemical markers of liver Failed/missing 8 (9) dysfunction—was the most frequent PEG-ASP-related toxicity Complex karyotype (36.5%, n = 27). Venous thromboembolism (4.1%, n = 3), allergic Absent 64 (71) reaction (4.1%, n = 3) and pancreatitis (2.7%, n =2) were all Present 5 (6) reported but were relatively uncommon. A complete line-listing Failed/missing 21 (23) of all AE/serious AE as well as the subset known to be recognised toxicities of PEG-ASP from which Table 4 is derived Performance status is giveninSupplementary Supplementary TableS1. As liver 0 55 (61) toxicity was so prominent and can be a key determinant of 1 28 (31) 25(6) subsequent on-time therapy delivery, an analysis of any 3 1 (1) pretreatment factors associated with grade 3–4 hepatotoxicity Missing 1 (1) was carried out. This is shown in Table 5. Older age and BMI were the only factors that showed a significant association (OR: BMI 2.88 (1.62–15.44), P = 0.005, for patients aged 440 years Normal/underweight 31 (34) compared with those ⩽ 40 years and OR: 1.58 (1.02–2.44), Overweight 25 (28) P = 0.041, for a 5 unit increase in BMI). Obese 34 (38) Abbreviations: BMI, body mass index; WBC, white blood cell. High risk: Asparaginase activity, antiasparaginase antibody formation and t(9;22), t(4;11) low hypodiploidy/near triploidy or complex karyotypes. b c correlation with MRD response No high-risk factors and at least one risk factor is missing or failed. 30 in 7,13 the normal range and 1 patient with a BMI of 17. A trough level of asparaginase activity by MAAT testing was assessed 14 days after the first (D4) PEG-ASP dose in 49 patients in whom serum was available (n = 49). Therapeutic activity (enzyme level 4100IU/l) was achieved in 42 of 49 (86%). The median enzyme level in those achieving therapeutic enzyme levels was already listed in the Summary of Product Characteristics 234 IU/l (range 101.5–602.8) as compared with 44.8IU/l (0–97.5) as occurring in 1:⩾ 1000 patients, or less common but in those with subtherapeutic levels. There was no evidence of an clearly recognised as being related to PEG-ASP). There was no association between age and achievement of therapeutic enzyme obvious association between baseline comorbidities and level. Molecular MRD at the end of phase 1 induction was induction death. documented in 27 patients. Molecular remission rates did not All patients received D4 PEG-ASP. Sixty-four, including 5 of significantly differ between those achieving therapeutic enzyme the 16 who suffered induction deaths, received the second levels of PEG-ASP and those who did not (14/26 compared with Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al Figure 2. Flow chart of progress of the 91 patients enrolled. Grade 4 sepsis n = 4, grade IV organ toxicity n= 4 (hepatotoxicity n= 1, pancreatitis n = 1, hepatotoxicity plus neurological event n= 1, hepatotoxicity plus thromboembolism together with sepsis n= 1 and wrong diagnosis n= 1, withdrawal of consent, n= 1. Table 2. Summary of deaths during induction ID Patient details Comorbidities Hepatotoxicity Neutropenic sepsis Haemorrhage Thrombosis/ Pancreatitis Other PEG-ASP Days from last (grade) (organism) (site) visceral doses PEG-ASP dose ischaemia (site) 1003 Age 54 years PH − Liver 4 Not known D4 and 18 19 cirrhosis 1004 Age 46 years PH+ None Pseudomonas Acute coronary D4 16 aeruginosa syndrome 1011 Age 43 years PH+ None 4 Escherichia coli Renal failure D4 & 18 8 1021 Age 65 years PH − None 4 Pseudomonas Gastrointestinal D4 50 aeruginosa 1026 Age 64 years PH+ Depression 4 Pseudomonas D4 20 aeruginosa 1028 Age 38 years PH+ None Enterococcus faecium D4 15 1029 Age 60 years PH+ IHD 4 Escherichia coli D4 14 1030 Age 49 years PH+ None Pulmonary D4 6 1039 Age 62 years PH+ None 2 Small bowel D4 10 1043 Age 63 years PH − Grade 4 4 Klebsiella Carotid artery D4 and D18 43 renal failure pneumoniae puncture site 1049 Age 56 years PH+ None 4 Pseudomonas D4 11 aeruginosa 1057 Age 57 years PH − None 4 Small bowel D4 20 1061 Age 54 years PH+ Paroxysmal 3 Yes GI perforation D4 10 atrial fibrillation 1063 Age 62 years PH+ None Coagulase-negative D4 and D18 12 staph/Enterococcus faecium 1068 Age 64 years PH+ None 4 Respiratory syncytial Renal failure D4 21 virus 2007 Age 55 years PH − None Pseudomonas D4 and D18 8 aeruginosa Abbreviations: IHD, ischaemic heart disease; PEG-ASP, pegylated asparaginase. 3/4), suggesting that an early complete molecular response in this DISCUSSION setting is not contingent upon therapeutic asparaginase enzyme Successful achievement of CR during induction therapy for activity. Anti-PEG-ASP antibody formation at D18 was assessed in ALL is an absolute prerequisite for long-term disease-free 59 patients, and at that time point, there were no instances of survival. Numerous previous studies have suggested that seroconversion. induction regimens typically used in children give a better Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al Table 3. Univariate and multivariate analysis of risk factors for induction death Risk factor Events/n Univariable Multivariable Odds ratio (95% CI) P-value Odds ratio (95% CI) P-value Age, years ⩽ 40 1/31 1.00 0.03 18.50 (2.02–169.0) 0.01 440 15/59 10.23 (1.28–81.59) Gender Male 8/48 1.00 0.77 —— Female 8/42 1.18 (0.40–3.47) Baseline WBC per × 10 /l increment 16/90 1.00 (0.99–1.01) 0.56 — Cytogenetics Standard risk 2/28 1.00 0.0029 —— High risk 13/42 5.83 (1.20–28.29) Ph Absent 5/64 1.00 o0.001 13.60 (3.53–52.36) o0.001 Present 11/26 8.65 (2.61–28.71) Base albumin (g/l) (10 unit increment) 16/90 1.03 (0.40–2.64) 0.95 —— Base bilirubin (μmol/l) (10 unit increment) 16/90 0.91 (0.59–1.42) 0.69 —— BMI (5 unit increment) 16/90 1.29 (0.82–2.02) 0.27 —— Abbreviations: BMI, body mass index; CI, confidence interval; WBC, white blood cell. Analysed as no high-risk factors versus high-risk Ph and high-risk Ph+ gives HRs of 1.86 (0.24–14.64) and 9.53 (1.86–49.91), respectively. outcome for teenagers and younger adults than typical ‘adult’ the overlapping toxicity. The fact that sepsis was a major 14–18 regimens. As a consequence, there is general acceptance contributor to the mortality supports that contention. of testing the outcome of increasing the intensity of non- To date, only two other studies reporting the use of PEG-ASP myelosuppressive agents such as PEG-ASP in regimens used for specifically in adults have been published, both of which report a lower dose and/or different schedule of anthracycline. A phase 2 older adults. (ref. 11) Within the first 91 patients enrolled, we noted significantly greater trial CALGB 9511 reported on 102 adults treated with PEG- 2 2 induction mortality in UKALL14 than in our previous trial, UKALL12. ASP at 2000 U/m subcutaneously, capped at 3750 U/m , starting Induction death occurred in 16 of the first 90 (17.8%) treated on D5 of the five-drug induction regimen. Although the regimen patients, and 15 of the first 59 (25%) participants being aged 440 was reported to be 'tolerable', bilirubin 451.3 μM (3 mg/dl) years (10/29 (33%) being aged 455 years). The median age of the occurred in 54% of patients. CR rate was only 77% but induction patient population enrolled in this period was 46.5 years, with 29% deaths are not separated from induction failures within the report. of patients being aged 455 years. By comparison, the induction There was a statistically significant difference in median age of death rate in our previous trial, UKALL12/ECOG2993, was 6% those achieving full dose delivery and asparagine depletion—32 12 20 overall (ages 15–60 years, median age 36 years) and 15% in the years versus 48 years. In a more recent study from Douer et al. in 55–65-year range (median age 56 years). UKALL14 did not 51 adults median age 32 years, upper age limit 57 years reported exclude any patient with poor organ function or comorbidity at no deaths directly as a result of PEG-ASP in regimen, which diagnosis, but we did not find any evidence of these factors included 2000 IU/m PEG-ASP given on D15. However, 3 of the 51 having a causal contribution to PEG-ASP-related mortality. (6%) patients died of neutropenic sepsis during consolidation. In Analysis of the cause of each death in UKALL14 included a this case, daunorubicin was given at 60 mg/m intravenously on complete written narrative from the treating physician as well as D1–D3. Grade 3–4 hyperbilirubinaemia (1/3 patients) or transami- the standard case report forms for serious AE collection. Bacterial nitis (2/3 of patients) was very common. Douer et al. also sepsis was revealed as a major contributor to the deaths. However, reported long median intervals from PEG-ASP to bilirubin concomitant grade 3–4 PEG-ASP toxicities were very common recovery, which affected subsequent chemotherapy delivery. among those suffering induction death, such that a recognised The younger median age of patients in that study, the small PEG-ASP toxicity was associated with half of the 16 induction deaths. number receiving concurrent imatinib (N = 5), a more modest It is impossible to disentangle the role of the investigational anthracycline dose and different scheduling of PEG-ASP admin- medicinal product (IMP) PEG-ASP from that of concomitant non-IMP istration so as not to coincide with the maximal myelosuppression induction agents. However, the introduction of dexamethasone may all have contributed to the difference in toxicity. instead of prednisolone was the only change that had been made to The German Multicentre Adult ALL Group have reported in the standard backbone regimen between UKALL12 and UKALL14. abstract form on 1000 adult patients aged 15–55 years, treated It is noteworthy that most of the induction deaths reported here on the German 07/2003 study in which a single dose of 1000– occurred after an early, single (D4) dose of PEG-ASP, any toxicity of 2000 U/m PEG-ASP was administered on D3 during induction which would overlap with the myelosuppressive toxicity of with a reported rate of induction death rate of o5% and a anthracycline administered on D1, D8, D15 and D22. The 60 mg/ grade IV hyperbilirubinaemia incidence of 16%. As with the 2 20 m dose of anthracycline given in the UKALL12 regimen was well study by Douer et al., the younger median age (35 years) of the tolerated, but asparaginase was not started until D17. The earlier cohort in addition to the lower dose of anthracycline (45 versus addition of PEG-ASP-associated liver dysfunction to subsequent the 60 mg/m used in the current study) may underpin the myelosuppression-related sepsis may have been responsible for differences in toxicity. Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al Table 4. Patients who did not die during induction: summary of the Table 5. Analysis of risk factors for liver-related grade 3/4 adverse grade 3/4 AEs recognised in SPC as being related to PEG-ASP events during phase 1 induction in patients who did not have an induction death SOC/event term Grade 3+ PEG-ASP known AEs, N (%) Risk factor Grade 3/4 liver AEs Gastrointestinal disorders 2 (3) Events/n Odds ratio P-value Pancreatitis 2 (3) (95% CI) Hepatobiliary disorders 3 (4) Age Liver failure 1 (1) ⩽ 40 5/30 1.00 0.005 Liver dysfunction 2 (3) 440 22/44 2.9 (1.62–15.44) Immune system disorders 3 (4) Allergic reaction 3 (4) Sex Male 16/40 1.00 0.50 Investigations 29 (39) Female 11/34 0.72 (0.28–1.87) Lipase increased 1 (1) Serum amylase increased 3 (4) Baseline WBC per × 10 /l 27/74 1.00 (0.99–1.01) 0.71 Alkaline phosphatase increased 15 (20) increment Aspartate aminotransferase 4 (5) increased Cytogenetics Blood bilirubin increased 17 (23) Standard risk 10/26 1.00 0.97 Alanine aminotransferase 10 (14) High risk 11/29 0.98 (0.33–2.91) increased GGT increased 5 (7) Ph Absent 20/59 1.00 0.36 Metabolism and nutrition disorders 3 (4) Present 7/15 1.71 (0.54–5.38) Increased triglycerides 1 (1) Hypoalbuminaemia 2 (3) Base albumin (g/l) (10 unit 27/74 0.89 (0.41–1.92) 0.77 increment) Nervous system disorders 1 (1) Base bilirubin (μmol/l) (10 unit 27/74 1.02 (0.81–1.30) 0.86 Intracranial haemorrhage 1 (1) increment) BMI (5 unit increment) 27/74 1.58 (1.02–2.44) 0.041 Vascular disorders 4 (5) Pulmonary embolism 1 (1) Abbreviations: AE, adverse event; BMI, body mass index; CI, confidence Thromboembolic event 3 (4) interval; WBC, white blood cell. Non-CTCAE terms Coagulation disorder 3 (4) death, suggesting that the concomitant imatinib therapy only Any liver event 27 (36) Any toxicity 37 (50) received by those with Ph+ ALL may have compounded the potential for PEG-ASP toxicity. The precise mechanism by which Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria; this might occur is not known. However, from the Summary of GGT, gamma glutamyl transpeptidase; PEG-ASP, pegylated asparaginase; Product Characteristics for imatinib, ‘increased hepatic enzymes’ is SPC, Summary of Product Characteristics; SOC, System Organ Class. reported as common (1:10 to 1:100), hyperbilirubinaemia occurs in A complete line listing of grade 3+ AE/serious AE according to CTCAE criteria with assignment of causality by both site and by trial management between 1:100 and 1:1000 patients and, finally, hepatic failure is group is provided in Supplementary Table S1. noted as ‘rare’, namely, occurring between 1:1000 and 1:10 000 cases. Hence, the potential for overlapping hepatotoxicity of PEG- ASP and imatinib is clearly present. It should be noted that the French GRAAALL group also Half of the patients who did not experience an induction death reported that advancing age resulted in a higher cumulative experienced one or more grade 3–4 PEG-ASP toxicities from which incidence of chemotherapy-related deaths (23% versus 5%, they eventually recovered—most commonly, hepatotoxicity. respectively; Po0.001) and deaths in first CR (22% versus 5%, Twenty-three percent of patients in this study experienced grade respectively; Po0.001) during 'paediatric-style' therapy, even ⩾ 3 hyperbilirubinaemia; by definition, a limitation or exclusion to when non-pegylated asparaginsae was used. In the study reported further dosing with many commonly used ALL therapeutics. On by Huguet et al., ⩾ 45 years of age was the strongest predictor of analysis of treatment delays in our previous trial, UKALL12/E2993 severe toxicity, study showed that delays of 44 weeks were associated with As a consequence of the toxicity reported here, the UKALL14 poorer overall survival and event-free survival in patients under- protocol was amended to omit D4 PEG-ASP for those aged 440 going allogeneic hematopoietic stem cell transplantation but not years. Furthermore, PEG-ASP was completely removed from in patients undergoing postremission chemotherapy. Any long- induction treatment for all patients with Ph+ ALL. In addition, term impact of any delays engendered by toxicity during initial owing to the high level of sepsis related to profound myelosup- induction therapy in this study will become clear when the trial is pression, the daunorubicin dose was halved to 30 mg/m on D1, completed and we can evaluate any delays in relation to our D8, D15 and D22. One year following this amendment, when an primary end point, event-free survival. additional 302 further patients had been recruited with 244 Our pharmacokinetic studies indicate that a single dose of patients assessable for induction death, a repeat analysis showed 1000 IU/m PEG-ASP generates therapeutic enzyme levels in most only 6 (2.5%) phase 1 induction deaths (data not shown). patients—86% of assessable patients had therapeutic levels of Univariate analysis demonstrated that older age and poor-risk PEG-ASP activity 14 days after administration. A recent long- cytogenetics—including t(9;22)—were significantly associated itudinal analysis of PEG-ASP pharmacokinetics during a ‘paediatric’ with induction death. On multivariable analysis, age and Ph regimen in adult ALL demonstrated therapeutic enzyme activity in positivity remained as independent risk factors for induction a similar proportion of adult patients for up to 21 days. In our Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al study, antiasparaginase antibodies were not seen at the early time induction in adults aged 55 years or younger with newly diagnosed acute lym- phoblastic leukemia. Blood 2007; 109: 2744–2750. point documented. 10 Stock W, Douer D, Deangelo DJ, Arellano M, Advani A, Damon L et al. Prevention In conclusion, we have shown that PEG-ASP achieves very and management of asparaginase/pegasparaginase-associated toxicities in adults effective asparagine depletion without antiasparaginase antibody and older adolescents: recommendations of an expert panel. Leuk Lymphoma formation in the majority of adult patients. However, toxicity can 2011; 52: 2237–2253. be substantial in older patients, making a 'paediatric-inspired' 11 Wetzler M, Sanford BL, Kurtzberg J, Deoliveira D, Frankel SR, Powell BL et al. regimen of the type commonly used used in paediatric and young Effective asparagine depletion with pegylated asparaginase results in improved adult therapy difficult to deliver safely to those aged 440 years. outcomes in adult acute lymphoblastic leukemia -- Cancer and Leukemia Group B Avoidance of overlapping toxicities and careful timing of Study 9511. Blood 2007; 109: 4164–4167. 12 Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction administration will be of key importance to the more widespread therapy for adults with acute lymphoblastic leukemia: results of more than 1500 use of this type of regimen in older adults. patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; As remission can be induced with minimal mortality in patients 106:3760–3767. 23,24 with Ph+ ALL, we suggest that PEG-ASP is never coadminis- 13 Fabry U, Korholz D, Jurgens H, Gobel U, Wahn V. Anaphylaxis to L-asparaginase tered with imatinib during induction therapy. during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism. Pediatr Res 1985; 19: 400–408. 14 DeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, Couban S, Supko JG et al. CONFLICT OF INTEREST Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years Fielding received lab funding from Medac GmBH to carry out part of this work and with newly diagnosed acute lymphoblastic leukemia. Leukemia 2015; 29:526–534. that company were the supplier of PEG-ASP at the time of this work. The remaining 15 Boissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc T et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or authors declare no conflict of interest. young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 2003; 21:774–780. 16 de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters ACKNOWLEDGEMENTS R. Significant difference in outcome for adolescents with acute lymphoblastic UKALL14 was funded by Cancer Research UK grant CRUK/09/006 to AKF. The MAAT leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia testing and antiasparaginase antibody testing was funded by a 2-year, unrestricted 2004; 18: 2032–2035. educational grant from Medac GMBH to AKF between 2010 and 2012. BP was funded by 17 Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al. Bloodwise grant 07062. We thank all centres and patients who contributed to this study. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007; 48:254–261. AUTHOR CONTRIBUTIONS 18 Stock W, La M, Sanford B, Bloomfield C, Vardiman J, Gaynon P et al. What BP, AK and AKF wrote the paper. AKF designed the study, contributed data and determines the outcomes for adolescents and young adults with acute lym- was Chief Investigator of the trial. AK analysed data. PS, LM, SP and PP co-ordinated phoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; the study, collected data and contributed to the analysis. AD carried out the MAAT 112:1646–1654. testing. CJR, TM, AKMcM and DM contributed data and managed the trial. 19 Sive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S et al. Outcomes in All authors contributed to writing the manuscript and approved the final version. older adults with acute lymphoblastic leukaemia (ALL): results from the interna- tional MRC UKALL XII/ECOG2993 trial. Br J Haematol 2012; 157:463–471. 20 Douer D, Aldoss I, Lunning MA, Burke PW, Ramezani L, Mark L et al. REFERENCES Pharmacokinetics-based integration of multiple doses of intravenous pegas- 1 Sallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei E 3rd, Nathan DG. pargase in a pediatric regimen for adults with newly diagnosed acute lympho- Influence of intensive asparaginase in the treatment of childhood non-T-cell acute blastic leukemia. J Clin Oncol 2014; 32: 905–911. lymphoblastic leukemia. Cancer Res 1983; 43: 5601–5607. 21 Goekbuget N. PEG-asparaginase intensification in adult acute lymphoblastic 2 Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ et al. leukemia (ALL): significant improvement of outcome with moderate increase of A randomized comparison of native Escherichia coli asparaginase and poly- liver toxicity in the German Multicenter Study Group for Adult ALL (GMALL) Study ethylene glycol conjugated asparaginase for treatment of children with newly 07/2003. ASH Annu Meeting Abstr 2010; 116: 494. diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer 22 Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E et al. Group study. Blood 2002; 99: 1986–1994. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative 3 Seibel NL. Treatment of acute lymphoblastic leukemia in children and adolescents: acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; peaks and pitfalls. Hematology Am Soc Hematol Educ Program 2008, 374–380. 27:911–918. 4 Avramis VI, Spence SA. Clinical pharmacology of asparaginases in the United 23 Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F et al. Ima- States: asparaginase population pharmacokinetic and pharmacodynamic (PK-PD) tinib plus steroids induces complete remissions and prolonged survival in models (NONMEM) in adult and pediatric ALL patients. J Pediatr Hematol Oncol elderly Philadelphia chromosome-positive patients with acute lymphoblastic 2007; 29: 239–247. leukemia without additional chemotherapy: results of the Gruppo Italiano 5 Kurtzberg J, Asselin B, Bernstein M, Buchanan GR, Pollock BH, Camitta BM. Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood 2007; Polyethylene glycol-conjugated L-asparaginase versus native L-asparaginase in 109:3676–3678. combination with standard agents for children with acute lymphoblastic leuke- 24 Foa R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS et al. Dasatinib as mia in second bone marrow relapse: a Children's Oncology Group Study first-line treatment for adult patients with Philadelphia chromosome-positive (POG 8866). J Pediatr Hematol Oncol 2011; 33:610–616. acute lymphoblastic leukemia. Blood 2011; 118: 6521–6528. 6 Pession A, Valsecchi MG, Masera G, Kamps WA, Magyarosy E, Rizzari C et al. Long-term results of a randomized trial on extended use of high dose L-aspar- aginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol This work is licensed under a Creative Commons Attribution 4.0 2005; 23: 7161–7167. International License. The images or other third party material in this 7 Asselin BL, Whitin JC, Coppola DJ, Rupp IP, Sallan SE, Cohen HJ. Comparative article are included in the article’s Creative Commons license, unless indicated otherwise in pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 1993; 11: the credit line; if the material is not included under the Creative Commons license, users 1780–1786. will need to obtain permission from the license holder to reproduce the material. To view a 8 Douer D. Is asparaginase a critical component in the treatment of acute copy of this license, visit http://creativecommons.org/licenses/by/4.0/ lymphoblastic leukemia? Best Pract Res Clin Haematol 2008; 21: 647–658. 9 Douer D, Yampolsky H, Cohen LJ, Watkins K, Levine AM, Periclou AP et al. Pharmacodynamics and safety of intravenous pegaspargase during remission © The Author(s) 2017 Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) Leukemia (2017) 58 – 64 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Leukemia Springer Journals

Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial

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Medicine & Public Health; Medicine/Public Health, general; Internal Medicine; Intensive / Critical Care Medicine; Cancer Research; Oncology; Hematology
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OPEN Leukemia (2017) 31, 58–64 www.nature.com/leu ORIGINAL ARTICLE Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial 1 2 3 4 5 6 2 2 2 7 B Patel , AA Kirkwood , A Dey , DI Marks , AK McMillan , TF Menne , L Micklewright , P Patrick , S Purnell , CJ Rowntree , 2 3 P Smith and AK Fielding Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/ m PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25–65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death 440 versus ⩽ 40 years, odds ratio (OR) 18.5 (2.02–169.0), P=0.01; Ph − versus Ph+ disease, OR 13.60 (3.52–52.36), Po0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG- ASP-related adverse event, most commonly hepatotoxicity (36.5%, n = 27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged 440 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib. Leukemia (2017) 31, 58–64; doi:10.1038/leu.2016.219 INTRODUCTION remission (CR), overall survival, minimal residual disease (MRD) quantitation at the end of the first phase of induction and Depletion of extracellular asparagine by parenteral administration antiasparaginase antibody formation. Here we report on of the enzyme L-asparaginase is a key component of most current the outcome of PEG-ASP administered during induction in the therapeutic strategies in acute lymphoblastic leukaemia (ALL). In first consecutive 91 trial subjects. At this point, it was judged children, intensive L-asparaginase treatment, typically delivered by by the trial management group that a toxicity end point pegylated Escherichia coli-derived L-asparaginase (PEG-ASP), 1–6 7 had been reached and a change was made to the PEG-ASP improves clinical outcome, offering a longer half-life and a trial therapy. lower risk of antiasparaginase antibody formation. Safety and 8,9 efficacy is less well established in older adults, and toxicity can be substantial —in a phase 2 trial, failure to deliver the intended doses was closely correlated with advancing age. MATERIALS AND METHODS UKALL14 (NCT01085617) is an on-going, multicentre, phase 3 UKALL14 induction phase 1 treatment study that addresses several questions in the treatment of Eligible patients were aged ⩾ 25 and ⩽ 65 years with newly diagnosed ALL, newly diagnosed adult ALL. A major study aim is to evaluate irrespective of Philadelphia (Ph) chromosome status. There was no the addition of two doses of 1000 IU/m PEG-ASP to the standard exclusion for poor organ function or performance status at diagnosis. induction regimen that had been evaluated in our previous study, Ethical approval was obtained from the UK National Research Ethics UKALL12, in which non-pegylated E. coli L-asparaginase was Committee. All patients gave written, informed consent, according to the given at 10 000 IU daily on days 17–28 of phase 1 induction. Declaration of Helsinki. Patients received a 5–7-day prephase of dexamethasone 6 mg/m /day followed by two sequential courses of The only other change to the ‘backbone’ induction regimen induction therapy, termed induction phase 1 and induction phase 2, between the two consecutive national trials was the addition of a respectively. Patients with precursor B lineage ALL were randomised steroid prephase and the substitution of pulsed dexamethasone to receive chemotherapy alone or chemotherapy plus four doses of for prednisolone. The aim of these changes was to make our rituximab given on day (D) 3, D10, D17 and D24, PEG-ASP 1000 IU/m regimen more compatible with a 'paediatric-inspired' intensive 2 2 on D4 and D18, daunorubicin 60 mg/m and vincristine 1.4 mg/m approach. (2 mg max.) on D1, D8, D15 and D21, dexamethasone 10 mg/m D1, The overall end point of the trial is event-free survival. However, − D4, D8–D11 and D15–D18 and a single 12.5 mg intrathecal methotrexate a specific end point of the PEG-ASP evaluation is toxicity related dose on D14. Patients with Ph chromosome-positive (Ph+) disease to PEG-ASP. Secondary end points include rate of complete received continuous oral imatinib from D1, starting at 400 mg and 1 2 3 Barts Cancer Institute, The London School of Medicine, Queen Mary University of London, London, UK; CR UK and UCL Cancer Trials Centre, London, UK; Cancer Institute, 4 5 6 University College London, London, UK; Centre for Clinical Haematology, Nottingham City Hospital, Nottingham, UK; United Bristol Healthcare Trust, Bristol, UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK and Cardiff and Vale UHB, London, UK. Correspondence: Professor AK Fielding, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. E-mail a.fielding@ucl.ac.uk Received 22 April 2016; revised 6 July 2016; accepted 8 July 2016; accepted article preview online 2 August 2016; advance online publication, 9 September 2016 Toxicity during UKALL14 induction therapy for ALL B Patel et al Figure 1. Schematic of UKALL14 treatment protocol. High risk features: karyotypes: t(9;22) t(4;11), low hypodiploidy near triploidy or complex, 9 9 − 4 age440 years, WBC ⩾ 30 × 10 /l (precursor B lineage ALL), ⩾ 100 × 10 /l (T-cell-ALL), molecular minimal residual disease positivity (41×10 ) after induction phase 2. escalating to 600 mg given daily throughout induction. Antibacterial, used to examine risk potential factors for induction death and grade 3/4 antiviral and antifungal prophylaxis was mandated, but centres used adverse events (AEs). Factors with a conservative Po0.2 in the univariate local policy for choice of agents. Granulocyte colony-stimulating analysis were included in the multivariable analyses. All analyses were factor support was strongly recommended. Routine antithrombotic conducted using Stata 14.0 (Stata Corporation, College Station, TX, USA). prophylaxis was suggested but not mandated for all patients with Non-fatal grade III–IV AEs causally related to PEG-ASP were those classified platelet counts 450 × 10 /l. Anticoagulation with antithrombin replace- as probably or definitely related. All AEs were graded according to CTCAE ment was recommended in the case of thrombosis. Routine coagulation version 4.0. factor replacement for laboratory-detected coagulopathy was specifi- cally discouraged. All patients had an initial assessment of response—including MRD RESULTS response by BCR-ABL transcript monitoring or clonal immunoglobulin Patient characteristics (Ig)/T-cell receptor gene rearrangement quantification—at the end of Ninety-one eligible patients (from 37 centres) were enrolled induction phase 1, which did not affect treatment decision. Formal assessment of response to induction therapy (outside the scope of this onto UKALL14 between 30 December 2010 and 19 April 2012. report) was documented after phase 2 induction. One patient died before starting any treatment and has been A simplified schema of the remainder of UKALL14 treatment is provided excluded from all analyses. Patient characteristics at diagnosis in Figure 1. are summarised in Table 1. The majority (59 of 90, 66%) of patients were aged 440 years and nearly a third (26/90, 29%) Causality assessment for toxicity and death had Ph+ ALL. Most patients (92%) had performance scores of The standard Common Terminology Criteria for Adverse Events (CTCAE) 0–1 at diagnosis. Median follow-up was 36.0 months (12 days– reporting system (http://ctep.cancer.gov/protocolDevelopment/electronic_ 50.4 months). applications/ctc.htm) was used. Causality of events was attributed, as is standard practice, by both the local site Principal Investigator and the Induction deaths central study clinical team. Additional detailed questionnaires and Principal Investigator's narratives were received for all induction deaths allowing a Progress through the induction therapy blocks is shown in more detailed analysis of individual events. Figure 2. Among those commencing phase 1 induction therapy (n = 90), there were 18 early deaths. Two patients died of progressive ALL and the other 16 (16/90, 18%) deaths were PEG-ASP antibody assays related to induction treatment, occurring at a median time from Antibodies against PEG-ASP (IgG and IgE) were measured by two indirect start to induction of 23 days (range 10–53). enzyme-linked immunosorbent assays, which detected anti-PEG-ASP and non-pegylated anti-E. coli (non-pegylated asparaginase). Seroconversion The causes of induction deaths are summarised in Table 2. In 12 was reported with positivity in at least one assay with a clearly negative of the 16 (75%), the causes of death were most often multi- predose sample. Anti-asparaginase antibody ratio over negative control factorial; sepsis together with hepatotoxicity occurred in 8 of 16, 41.1 was used to define positivity. 50.0%. Neutropenic sepsis alone occurred in 3 of the 16 patients, (18.8%). A causative organism was identified in 11 of the cases of Serum asparaginase activity by MAAT testing sepsis, with a Gram-negative bacterial infection being responsible PEG-ASP enzyme activity was quantified in sera using the MAAT assay. in 8 of those. Additional causes of death were: hepatotoxicity plus Therapeutic enzyme levels were defined as 4100 IU/l. bowel ischaemia (n = 2), acute coronary syndrome plus neutro- penic sepsis (n = 1), hepatotoxicity plus pancreatitis (n = 1), and pulmonary haemorrhage (n = 1). Nine of the 11 hepatotoxicity- Statistical analysis related induction deaths were associated with grade 3–4 Induction phase 1 treatment-related death was defined as any death hyperbilirubinaemia. In total, half of the induction deaths were occurring before the start of phase 2 induction where the cause of death was not primarily attributable to progressive ALL. Logistic regression was accompanied by recognised PEG-ASP toxicities (namely, those Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al dose on D18. For patients who died during induction, the Table 1. Patient characteristics at diagnosis median time from last dose of PEG-ASP to death was 13 days (range 6–50). Characteristic N (%) Lineage Risk factors for induction death B-precursor 77 (86) Table 3 shows a univariate analysis of factors predictive of T-cell 13 (14) induction death. Age, Ph positivity and high-risk cytogenetics were all risk factors. Patients aged over 40 years had a more than Sex Male 48 (53) 10-fold increase in risk of death during induction with Ph+ disease Female 42 (47) conferring a more than 8-fold increase compared with Ph − disease (odds ratio (OR): 8.65 (2.61–28.71), Po0.001). There Age at entry (years) was no relationship to baseline albumin levels or body mass index Median (range) 46.50 (25–65) (BMI). The data monitoring committee also confirmed that there ⩾ 55 29 (32) was no relationship to rituximab randomisation arm. The multi- ⩾ 41 59 (66) variable analysis is also shown in Table 3. Although high-risk cytogenetics appeared to be associated with induction death, this Presenting WBC (×10 /l) Median (range) 9.26 (0.52–297.4) was driven by the presence of t(9;22), so this factor alone was o30 62 (69) included in the multivariable analysis. Age and Ph status remained 30–99.9 15 (17) significantly associated with induction death; in patients who were 100+ 13 (14) Ph − , there were no deaths in the 21 patients aged ⩽ 40 years and 5 in the 43 patients aged440 years. In patients with Ph+ ALL, 1 of Cytogenetic risk status a the 10 patients aged ⩽ 40 years died compared with 10 of the 16 High risk 28 (31) who were aged 440 years. Low risk 42 (47) Unknown 20 (22) AEs during phase 1 induction therapy t(9;22) Including the patients discussed above who subsequently Absent 64 (71) died, 87 of the 91 patients (97%) experienced a grade 3–5AE Present 26 (29) during induction phase 1; among these 46 (51%) suffered one or Low hypodiploidy/near triploidy more recognised PEG-ASP toxicities; 34 had grade 3–5AEs Absent 65 (72) indicating liver dysfunction, including 22 with raised bilirubin. Present 4 (4) Other PEG-ASP toxicities included pancreatitis (n = 3), intracra- Failed/missing 21 (23) nial haemorrhage (n = 1), allergic reaction (n = 3), coagulation disorder (n = 4) and vascular events (n = 6). Thirty-seven of the 74 t(4;11) surviving patients (50.0%) experienced at least one recognised Absent 75 (83) grade 3–4 PEG-ASP-related, non-fatal toxicity summarised in Present 7 ( 8) Table 4. Hepatotoxicity—including biochemical markers of liver Failed/missing 8 (9) dysfunction—was the most frequent PEG-ASP-related toxicity Complex karyotype (36.5%, n = 27). Venous thromboembolism (4.1%, n = 3), allergic Absent 64 (71) reaction (4.1%, n = 3) and pancreatitis (2.7%, n =2) were all Present 5 (6) reported but were relatively uncommon. A complete line-listing Failed/missing 21 (23) of all AE/serious AE as well as the subset known to be recognised toxicities of PEG-ASP from which Table 4 is derived Performance status is giveninSupplementary Supplementary TableS1. As liver 0 55 (61) toxicity was so prominent and can be a key determinant of 1 28 (31) 25(6) subsequent on-time therapy delivery, an analysis of any 3 1 (1) pretreatment factors associated with grade 3–4 hepatotoxicity Missing 1 (1) was carried out. This is shown in Table 5. Older age and BMI were the only factors that showed a significant association (OR: BMI 2.88 (1.62–15.44), P = 0.005, for patients aged 440 years Normal/underweight 31 (34) compared with those ⩽ 40 years and OR: 1.58 (1.02–2.44), Overweight 25 (28) P = 0.041, for a 5 unit increase in BMI). Obese 34 (38) Abbreviations: BMI, body mass index; WBC, white blood cell. High risk: Asparaginase activity, antiasparaginase antibody formation and t(9;22), t(4;11) low hypodiploidy/near triploidy or complex karyotypes. b c correlation with MRD response No high-risk factors and at least one risk factor is missing or failed. 30 in 7,13 the normal range and 1 patient with a BMI of 17. A trough level of asparaginase activity by MAAT testing was assessed 14 days after the first (D4) PEG-ASP dose in 49 patients in whom serum was available (n = 49). Therapeutic activity (enzyme level 4100IU/l) was achieved in 42 of 49 (86%). The median enzyme level in those achieving therapeutic enzyme levels was already listed in the Summary of Product Characteristics 234 IU/l (range 101.5–602.8) as compared with 44.8IU/l (0–97.5) as occurring in 1:⩾ 1000 patients, or less common but in those with subtherapeutic levels. There was no evidence of an clearly recognised as being related to PEG-ASP). There was no association between age and achievement of therapeutic enzyme obvious association between baseline comorbidities and level. Molecular MRD at the end of phase 1 induction was induction death. documented in 27 patients. Molecular remission rates did not All patients received D4 PEG-ASP. Sixty-four, including 5 of significantly differ between those achieving therapeutic enzyme the 16 who suffered induction deaths, received the second levels of PEG-ASP and those who did not (14/26 compared with Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al Figure 2. Flow chart of progress of the 91 patients enrolled. Grade 4 sepsis n = 4, grade IV organ toxicity n= 4 (hepatotoxicity n= 1, pancreatitis n = 1, hepatotoxicity plus neurological event n= 1, hepatotoxicity plus thromboembolism together with sepsis n= 1 and wrong diagnosis n= 1, withdrawal of consent, n= 1. Table 2. Summary of deaths during induction ID Patient details Comorbidities Hepatotoxicity Neutropenic sepsis Haemorrhage Thrombosis/ Pancreatitis Other PEG-ASP Days from last (grade) (organism) (site) visceral doses PEG-ASP dose ischaemia (site) 1003 Age 54 years PH − Liver 4 Not known D4 and 18 19 cirrhosis 1004 Age 46 years PH+ None Pseudomonas Acute coronary D4 16 aeruginosa syndrome 1011 Age 43 years PH+ None 4 Escherichia coli Renal failure D4 & 18 8 1021 Age 65 years PH − None 4 Pseudomonas Gastrointestinal D4 50 aeruginosa 1026 Age 64 years PH+ Depression 4 Pseudomonas D4 20 aeruginosa 1028 Age 38 years PH+ None Enterococcus faecium D4 15 1029 Age 60 years PH+ IHD 4 Escherichia coli D4 14 1030 Age 49 years PH+ None Pulmonary D4 6 1039 Age 62 years PH+ None 2 Small bowel D4 10 1043 Age 63 years PH − Grade 4 4 Klebsiella Carotid artery D4 and D18 43 renal failure pneumoniae puncture site 1049 Age 56 years PH+ None 4 Pseudomonas D4 11 aeruginosa 1057 Age 57 years PH − None 4 Small bowel D4 20 1061 Age 54 years PH+ Paroxysmal 3 Yes GI perforation D4 10 atrial fibrillation 1063 Age 62 years PH+ None Coagulase-negative D4 and D18 12 staph/Enterococcus faecium 1068 Age 64 years PH+ None 4 Respiratory syncytial Renal failure D4 21 virus 2007 Age 55 years PH − None Pseudomonas D4 and D18 8 aeruginosa Abbreviations: IHD, ischaemic heart disease; PEG-ASP, pegylated asparaginase. 3/4), suggesting that an early complete molecular response in this DISCUSSION setting is not contingent upon therapeutic asparaginase enzyme Successful achievement of CR during induction therapy for activity. Anti-PEG-ASP antibody formation at D18 was assessed in ALL is an absolute prerequisite for long-term disease-free 59 patients, and at that time point, there were no instances of survival. Numerous previous studies have suggested that seroconversion. induction regimens typically used in children give a better Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al Table 3. Univariate and multivariate analysis of risk factors for induction death Risk factor Events/n Univariable Multivariable Odds ratio (95% CI) P-value Odds ratio (95% CI) P-value Age, years ⩽ 40 1/31 1.00 0.03 18.50 (2.02–169.0) 0.01 440 15/59 10.23 (1.28–81.59) Gender Male 8/48 1.00 0.77 —— Female 8/42 1.18 (0.40–3.47) Baseline WBC per × 10 /l increment 16/90 1.00 (0.99–1.01) 0.56 — Cytogenetics Standard risk 2/28 1.00 0.0029 —— High risk 13/42 5.83 (1.20–28.29) Ph Absent 5/64 1.00 o0.001 13.60 (3.53–52.36) o0.001 Present 11/26 8.65 (2.61–28.71) Base albumin (g/l) (10 unit increment) 16/90 1.03 (0.40–2.64) 0.95 —— Base bilirubin (μmol/l) (10 unit increment) 16/90 0.91 (0.59–1.42) 0.69 —— BMI (5 unit increment) 16/90 1.29 (0.82–2.02) 0.27 —— Abbreviations: BMI, body mass index; CI, confidence interval; WBC, white blood cell. Analysed as no high-risk factors versus high-risk Ph and high-risk Ph+ gives HRs of 1.86 (0.24–14.64) and 9.53 (1.86–49.91), respectively. outcome for teenagers and younger adults than typical ‘adult’ the overlapping toxicity. The fact that sepsis was a major 14–18 regimens. As a consequence, there is general acceptance contributor to the mortality supports that contention. of testing the outcome of increasing the intensity of non- To date, only two other studies reporting the use of PEG-ASP myelosuppressive agents such as PEG-ASP in regimens used for specifically in adults have been published, both of which report a lower dose and/or different schedule of anthracycline. A phase 2 older adults. (ref. 11) Within the first 91 patients enrolled, we noted significantly greater trial CALGB 9511 reported on 102 adults treated with PEG- 2 2 induction mortality in UKALL14 than in our previous trial, UKALL12. ASP at 2000 U/m subcutaneously, capped at 3750 U/m , starting Induction death occurred in 16 of the first 90 (17.8%) treated on D5 of the five-drug induction regimen. Although the regimen patients, and 15 of the first 59 (25%) participants being aged 440 was reported to be 'tolerable', bilirubin 451.3 μM (3 mg/dl) years (10/29 (33%) being aged 455 years). The median age of the occurred in 54% of patients. CR rate was only 77% but induction patient population enrolled in this period was 46.5 years, with 29% deaths are not separated from induction failures within the report. of patients being aged 455 years. By comparison, the induction There was a statistically significant difference in median age of death rate in our previous trial, UKALL12/ECOG2993, was 6% those achieving full dose delivery and asparagine depletion—32 12 20 overall (ages 15–60 years, median age 36 years) and 15% in the years versus 48 years. In a more recent study from Douer et al. in 55–65-year range (median age 56 years). UKALL14 did not 51 adults median age 32 years, upper age limit 57 years reported exclude any patient with poor organ function or comorbidity at no deaths directly as a result of PEG-ASP in regimen, which diagnosis, but we did not find any evidence of these factors included 2000 IU/m PEG-ASP given on D15. However, 3 of the 51 having a causal contribution to PEG-ASP-related mortality. (6%) patients died of neutropenic sepsis during consolidation. In Analysis of the cause of each death in UKALL14 included a this case, daunorubicin was given at 60 mg/m intravenously on complete written narrative from the treating physician as well as D1–D3. Grade 3–4 hyperbilirubinaemia (1/3 patients) or transami- the standard case report forms for serious AE collection. Bacterial nitis (2/3 of patients) was very common. Douer et al. also sepsis was revealed as a major contributor to the deaths. However, reported long median intervals from PEG-ASP to bilirubin concomitant grade 3–4 PEG-ASP toxicities were very common recovery, which affected subsequent chemotherapy delivery. among those suffering induction death, such that a recognised The younger median age of patients in that study, the small PEG-ASP toxicity was associated with half of the 16 induction deaths. number receiving concurrent imatinib (N = 5), a more modest It is impossible to disentangle the role of the investigational anthracycline dose and different scheduling of PEG-ASP admin- medicinal product (IMP) PEG-ASP from that of concomitant non-IMP istration so as not to coincide with the maximal myelosuppression induction agents. However, the introduction of dexamethasone may all have contributed to the difference in toxicity. instead of prednisolone was the only change that had been made to The German Multicentre Adult ALL Group have reported in the standard backbone regimen between UKALL12 and UKALL14. abstract form on 1000 adult patients aged 15–55 years, treated It is noteworthy that most of the induction deaths reported here on the German 07/2003 study in which a single dose of 1000– occurred after an early, single (D4) dose of PEG-ASP, any toxicity of 2000 U/m PEG-ASP was administered on D3 during induction which would overlap with the myelosuppressive toxicity of with a reported rate of induction death rate of o5% and a anthracycline administered on D1, D8, D15 and D22. The 60 mg/ grade IV hyperbilirubinaemia incidence of 16%. As with the 2 20 m dose of anthracycline given in the UKALL12 regimen was well study by Douer et al., the younger median age (35 years) of the tolerated, but asparaginase was not started until D17. The earlier cohort in addition to the lower dose of anthracycline (45 versus addition of PEG-ASP-associated liver dysfunction to subsequent the 60 mg/m used in the current study) may underpin the myelosuppression-related sepsis may have been responsible for differences in toxicity. Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al Table 4. Patients who did not die during induction: summary of the Table 5. Analysis of risk factors for liver-related grade 3/4 adverse grade 3/4 AEs recognised in SPC as being related to PEG-ASP events during phase 1 induction in patients who did not have an induction death SOC/event term Grade 3+ PEG-ASP known AEs, N (%) Risk factor Grade 3/4 liver AEs Gastrointestinal disorders 2 (3) Events/n Odds ratio P-value Pancreatitis 2 (3) (95% CI) Hepatobiliary disorders 3 (4) Age Liver failure 1 (1) ⩽ 40 5/30 1.00 0.005 Liver dysfunction 2 (3) 440 22/44 2.9 (1.62–15.44) Immune system disorders 3 (4) Allergic reaction 3 (4) Sex Male 16/40 1.00 0.50 Investigations 29 (39) Female 11/34 0.72 (0.28–1.87) Lipase increased 1 (1) Serum amylase increased 3 (4) Baseline WBC per × 10 /l 27/74 1.00 (0.99–1.01) 0.71 Alkaline phosphatase increased 15 (20) increment Aspartate aminotransferase 4 (5) increased Cytogenetics Blood bilirubin increased 17 (23) Standard risk 10/26 1.00 0.97 Alanine aminotransferase 10 (14) High risk 11/29 0.98 (0.33–2.91) increased GGT increased 5 (7) Ph Absent 20/59 1.00 0.36 Metabolism and nutrition disorders 3 (4) Present 7/15 1.71 (0.54–5.38) Increased triglycerides 1 (1) Hypoalbuminaemia 2 (3) Base albumin (g/l) (10 unit 27/74 0.89 (0.41–1.92) 0.77 increment) Nervous system disorders 1 (1) Base bilirubin (μmol/l) (10 unit 27/74 1.02 (0.81–1.30) 0.86 Intracranial haemorrhage 1 (1) increment) BMI (5 unit increment) 27/74 1.58 (1.02–2.44) 0.041 Vascular disorders 4 (5) Pulmonary embolism 1 (1) Abbreviations: AE, adverse event; BMI, body mass index; CI, confidence Thromboembolic event 3 (4) interval; WBC, white blood cell. Non-CTCAE terms Coagulation disorder 3 (4) death, suggesting that the concomitant imatinib therapy only Any liver event 27 (36) Any toxicity 37 (50) received by those with Ph+ ALL may have compounded the potential for PEG-ASP toxicity. The precise mechanism by which Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria; this might occur is not known. However, from the Summary of GGT, gamma glutamyl transpeptidase; PEG-ASP, pegylated asparaginase; Product Characteristics for imatinib, ‘increased hepatic enzymes’ is SPC, Summary of Product Characteristics; SOC, System Organ Class. reported as common (1:10 to 1:100), hyperbilirubinaemia occurs in A complete line listing of grade 3+ AE/serious AE according to CTCAE criteria with assignment of causality by both site and by trial management between 1:100 and 1:1000 patients and, finally, hepatic failure is group is provided in Supplementary Table S1. noted as ‘rare’, namely, occurring between 1:1000 and 1:10 000 cases. Hence, the potential for overlapping hepatotoxicity of PEG- ASP and imatinib is clearly present. It should be noted that the French GRAAALL group also Half of the patients who did not experience an induction death reported that advancing age resulted in a higher cumulative experienced one or more grade 3–4 PEG-ASP toxicities from which incidence of chemotherapy-related deaths (23% versus 5%, they eventually recovered—most commonly, hepatotoxicity. respectively; Po0.001) and deaths in first CR (22% versus 5%, Twenty-three percent of patients in this study experienced grade respectively; Po0.001) during 'paediatric-style' therapy, even ⩾ 3 hyperbilirubinaemia; by definition, a limitation or exclusion to when non-pegylated asparaginsae was used. In the study reported further dosing with many commonly used ALL therapeutics. On by Huguet et al., ⩾ 45 years of age was the strongest predictor of analysis of treatment delays in our previous trial, UKALL12/E2993 severe toxicity, study showed that delays of 44 weeks were associated with As a consequence of the toxicity reported here, the UKALL14 poorer overall survival and event-free survival in patients under- protocol was amended to omit D4 PEG-ASP for those aged 440 going allogeneic hematopoietic stem cell transplantation but not years. Furthermore, PEG-ASP was completely removed from in patients undergoing postremission chemotherapy. Any long- induction treatment for all patients with Ph+ ALL. In addition, term impact of any delays engendered by toxicity during initial owing to the high level of sepsis related to profound myelosup- induction therapy in this study will become clear when the trial is pression, the daunorubicin dose was halved to 30 mg/m on D1, completed and we can evaluate any delays in relation to our D8, D15 and D22. One year following this amendment, when an primary end point, event-free survival. additional 302 further patients had been recruited with 244 Our pharmacokinetic studies indicate that a single dose of patients assessable for induction death, a repeat analysis showed 1000 IU/m PEG-ASP generates therapeutic enzyme levels in most only 6 (2.5%) phase 1 induction deaths (data not shown). patients—86% of assessable patients had therapeutic levels of Univariate analysis demonstrated that older age and poor-risk PEG-ASP activity 14 days after administration. A recent long- cytogenetics—including t(9;22)—were significantly associated itudinal analysis of PEG-ASP pharmacokinetics during a ‘paediatric’ with induction death. On multivariable analysis, age and Ph regimen in adult ALL demonstrated therapeutic enzyme activity in positivity remained as independent risk factors for induction a similar proportion of adult patients for up to 21 days. In our Leukemia (2017) 58 – 64 Toxicity during UKALL14 induction therapy for ALL B Patel et al study, antiasparaginase antibodies were not seen at the early time induction in adults aged 55 years or younger with newly diagnosed acute lym- phoblastic leukemia. Blood 2007; 109: 2744–2750. point documented. 10 Stock W, Douer D, Deangelo DJ, Arellano M, Advani A, Damon L et al. Prevention In conclusion, we have shown that PEG-ASP achieves very and management of asparaginase/pegasparaginase-associated toxicities in adults effective asparagine depletion without antiasparaginase antibody and older adolescents: recommendations of an expert panel. Leuk Lymphoma formation in the majority of adult patients. However, toxicity can 2011; 52: 2237–2253. be substantial in older patients, making a 'paediatric-inspired' 11 Wetzler M, Sanford BL, Kurtzberg J, Deoliveira D, Frankel SR, Powell BL et al. regimen of the type commonly used used in paediatric and young Effective asparagine depletion with pegylated asparaginase results in improved adult therapy difficult to deliver safely to those aged 440 years. outcomes in adult acute lymphoblastic leukemia -- Cancer and Leukemia Group B Avoidance of overlapping toxicities and careful timing of Study 9511. Blood 2007; 109: 4164–4167. 12 Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction administration will be of key importance to the more widespread therapy for adults with acute lymphoblastic leukemia: results of more than 1500 use of this type of regimen in older adults. patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; As remission can be induced with minimal mortality in patients 106:3760–3767. 23,24 with Ph+ ALL, we suggest that PEG-ASP is never coadminis- 13 Fabry U, Korholz D, Jurgens H, Gobel U, Wahn V. Anaphylaxis to L-asparaginase tered with imatinib during induction therapy. during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism. Pediatr Res 1985; 19: 400–408. 14 DeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, Couban S, Supko JG et al. CONFLICT OF INTEREST Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years Fielding received lab funding from Medac GmBH to carry out part of this work and with newly diagnosed acute lymphoblastic leukemia. Leukemia 2015; 29:526–534. that company were the supplier of PEG-ASP at the time of this work. The remaining 15 Boissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc T et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or authors declare no conflict of interest. young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 2003; 21:774–780. 16 de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters ACKNOWLEDGEMENTS R. Significant difference in outcome for adolescents with acute lymphoblastic UKALL14 was funded by Cancer Research UK grant CRUK/09/006 to AKF. The MAAT leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia testing and antiasparaginase antibody testing was funded by a 2-year, unrestricted 2004; 18: 2032–2035. educational grant from Medac GMBH to AKF between 2010 and 2012. BP was funded by 17 Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al. Bloodwise grant 07062. We thank all centres and patients who contributed to this study. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007; 48:254–261. AUTHOR CONTRIBUTIONS 18 Stock W, La M, Sanford B, Bloomfield C, Vardiman J, Gaynon P et al. What BP, AK and AKF wrote the paper. AKF designed the study, contributed data and determines the outcomes for adolescents and young adults with acute lym- was Chief Investigator of the trial. AK analysed data. PS, LM, SP and PP co-ordinated phoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; the study, collected data and contributed to the analysis. AD carried out the MAAT 112:1646–1654. testing. CJR, TM, AKMcM and DM contributed data and managed the trial. 19 Sive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S et al. Outcomes in All authors contributed to writing the manuscript and approved the final version. older adults with acute lymphoblastic leukaemia (ALL): results from the interna- tional MRC UKALL XII/ECOG2993 trial. Br J Haematol 2012; 157:463–471. 20 Douer D, Aldoss I, Lunning MA, Burke PW, Ramezani L, Mark L et al. REFERENCES Pharmacokinetics-based integration of multiple doses of intravenous pegas- 1 Sallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei E 3rd, Nathan DG. pargase in a pediatric regimen for adults with newly diagnosed acute lympho- Influence of intensive asparaginase in the treatment of childhood non-T-cell acute blastic leukemia. J Clin Oncol 2014; 32: 905–911. lymphoblastic leukemia. Cancer Res 1983; 43: 5601–5607. 21 Goekbuget N. 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Comparative article are included in the article’s Creative Commons license, unless indicated otherwise in pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 1993; 11: the credit line; if the material is not included under the Creative Commons license, users 1780–1786. will need to obtain permission from the license holder to reproduce the material. To view a 8 Douer D. Is asparaginase a critical component in the treatment of acute copy of this license, visit http://creativecommons.org/licenses/by/4.0/ lymphoblastic leukemia? Best Pract Res Clin Haematol 2008; 21: 647–658. 9 Douer D, Yampolsky H, Cohen LJ, Watkins K, Levine AM, Periclou AP et al. Pharmacodynamics and safety of intravenous pegaspargase during remission © The Author(s) 2017 Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) Leukemia (2017) 58 – 64

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