Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse. (C) 2019 by American Society of Clinical OncologyPeer reviewe

A randomised comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial

Liposomal daunorubicin and cytarabine (CPX-351) improves overall survival (OS) compared to 7+3 chemotherapy in older patients with secondary acute myeloid leukaemia (AML); to date there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly-diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). 189 patients were randomized (median age 56y). By clinical criteria 49% had de novo AML, 20% secondary AML and 30% high risk MDS. MDS-related cytogenetics were present in 73% of patients, with complex karyotype in 49%. TP53 was the most commonly mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 patients (44%). The overall response rate (CR + CRi) after course two was 64% and 76% for CPX-351 and FLAG-Ida (OR:0.54, 95%CI 0.28-1.04, p=0.06). There was no difference in OS (13.3 months vs 11.4 months, HR:0.78, 95%CI 0.55-1.12, p=0.17) or event-free survival (HR:0.90, 95%CI 0.64-1.27, p=0.55) in multivariable analyses. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months, HR:0.58, 95% CI 0.36-0.95, p=0.03). There was no difference between the treatment arms in patients with clinically defined secondary AML (HR:1.1, 95%CI 0.52-2.30) or those with MDS-related cytogenetic abnormalities (HR:0.94, 95%CI 0.63-1.40), however an exploratory sub-group of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months, HR:0.42, 95%CI 0.21-0.84, heterogeneity p=0.05). In conclusion, OS in younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Genomic correlates of outcome in a randomised comparison of CPX-351 and FLAG-Ida in high-risk acute myeloid leukaemia and myelodysplastic syndrome: results from the UK NCRI AML19 Trial

Background Liposomal daunorubicin and cytarabine (CPX-351) improves survival compared to 3+7 chemotherapy in patients aged 60 years with secondary AML defined by clinical or cytogenetic criteria (Lancet JE, JCO 2018). It is increasingly recognised that secondary AML may be better defined by mutational profile than clinical history (Döhner, Blood 2022; Khoury, Leukemia 2022), however patients with molecularly defined secondary AML were not specifically included in previous studies. Moreover, no randomised data for CPX-351 in patients aged <60y were available prior to this study. Previous UK NCRI trials established the FLAG-Ida regimen as a preferred regimen in patients aged <60y with high-risk and secondary AML (Burnett AK, Leukemia 2018). The UK NCRI AML19 trial randomised patients with AML or high grade MDS between induction therapy with CPX-351 and FLAG-Ida. Initial results reporting similar event-free and overall survival (OS) have been previously presented (Russell NH, HemaSphere 2022). Here we present an exploratory analysis of outcomes stratified by genomic, cytogenetic and clinical definitions of secondary AML. Methods AML19 (ISRCTN78449203) enrolled patients with previously untreated AML, MDS-EB2, or MDS-EB1 with IPSS score >3.5, predominantly aged <60 years. Patients known to have an adverse karyotype at diagnosis according to MRC criteria were randomised between CPX-351 and FLAG-Ida. Treatment consisted of up to 4 courses of CPX-351 or 2 courses of FLAG-Ida followed by MACE/MidAC consolidation with allogeneic transplant recommended after 2 cycles if feasible. Of note, patients could also enter the FLAG-IDA vs CPX randomisation if they became high risk at other defined points after induction, the results of which will be reported separately. Cytogenetic testing was performed in local laboratories with results reviewed and coded centrally. Complex karyotype was defined as ≥4 unrelated abnormalities. Following the completion of the trial, banked diagnostic DNA was analysed for variants in 41 recurrently mutated myeloid genes, including the entire coding regions of all myelodysplasia-related genes according to 2022 WHO and ELN criteria (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) (Döhner, Blood 2022; Khoury, Leukemia 2022). Libraries were prepared using the Agilent SureSelect XT HS2 platform and sequenced on an Illumina NextSeq2000 to a depth of >1000x. Results In total, 195 patients entered were randomised at trial entry, and NGS was performed on 173. Of the whole cohort, 49% were classified by clinical features as de novo AML, 20% as secondary AML and 31% as high-risk MDS. Myelodysplasia-related cytogenetic abnormalities were present in 70% of patients, with a complex karyotype in 51%. TP53 was the most commonly mutated gene in 43% of patients, followed by DNMT3A in 19% and ASXL1 in 18% (Figure A). A mutation in at least one myelodysplasia-related gene was present in 75 (43%) patients, of whom 60 (35%) were categorised as secondary AML by mutational status, which by ELN 2022 criteria requires the absence of TP53 variants. As previously reported, OS did not differ between the two randomisation arms (Hazard Ratio [HR] for CPX-351 0.84, 95% confidence interval [95CI] 0.59 - 1.20). In patients with clinically defined secondary AML, there was no OS benefit for CPX-351 (HR 1.1, 95CI 0.53 - 2.30), while high-risk MDS had a trend to benefit (HR 0.54, 95CI 0.28 - 1.00) (Figure B). When secondary disease was defined by the presence of myelodysplasia-related cytogenetic abnormalities, CPX-351 did not provide benefit (HR 1.04, 95CI 0.77 - 1.55). However, in patients with mutationally defined secondary AML, there was an OS benefit from CPX-351 (HR 0.42, 95CI 0.21 - 0.84, p value for heterogeneity 0.05) (Figure B). Patients with TP53 mutations had an adverse prognosis, with median OS of 7 months compared to 28 months in those with wild-type TP53. CPX-351 did not provide benefit compared to FLAG-Ida in this group (HR 0.92, 95CI 0.57 - 1.49). Conclusion In this exploratory subgroup analysis, CPX-351 had a significant survival benefit over FLAG-Ida in young high-risk patients with secondary AML/MDS as defined by the presence of myelodysplasia-related gene mutations, but not by clinical criteria. We observed no significant difference in patients with TP53 mutations

FLAG-Ida combined with Gemtuzumab Ozogamicin (GO) improves event free survival in younger patients with newly diagnosed Acute Myeloid Leukaemia (AML) and shows an overall survival benefit in NPM1 and FLT3 mutated subgroups. Results from the UK NCRI AML19 trial

Background The optimal induction regimen for younger patients with newly diagnosed AML is uncertain. The MRC AML15 trial suggested a higher response rate and reduced relapse risk with FLAG-Ida compared to a Daunorubicin-araC (DA) +etoposide but did not show an overall survival (OS) benefit (Burnett, JCO,2013,31,3360). GO has been shown to improve survival in patients with favourable and intermediate risk cytogenetics, although it is unclear whether a single or fractionated dose is optimal. (Hills, Lancet Oncology,2014, 15,986) Methods The NCRI AML19 trial (ISRCTN78449203) randomised 1475 patients with newly diagnosed AML or MDS-EB2, not known to have adverse cytogenetics, between FLAG-Ida ( n=738) and DA (Daunorubicin, AraC, n=737). Of these, 1031 were also randomised to receive a single dose of GO (GO1, 3mg/m2 on D1, n=513) or a fractionated schedule (GO2, max 5mg on D1+4 , n=518). Post-remission therapy consisted a second course of DA or FLAG-Ida without GO followed by up to 2 courses of HDAC . No FLT3 inhibition was used. Patients were designated as high risk after course 1 based on a validated risk score, or if they had the genotype FLT3-ITD+, NPM1-. After course 2, patients could be designated high risk based on measurable residual disease (MRD) positivity (i.e. detectable NPM1 mutated transcripts in the peripheral blood (PB) or following protocol amendment, flow cytometric MRD >0.1% in the bone marrow). High-risk patients were recommended for transplant and could enter a separate randomisation, but are included in this analysis. The primary endpoint was OS. Secondary endpoints included event free survival (EFS), relapse free survival (RFS), response defined according to ELN criteria and MRD. Patients aged 18-60 years were eligible but older patients could be enrolled at the investigators discretion. Here we report the outcomes of the patients randomised between FLAG-Ida-GO and DA-GO. Results The median age was 51.5 yrs. 88% had de novo AML, 7% secondary AML and 5% MDS-EB2. MRC defined cytogenetic risk was favourable in 12%, intermediate in 75% and adverse in 9%, the remaining had missing data. Of major molecular subgroups, 30% had NPM1 and 26% FLT3 ITD or TKD mutations. Median follow-up was 32 months. Complete remission (CR/CRi) was 91% for DA-GO and 93% for FLAG-Ida-GO and did not differ by GO dose (92.3% for GO1 and 91.2% for GO2). Day 30 and 60 mortality were not different between DA and FLAG-Ida (D30, 2.9% vs 3.1%, p=0.37; D60 4.6% vs 4.3%, p=0.27) or between GO1 and GO2 (D30, 2.15% vs 3.3%, p=0.1; D60 3.3% vs 5.6%, p=0.07). There was no difference in OS or EFS by GO dose so further outcome analyses were undertaken combined. EFS was significantly better with FLAG-Ida-GO compared to DA-GO (HR 0.73, CI 0.61-0.87, p<0.001) but there was no difference in OS (HR 0.92, CI 0.75-1.13, p=0.41) (Figure 1a and 1b). RFS also favoured FLAG-Ida-GO. In subgroup analysis OS benefit was observed for FLAG-Ida-GO in patients with NPM1 mutation (OS 82% vs 64% at 3 yrs, HR 0.5, CI 0.31-0.81, p=0.005). Furthermore NPM1 MRD positivity by RT-qPCR in the PB after 2 courses of induction was 23% (30/130) with DA-GO compared to 12% (16/130) (p=0.03) with FLAG-Ida-GO. The survival benefit for FLAG-Ida-GO was also seen in FLT3+ve AML (OS of 64% vs 54% at 3 yrs, HR 0.67, CI 0.45 -0.99, p=0.047) with the greatest benefit seen in NPM1 co-mutated patients (HR 0.32 CI 0.16 -0.61). In patients with favourable risk cytogenetics, there was no EFS or OS benefit for FLAG-Ida-GO over DA-GO. Fewer transplants were performed in the FLAG-Ida-GO arm overall, 237 (46%) compared to 278 (54%) with DA-GO including fewer in CR1 (177 compared to 194) reflecting the application of MRD negativity to guide transplant decisions and the reduced relapse risk with FLAG-Ida. Conclusion In this large, randomized comparison we observed no benefit for a fractionated GO schedule but FLAG-Ida-GO significantly improved EFS compared to DA-GO. Although there was no overall survival benefit for FLAG-Ida-GO, there was evidence of an OS benefit in major sub-groups, including patients with NPM1 and FLT3 mutations. This finding was supported by MRD analysis that showed a reduction in NPM1 MRD positivity after two courses of FLAG-Ida-GO. Furthermore this survival benefit was associated with a reduction in the requirements for transplant in CR1 and overall. Given the benefit observed in FLT3 mutated AML in the absence of a FLT3 inhibitor, studies combining FLAG-Ida-GO with Midostaurin are warranted

Thiopurine Enhanced ALL Maintenance (TEAM):study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0–45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

Abstract Background: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods: TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m²/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m²/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion: TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms. Trial registration: EudraCT, 2018–001795-38. Registered 2020-05-15