The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second-or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. Cancer 2011;117:238-49.

The best strategy for incorporating imatinib in front-line treatment of Ph ؉ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph ؉ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P ‫؍‬ .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic

BackgroundNOTCH1 mutations have been associated with a favorable outcome in pediatric acute Tlymphoblastic leukemia. However, the results of studies on the prognostic significance of NOTCH1 mutations in adult T-lymphoblastic leukemia remain controversial. Design and MethodsHere we have investigated the prognostic impact of mutations in the NOTCH1 pathway, in particular, the NOTCH1 and FBXW7 genes, in a large cohort of adult patients with Tlymphoblastic leukemia (n=126). We determined the occurrence of mutations in NOTCH1 and FBXW7 by DNA amplification and direct sequencing of polymerase chain reaction products. ResultsMutations were identified in 57% and 12% of the NOTCH1 and FBXW7 genes, respectively. The characteristics of patients carrying NOTCH1 and/or FBXW7 (NOTCH1-FBXW7) mutations were similar to those with wild-type genes. Patients with NOTCH1-FBXW7 mutations more often showed a thymic immunophenotype (p=0.001). In the overall cohort, no significant differences were seen in the complete remission or event-free survival rates between patients with mutated or wild-type NOTCH1-FBXW7 (p=0.39). ConclusionsNOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of adult patients with T-lymphoblastic leukemia, but there was a trend towards a favorable prognostic impact of NOTCH1-FBXW7 mutations in the small subgroup of patients with low-risk ERG/BAALC expression status. Our findings further confirm the high frequency of NOTCH1 mutations in adult T-lymphoblastic leukemia.Key words: acute T-lymphoblastic leukemia, NOTCH1, FBXW7, mutations. T-lymphoblastic leukemia. Haematologica 2009;94:1383-1390. doi:10.3324/haematol.2008 This is an open-access paper. Citation: Baldus CD, Thibaut J, Goekbuget N, Stroux A, Schlee C, Mossner M, Burmeister T, Schwartz S, Bloomfield CD, Hoelzer D, Thiel E, and Hofmann W-K. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia

We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival ( = .023), disease-free survival ( = .012), and remission duration ( = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

494 Several randomised pediatric trials have demonstrated that intensification of Asparaginase (ASP) treatment in ALL can contribute to improved outcome. In adult ALL few data are availabe and optimal ASP preparation, schedule and intensity with respect to efficacy and tolerability have to be defined. The optimisation of ASP treatment is therefore an essential aim of the GMALL. Treatment: Induction treatment of the ongoing study 07/2003 consists of dexamethasone, vincristine, daunorubicine, pegylated asparaginase (PEG-ASP) (phase I), mercaptopurine, cyclophosphamide and cytarabine (phase II) as previously described (Brueggemann et al, Blood 2006: 107; 1116). During the study the dose for PEG-ASP was increased from 1000 to 2000 U/m2 in induction and from 500 to 2000 U/m2 in consolidation (combined with HDMTX and MP) for pts aged between 15 and 55 years. 1 application for high risk and 7 applications for standard risk (SR) were scheduled during the first year and the aim was improvement of overall survival (OS) and remission duration (RD). Patients: From more than 100 centers in Germany 1226 pts with a median age of 35 (15-55) yrs were evaluable. 826 pts were treated with 1000 U/m2 (cohort 1) and 400 pts with 2000 U/m2 (cohort 2) and both groups were comparable regarding major entry criteria. The analysis was restricted to pts who received one of the scheduled PEG-ASP doses during induction. Outcome: CR rate after induction was 91% vs 91% in cohort 1 and 2 resp., with comparable rates for early death (4% vs 5%) and failure (5% vs 4%). Data on molecular response (MRD below 10−4) after induction are available in a subset and showed no difference between both cohorts after induction (79% vs 82%). OS after 3 years was improved in cohort 2 (60% vs 67%; p>.05). The positive effect was specifically evident in SR patients (N=407 vs 190) with respect to OS (68% vs 80%; p=.02) and RD (61% vs 74%; p=.02). It was demonstrated in younger pts (15-45 yrs) (71% vs 82%; p=.02) and older pt (45-55 yrs) (56% vs 74%; p>.05). Excellent results were achieved in young adults (15-25 years) with respect to OS (77% vs 86%; p>.05) and RD (60% vs 78%; p>.05). Toxicity: The analysis of toxicity was focused on grade III-IV events during induction with potential correlation to PEG-ASP (764/382 pts in cohort 1/cohort 2)). Incidences are as follows: GOT or GPT (30%/30%), bilirubine (10%/16%), thrombosis (5%/5%) and hypersensitivity (<1%/<1%). In a subset of pts additional AEs were assessed as amylase (5%/13%), lipase (23%/15%) and glucose (10%/12%). Significantly less toxicity was observed during consolidation cycles. Bilirubine °III/IV occurred median 16d after PEG-ASP during phase II of induction. In univariate analysis it was correlated to dose (10% vs 16%; p=.004), age <> 45 yrs (11% vs 17%; p=.005), BMI <> 30 (12% vs 18%; p=.04) and rituximab application (11% vs 18%; p=.009). Hepatomegaly, infections or imatinib application had no significant effect. In multivariate analysis dose and age remained independent significant prognostic factors. Bilirubine increase during induction was associated with treatment delays and inferior prognosis. Conclusions: This is the largest cohort of adult ALL treated with PEG-ASP. Due to prolonged activity fewer applications are required which is a pre-requisite for realisation of ASP intensification in the context of an intensive multidrug chemotherapy for adult ALL. Although CR rate and molecular CR were not significantly improved PEG-ASP intensification was associated with an improved OS and RD. The improvement was specifically evident in SR pts treated with up to 7 doses of PEG-ASP. Overall intensified PEG-ASP was feasible. The rate of grade III-IV bilirubine elevation increased after dose escalation and led to treatment delays in individual pts which were prognostically relevant. It would be an important goal to identify parameters to predict severe ASP related toxicity. Further intensification of ASP by additional applications would be of interest. Supported by Deutsche Krebshilfe 70–2657-Ho2 and partly BMBF 01GI 9971 and Medac GmbH. Disclosures: Goekbuget: Medac: Consultancy, Research Funding, Speakers Bureau. Hoelzer: Medac: Speakers Bureau.

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1493 Few older ALL pts are entered into prospective trials and data on characteristics and outcome are scarce. The GMALL started a prospective trial in older ALL (>55 yrs) in 2003. In Ph-neg ALL a prephase (Dexa, Cyclo, MTX i.th.) was followed by induction I (Dexa, VCR, Idarubicin), induction II (Cyclo, AraC), alternating consolidation with IDMTX (d 1,15) ×3, VM26/AraC ×2, reinduction (VCR, Ida, Cyclo, AraC) and maintenance (MP, MTX) up to 2 yrs. In CD20+ ALL Rituximab ×8 was added. CNS-prophylaxis consisted of i.th. triple combination (MTX, AraC, Dexa) ×4 during induction, ×8 during consolidation/maintenance. The original protocol (group 1) was amended to optimize CNS prophylaxis and consolidation (group 2). I.th. therapy was then performed with liposomal cytarabine, 3x during induction, 3x during consolidation. IDMTX dose was increased from 500 to 1000 mg/m2 and native E.coli ASP (10.000 U/m2) was added on d2 and d16 of IDMTX. VM26/AraC was replaced by IDAraC (1000 mg/m2 d1,3,5). In a further amendment the original i.th. prophylaxis was reinserted until final analysis of liposomal AraC became available. Furthermore, after induction, one cycle with pegylated ASP (500 U/m2) (PEG-ASP) was scheduled to evaluate feasibility in older pts (group 3). Results of induction were compared for groups 1–3; outcome analysis was restricted to 1–2 due to still short follow-up for group 3. 268 pts with a median age of 67 (55–85) yrs treated in 94 hospitals were evaluable (180, 43 and 45 pts in groups 1, 2 and 3 resp.). 39% were aged 55–65 yrs, 51% 66–75 yrs and 10% above 75 yrs. 67% had c/pre-B-ALL, 18% pro-B-ALL and 15% T-ALL. WBC was >30/nL in 27%. Poor ECOG status (≥2) before (ECOGb) or after (ECOGa) onset of ALL was described in 7% or 38% resp. 78% had any comorbidity and 9% had a Charlson score (ChS) ≥3. No significant differences were detected between groups 1–3. Overall 76% (N=203) achieved CR after induction, 14% experienced early death (ED) and 10% did not achieve CR. In groups 1–3 CR rates were 72%, 86% and 82% resp. and ED rates 18%, 0% and 11% resp. (p=.03). CR rates were 84%, 74% and 52% in three age groups (p=.002) with ED rates of 7%, 14% and 37% resp. (p=.0004). Immunophenotype and WBC (<> 30.000) correlated with CR but not ED rate. ECOGb 0–1 vs ≥2 correlated with CR (82% vs 33%;p<.0001) and ED (7% vs 53%;p<.0001). Also ECOGa correlated with CR (85% vs 67%;p=.003) and ED (6% vs 19%;p=.003). CR and ED rates were not influenced by comorbidity itself but by ChS < vs ≥3: CR (78% vs 59%;p=.003) and ED (11% vs 33%;p=.0007). Multivariate analysis confirmed ECOGb, WBC and age for CR rate, and ECOGb, age and ChS for ED. Overall survival (OS) at 5 yrs was 23%; 33% at 2 yrs for group 1 and 52% for group 2 resp. (p=.01). Mortality in CR was 6% and 15% of the pts were withdrawn in CR. Probability of continuous complete remission (CCR) was 32% at 5 yrs, 42% and 43% at 2 yrs for group 1 and group 2 resp. (p=>.05). Age (42% vs 37% vs 8%;p=.0007), WBC (43% vs 15%;p<.0006), ECOGb (40% vs 14%;p=.0008) and ECOGa (42% vs 30%;p=.0023) were correlated with OS in contrast to comorbidity and ChS. Age, treatment group, WBC, ECOGb and ECOGa were confirmed in multivariate analysis. Pts younger than 75 yrs with ECOGb below 2 had an 86% CR rate with 10% ED and 36% OS at 3 yrs. WBC and MRD were significant prognostic factors for CCR. MRD results after consolidation I were available in 33 pts. CCR was 11% in molecular failure vs 68% in molecular CR. Preliminary results confirmed feasibility of PEG-ASP. With this age adapted regimen a favorable CR rate was achieved in a large patient group with a median age of 67 yrs. CR was increased (86%) and mortality was decreased (0%) significantly with liposomal cytarabine compared to triple i.th. prophylaxis during induction, since the latter probably induced more bone marrow toxicity. Reduced ED contributed considerably to improved OS. Moderate intensive consolidation was feasible and ASP, including PEG-ASP, was well tolerated. Age was correlated with outcome and 75 yrs appears to be the upper limit for this regimen. General condition was an additional highly relevant prognostic factor whereas comorbidity, measured by Charlson score was associated with ED but not with OS. These results encourage further treatment optimisation in older ALL pts, including those with comorbidities, based on comprehensive diagnostics, geriatric assessment, MRD evaluation, intensified consolidation, use of ASP, dose-reduced stem cell transplantation and integration of new, targeted drugs. Disclosures: Goekbuget: Medac: Consultancy, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Research Funding; Genzyme: Research Funding; Mundipharma: Research Funding, Speakers Bureau; Glaxo: Research Funding, Speakers Bureau; Micromet/AMGEN: Consultancy; Sigma Tau: Consultancy. Off Label Use: Liposomal cytarabine in prophylaxsis of CNS relapse in ALL.