•The ESMO-MCBS:H is the first version of the ESMO-MCBS designed specifically for haematological malignancies.•The scale has been developed in a joint project of ESMO and EHA following all the validation steps of the solid tumour version.•The ESMO-MCBS:H is ready to use hand-in-hand with the solid tumour version.•The ESMO-MCBS:H will support the shared mission of ESMO and EHA to identify novel treatments that bring a substantial clinical benefit to the patient.

Background: The prognostic significance of FLT3-internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) in relation to the allelic mutational burden and other concurrent gene mutations at diagnosis remains subject of scientific controversy. Increasing evidence indicates that treatment outcome prediction can be improved by assessing the kinetics and depth of response during therapy by detection of minimal residual disease (MRD). Until now, FLT3-ITD MRD detection by RQ-PCR has been hampered by the variety in patient specific FLT3-ITD (i.e. sequence, position and length) and is currently not recommended because of potential instability of FLT3-ITD clones during relapse. However, systematic studies evaluating the applicability of FLT3-ITD MRD detection with next-generation sequencing (NGS) in AML are currently lacking. Aims: Here, we set out to compressively investigate the impact of NGS-based FLT3-ITD MRD detection on treatment outcome in a cohort of newly diagnosed patients with AML in the context of current prognostic factors at diagnosis and other MRD measurements during therapy, including mutant NPM1 and multiparameter flow cytometry (MFC). Methods: In 176 de novo FLT3-ITD AML patients who were treated in HOVON-SAKK multicenter prospective phase III clinical trials, NGS was performed at diagnosis and in complete remission (CR) following two cycles of standard induction chemotherapy. The NGS libraries were paired-end sequenced (2×221-bp) with custom primers on an Illumina MiSeq according to manufacturer’s recommendation (Illumina, San Diego, CA). We used our in-house data analysis pipeline for variant calling. The primary endpoints of the study were relapse and overall survival. The Cumulative Incidence of Relapse (CIR) was estimated with competing-risks regression analyses according to the method of Fine & Gray. The Cox proportional hazard model was used to calculate overall survival estimates. Results: NGS-based FLT3-ITD MRD was present in 43 of 176 (24%) AML patients with a median variant allele frequency of 0.01% (range 3.1x10-4% to 3.10%). Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year risk of relapse, 79% FLT3-ITD MRD vs. 34% no FLT3-ITD MRD; P<0.001) and inferior overall survival (4-year rate of overall survival, 27% FLT3-ITD MRD vs. 57% no FLT3-ITD MRD; P<0.001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 4.00; P<0.001) and overall survival (hazard ratio 2.78; P<0.001). Strikingly, FLT3-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including FLT3-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or MFC. Image:Summary/Conclusion: NGS-based detection of FLT3-ITD MRD in CR identifies AML patients with a profound risk of relapse and death that outcompetes the significance of most accepted prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.

Background:Risk stratification in AML is evolving as a consequence of characterizing cytogenetic abnormalities and mutational profiling. The latter is especially important in patients (pts) lacking karyotypic abnormalities1. Approximately 30% of adult pts with newly diagnosed AML have an activating mutation in the FLT3 gene, usually either an ITD mutation (in approximately 20% of AML pts), or an activating point mutation in the activating loop of the TKD (approximately 6‐8% of AML pts)2. FLT3‐ITD mutations are associated with poor prognosis, particularly when they are present at a high allelic ratio relative to FLT3‐WT (FLT3‐wild type)3,4.A randomized, double‐blind, multi‐center, placebo‐controlled phase III study has been initiated (currently enrolling pts) to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML pts with FLT3 mutations but also in FLT3‐WT (Signal Ratio [SR] < 0.05) AML.Aims:The study is designed to evaluate the efficacy and safety of midostaurin combined with intensive chemotherapy and post‐consolidation in pts with FLT3‐MN AML.Methods:502 adult pts with newly diagnosed AML demonstrating FLT3‐MN (SR < 0.05), as determined by a central laboratory testing, will be enrolled at approximately 150‐180 sites worldwide. Pts will be stratified by age (<60 vs. ≥ 60 years). Key exclusion criteria: central nervous system (CNS) leukemia, therapy‐related AML, isolated extramedullary leukemia, prior therapy for leukemia or myelodysplasia with exceptions. All pts/HCP will provide written consent for participation.The treatment arms will be midostaurin (PKC412) or placebo in combination with idarubicin/daunorubicin and cytarabine for induction therapy, intermediate‐dose cytarabine for consolidation therapy, followed by post‐consolidation therapy with midostaurin or placebo (figure).In induction phase, treatment will start with chemotherapy and patients will be randomized to midostaurin or placebo on day 8. Patient with CR or CRi with adequate blood count recovery with one or 2 cycles of induction will move to 4 or 3 cycles of consolidation treatment respectively.Pts will receive midostaurin (two 25 mg capsules) or placebo (2 capsules) twice daily orally from day 4 until 48 hours prior to the start of the next consolidation cycle. After the final cycle of consolidation therapy, pts will receive 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice daily at 50 mg. Pts who underwent hematopoietic cell transplantation (HCT after achieving CR or CRi with adequate blood count recovery will receive midostaurin or placebo 50 mg twice daily as post‐consolidation therapy, continuously, for up to 12 cycles (28 days/cycle). Post HCT therapy will begin >30 days but not later than 100 days following HCT.Primary outcome is to determine if the addition of midostaurin to standard induction and consolidation therapy, followed by single agent post‐consolidation therapy improves event‐free survival (EFS) in pts with newly diagnosed FLT3‐MN (SR < 0.05) AML. Key secondary outcome is to determine if Midostaurin improves OS. Other secondary endpoints includes Measurable Residual Disease negativity (MRD‐) rate.Results:‐Summary/Conclusion:This multicenter study will evaluate the efficacy and safety of midostaurin combined with intensive chemotherapy and post‐consolidation in pts with AML.image

Background:The HARMONY Alliance is the the largest Innovative Medicines Initiative (IMI) European public‐private partnership that aims to improve outcomes of patients with hematological malignancies (HMs) by establishing consensus outcomes among all stakeholders through the analysis of data on a large “Big Data” platform. HARMONY is currently composed of 53 Partners and 32 Associated Members from 22 countries, including the pharmaceutical industry, hospitals, academic, research institutions, regulatory agencies, health technology assessment bodies, and patients’ organizations. HMs within scope are acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome, non‐Hodgkin lymphoma and pediatric HMs.Aims:To establish and test the HARMONY platform, we have performed a “Proof‐of‐Principle” study in AML.Methods:For this study we have implemented standardized operating procedures and a de facto anonymization process for data intake, quality evaluation, storage, and analysis compliant with the European General Data Protection Regulation. We have established a Big Data Platform allowing the analysis and interpretation of data from different Cooperative Working Groups (CWGs), large single academic institutions, and EFPIA (European Federation of Pharmaceutical Industries and Associations) partners by harmonizing all incoming data using the Observational Medical Outcomes Partnership (OMOP) common data model. To date, we have started to incorporate AML data sets and based on this first comprehensive public‐private data set collection we are aiming to (i) further define gene‐gene interactions, (ii) evaluate the clinical impact of these gene‐gene interactions on outcome, and (iii) validate and further refine genomic AML classification.Results:So far, we have incorporated first AML data sets that include both comprehensive clinical information as well as data on targeted myeloid panel sequencing from over 3000 patients and we are expecting >5,000 by the end of March and a total of over 8000 by the middle of 2019. So far, CWG data sets include the AMLSG (∼1500), HOVON (∼700), AMLCG (∼600) and data sharing agreements will be signed for the MRC (∼1500), SAL (∼1000), ALFA (∼1000), GIMEMA (∼500), PETHEMA, CETLAM, and CELL (∼200 each). Data entered from large academic centers include Belfast (∼300), Madrid (∼200) and Berlin (∼300), and a first EFPIA data set was contributed by Novartis (∼600) with plans for additional studies to be incorporated by EFPIA members. In April a first integrative analysis will be performed on the data that has been included prior to then (>5000 AML cases). Gene‐gene interactions will be determined in accordance to our previous study on the genomic landscape of AML (Papaemmanuil et al. NEJM 2016) and results will be interpreted in the light of the current knowledge and publicly available data. This comprehensive analysis should help to further unravel the heterogeneity underlying AML and provide new insights into novel biomarkers and potential druggable gene‐gene interactions.Summary/Conclusion:The early achievements of the HARMONY Alliance prove that a public–private partnership involving all stakeholders and using OMOP harmonized big data is both feasible and can allow us to improve outcomes of patients with HMs. First results of the AML‐pilot study will be presented in order to demonstrate both the functionality of HARMONY and its synergistic effects by harmonizing European big data efforts to improve leukemia outcome.

Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo‐SCT).

In silico and preclinical drug screening identifies dasatinib as a targeted therapy for T-ALL

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

The EUTOS population-based registry includes data of all adult patients newly diagnosed with Ph+ and/or BCR-ABL1+ CML in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time 29 months. 80% of patients were treated first-line with imatinib, and 17% with a second generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months CCyR and MMR were achieved in 57 and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of OS and PFS for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new ELTS score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with TKIs resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provides a solid benchmark for the evaluation of new treatment policies.

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71±4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23±8% and 12±6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23±4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.

In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. ‘Death due to CML’ was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

POEMS syndrome is a rare paraneoplastic syndrome associated with clonal plasma cells. ASCT is believed to be an effective treatment in the control of the disease. Patient-, disease-& transplant-related variables were collected from the EBMT database. Systemic involvement & response was detailed utilizing an organ response tool pre- & post-ASCT. 127 patients underwent an ASCT between 1997-2010. The median age was 49.9 years (range 26.3, 69 years). The median time from diagnosis to ASCT was 7.5 months (range 0.8, 346). ASCT was preceded by induction therapy in 87.5% of patients & the performance score (PS) was good (40%), fair (29%) & poor (31%) at transplant. The graft source was PBSC with 57% of graft recipients receiving >4x106/kg (median CD34+ cell dose 4.3x106/kg). One hundred and twenty-three (99.2%) patients were reported as receiving Melphalan 200mg/m2 as conditioning chemotherapy & only 1 patient (0.8%) received TBI as part of the conditioning regimen. The disease status (haematological response; HR) at transplant was reported as CR/PR 47.6%, MR/SD 21.4%, PD 18.4% and untreated 12.6%. Successful engraftment was documented in 96.8% with engraftment failure reported in only 3 patients. The median time to neutrophil engraftment was 13 days. Engraftment syndrome (ESy) was reported in 29 patients (23%), with no difference in the incidence of ESy based on previous treatment (p=0.178). The HR post ASCT was documented as CRHR in 47.5% with a median time to CRHR of 15.9 months, PRHR in 22 patients (21.8%),

Minimal residual disease (MRD) has been found to offer an independent post-remission prognostic marker in acute myeloid leukaemia (AML). We have confirmed this in a large blinded study in which MRD was assessed in parallel to a HOVON therapy protocol. Subsequently, MRD is now included as part of a new risk classification in a HOVON/SAKK treatment protocol where intermediate risk patients, previously all scheduled for allogeneic stem cell transplantation, are scheduled for autologous transplantation in case of MRD-negativity. In parallel, leukaemia stem cell load at clinical follow up was identified as a factor that adds significantly to the prognostic value of MRD load. Especially relapse in MRD-negative patients can now be better predicted based on leukaemia stem cell (LSC) frequency. A single tube assay was therefore developed which facilitates stem cell load assessment and allows this in the majority of patients. Lastly, false-negative MRD and false-negative LSC cases may be identified by monitoring upcoming aberrant populations that, due to low frequencies, were not properly identified at diagnosis. Introduction Treatment of AML patients usually is performed according to classification in risk groups defined by molecular, cytogenetic and clinical parameters, which thereby identify patients with favourable, intermediate and poor/very poor risk.1 Although very useful, this classification is still far from the ideal situation in which patients should have individualized risk assessment, potentially allowing individualized therapy: all risk groups still harbour patients with good and poor outcome, even the most favourable patient group, while the poor risk patient group still harbours good performing patients. Parameters that would integrate all known and unknown factors contributing to individual patient's clinical outcome were therefore thought to be urgently needed. A post-remission parameter like MRD has been proposed to represent such a factor and is meanwhile extensively studied. 2 Our recent study in the HOVON/SAKK consortium (http://www. HOVON.nl) has shown for young patients (HO42A, for details see website) that MRD assessed by flowcytometry in an unbiased way (prospective sampling and MRD quantitation in a multiinstitutional way, with complete lack of knowledge on clinical outcome until final analysis) is an independent prognostic factor in all individual risk groups. However, despite these improvements, still a considerable portion of MRD-negative group (defined as having MRD below a threshold level of 0.1% of WBC) relapse. 3 Also, the terms MRDnegative and MRD-positive (above the threshold level of 0.1%) have a different meaning in the different risk groups: MRDpositive patients in the favourable risk group still have relatively good prognosis, while MRD-negative patients in the poor risk group still have relatively poor prognosis. Intrinsic properties of MRD cells may underlie this phenomenon and one of the factors may be the LSC load. LSC are hypothesized to initiate leukaemia, to be therapy resistant, and at the basis of re-growth of the leukaemia after treatment. 4 As a single independent parameter it has been shown that stem cell load at diagnosis is a prognostic marker5,6,7,8 and, more recently in the HO42A study, we also showed prognostic impact after therapy. 7 The stem cell load, when taken into account in a risk assessment that also includes MRD, may further improve MRD based risk assessment. Methods Flowcytometric MRD was performed using the approach in which leukaemia associated immunophenotypes (LAIP) were defined at diagnosis.3 In the HOVON42A study risk was based on the combination of cytogenetics, molecular aberrations and clinical parameters. LSC can be defined as CD34+CD38-. Strategies to define such population at diagnosis and at follow up have been described elsewhere. 7 LSC specific markers (not expressed on CD34+ CD38- normal hematopoietic stem cells, HSC), included lineage markers like CD7, CD19, CD569and, in addition, CLL- 1 (CLEC12A)10 , were originally included in the LSC panel. 7 In a new protocol, tested in more than 500 AML samples, additional markers have been included (e.g CD123, CD33, CD96, TIM-3, CD44). The combination of MRD and LSC frequencies after induction therapy was tested for relapse free survival in a small (n=91) patient group. Threshold levels used for LSC were much lower than for MRD: 1 in 100,000 cells to one in a million cells.7 Results MRD: Based on the prognostic impact of MRD in the HO42A clinical study, the present HO132 protocol contains a risk group previously designated as intermediate risk, but now, based on MRD positivity (MRD % >0.1) after induction courses, is part of the poor risk group. Since MRD had the strongest prognostic impact after the second induction course, for logistical and financial reasons it was decided to restrict the protocol toMRD assessment after the second induction course. MRD status after consolidation, although informative 3,11 is not considered in decision making, since it does not comply with the timely finding of an allogeneic donor for part of the patients. Based on previous validation study 12, it was decided to perform MRD assessment in a largely centralized way. Accrual of patients has started (target number 800; 83 patients already included). LSC +/-MRD: When combiningMRD load and stem cell load (Figure 1) it was found that: 1. The MRD negative group consists of two different groups with different prognosis based on LSC load; 2. The LSC negative group can be divided in a MRD-positive and aMRD-negative group with different prognosis; 3.Double negativity goes along with good prognosis, while double positivity goes along with very poor prognosis. Fig1: Combination of MRD and LSC in prognosis of patients. ForMRD a threshold value of 0.1% defines MRD positive group. For LSC similarly 0.0002% defines LSC positive group. Data for another threshold value have been published.7 LSC could be accurately determined in part of the patients only.7 Therefore, additional markers were studied with the aim to increase that part. Using the markers indicated inMethods, it is now possible to assess LSC in >90% of the patients. Based on extensive study of the redundancy of markers, we are now able to assess total LSC load in a givenAML both at diagnosis and after therapy in a one tube assay that includes 13 different markers. This approach is included as a side study in the HO132 protocol, where the possible contribution of LSC load assessment to prognosis will be studied. Immunophenotype shifts in MRD and LSC assessment: Although LSC markedly improves risk stratification based on well-known risk factors and now also includingMRD load, still the double negative patient group (MRD- LSC-) contains relapsing patients while the two single positive groups still contain both relapsing and non-relapsing patients (Figure 1). We and others found immunophenotype shifts in around 60% (median in different studies,13) of patients, and these contribute to MRD- and LSC false negatives. With the knowledge of immunophenotype and molecular shifts in mind, the present HO132 protocol, apart from the inclusion of LSC load assessment, also assesses the contribution of immunophenotype shifts to MRD (and LSC) negativity. Conclusions We conclude that, based on many studies, and especially on our recent unbiased MRD study, MRD contributes significantly to the existing risk group stratification that is based on cytogenetic and molecular factors as well as on clinical factors. The decision-making process whether a patient is allocated to an allogeneic stem cell transplantation can now be guided by MRD assessment. Moreover, the inclusion of other factors like stem cell load and immunophenotype changes, as seen forMRD and LSC, will contribute to the final goal of individualized therapy.