Outcome of adult ALL has improved considerably during the past decades by intensive chemotherapy, which still remains a challenge in older pts. This may be partly due to comorbidities. So far there are no standards to differentiate pts who will be able to tolerate even age-adapted chemotherapy (fit vs unfit). In addition, little is known about the prevalence of comorbidities. Clinical trials with new compounds often represent a selection of pts w/o comorbidities. There is also no generally accepted tool for comorbidity scoring. The goal of this analysis is to provide reference data for pre-existing comorbidities in a large set of adult ALL pts, to compare two different tools and to evaluate the impact on early death (ED) in older pts. The German Multicenter Study Group for Adult ALL (GMALL) has collected data from trials for younger (18-55 y) and older (>55 y) pts and from a prospective registry. Trials had very limited exclusion criteria and in the registry there are no exclusion criteria. The Charlson Comorbidity Index (CCI) was assessed in the GMALL Elderly trial, whereas the Sorror Score (HCT-CI) was used in trials for younger pts and in the registry. 879 pts had a documented HCT-CI score from GMALL 08/2013 trial (N=282;group 1) and 3 groups from the registry: >55 y but eligible for intensive therapy (N=56, group 2), > 55 y in GMALL Elderly protocol (N=505, group 3) and >55 y in GMALL Frail protocol (N=36; group 4) (Table 1). In addition the CCI was documented in 333 pts treated in the GMALL Elderly Trial. HCT-CI-Score: The most frequent comorbidities were infections (17%), prior malignancies (16%), diabetes (16%), cardiac (14%) and moderate pulmonary disease (12%), obesity (11%) and mild liver disease (10%). Arrhythmias (<1%, 5%, 12% and 22% resp. in groups 1, 2, 3, 4), cardiac disease (2%, 7%, 19% and 42% resp.), prior malignancies (2%, 11%, 25% and 22% resp.) and diabetes (4%, 16%, 22% and 22% resp.) increased with age. Infections (15%, 18%, 22% and 22% resp.) or obesity (9%, 7%, 11% and 14% resp.) were not strongly correlated to age. Comorbidity rates were lower in pts >55 y (group 2) considered eligible for intensive therapy (57%) compared to those considered for the Elderly protocol (76%) (group 3). The proportion of low risk (LR) scores decreased with age (54%, 43%, 25% and 8% resp.;p=.01), whereas high risk (HR) increased (18%, 25%, 50% and 59% resp; p=.01). CCI: The most frequent comorbidities were prior malignancy (14%), diabetes (25%) with (3%) or w/o (22%) end organ damage, cardiac (11%) and vascular disease (8%). The incidence of prior malignancy within the last 5 y was 7%. Risk classification was: LR (0) 51%, intermediate risk (IMR) (1-2) 42% and HR (≥3) 7%. HCT-CI vs CCI in pts >55 y: With HCT-CI the incidence of heart diseases (21% arrhythmias, cardiac disease or valve damage) was higher compared to CCI (9%), which differentiated better into cardiac failure (7%) and myocardial infarction (4%). Peripheral vascular disease (8% with CCI) is not assessed by HCT-CI. Liver disease was less frequent with CCI (1.5%) vs HCT-CI (14%) due to different definitions, whereas moderate pulmonary disease (12%) or infections (18%) are not assessed by CCI. The incidences of prior malignancies and diabetes were comparable. Of note, the overall incidence of distinct comorbidities e.g. cardiac was lower than the sum of subentities because some pts had several comorbidities. ED in pts >55 y: ED rates in pts >55 y in group 3 and in GMALL Elderly trial were comparable (13% vs 12% resp). In group 3 ED rates in risk groups (HCT-CI) were 7% vs 13% vs 15% (p>.05). In the GMALL Elderly trial ED in risk groups (CCI) were 9%, 12% and 35% (p=.05; p=.003 LR/IMR vs HR). Overall the analysis reveals a high incidence of comorbidities in older (57-92%) and even in younger pts (46%), which partly would represent contraindications in clinical trials with novel compounds; thus real world data in pts with comorbidities are required after marketing authorisation. HCT-CI and CCI have a different focus and shortcomings. For ALL pts a more specific score with different organ modules would be helpful. Comorbidity is significantly correlated to ED risk. CCI allows to identify a small HR group (7%) with a mortality of 35%. HCT-CI (24% of pts) and even more CCI (51% of pts) allow to identify LR groups with <10% early mortality. It will be of interest to analyse the impact of individual comorbidities on ED rate. Overall structured comorbidity assessment should be part of all clinical trials in ALL. Disclosures Viardot: Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Fiedler:Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Amgen: Other: support for meetíng attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Stelljes:JAZZ: Honoraria; MSD: Consultancy; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Serve:Bayer: Research Funding. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

The acute lymphoblastic leukemia (ALL) is a heterogenous rare malignant disease of lymphoblastic precursor cells. The peak of incidence lies in childhood (5.3/100 000), but the incidence rises again from the age of 50 onwards, showing a second peak at patients > 80 years old (2.3/100 000). The ALL is an acute life-threatening disease which untreated leads to death within a short time. The therapeutic objective is cure. By the characterization of subgroups, their targeted therapy and therapy optimization cure rates could be improved (from less than 10 % in the eighties) to more than 50 - 70 % (depending on the subgroup). To this achievement the approach has contributed with risk adapted therapy protocols, with improved supportive therapy and in particular with taking the minimal residual disease (the most important prognostic factor) as a basis for the therapy decision. Recently, with the new immunotherapies there exist further promising options of targeted therapies.

MRD in ALL is defined as the detection of leukemic cells in bone marrow below the microscopic threshold in complete remission (CR). Patients (pts) with molecular failure (MolFail) or molecular relapse (MolRel) after induction/consolidation therapy are at a high risk for hematologic relapse. Targeted therapies should prevent hematologic relapse, reduce MRD load and provide a bridging strategy to allogeneic stem cell transplantation (SCT) and thereby improve overall outcome of these pts. In pts without (wo) SCT option reduction of MRD load is an essential goal as well. Blinatumomab is an antibody construct that redirects CD3+ T cells to CD19+ target cells, resulting in a serial lysis of CD19+ B cells. In a study in pts with MRD ≥10-3, 78% achieved complete MRD response (Gökbuget N et al., Blood 2018). The MolAct1 trial was initiated by the GMALL study group to evaluate the efficacy and tolerability of Blinatumomab in MRD+ ALL including those with MRD below 10-3 and pts with MRD after SCT. Adults (≥18 yrs) with CD19+, Ph-negative BCP ALL in CR after ≥ 3 chemotherapies with MRD ≥10-4 were eligible (NCT03109093). Recruitment of pts with MRD ≥10-3 was stopped after marketing authorization for this entity. After an amendment, which became effective after 44 recruited pts, pts with MRD below 10-4 or non-quantifiable (nq) MRD were eligible. Blinatumomab 28 μg/day was given as 4-wk infusion, followed by a 2-wk break (1 cycle). Responders could receive up to 4 cycles or undergo HSCT after ≥ 1 cycle. MRD after 1 cycle was the primary endpoint. MRD was centrally assessed by allele-specific quantitative real-time PCR of clonal rearrangements of immunoglobulin or T-cell receptor genes. For definition of MRD at inclusion and at response assessment see table 1. 64 pts with a median age of 44 (18-83) yrs were included from 19 centers and 60 were evaluable. 63 pts were treated in first CR (5 after SCT). Overall, 67% achieved MolCR, 10% had MolFail, 23% MolNE. MolNE identifies an intermediate response with different options clarified table 1. 81% of the pts included with MRD ≥10-4 had a molecular response i.e. MolCR or MRD &lt; 10-4. No significant differences in terms of MRD response were observed according to MRD level at inclusion or other patient characteristics (table 1). 60 pts have completed study treatment (40 HSCT, 8 relapses during treatment, 4 completed 4 cycles wo SCT, 2 stopped earlier due to toxicities - 1 with subsequent SCT, 1 due to GvHD, 1 due to physicians' decision and 4 pts returned to standard treatment after 2 cycles). SCT pts had a median age of 42 (18-66) yrs and follow-up is available in 37 / 41 pts (29 CCR, 3 relapse, 5 death in CR). 16 relapses occurred: 8 during treatment (1 after MolCR, 5 MolNE1-3 and 2 with MolFail resp); after SCT in 3/41 pts; 5/11 with CR at end of treatment wo subsequent SCT. The median observation time of surviving pts is 12 (1-38) mo and the median survival is not reached. At 2 yrs the survival probability (OS) was 64%. OS was 70%, 64% and 43% in pts with MRD between 10-4-10-3, 10-3-10-2 and &gt;10-2 at inclusion, resp (p&gt;.05; Fig.1). OS was 71% vs 54% in pts MolFail vs MolRel at inclusion (p&gt;.05). OS was 72%, 40% and 56% in pts with MolCR, MolFail and MolNE after cycle 1 resp (P=0.02; Fig.2). Overall, the results from previous trials were confirmed. In addition, it was demonstrated that pts with MRD between 10-4 and 10-3 had a similar response and a trend towards better outcome compared to pts with higher MRD levels &gt;10-2. So far only 7 pts with MRD below 10-4 were included; more data are needed to evaluate the impact of Blinatumomab in this population; GMALL does currently not recommend SCT for these pts unless there is an indication due to other risk factors. Interestingly, a significant proportion of pts (23%) had an incomplete MRD response and the outcome results indicate that these pts together with those with MolFail may have an inferior survival compared to those with MolCR. The results underline that the clear definition of MRD categories and consideration of level and sensitivity is essential for interpretation, which is possible due to well defined standards for the PCR method used here. 68% of the pts received SCT in CR after Blinatumomab with a so far limited mortality (13%). Further follow-up is certainly required. The GMALL will continue to recruit patients with MRD levels below 10-3 in order to improve their chances for long-term survival This study was supported by Amgen Inc. Disclosures Goekbuget: Servier: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Erytech: Consultancy; Kite: Consultancy; Gilead: Consultancy. Schwartz:Pfizer: Other: personal fees ; AMGEN: Other: personal fees and non-financial support; BTG Intl Inc: Other: personal fees ; Gilead Sciences: Other: personal fees and non-financial support ; MSD Sharp & Dohme: Other: personal fees ; Basilea: Other: non-financial suppor; Novartis: Other: personal fees and non-financial support; Jazz Pharmaceuticals: Other: personal fees and non-financial support. Hüttmann:Lead Discovery Center GmbH: Consultancy; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria. Viardot:Roche: Honoraria, Other: advisory board; Kite/Gilead: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Amgen: Honoraria, Other: advisory board. Fiedler:Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding. Alakel:Pfizer: Consultancy. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Subklewe:Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Morphosys: Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy; Roche AG: Consultancy, Research Funding. Wäsch:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Vucinic:Celgene: Honoraria. Fransecky:Amgen: Consultancy. Bargou:Amgen: Consultancy, Honoraria, Patents & Royalties; Gemoab: Consultancy, Honoraria; Cellex: Consultancy, Honoraria; Catalym: Consultancy, Honoraria. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Brüggemann:Regeneron: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Incyte: Consultancy; Roche: Consultancy; Affimed: Research Funding; Janssen: Consultancy, Honoraria. OffLabel Disclosure: Blinatumomab in MRD positive disease below 10-3

No abstract

CAR-T-Zell-Therapien bei ErwachsenenAuch bei den CAR-T-Zell-erapien gab es neue Erkenntnisse. So wurden Ergebnisse der ZUMA-3-Studie bei Erwachsenen vorgestellt [Shah BD et al. ASH. 2017