ABSTRACT:Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT. We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multikinase inhibitor dasatinib in adult patients with CBF-AML. Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg daily on days 8 to 21 in induction, and on days 6 to 28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg daily. Primary end point was event-free survival (EFS). Secondary end points included overall survival, relapse-free survival, and cumulative incidence of relapse. A total of 202 patients were randomly assigned to the standard arm (n = 102) and to the dasatinib arm (n = 100). Median age was 49 years (range, 18-77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); and 58 (28.7%) patients had a KIT comutation. There was no statistically significant difference in EFS (hazard ratio, 0.92; 95% confidence interval, 0.63-1.33; P = .66) or secondary end points between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%). In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.ClinicalTrials.gov as NCT02013648.

KEY POINTS:Kidney involvement in patients with multiple myeloma has many different findings in kidney histology. Persistent dialysis requirement is a major cause of mortality. The rapid initiation of modern myeloma therapy is essential to prevent the need for dialysis and reduce mortality. BACKGROUND:Acute or CKD affects 20%-40% of patients with multiple myeloma (MM). While the negative prognostic effect of kidney involvement is established, the specific effect of different histological patterns remains poorly understood. We aimed to characterize the clinical outcomes associated with distinct kidney histologies in patients with MM. METHODS:We retrospectively analyzed 193 patients with MM who underwent kidney biopsy, comparing outcomes with 62 patients with MM without kidney disease. Patients were categorized by histological findings: cast nephropathy (CN, n =120), lightchain (AL) amyloidosis ( n =19), monoclonal Ig deposition disease (MIDD, n =8), and other renal disease ( n =46). We evaluated kidney function, dialysis requirements, treatment responses, and survival across histological subtypes and treatment modalities (conventional therapy versus modern agents including proteasome inhibitors, CD38 antibodies, and autologous stem cell transplantation). RESULTS:The CN and MIDD groups had the lowest median eGFR at biopsy (13.0 and 25.5 ml/min per 1.73 m 2 , respectively). Nephrotic-range proteinuria (>3.5 g/24 hours per Kidney Disease Improving Global Outcomes) was observed in the AL amyloidosis group (median 3910 mg/24 hours). KRT was initiated in 42.5% of patients. The proportion achieving KRT independence was 42.4% in the CN group and 50% in the other renal disease group, whereas none in the AL amyloidosis or MIDD groups recovered sufficient native kidney function. Modern combination therapy significantly improved renal outcomes, with 100% of patients receiving triple therapy showing renal response. KRT dependency was the strongest predictor of mortality: Patients remaining on KRT had significantly shorter survival compared with those never requiring KRT (12.7 versus 56.2 months, P < 0.001). The extent of improvement in kidney function did not influence survival; only dialysis status was prognostically relevant. CONCLUSIONS:Kidney histology determines distinct clinical trajectories in patients with MM, with CN showing potential for dialysis reversibility. Modern combination therapies significantly improve renal outcomes. The requirement for ongoing KRT was the primary predictor of overall survival.

While systemic treatment for HER-2-positive breast cancer is well established, strategies for local progression, particularly pleural infiltration, are less clearly defined. In this case, a 52-year-old female patient with HER-2-positive, hormone receptor-negative breast carcinoma and bilateral pleural effusions was initially treated systemically with docetaxel, trastuzumab, and pertuzumab, followed by a switch to trastuzumab deruxtecan (T-DXd) upon systemic progression. When a unilateral pleural effusion developed, an attempt was made to control the local progression through intrapleural administration of trastuzumab. Despite four doses, the effusion size remained unchanged, indicating insufficient local disease control. Subsequently, thoracic surgical intervention with pleurectomy and pleurodesis was performed. Histopathology confirmed HER-2-positive tumor cells in the pleura. The progression of the effusion led to an adjustment of systemic therapy to tucatinib, capecitabine, and trastuzumab. This case demonstrates that intrapleural administration of trastuzumab did not achieve adequate local control of pleural infiltration in HER-2-positive breast cancer.

Kidney involvement with resulting kidney failure leads to increased mortality in patients with multiple myeloma (MM). Cast nephropathy (CN), in particular, if left untreated, quickly leads to kidney failure requiring dialysis and has a very poor prognosis for the affected patient. The gold standard for diagnosing kidney involvement is a kidney biopsy. However, due to bleeding risk, this cannot be done in every patient. We recently reported that a quotient of urine light chain (LCurine) to glomerular filtration rate (eGFR) is a non-invasive diagnostic tool for patients with kidney involvement in MM. But this quotient has not yet been tested in everyday clinical practice. In this study, our LCurine/eGFR ratio was tested on 67 patients in two centers. Enrollment took place between January 2019 and September 2023. A total of 18 of the 67 patients had CN. With the threshold defined in our initial paper, we were able to show a sensitivity of 100% with a specificity of 85.7% for CN in patients with MM. As a result, the LCurine/eGFR quotient recognizes 100% of all CN and can therefore detect this group, which has a very poor prognosis, without the need for a kidney biopsy.

R earrangements of the histone-lysine-N-methyltransfer- ase ( KMT2A ) gene, formerly known as MLL , belong to the most frequent chromosomal aberrations with a high number of different fusion partners in patients with acute myeloid leukemia (AML) and acute lymphoblas- tic leukemia (ALL). 1,2 AML with t(9;11)(p21.3;q23.3) is rec-ognized as a disease entity. 2 Similarly, the presence of t(4;11) (q21.3;q23.3), which accounts for 8%–10% of B-cell precur- sor ALL in patients aged >20 years, defines a distinct entity termed B-lymphoblastic leukemia with t(v;11q23). 2,3 AML with t(9;11)(p21.3;q23.3)/ MLLT3::KMT2A are classified in the intermediate-risk category according to the 2017 and 2022 European LeukemiaNet risk stratification, but the remaining t(v;11q23.3)/ KMT2A -rearranged AML belong to the adverse- risk group and these leukemias still represent an unmet medi-cal need 1,4–6 given the poor long-term survival depending on the KMT2A fusion partner, presence of

Background Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia. Methods This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m(2) administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed. Findings Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0 center dot 83; 95% CI 0 center dot 65-1 center dot 04; p=0 center dot 10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0 center dot 90; 0 center dot 70-1 center dot 16; p=0 center dot 43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0 center dot 67; 95% CI 0 center dot 40-1 center dot 11; p=0 center dot 15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0 center dot 77; 0 center dot 54-1 center dot 10; p=0 center dot 18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0 center dot 63; 0 center dot 45-0 center dot 80; p=0 center dot 0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0 center dot 65; 0 center dot 49-0 center dot 86; p=0 center dot 0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1 center dot 03; 0 center dot 59-1 center dot 81; p=0 center dot 91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections. Interpretation The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

2][3][4] GO binds the CD33 antigen and is internalized; calicheamicin is released inside the blasts leading to DNA damage and death of leukemic cells. 2,5,6O was approved for the treatment of patients with acute myeloid leukemia (AML) with expression of CD33 on blasts by the European Medicines Agency (here only for newly diagnosed patients in combination with intensive therapy) and the Food and Drug Administration based on positive results from the ALFA-0701 trial. 1,7However, a number of clinical trials with GO yielded partially conflicting results emphasizing the importance of a better understanding of factors influencing the clinical response to GO. 6,7 Several factors can influence the response to GO.A meta-analysis by Hills et al. demonstrated a benefit of GO only in patients with Medical Research Council (MRC) favorable and intermediate cytogenetic risk, while GO did not improve outcome of patients with adverse cytogenetic risk. 7Another factor that might have an impact on the response to GO is the CD33-coding single nucleotide polymorphism (SNP) rs12459419 (NM_001772.4:c.41C>T; Ala14Val in exon 2) as GO needs to bind to CD33.CD33 consists of an amino-terminal V-set immunoglobulin (Ig)-like domain, coded by exon 2, and a C2-set Ig-like domain in its extracellular component.The presence of rs12459419 in exon 2 affects alternative splicing of CD33 resulting in the loss of exon 2 for the T allele which leads to a shorter isoform lacking the GO binding site.The C allele leads to the CD33 full-length isoform including the GO binding site. 3,6The genotype frequencies in the European population for the SNP are c.

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlyingmechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian AcuteMyeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD-mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

Background: Cast nephropathy (CN) is associated with a unfavourable outcome in monoclonal light chain (mLC) disease, but also more possible LC-related renal diseases as well as non-LC-related disease can occur. Thus, it is crucial to understand the underlying renal disease. On the other hand, LC can interfere with coagulation preventing kidney biopsy as the gold standard. We sought to develop a non-invasive algorithm to diagnose CN with a good sensitivity and specificity. Method: We analysed data from patients with mLC disease who underwent kidney biopsy. The patients were classified in 4 groups according the renal histology: CN, AL amyloidosis, light chain deposition disease, and other renal disease. Afterwards, different algorithms were calculated for their sensitivity and specificity. Results: CN showed a significant higher concentration of serum-free LC and urine LC (LCu), but there was a wide and overlapping range with the other groups. The best accuracy was achieved for a LCu/GFR ratio >2 in patients with lambda LC and either a LCu/GFR > 1 and proteinuria <8 g/24 h or a LCu/GFR > 5 in patients with proteinuria >8 g/24 h in patients with kappa LC. In lambda LC, the sensitivity and specificity for CN was 94% and 90%, respectively; in kappa LC 87% and 81%, respectively. Discussion: In patients with coagulation disturbances due to LC, a non-invasive algorithm can separate patients with CN from other renal disease in mLC disease.

The outbreak of coronavirus disease 2019 (COVID-19) pandemic has caused worldwide problems in the care of patients with hematological malignancies. Since the first reports on the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the Chinese city of Wuhan, many health systems have been pushed to their limits and beyond. In particular, the therapy of patients with hematological malignancies, both outpatient and inpatient, was substantially impacted by the major restrictions due to the isolation and hygiene measures. Not only the restriction of treatment under pandemic conditions but also a SARS-CoV-2 infection itself poses a risk for patients with malignancies. In fact, first studies have consistently shown increased mortality from COVID-19 infection in cancer patients.1–3 Because of frequently compromised immune responses in cancer patients, vaccines have only limited effectiveness and, to date, only few antiviral agents are available.4,5 Neutralizing antibodies might become an important pillar in the treatment of COVID-19 infection in immunocompromised patients. Monoclonal antibodies (MoAbs) against SARS-CoV-2 can be used in both settings, prevention and treatment. Most of the currently used MoAbs target the spike protein, which enables SARS-CoV-2 to penetrate the target cell via the angiotensin converting enzyme-2 receptor.6 Due to a long half-life of MoAbs of about 3 weeks for IgG1, a single antibody infusion appears to be sufficient. Limitations in therapy with neutralizing antibodies are mainly the unknown bioavailability in individual organs and possible resistances due to mutations in the spike protein. Here, we report on 2 patients with hematological malignancies from our department, where we have used neutralizing antibodies for both the prevention and therapy of SARS-CoV-2 infection. Case 1: Bamlanivimab for prevention of SARS-CoV-2 infection A 21-year-old woman with advanced-stage Hodgkin disease was receiving intensive chemotherapy according to the bleomcyin, etoposide, doxorubicin, cyclophospamide, vincristine, procarbazine, prednisone protocol. She was in good general condition (performance status 0) and at the time of contact with a COVID-19 positive individual, she received 4 of 6 cycles of planned chemotherapy. The contact person was patient's father, who presented with respiratory symptoms and tested positive for SARS-CoV-2 by a polymerase chain reaction (PCR) test. After a PCR test also her mother tested positive, while the patient remained negative. Sequencing results from patient´s mother showed the B.1.1.7 variant ("British variant") of SARS-CoV-2. Since 2 additional chemotherapy cycles of a strong immunosuppressive therapy were still intended for further treatment (only a partial remission in the interim positron emission tomography-computerized tomography after 2 cycles of chemotherapy), we decided to administer once the MoAb Bamlanivimab (LY-CoV555) intravenously at the recommended dose of 700 mg. The MoAb infusion was well tolerated. Subsequently, the patient did not develop any clinical symptoms and a PCR test carried out 1 week after the MoAb infusion was still negative for SARS-CoV-2. After being released from quarantine at home, the patient was able to continue the therapy in outpatient setting with a 10-day delay. Case 2: Bamlanivimab for treatment of SARS-CoV-2 infection A 52-year-old male patient admitted to our hospital due to pancytopenia was diagnosed with a BCR-ABL1 positive (highest risk) acute lymphoblastic leukemia (ALL). The patient was in good general condition. In patient´s history, an immunoglobulin deficiency had been known for many years, but immunoglobulin substitution had never taken place before. A first SARS-CoV-2 PCR test was negative. Treatment was started with the administration of dexamethasone and cyclophosphamide. Given the detection of a BCR-ABL1 fusion gene, targeted treatment with imatinib 600 mg qd was added to the therapy. However, in a routine PCR test, the patient tested positive 4 days after therapy with imatinib was initiated. At this time, the patient did not suffer from any symptoms that could be linked to a SARS-CoV-2 infection. The patient was transferred to the isolation unit. The imatinib therapy was continued, but vincristine and pegylated asparaginase were not administered as foreseen in the induction phase of the initial treatment to prevent additional immunosuppression and also not to increase the thromboembolic risk by asparaginase. The B.1.1.7 SARS-CoV-2 variant was detected in the patient with no evidence for resistance mutations (E484K and L452R) against Bamlanivimab. Due to a deep immunosuppression and the higher risk of a severe and protracted course of SARS-CoV-2 infection in the patient, we decided—given lack of resistance mutations—to administer immediately—48 hours after the detection of the SARS-CoV-2 infection—the MoAb Bamlanivimab once at the dose of 700 mg. As the patient developed fever, intravenous antibiotics and oral antimycotic therapy with voriconazole were started. Because of the known immunoglobulin deficiency, also polyclonal immunoglobulins (Pentaglobin 20 g IV) were administered. No severe symptoms occurred during the further course. The patient required nasal oxygen only for 24 hours. Thirteen days after the first positive PCR test, the patient was PCR negative again. However, the PCR test turned positive again in a subsequent routine PCR test, so that the treatment of leukemia had to be further delayed. The phenomenon in immunocompromised/immunosuppressed SARS-CoV-2 infected patients to require longer time in order to ultimately turn negative by PCR is known as "shedding." The detailed course of the PCR results during the first treatment period of the ALL therapy is shown in Figure 1. The patient was discharged from the hospital after the induction treatment was completed. During the further treatment course, the patient experienced a neutropenic infection requiring admission and treatment at the intensive care unit, but he finally did recover.Figure 1.: PCR course of the E gene of SARS-CoV-2 in the nasal swab together with the therapy of ALL. ALL = acute lymphoblastic leukemia; MoAb = monoclonal antibody; PCR = polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.Both patients have so far not been vaccinated. They have not been tested for the presence of COVID-19 antibodies before and directly after Bamlanivimab infusion. Cancer and immunocompromised patients are at a higher risk of SARS-CoV-2 infection. Several studies also indicate that patients with active cancer have a significantly higher mortality rate than those without active tumor disease.2,7,8 However, to date, it is not clear whether this is due to the malignant disease itself or the advanced age of cancer patients as well as concomitant diseases. The tumor therapy itself does not seem to be an independent risk factor for a severe course of SARS-CoV-2 infection.9 There are indications that there is prolonged viral shedding in tumor patients, which might contribute to an increased mortality. A Spanish study showed that prolonged positivity for SARS-CoV-2 by PCR after 6 weeks was associated with a significantly increased mortality compared with patients who became negative (54.4% versus 1.4%; P < 0.001).7,10 In patients with cancer, not only a higher mortality but also reduced responses to the currently available vaccines are suspected. Patients with hematological neoplasms seem to have an even lower responses following a vaccination than those with solid tumors. In several studies, lower seroconversion rates of anti-spike IgG antibodies after COVID-19 vaccination were observed in tumor patients compared with a healthy comparison group.11–13 Less effective immune responses in patients receiving immunosuppression due to a rheumatic condition to a vaccination were reported not only for vaccines against SARS-CoV-2 but also for other as, for example, influenza or pneumococcal vaccine.14 Currently, there are no evidence-based recommendations for a modified vaccination schedule in cancer patients. MoAbs act directly as antiviral agents. All currently available antibodies are directed against different epitopes of the SARS-CoV-2 spike protein, but studies with Middle East respiratory syndrome coronavirus show that other epitopes are also feasible.15 All currently commercially MoAbs (LY-CoV555 = Bamlanivimab, LY-CoV016 = Etesevimab and REGN-COV2 = Casirivimab + Imdevimab) have been shown to reduce viral load and hospitalization rates, but so far, no benefit on survival has been demonstrated.16,17 MoAbs are likely to have the greatest effect in the early, oligosymptomatic phase of the infection, where virus replication plays a major role. This is indicated by the data from the approval studies and the lack of effect of Bamlanivimab in hospitalized patients from the pivotal ACTIV-3 study (ClinicalTrials.gov Identifier: NCT04501978). A beneficial effect might also be expected in seronegative patients as postexposure prophylaxis. This is suggested by the first results from studies using either the antibody mix of Casirivimab + Imdevimab or Bamlanivimab as single agent (BLAZE-2 study); ClinicalTrials.gov Identifier: NCT04497987.16,17 The beneficial impact of MoAbs in the early phase of the disease is also supported by one recent retrospective study in 616 high-risk patients with COVID-19.16 In this study, the early use (within 5 days of diagnosis) of MoAbs not only significantly reduced the hospitalization rate (1.7% versus 24%; P < 0.005) but also appeared to be associated with a lower mortality rate (0% versus 2.7%).18 There is only very limited experience with the use of MoAbs in a preventive setting. A recently published study suggests a positive protective effect on contact in one's own household for Casirivimab and Imdevimab. SARS-CoV-2 negative persons who received Casirivimab and Imdevimab SC within 96 hours after contact with SARS-CoV-2 not only seemed to have a lower risk of developing COVID-19 (1.5% versus 7.8%; P < 0.001), but in those developing COVID-19, the duration of the symptomatic infection was 2 weeks shorter than in those who received placebo.19 Although such data are not specifically available for Bamlanivimab, these first encouraging results provide some rationale to further explore the preventive use of moAbs. All currently available MoAbs are directed against the "receptor-binding domain" of the SARS-CoV-2 virus. The antibody design was based on the first virus isolates from the patients in Wuhan. However, there is currently a significant increase of variant mutations such as B.1.1.7 ("British variant"), B.1.135 ("South African variant"), or P.1 ("Brazilian variant"). Since the B.1.135 and P1 variants in particular have developed resistance to the available MoAbs, the result of the sequencing needs to be available before the use of the antibodies. If this is not the case, the local epidemiological situation should be taken into account.20 Pre-eliminary data from a recent single center study suggest that in immunocompromised patients with COVID-19 treated with Bamlanivimab, the occurrence of an E484k mutation might confer resistance to Bamlanivimab resulting in a viral rebound.21 In the light of these results, a combination of MoAbs might be a potential treatment option for immunocompromised patients. This concept is supported by the data form a phase 2/3 study including patients presenting with a mild to moderate COVID-19 course and suffering from a cancer or undergoing immunosuppressive therapy.22 In this study, a combination of Bamlanivimab and Etesevimab was tested against placebo. In fact, patients receiving the antibody combination had a lower hospitalization rate (2.1% versus 7.0%; P < 0.001) and a significantly greater reduction in viral load on day 7 after administration of the study medication compared with the placebo group.22 Patients with hematological neoplasms frequently require urgent and intensive treatment, even in the context of a concomitant SARS-CoV-2 infection. Specific MoAbs might prevent a severe clinical course of a SARS-CoV-2 infection allowing a timely treatment of a potentially life-threatening hematologic disease. Our case reports show favorable clinical outcomes in patients with hematologic malignancies requiring intensive treatment after administration of Bamlanivimab for both prevention and treatment of a SARS-CoV-2 infection and emphasize the need for prospective studies using MoAbs for the treatment of SARS-CoV-2 infection as well as in preventive setting in patients with hematologic malignancies. Disclosures The authors have no conflicts of interest to disclose.

Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the prognostic role of clonal hematopoiesis-associated DNMT3A, TET2, and ASXL1 (DTA) and non-DTA mutations for MRD monitoring post-alloHCT to refine MRD marker selection. Of 154 patients with AML, 138 (90%) had at least one mutation at diagnosis, which were retrospectively monitored by amplicon-based error-corrected NGS on day 90 and/or day 180 post-alloHCT. MRD was detected in 34 patients on day 90 and/or day 180 (25%). The rate of MRD positivity was similar when DTA and non-DTA mutations were considered separately (17.6% vs 19.8%). DTA mutations had no prognostic impact on cumulative incidence of relapse, relapse-free survival, or overall survival in our study and were removed from further analysis. In the remaining 131 patients with at least 1 non-DTA mutation, clinical and transplantation-associated characteristics were similarly distributed between MRD-positive and MRD-negative patients. In multivariate analysis, MRD positivity was an independent adverse predictor of cumulative incidence of relapse, relapse-free survival, and overall survival but not of nonrelapse mortality. The prognostic effect was independent of different cutoffs (above limit of detection, 0.1% and 1% variant allele frequency). MRD log-reduction between diagnosis and post-alloHCT assessment had no prognostic value. MRD status post-alloHCT had the strongest impact in patients who were MRD positive prior to alloHCT. In conclusion, non-DTA mutations are prognostic NGS-MRD markers post-alloHCT, whereas the prognostic role of DTA mutations in the posttransplant setting remains open.

We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Background Standard low dose cytarabine (LDAC) monotherapy in elderly previously-treated relapsed and primary resistant/refractory (R/R) AML patients unfit for intensive chemotherapy shows limited response (CR rate of up to 17%) and survival benefit (mOS 4-6 mos, Sarkozy, 2013). Hence this vulnerable patient population has significant unmet need for well tolerated and efficacious new treatments. Bemcentinib (BEM) is a selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor mediating resistance to chemotherapeutic agents and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents a potential novel target in patients with AML. The ongoing BGBC003 phase II trial includes newly diagnosed (ND), and previously treated R/R AML patients unfit for intensive chemotherapy receiving BEM+LDAC combination treatment. A previously-treated AML patient cohort was selected for expansion, with the objective to explore safety and efficacy and to undertake translational biomarker analysis. Here, we report on preliminary efficacy together with a safety overview for all patients treated with the combination. Methods and Patient Disposition AML patients unfit for intensive therapy received BEM at the RP2D (200mg PO/d) + 10-day LDAC in 21-day cycles. Efficacy endpoints included objective response (OR: CR, CRi, PR) and clinical benefit (CB: OR + SD for ≥ 3 treatment cycles). Secondary objectives include overall survival (OS) and exploratory biomarker analyses. The BEM+LDAC cohorts (n=24); with a data cut-off date of 21 July 2020, comprised 7 newly diagnosed and 17 previously-treated (10 relapsed, 7 refractory) AML patients; with a median of 2 prior therapies (ranges: 1-8 relapsed; 1-4 refractory). Median age was 76 years for previously-treated R/R (range 66-81), and 78 for ND patients (range 75-83). Six (35%) R/R and 0% ND pts had a poor cytogenetic risk profile. Median bone marrow (BM) myeloblasts at screening for R/R AML patients was 33.5% (range 3-94%) and 34% (range 3-54) for ND patients. Plasma protein biomarker levels including soluble AXL (sAXL) were measured at screening and following treatment. Single cell RNA sequencing and T-cell repertoire analysis are being conducted to determine the effect of BEM + LDAC on direct tumor-cell killing and antitumor immunity. Results At the time of data cut off, previously-treated relapsed patients (n=8) were evaluable for response (as per BM assessment at C2D1; 4/8 (50%) relapsed patients achieved objective response (2 CR, 1 CRi, 1PR) and 6/8 (75%) showed clinical benefit. mDOR was 12.1 wks (range 11.9-16.1 wks, ongoing) with a median time-on-trial of 20.4 wks. Notably responses were reported between wk20 (C5) - wk28 (C7). These later onset responses may reflect the importance of AXL-related immunological mechanisms for relatively chemo-resistant relapsed patients and contribute to a longer time-on-treatment. Three relapsed patients remain on study treatment. In contrast, no refractory patients showed response (0/7) with 2/7 (28%) reporting clinical benefit; median time on trial was 8.6 wks. For evaluable newly-diagnosed patients, response was observed in 3/7 (48%, all CR), and clinical benefit in 5/7 (71%). The mDOR was 69.3 wks (range 62.9-105.1 wks, ongoing) and 2 patients remain on study. Overall, the combination was well tolerated, and in keeping with the known safety profile of LDAC. Treatment related AEs of ≥ Grade 3 observed in ≥ 5% of pts (n=24) across all cohorts were anemia, 4 (16%), thrombocytopenia, 3 (12%), febrile neutropenia 2, (8%) and QTcF prolongation, 1 (4%). Conclusions These data show that BEM+LDAC is efficacious and well tolerated in the unfit previously-treated relapsed and newly diagnosed AML populations. No activity was seen in primary resistant/refractory AML patients. An in-depth translational research program aiming to identify predictive molecular and biological factors associated with response in ongoing. Thus, the BEM+LDAC combination warrants further investigation and development in randomized trials with the potential to improve survival outcomes for elderly and unfit AML patients. Disclosures Loges: BerGenBio ASA: Research Funding. Heuser:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy; PriME Oncology: Honoraria; Karyopharm: Research Funding; Amgen: Research Funding; Bayer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Janssen: Consultancy; Roche: Research Funding; Astellas: Research Funding; Abbvie: Consultancy. Chromik:BerGenBio ASA: Research Funding. Vigil:BerGenBio ASA: Research Funding. Paschka:BerGenBio ASA: Research Funding; Sunesis Pharmaceuticals: Consultancy; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Amgen: Other; Astellas Pharma: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Consultancy; Celgene: Consultancy, Other: Travel, accommodations or expenses; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Agios Pharmaceuticals: Consultancy, Speakers Bureau. Re:BerGenBio ASA: Research Funding. Di Renzo:BerGenBio ASA: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mattei:BerGenBio ASA: Research Funding. Ben-Batalla:BerGenBio ASA: Research Funding. Hellesoy:BerGenBio ASA: Research Funding. Lorens:BerGenBio ASA: Current Employment. Birkett:BerGenBio ASA: Consultancy. McPherson:BerGenBio ASA: Current Employment. Nautiyal:BerGenBio ASA: Current Employment. Micklem:BerGenBio ASA: Current Employment. Gabra:BerGenBio ASA: Current Employment. Lorens:BerGenBio ASA: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Patents & Royalties. Fiedler:Gilead: Honoraria; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Celgene: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Servier: Honoraria, Other; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; BMS: Honoraria. Alvarado:Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding. Gjertsen:Alden Cancer Therapy AS: Current equity holder in private company; Pfizer Inc: Consultancy; BerGenBio AS: Consultancy, Research Funding; Novartis: Consultancy; KinN Therapeutics AS: Current equity holder in private company.

Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study. Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain. Methods: Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study's eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan-Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types). Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs < 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p < 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population. Disclosures Paschka: Amgen: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Astex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Speakers Bureau; BerGenBio ASA: Research Funding. Dombret:Novartis: Consultancy; Cellectis: Consultancy; Sunesis: Consultancy; Abbvie: Consultancy; Immunogen: Consultancy; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shire: Honoraria; Otsuka: Consultancy, Honoraria; Menarini: Honoraria; Daiichi Sankyo: Consultancy, Other: travel, accommodation expenses; Incyte: Consultancy, Other: travel, accommodation expenses; Celyad: Consultancy. Montesinos Fernandez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: 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, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Kreuzer:Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Grifols: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Hexal: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Biotest: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau. Heuser:Karyopharm: Research Funding; Janssen: Consultancy; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding; PriME Oncology: Honoraria. Metzeler:Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas: Honoraria. Quesnel:Abbvie: Other: travel expenses; Daichii Sankyo: Other: travel expenses, Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria. Döhner:Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Astellas Pharma: Consultancy; Astex Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Agios: Consultancy; Novartis: Honoraria, Research Funding; Abbvie: Consultancy. Milkovich:RJM Group LLC: Current Employment. Reitan:RJM Group LLC: Current Employment. MacDonald:IQVIA: Current Employment. Casso:IQVIA: Current Employment. Storm:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Liu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Kapsalis:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Attar:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Döhner:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Sunesis: Other, Research Funding.