ALBERT

Description: Abstract 4747 Introduction: Recent advances in the treatment of patients with acute leukemia have increased their long-term survival. However, the side effects of aggressive chemotherapy can have a significant impact on different dimensions of quality of life and various aspects of psychological well-being. Objective: To assess depression, emotional well-being, and quality of life before and after induction treatment in de novo acute leukemia patients. Methods: Current longitudinal-prospective study of adult de novo acute leukaemia patients, treated with induction chemotherapy at Hematology Department, UZ Ghent, Belgium. After enrollment, eligible patients are administered a number of self-report questionnaires, within five days after admission (pre-induction) and after completion of induction (pre-consolidation). We used the CES-D, the shortened version of the POMS, and the EORTC QLQ-C 30, to measure depression, emotional aspects of subjective well-being, and quality of life. Results: Twenty adult de novo acute leukemia patients were enrolled between 01/2009 and 06/2010. The median age was 43 years, 50% were male, 80% had AML (20% ALL), and their median years of education was 12 years. At baseline, patients had a low quality of life, and low role functioning, but also a high level of fatigue. Global health status related with social functioning (r=0.76, p=0.000), and role functioning related with fatigue (r=-0.58, p=0.008). A positive correlation was found between fatigue and nausea (r=0.55, p=0.011), but also pain (r=0.52, p=0.020). Diagnosis of de novo acute leukemia had a clear influence on different aspects of subjective well-being, in particular sixty-five percent of the patients had significant levels of depression (i.e. CES-D≥16) at baseline. Depressed patients had a significant lower global health status, emotional and social functioning (EORTC QLQ-C 30), but also less emotional vigor and more emotional tension (POMS) compared to non-depressed patients. Change in self-assessed measures was found in global health status (p=0.000), emotional functioning (p=0.000), and symptom scales fatigue (p=0.051) and nausea (p=0.005), all five scales of the POMS, and depression (all p

Description: Abstract 2063 Background: Chemotherapy for acute leukemia can have an effect on cognitive functions and health-related quality of life measures. Cognitive impairment and fatigue have been described in patients with AML/MDS, even before the initiation of treatment. Objective: To assess baseline cognitive functions, short-term cognitive evolution, and to measure both depression and health-related quality of life outcomes in adult acute leukemia patients, before and after induction treatment. Methods: Current longitudinal-prospective study of adult acute leukemia patients treated with aggressive chemotherapy. The current study has been approved by the Institutional Ethical Committee and each patient has signed an informed consent before inclusion. Eligible patients are enrolled and are administered a comprehensive cognitive test battery, within five days after admission (T0) and after completion of induction treatment (T1). Cognitive functions assessed are attention, executive functions, motor dexterity, and verbal memory (with AVLT, COWA, PPT, SCWT, TMT). Both depression and health-related quality of life outcomes are assessed with self-report questionnaires (with CES-D and EORTC-QLQ-C30). Results: Thirty adult acute leukemia patients were included between 01/2009 and 07/2011. The median age was 46 years, 53% were male. The median duration of education was 13 years. 87% had AML and 13% had ALL. Baseline mean hematological values were: WBC count (8,2 10E3/uL), RBC count (3,1 10E6/uL), and HgB (9,8 g/dL). Induction treatment used in AML patients was the AML 2/95 protocol (n=22) or the HOVON 102 AML protocol (n=4), and in ALL patients the GMALL 7/03 protocol (n=4) was used. Baseline cognitive functions were normal in different cognitive domains, mainly in attention and executive functions (COWA and SCWT), except for mild cognitive deficits in verbal learning (AVLT A1–5), and especially in motor dexterity (PPT). These deficits were heterogeneous, ranging from severely impaired to good, within a specific cognitive domain. Short-term evolution on cognitive functions was observed in executive functions and verbal learning. Baseline levels of distress or depression were clinically significant, and adult acute leukemia patients showed problems on all function scales, except cognitive function, and on only two symptom scales, namely fatigue and pain. Short-term changes were found in depression, global health scale, functional scale emotional function, and symptom scale pain (also see Table). Conclusions: At baseline, adult acute leukemia patients had normal cognitive functions, except for verbal learning and especially motor dexterity. Cognitive impairment and fatigue were found similar to a previous reported research. However, our data showed less impaired motor dexterity, and we also noted a partial cognitive improvement. Depression and problems on the health-related quality of life outcomes were observed at baseline, whereas at follow-up only role and social function, and fatigue were still problematic. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Bortezomib (B) has been reported to be very effective in AL amyloidosis with overall response rates (ORR) varying between 50-80%. However, no prospective data have been published from multicenter studies on B treatment in de novo patients. Previously, we have demonstrated the positive long term effect of induction therapy followed by high dose melphalan (HDM) and autologous stem cell transplantation (SCT). We therefore investigated the efficacy and safety of B-Dexamethasone (BD) induction treatment followed by HDM + SCT to improve the complete response rate (CR) in de novo AL amyloidosis patients. This report is on the first 25 patients. Methods The HOVON 104 trial was performed in the Netherlands, Belgium and Germany from Jan 2012 to April 2016 and started with a randomized phase III design of BD versus dexamethasone (D) induction treatment followed by HDM + SCT. Due to slow accrual the D arm closed after including 7 patients. Patients with biopsy proven AL amyloidosis, aged between 18-70 years, with detectable M-protein and/or level of involved FLC 〉 50 mg/L, WHO performance status 0-2, NYHA stage 1-2 and ejection fraction 〉 45% were included. Major exclusion criteria were symptomatic orthostatic hypotension, NT proBNP level 〉 5000 pg/ml, Troponin T〉 0.06 ug/l, Bilirubin 〉 2x ULN, eGFR 〈 30 ml/min, CTCAE grade peripheral sensory neuropathy 〉 grade 2 or 〉 grade 1 with pain. Inclusion and exclusion criteria were installed both at entry and before stem cell mobilization (SCM). B was given subcutaneously 1.3 mg/m2 twice a week for 2 weeks in a 21-day cycle, D 20 mg orally on each B and the following day. HDM dosage was 200 mg/m2. Hematological responses were defined according to consensus criteria with the addition of very good partial response (VGPR), defined as the difference between involved and uninvolved FLC (dFLC) 〈 40 mg/L. Cardiac, renal and liver response and progression criteria were defined according to consensus criteria with addition of NT proBNP. The primary endpoint was the proportion of patients with CR at 6 months after SCT. To demonstrate improvement from 30 to 50% with 80% power, 44 eligible patients were needed and 50 patients were registered. Results Median age was 60 years (range 26-70) and 68% were male. WHO performance status (PS) was 0-1 in 88% of patients and NYHA stage 1 in 52% and 2 in 44% of patients. Mayo cardiac risk score (2004) was I (28%), II (32%), III (36%). Organ involvement was 88% renal, 76% heart, 20% liver, 12% neurological, 4% gastrointestinal and 72% of patients had 2 or more organs involved. Bone marrow plasmacells were 〉 10% in 11 patients. Six of the 25 (24%) patients could not proceed to SCM. One patient due to low PS, one because of B related toxicity, two due to amyloidosis related complications and two patients died, both amyloidosis related. Of these 19 patients, 2 went subsequently off protocol because of ineligibility for HDM and one due to hematological progression. Sixteen out of 25 patients (64%) received HDM + SCT which was performed without any treatment related mortality (TRM). In total 29 SAEs were reported in 18 patients. The ORR after induction was 72% and ≥ VGPR in 56% of patients. The ORR in the 16 patients at 6 months after SCT was 75% and ≥ VGPR 63%. Median time to first response was 1 month. Intention to treat analysis demonstrated that the primary endpoint was met in 6 (24%) patients. Organ responses after induction were 9/22 renal and 3/19 heart, and at 6 months after SCT 9/14 renal and 5/13 heart. The first two BD cycles were given as planned in most patients, 80 and 70%, respectively, but doses were reduced and delayed thereafter for B in half of patients, mostly because of neurotoxicity. Mean cumulative dosage of B was 80% of planned. Also D was reduced in almost half of patients due to toxicity. The most common AEs during induction are shown in Table 1. Conclusions Analysis of 25 patients demonstrates that with BD treatment the dropout rate before HDM is 36% which is comparable to previous induction treatments. We therefore conclude that BD, given twice weekly, despite good efficacy, cannot prevent early amyloidosis related toxicity. The SCT procedure was without TRM. The hematological response rate is comparable to previously reported and renal response are 41% after BD and 64% at 6 months after SCT. Trial registration www.trialregister.nl ( NTR 3220), EudraCT 2010-021445-42 , supported by the Dutch Cancer Society (UU 2010-4884 ) and by an unrestricted grant from Janssen-Cilag Disclosures Minnema: Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Hazenberg:GSK: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Hegenbart:Jansen Cilag: Honoraria, Other: financial support of conference participation. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Broijl:Celgene: Honoraria; Jansen Cilag: Honoraria; Amgen: Honoraria. Sonneveld:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 2972 Introduction Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage). Methods Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS

Description: Imatinib mesylate (imatinib) has been shown to be highly efficacious in the treatment of chronic myeloid leukemia (CML). Continuous and adequate dosing is essential for optimal outcomes and with imatinib treatment possibly being lifelong, patient adherence is critical. The ADAGIO (Adherence Assessment with Glivec: Indicators and Outcomes) study aimed to assess prospectively over a 90-day period the prevalence of imatinib nonadherence in patients with CML; to develop a multivariate canonical correlation model of how various determinants may be associated with various measures of nonadherence; and to examine whether treatment response is associated with adherence levels. A total of 202 patients were recruited from 34 centers in Belgium, of whom 169 were evaluable. One-third of patients were considered to be nonadherent. Only 14.2% of patients were perfectly adherent with 100% of prescribed imatinib taken. On average, patients with suboptimal response had significantly higher mean percentages of imatinib not taken (23.2%, standard deviation [SD] = 23.8) than did those with optimal response (7.3%, SD = 19.3, P = .005; percentages calculated as proportions × 100). Nonadherence is more prevalent than patients, physicians, and family members believe it is, and therefore should be assessed routinely. It is associated with poorer response to imatinib. Several determinants may serve as alert signals, many of which are clinically modifiable.

Description: While recent studies showed that the allogeneic graft versus leukemia (GVL) effect is operational in poor-risk acute myeloid leukemia (AML), the relapse rate remains high. In order to exploit GVL more effectively, we explored the early initiation of epigenetic therapy after alloHSCT, interspersed with successive, low dosage DLI in patients (pts) with AML, characterized as poor- or very poor-risk, according to the latest (2015) HOVON-SAKK AML risk classification. This study started as a phase I study in very poor-risk AML pts exploring the feasibility of combination epigenetic therapy at dose levels 1, 2, and 3, consisting of either panobinostat (PNB) alone (20 mg at days 1, 4, 8, 11 of a 4 wk-cycle) or PNB combined with decitabine (DCB, 10 or 20 mg/m2 at days 1-3 of every 4 wk-cycle). DLI consisted of 106 CD3 T-cells/kg at day 90 and 3 x 106 at day 180 in case of a matched sibling (sib) donor and 30% of that dose in case of a matched unrelated donor (MUD). Reduced intensity conditioning was applied by a combination of cyclophosphamide, fludarabine, and reduced-dose total body irradiation (TBI). Graft versus host disease (GVHD) prophylaxis consisted of post-transplant (PT) cyclophosphamide and short course cyclosporine. Phase II is focusing on actual delivery of transplantation, epigenetic therapy, and subsequent DLI in newly diagnosed AML pts upon confirmation of poor-risk or very poor-risk status, at which time point pts are registered for the study. Secondary endpoints include toxicities, GVHD, non-relapse mortality (NRM), relapse, overall survival (OS), and relapse free survival (RFS) as from transplantation. Pts lacking a sib or MUD proceeded off-protocol to alloHSCT with an alternative donor. Currently (July 2016), 94 pts are registered early after diagnosis during induction chemotherapy and so far 59 of them have actually proceeded to alloHSCT by either a MUD or sib donor. Interim results refer to 54 pts actually transplanted, and with sufficient follow-up (median: 9 months, range: 2-25 after transplantation). Pts received their transplant at a median number of 109 days (range: 69-200) after diagnosis. After 2 cycles of induction therapy, 35 pts were in hematological CR, 16 in CR without complete blood recovery, and 3 in PR. Median percentage of blasts prior to alloHSCT was 2 (range: 0-10). Median age was 54 years (18-70), 48 pts were classified as very poor-risk, 6 pts as poor-risk AML. Donors included 23 sib and 31 MUD. OS at 12 months from transplantation is 81% (±7). 10 pts died, including 5 due to NRM and 5 due to relapse. RFS at 12 months is 66% (±9). A historical HOVON control group of very poor-risk AML CR1 recipients of alloHSCT showed OS of 52% ±6 at 12 months and RFS of 43% ±5. Forty-one out of 54 pts received PT epigenetic therapy, including 13 PNB alone, 13 PNB/DCB (20 mg/m2), and 15 PNB/DCB. Pts started at a median time point of 33 days (range: 27-54) after transplantation. Combining PNB with DCB at a dose of 20 mg/m2 proved not feasible due to cytopenia, causing extension of successive cycles of PNB/DCB, which was considered a dose limiting toxicity (DLT). CTC grade 3 and 4 side-effects after the first cycle of PNB/DCB included gastrointestinal nausea in 2 pts (grade 3), neutropenia in 3 pts and general fatigue in 1 pt. After the second cycle PNB/DCB, 1 pt experienced nausea (grade 3), and 1 pt fatigue (grade 3). No opportunistic CTC grade 3 and 4 infections were observed after the first 2 cycles of PNB/DCB. DLI could so far be administered in 34 pts, including 19 receiving 2 DLI's, and 9 pts a third DLI. None of the pts developed grade 3 or 4 acute GVHD before DLI. Out of 34 recipients of DLI, severe chronic GVHD occurred in 5 (15%) pts. Collectively, these results suggest that: 1. alloHSCT with GVHD-prophylaxis by cyclophosphamide PT allows for early initiation of epigenetic therapy and DLI, and 2. as compared to historical HOVON-data in very poor-risk AML pts receiving alloHSCT, encouraging results with respect to relapse, DFS, and OS are observed in patients actually receiving PNB alone or PNB combined with DCB, followed by DLI. 3. Limited side effects were observed in recipients of PNB alone or the combination of PNB and DCB at a dose of 10 mg/m2; the incidence GVHD also appeared limited. Altogether these results might suggest enhanced GVL and, therefore, have set the stage for an international prospective randomized study in (very) poor-risk AML patients. Disclosures Maertens: Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy.

Description: BACKGROUND. Imatinib therapy for chronic myeloid leukemia (CML) is a long-term treatment potentially compromised by patient nonadherence. OBJECTIVE. To examine whether patients (pts) at different levels of treatment response differ in adherence to imatinib treatment. DESIGN & PATIENTS. The ADAGIO study1 is a prospective, 90-day (90d) observational, open-label, multicenter study of pts with chronic myeloid leukemia (CML) and treated with imatinib. 169 evaluable pts who had been on imatinib for a minimum 30 days at enrollment were studied. A sub-analysis included pts with optimal vs. suboptimal response (all patients) and complete vs. incomplete cytogenetic response (CgR; all patients and those treated with imatinib ≥12 months). MEASUREMENTS. Adherence: imatinib pill count over 90d expressed as % of prescribed imatinib taken. Suboptimal response (SR): incomplete hematologic response at 3 months, and/or less than partial CgR at 6 months, and/or less than major molecular response and, in case of loss of major molecular response, other limitations or chromosomal abnormalities at 18 months (all else: optimal response [OR]). CgR: complete (0% Ph+ metaphases) or incomplete (≥1 Ph+ metaphases). RESULTS. Pill count percentages ranged from 29%–202% of prescribed dose (M=90.9±20.1). Pts with SR (n=14) had significantly higher %s of imatinib not taken (23.2±23.8) than did those with OR (n=124; 7.3±19.3, P=0.005). Among pts treated with imatinib ≥12 months, those with complete CgR (n=98) had significantly lower mean percentages of imatinib not taken (9.0±18.6) than those with incomplete CgR (n=9; 26.0±24.4, P=0.012). Among all patients regardless of length of treatment, those with complete CgR (n=109) also had significantly lower mean percentages of drug not taken (9.1±18.1) than those with incomplete CgR (n=19; 23.9±19.2, P=0.004). CONCLUSIONS. Proportions of CML patients with poor treatment response are low (10.1%, 8.4%, and 14.8% resp. for parameters above), underscoring the high efficacy of imatinib in CML. Pts with poor response tended to have higher % of imatinib not taken over 90d, an index of overall adherence behavior. Clinicians should be aware of the association between adherence and imatinib response and should query patients about their adherence behavior. Nonadherence should be ruled out prior to classifying a patient as imatinib-resistant. Enhanced adherence is likely to optimize the effectiveness of imatinib treatment in CML.

Description: Abstract 4746 Introduction: A significant percentage of cancer patients develop or have chemotherapy-induced cognitive impairment, during and even long after completion of aggressive treatment. Cognitive deficits are usually subtle and mild, and can occur in various cognitive domains. In AML/MDS patients, impaired cognitive functions, even prior to initiation of chemotherapy, have been described. Objective: To assess baseline cognitive functions and short-term cognitive evolution in de novo acute leukemia patients during induction treatment, and to compare our data with previous research. Methods: Current longitudinal-prospective study of adult de novo AML/ALL patients, treated with induction chemotherapy at the Hematology Department, UZ Ghent, Belgium. Eligible patients are enrolled and investigated with a comprehensive cognitive test battery, within on average five days after admission (pre-induction) and after completion of induction chemotherapy, on average after two months (pre-consolidation). Cognitive functions are assessed across various domains, including attention, executive functions, motor dexterity, and verbal/visual memory. Patients’ psychological functions and quality of life are assessed simultaneously. Results: Twenty adult patients were enrolled between 01/2009 and 06/2010. The median age was 43 years, 50% were male, 80% had AML (20% ALL), and median years of education was 12 years. Baseline hematological values were assessed, with WBC count (mean: 10,4 10E3/uL), RBC count (mean: 3,1 10E6/uL), and HgB (mean: 9,8 g/dL). Adult patients had normal cognitive functions (range: 1,0 SD below normative mean) in different cognitive domains, and mainly in attention and executive functions (COWA letter fluency & semantic fluency, and SCWT mental flexibility), except for mild cognitive deficits in verbal learning (AVLT A1-5), but especially in motor dexterity (PPT left and right hand). These functions were heterogeneous at baseline, ranging from severely impaired to good within a cognitive domain. At follow-up, attention, executive functions, motor dexterity, and verbal learning had all improved significantly (p

Description: Abstract 361 Chromosomal rearrangements involving the EVI1 gene are a recurrent finding in malignant myeloid disorders. These translocations or inversions contribute to ectopic expression or to the formation of fusion genes involving the EVI1 gene. EVI1 transcriptional activation has been reported in up to 10% of acute myeloid leukemia (AML) and is a prognostic marker of poor outcome. MicroRNA (miRNA) deregulation was recently identified as a major contributor to cancer initiation and progression. As miRNA genes were shown to be directly regulated by activated proto-oncogenes, we aimed to identify miRNAs under direct or indirect control of EVI1. To this purpose, we analyzed the expression of 366 miRNAs in 38 EVI1 rearranged/overexpressing patient samples, 6 normal bone marrow controls and 2 EVI1 knockdown model systems (siRNA mediated EVI1 knockdown in the EVI1 rearranged/overexpressing cell lines Kasumi-3 and UCSD-AML1). In total, 24 upregulated and 25 downregulated miRNAs (p