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Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post-allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74. ispartof: BLOOD ADVANCES vol:4 issue:18 pages:4430-4437 ispartof: location:United States status: published

The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 116 eligible patients were randomly (1:1) assigned to either observation (N = 60) or azacitidine maintenance (N = 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks) until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with azacitidine was feasible. DFS was significantly better for the azacitidine treatment group (logrank; P = .04), as well as after adjustment for poor-risk cytogenetic abnormalities at diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression; hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P = .026). The 12-month DFS was estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups, with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often in the observation group (n = 32) than in the azacitidine maintenance group (n = 9). We conclude that azacitidine maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15).

Despite the fact that 80% of adult acute myeloid leukaemia patients reach complete morphological remission after induction chemotherapy, many of them relapse. Many studies have shown that detection of minimal residual disease (defined as 'any detectable evidence of persistent leukaemic cells during complete morphological remission') has an added value in prediction of relapse and survival, and is more than just a surrogate marker for already known risk factors in AML. As such, the behaviour of the disease during treatment might become equally or even more important to decide whether or not an upgrade of treatment (such as an allogeneic stem cell transplantation) is necessary to improve outcome. However, there are still many open issues as to what the ideal time point is to measure MRD, which threshold is clinically significant, what sample (peripheral blood or bone marrow) should be used and how we can standardize tests so that results from different labs become comparable. This review gives an overview of currently available evidence regarding technical issues, prognostic impact and MRD-directed treatment in AML.

Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38− fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38−LSC levels at diagnosis (n = 594), and, to identify LSClow/LSChigh (n = 302) and MRDlow/MRDhigh patients (n = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34+CD38− LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRDhigh/LSChigh patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRDlow/LSChigh, MRDhigh/LSClow, and especially MRDlow/LSClow patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.

International audience; This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/ refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Tefinostat (CHR-2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first-in-human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20-640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti-proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte-targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose-limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug-related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte-targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non-targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508).

Systemic amyloidosis with hepatic involvement is a rare disorder, which is characterized by the deposits of amyloid fibrils in the liver. The prognosis is poor and the median survival is 13 months. Bleeding problems resulting from coagulopathy frequently complicates systemic amyloidosis. We present two patients with a severe factor X deficiency and hepatomegaly as the presenting abnormalities of systemic amyloidosis. One of the patients was treated with high dose melphalan chemotherapy and autologous stem cell reinfusion, resulting in a normalization of the liver enzyme tests and the factor X level. The diagnosis and treatment of systemic amyloidosis with hepatic involvement and the management of the multifactorial coagulopathy in these cases is discussed.

Background: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). Methods: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (>= 6 versus < 6 months) and quality of chelation (adequate versus weak). Results: Crude chelation rate was 63% but 88% among patients with serum ferritin >= 1000 mu g/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated >= 6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p < 0.001). For patients chelated >= 6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR = 1.08, p = 0.04) but was lower in patients receiving adequate chelation or chelation = 6 m( HR = 0.24, p < 0.001). Conclusion: Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS. (C) 2014 Elsevier Ltd. All rights reserved.

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.

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m2 every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 × 109/L and neutrophils 0.5 × 109/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.

Most adult patients with acute myeloid leukemia (AML) who reach a complete remission (CR) after induction chemotherapy will relapse if they do not receive further therapy. Autologous stem cell transplantation (SCT) represents one of the options of postremission therapy in AML. Here we discuss the therapeutic impact of consolidation treatment with autologous SCT that has been studied extensively. Meta-analyses of published randomized trials using bone marrow as the source of stem cells show a modest improvement of disease-free survival as compared to nonmyeloablative chemotherapy. However, there is no apparent improvement of overall survival, probably due to the slightly increased mortality associated with autologous bone marrow transplantation (BMT). Subsequently, the value of autologous SCT in different prognostic subsets of AML is discussed. Autologous mobilized peripheral blood stem cell (PBSC) transplantation offers a much faster hematopoietic recovery and is associated with reduced morbidity and treatment-related mortality. To fully appreciate the role of autologous PBSC transplantation, the results of a recently closed randomized trial must be awaited.

To the editor: Acute myeloid leukemia (AML) with monosomal karyotype (MK) at diagnosis has been established as a subset of AML patients with very poor prognosis. After the initial publication by the Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON/

Abstract 159 AlloHSCT is considered standard consolidation therapy in adults with intermediate and poor-risk acute myeloid leukemia (AML) in first complete remission (CR1). Myeloablative (MAB) alloHSCT confers a survival advantage in younger AML patients (pts), but non-relapse mortality (NRM) may counterbalance a favorable effect on relapse, resulting in limited benefit in older pts. Meta-analyses have suggested that the advantage may already be limited beyond the age of 40. Reduced intensity conditioning (RIC) regimens were introduced to reduce NRM, while sparing graft versus leukemia (GVL) effects in older pts. Retrospective comparative studies have confirmed less NRM, but suggested that the net result in terms of overall outcome may not differ, as less NRM may be counterbalanced by more relapse. We evaluated within 4 consecutive prospective HOVON/SAKK cooperative studies (H29, H42, H42A, and H92) alloHSCT versus conventional consolidation in AML-CR1 pts between 40–60 years, with integrated comparison of alloHSCT using MAB versus RIC. Outcome measures included overall survival (OS), relapse free survival (RFS), as determined by relapse and NRM. The choice of conditioning regimen prior to alloHSCT (MAB or RIC) was solely based on center preference throughout the study period. 1105 pts between 40 and 60 years of age with newly diagnosed AML receiving consolidation in CR1, were studied, including 237 pts proceeding to MAB and 144 to RIC alloHSCT. 724 pts were consolidated with either a third cycle of chemotherapy (n=470) or an autograft (n=254). More pts with unfavourable karyotype or late CR proceeded to alloHSCT than to alternative consolidation. Recipients of MAB or RIC were comparable with respect to age, leukemia risk-status, donor/recipient gender combination, CMV-serology, time from diagnosis to HSCT, EBMT risk-score, and follow-up (median 24 versus 25 months, in RIC and MAB, respectively). Significant differences with respect to stem cell source, graft manipulation, and year of transplant were observed, with a higher proportion of RIC in recent years. Pts with alloHSCT showed better OS (55% ± 4) than pts receiving alternative consolidation (46% ±2), p In conclusion, consolidation by alloHSCT significantly improves outcome as compared to either chemotherapy or autologous transplantation in CR1 pts aged 40–60 years, which was largely accounted for by RIC alloHSCT. These results suggest that: 1. similar to younger pts, alloHSCT can be considered standard consolidation therapy in intermediate and poor-risk AML in CR1, aged 40–60 years; 2. RIC and MAB alloHSCT may only slightly differ with respect to reduction of relapse in pts having benefited from intensive preceding induction/consolidation chemotherapy, while RIC is additionally associated with a significant reduction of NRM; 3. a prospective randomized trial comparing RIC and MAB in similarly pretreated AML pts, including younger pts in CR1, is advocated. Disclosures: Wijermans: Centocor Ortho Biotech Research & Development: Research Funding. Janssen:Novartis: Consultancy.

Abstract 3279 CHR-2845 is a novel type of histone deacetylase inhibitor (HDACi) for use in cancer, which is targeted specifically to cells of the monocyte-macrophage lineage. CHR-2845 is a cell-permeant ester that is cleaved to an active acid, CHR-2847, by an intracellular esterase (human carboxylesterase-1, hCE-1) that is primarily found in cells of the monocyte lineage including macrophages, monocytes and Kupffer cells, and also hepatocytes. CHR-2847, being a charged molecule, cannot readily leave cells and, hence, selectively accumulates and is active within hCE-1-expressing cells, resulting in a 20–100 fold increase in anti-proliferative potency of CHR-2845 for monocytic over non-monocytic tumour cells. This selectivity should lead to an increased therapeutic window in haematological malignancies involving cells of the monocyte lineage (AML-M4, AML-M5 and CMML). In addition, there is increasing evidence that macrophages associated with progressive, solid tumours (tumour-associated macrophages (TAMs)) and lymphomas are involved in supporting the growth and spread of the tumour. Circulating monocytes differentiate into resident tissue macrophages and, depending on the local microenvironment, acquire specialised phenotypic characteristics and diverse functions. In tumours, macrophages are reprogrammed by neighbouring tumour cells to induce immune suppression of host defences, facilitating progressive tumour growth and tumour cell dissemination. Targeting TAMs with CHR-2845 could, therefore, also have a beneficial effect in non-monocyte derived tumours. The CHR-2845-001 trial recruited patients with advanced haematological malignancies, who are either refractory to standard therapy or for whom no standard therapy exists. This study is a first in man, open label, dose escalating, multi-centre, phase I study of oral CHR-2845 given once a day over a 28 day course of treatment, with the next cycle started at day 29. Cohorts of 3 to 6 patients were treated at increasing dose levels to establish the MTD. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were taken from all patients in all cohorts. The PD evaluation consisted of a FACS-based assay to compare histone acetylation in monocytes, granulocytes and lymphocytes. 18 patients, 7 F:11 M, median age 73 yrs (51 - 80) were enrolled at doses of 20 (n=3), 40 (n=3), 80 (n=3), 160 (n=3), 320 (n=3) and 640 mg (n=3). Intra-subject dose escalations were allowed, with 2 patients receiving 3 dose levels, and 3 patients receiving 2 different dose levels. The median number of cycles administered was 3 (1 – 9). One patient with AML M2 was treated for 7 cycles, a patient with NHL is ongoing at 7 cycles, and a patient with CMML was on treatment for 9 cycles and achieved a bone marrow response and symptomatic relief, although no impact on peripheral monocytes was seen. Dose limiting toxicities (DLT) have not been observed at any dose, possibly due to the targeted nature of CHR-2845. Dose escalation has been halted at 640 mg. Of 197 AEs reported to date, 54 were considered at least possibly related to CHR-2845. Most were grade 1/2, with only 3 grade 3 (anorexia, asthenia, acute confused state). The most frequent drug-related AEs were nausea (11), anorexia (6) and fatigue (5). No liver enzyme disturbances have been noted. PK analysis of CHR-2845 distribution revealed rapid absorption (Tmax 0.9 – 2.1h) and mean elimination plasma half-life of 2.5 hrs. Cmax and AUC(0-t) increased dose proportionally, although there was high variability between patients. There was no substantial accumulation of CHR-2845 observed on Day 28. Preliminary analysis of histone acetylation in PBMCs shows a pattern of monocyte-specific increases in histone acetylation, with no increase in histone acetylation in granulocytes and lymphocytes. Evaluation of PD samples is continuing and an updated analysis will be presented at the meeting. Conclusions: CHR-2845 is well tolerated, with very few of the drug-related adverse events (like nausea, fatigue, diarrhea) commonly seen with HDACi. Plasma concentrations of CHR-2845 achieved in this trial exceed those required for in vitro anti-proliferative activity in the absence of significant toxicity. Updated results will be presented at the meeting, including an assessment of histone acetylation as a pharmacodynamic biomarker in a FACS based assay which can distinguish between targeted acetylation in monocytes versus granulocytes and lymphocytes. Disclosures: Debnam: Chroma Therapeutics: Employment, Equity Ownership. Needham:Chroma Therapeutics: Employment, Equity Ownership. Bawden:Chroma Therapeutics: Employment, Equity Ownership. Hooftman:Chroma Therapeutics: Employment, Equity Ownership.

Abstract 2028 Poster Board II-5 Background. Based on the dismal outcome of older patients with ALL and a promising pilot study in a single institution, HOVON started a multicenter phase 2 feasibility study to assess efficacy and safety of a novel chemotherapy regimen for patients between 40 and 70 years of age (younger patients being eligible for a pediatric treatment schedule in a parallel study). The innovative part of the study consisted of a relatively intensive “pre-induction” course for rapid reduction of the tumor load. Treatment schedule. The pre-induction course consisted of cytarabine 200 mg/m2 and etoposide 120 mg/m2 on day 1, and 8 and MTX 500 mg/m2 on day 4, and 11. This was followed on day 15 by an induction course of vincristine 1 mg/wk x 3, dexamethasone 8-12 mg/d x 21 depending on body weight, and adriamycine 40 mg (>60 yr: 30 mg)/m2/d on day 2-4 (ODA). After regeneration of the bone marrow, ODA was repeated once in patients with at least a partial remission. Subsequently, consolidation with cytarabine 1000 mg/m2/12 hr x 4 followed by asparaginase 6,000 IU/m2/d x 10 was given, and, finally, regular maintenance therapy for 30 cycles. Intrathecal prophylaxis consisted of weekly MTX 15 (>60 yr: 10) mg x 4 followed by monthly MTX 15 (> 60 yr: 10) mg x 6. Patients with t(9;22) also received imatinib 600 mg/d, except during asparaginase administration; patients in complete remission (CR) were eligible for nonmyeloablative allogeneic stem cell transplantation (SCT) using either sibling (sib) or matched unrelated donors (MUD). Results. Sixty patients, 27 males and 33 females, with a median age of 57 years (range 40–69) were enrolled; 40% were over 60 years. B-lineage ALL was present in 54. Median WBC count at diagnosis was 6.3 × 109/l (range 0.7-186). t(9;22) was present in 16 (34%) and t(4;11) in 4 (9%) of 47 patients with available karyotype or FISH data. Based on WBC, cytogenetics, and time to CR 31 patients (52%) were considered high risk and 29 (48%) standard risk. Fifty-one patients (85%) attained CR, 47 of them after the first ODA course. One patient was a nonresponder. Ten patients (17%) died during the early phases of intensive chemotherapy mainly due to infection. Moreover, treatment had to be withdrawn or delayed in 12 (20%) because of side effects such as grade 3-4 mucositis and infection. Seventeen patients underwent allo-SCT (10 sib, 7 MUD) in first CR. After a median follow-up of 21 months (range 15–37), 37 patients (62%) were alive; 13 (22%) relapsed, 6 of them after SCT. The 2-year EFS was 48% (95% CI 32-63%), 2-year DFS 51% (32-68%), and 2-year OS 61% (47-73%). Conclusion. Notwithstanding considerable toxicity including early mortality of 17%, this schedule produced high survival and low relapse rates, especially when considering the median age of 57 years and the relatively high number of high risk patients. The pre-induction course induced a rapid reduction of (circulating) blasts in all patients. Based on this phase 2 study a prospective randomized trial has recently been initiated. In order to reduce toxicity the protocol has been amended by replacing dexamethasone by prednisone, allowing time for hematological recovery after the pre-induction course, growth factor support, and optimizing antibiotic prophylaxis. Disclosures: No relevant conflicts of interest to declare.

Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that are usually short lived. Previously proposed prognostic classification methods serving therapeutic decisions and evaluation of investigational treatment strategies at relapse of AML have been based on the duration of the relapse free interval and have largely neglected the influence of other known prognostic factors. Here we present an improved clinically useful prognostic index. This index has been developed from a multivariate analysis of 667 AML patients in first relapse among 1540 newly diagnosed non-M3 AML patients of age 15 to 60 years entered into three successive HOVON/SAKK Collaborative Group trials. The score, which has a range of 0 to 14 points, uses four relevant parameters. The parameters are: length of relapse free interval after first complete remission (more than 18 months: 0 points; 7 to 18 months: 3 points; 6 months or less: 5 points), cytogenetics at diagnosis (t(16;16) or inv(16): 0 points; t(8;21): 3 points; other cytogenetics: 5 points), age at relapse (35 years or younger: 0 points; 36 to 45 years: 1 point; older than 45 years: 2 points) and whether or not a previous stem cell transplantation (SCT) has been undertaken in first complete remission (no SCT: 0 points; previous SCT: 2 points). These points were assigned following estimations of the relative values of each of these factors contributing to outcome. Ultimately, three risk groups were defined: a favorable prognostic group A (0 to 6 points; overall survival of 70% at one year and 46% at five years), an intermediate risk group B (7 to 9 points; overall survival of 49% at one year and 18% at five years), and an unfavorable risk group C (10 to 14 points; overall survival of 16% at one year and 4% at five years). Thus, four commonly applied clinical parameters may identify among patients with AML in first relapse those for salvage or investigational therapy.