Kurzfassung: BACKGROUND. At the time of diagnosis, myeloma cells are characterized by a low proliferation rate that increases in relapse. Presence of proliferation correlates with adverse prognosis. At the same time, myeloma cells harbor a high median number of chromosomal aberrations, often associated with genetic instability. Cellular proliferation and genetic instability in turn have been associated with Aurora-kinase expression in several cancer entities, including multiple myeloma. PATIENTS AND METHODS. Expression of Aurora-A, -B and -C was assessed using Affymetrix DNA-microarrays in 784 samples including two independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive iFISH using a set of probes for the chromosomal regions 1q21, 6q21, 8p21, 9q34, 11q23, 11q13, 13q14.3, 14q32, 15q22, 17p13, 19q13, 22q11, as well as the translocations t(4;14)(p16.3;q32.3) and t(11;14) (q13;q32.3). Proliferation of primary myeloma cells (n=67) was determined by propidium iodine staining. The effect of the clinical Aurora-kinase inhibitor VX680 on proliferation of 20 human myeloma cell lines and survival of 5 primary myeloma cell-samples was tested. RESULTS. We found Aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient-cohorts, including 23% for Aurora A in our first cohort of patients treated with high dose therapy (see figure shown below). Aurora-C expression was found in testis-samples only. Myeloma cell-samples with detectable Aurora-A expression show a significantly higher proliferation rate, whereas the number of chromosomal aberrations (aneuploidy) is not higher compared to myeloma-cells with absent Aurora-A expression. The same holds true for subclonal aberrations (i.e. genetic instability). The Aurora-kinase inhibitor VX680 induces apoptosis in all myeloma cell lines and primary myeloma cell-samples tested. Presence of Aurora-A expression delineates significantly inferior event-free and overall survival in two independent cohorts of patients undergoing high-dose chemotherapy and autologous stem cell transplantation. This observation is independent of conventional prognostic factors, i.e. serum-ß2-microglobulin or ISS-stage. CONCLUSION. Aurora-kinase inhibitors (including VX680 tested here) are very active on myeloma cell lines as well as primary myeloma cells and represent a promising weapon in the therapeutic arsenal against multiple myeloma. Gene expression profiling allows the assessment of Aurora-kinase expression and thus in turn a tailoring of treatment to patients expressing Aurora-A associated with adverse prognosis. Figure Figure

Kurzfassung: Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.

Kurzfassung: We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P 〈 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P 〈 .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

Kurzfassung: Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p 〈 0.001). The median total dose of idarubicin received in the 2 consolidation courses was 36 mg/m2 (range 17-45), or 99% (47-125%) of the protocol dose in the standard arm, versus 53 mg/m2 (18-73), or 98% (33-136%) of the protocol dose in the intensive arm. The durations of grades 3-4 neutropenia and thrombocytopenia were significantly longer in the intensive arm, but there were no differences in grade 3 or 4 non-hematological toxicities. There were no non-relapse deaths during consolidation on the standard arm and 2 in the intensive (0% vs 1%; p =0.50). Subsequently, 41 patients in the standard arm and 37 in the intensive arm underwent elective allogeneic BMT during first remission. On intention to-treat analysis uncensored for transplant and with a median follow-up time of 5.3 years (range 0.6 - 9.9), there was improvement in LFS in the intensive arm compared with the standard arm (3 year LFS 47% (95% CI 40-56%) versus 35% (28-44%); HR 0.74 (95% CI 0.55-0.99); p=0.045) (Figure 1). The 3 year OS for the intensive arm was 61% (95% CI 54-70%) and 50% (95% CI 43-59%) for the standard arm; HR 0.75 (95% CI 0.54-1.05); p=0.092). Although adverse cytogenetics, presence of FLT3-ITD mutation, and absence of NPM1 mutation were all associated with poorer outcomes, there was no evidence of a benefit of intensive consolidation being confined to specific cytogenetic or gene mutation sub-groups. Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: Inhibition of SPHK1 in human AML cells induces MCL1 degradation and caspase-dependent cell death. SPHK1 inhibitors reduce leukemic burden and prolong survival in orthotopic patient-derived xenografts of AML.

Kurzfassung: Introduction: Early ASCT improves progression-free survival (PFS) but not overall survival (OS) in poor prognosis DLBCL treated with R-CHOP immuno-chemotherapy (Stiff P et al., NEJM 2013). Furthermore, indiscriminate ASCT exposes those poor-risk patients destined to remain in CR with R-CHOP alone to unnecessary toxicity. Here, the role of interim PET/CT to risk-stratify is controversial. One confounding factor is that interim PET/CT is typically performed after 2 (or 3) cycles of chemotherapy when FDG-avidity likely reflects a mix of residual cancer cells and inflammation; in contrast, interim PET/CT after cycle 4 may be more representative of resistant lymphoma. We hypothesized that: 1. assessment of DLBCL patients by interim PET/CT after 4 cycles (iPET4) of R-CHOP-14 allows greater specificity of FDG-avidity; and, 2. for patients with iPET4-positivity, early treatment intensification with R-ICE chemotherapy followed by Zevalin-BEAM conditioning and ASCT results in 2-yr PFS that is equivalent to interim-PET/CT-negative patients treated with R-CHOP alone. Methods: We conducted a prospective multicenter phase 2 study which enrolled DLBCL patients ≤ 70 yrs with either IPI=2-5, or IPI =0-1 with tumor bulk (≥ 7.5 cm), and who were considered fit for ASCT. All patients underwent a diagnostic PET/CT at study entry and were planned to receive 4 cycles of R-CHOP-14 and supported with Pegfilgrastim. Cycle 5 of R-CHOP-14 was delayed 7 days, and an interim PET/CT scan was undertaken at d17-d20 post-4th R-CHOP-14, the delay intended to reduce the impact of rebound inflammation after R-CHOP. All interim PET/CT scans were assessed centrally by a core group of imaging specialists using International Harmonization Project (IHP) criteria with mediastinal blood pool as the reference. Biopsy to confirm residual tumor was not mandated. iPET4-positive patients received 3 cycles of R-ICE followed by ASCT with Zevalin-BEAM conditioning; those who were iPET4-negative received a further 2 cycles of R-CHOP-14 plus 2 doses of Rituximab. Results: A total of 162 patients were enrolled from 20 Australian centers; 11 patients were excluded because of failure to meet inclusion criteria. Baseline characteristics of the 151 evaluable patients included: median age 57 yrs (range, 21 to 69), 40% aged 〉 60 yrs, 62% males, 79% stages 3 or 4, 13% ECOG PS 〉 1, 78% elevated LDH, 48% extranodal sites 〉 1, 54% bulky disease ≥ 7.5 cm, 20% IPI=0-1, 27% IPI=2, 31% IPI=3, and 23% IPI=4-5. No interim PET/CT scan was performed in 8 patients due to progressive disease (PD) (1), bowel perforation (2), toxicity (3), and dose delays ≥ 2 weeks (2). Interim PET/CT scans were undertaken at d17-d20 in 62% and d14-d16 in another 23%. Of the 143 patients with interim PET/CT, 101 (71%) were deemed iPET4-negative and 42 (29%) were iPET4-positive. Interestingly, the baseline characteristics were comparable between iPET4-negative and iPET4-positive patients. Of the 101 iPET4-negative patients, 5 failed to complete therapy due to PD (3), toxicity (1), or infection (1). Of the 42 iPET4-positive patients, 10 failed to complete intensification therapy due to PD (6), 2nd malignancy (1), or consent withdrawal (3). Among iPET4-positive patients undergoing ASCT, there was 1 treatment-related death due to viral infection. At a median follow-up of 35 months, the Kaplan-Meier (KM) estimate of 2-yr PFS and OS for the entire eligible cohort of 151 pts was 72% and 85%, respectively. For the 101 iPET4-negative and 42 iPET4-positive patients, 2-yr PFS was 74% and 67% (P =0.32) (Figure 1), and 2-yr OS was 88% and 78% (P=0.11) (Figure 2), respectively. Among iPET4-negative and iPET4-positive patients with IPI=3-5, 2-yr PFS was 65% and 69% (P=0.74), and 2-yr OS was 81% and 83% (P =0.85), respectively. Conclusions: Patients with poor risk DLBCL who are interim PET/CT-positive after 4 cycles of R-CHOP-14 and switched to intensification with R-ICE followed by ASCT with Zevalin-BEAM have favorable rates of PFS and OS that are equivalent to that seen for patients who are interim PET/CT-negative. This study supports further investigation of treatment intensification in patients with poor risk DLBCL who are interim PET/CT-positive after 4 cycles of immuno-chemotherapy. The study was supported in part by Roche Products Pty. Ltd, Amgen Australia Pty. Ltd, and Bayer Australia Ltd. Figure 1. Progression Free Survival by Interim PET/CT Figure 1. Progression Free Survival by Interim PET/CT Figure 2. Overall survival by Interim PET/CT Figure 2. Overall survival by Interim PET/CT Disclosures Hertzberg: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gill:AbbVie: Honoraria; Roche: Research Funding; Sanofi Aventis: Research Funding; Roche: Honoraria. Ho:Celgene: Other: Travel. Cull:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel. Grigg:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lewis:Amgen: Other: Travel; Roche: Honoraria, Other: Travel. Renwick:Amgen: Other: Travel; Bayer: Speakers Bureau. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: The combination of rituximab, lenalidomide, and ibrutinib is associated with a high incidence of rash in follicular lymphoma (all grades 82%). Efficacy of the triplet appears similar to rituximab-lenalidomide in the same patient population.

Kurzfassung: A good correlation exists between zinc content and carbonic anhydrase activity of the red blood cells under all conditions studied, including anemia and polycythemia. In almost all patients with anemias other than pernicious anemia, both zinc and carbonic anhydrase levels were lowered in parallel fashion. These changes were proportional to decreases in hematocrit and hemoglobin levels and erythrocyte counts so that both zinc and carbonic anhydrase values per unit of RBC were in the normal range. In a few instances of anemia associated with leukemia and in one of sickle cell anemia, neither zinc content nor carbonic anhydrase activity was decreased in proportion to the anemia; in these cases the zinc and carbonic anhydrase levels per unit of blood were both elevated to the same degree. Patients with pernicious anemia showed no decrease in absolute values for zinc and carbonic anhydrase activity in spite of marked lowering of hematocrit and hemoglobin levels and of erythrocyte count. Accordingly, both zinc concentration and carbonic anhydrase activity per unit of blood were elevated, often to a marked degree. These increases were parallel, varying inversely with the degree of anemia; when they regressed under treatment, both did so at the same rate. There are no methods available for estimating carbonic anhydrase concentration; all methods now in use measure only the activity of the enzyme. It is suggested that zinc concentration could be used as an indicator of carbonic anhydrase content of the red blood cells.

Kurzfassung: Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Kurzfassung: Background: Current chemotherapy regimens in children with ALL produce disease-free survival (DFS) rates of greater than 80%. In contrast, adults with ALL have a much poorer prognosis, with DFS rates of 30-40%. Recent prospective studies suggest that young adults may have superior outcomes when treated with intensive pediatric regimens. We recently reported a 4-yr DFS and overall survival (OS) of 69% (n=78 who achieved CR) and 67% (n=92), respectively (DeAngelo et al. Leukemia 2015) using a native E. coliasparaginase based regimen. This phase II successor trial was performed to determine if a pediatric regimen using pegylated-asparaginase (peg-asp) could be feasibly administered to adults. Methods: Patients (pts) between 18-50 yrs with de novo ALL were eligible. The primary objective of this study was to determine the feasibility of a single dose of peg-asp during induction and of delivering peg-asp every 2 wks during a 30 wk consolidation period. The therapeutic backbone of this protocol was based on the very high-risk arm of the DFCI Childhood ALL Consortium Protocol 05-01. Pts received induction chemotherapy, which included doxorubicin, prednisone, vincristine, pegylated-asparaginase (peg-asp), and triple intrathecal therapy. Consolidation I consisted of a course of high-dose methotrexate, followed by a BFM-like intensification and a course of high-dose cytarabine, etoposide and dexamethasone. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of eight 3-wk courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 wks of IV peg-asp initially dosed at 2500 IU/m2every 2 wks. Continuation therapy consisted of 3 wk courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 yrs from complete remission (CR). Imatinib at 600 mg/d was administered to those pts who were Philadelphia chromosome (Ph) positive. Results: Of 112 pts enrolled, 110 were eligible. The first 65 pts were treated with the initial study design of IV peg-asp during induction and peg-asp every two wks for 15 doses during consolidation. However, due to the high frequency of asparaginase toxicities mainly hyperbilirubinemia, peg-asp was replaced with native E. coli asp at a dose of 25,000 IU/m2 IM during induction and the dose and frequency peg-asp was decreased to 2000 IU/m2 every 3 wks during the consolidation phase in the subsequent 45 pts. The median age was 32 yrs, (range, 18-50), 61% were male, 82% had B-lineage phenotype, and 21 were Ph positive. The CR rate after 4 wks was 89%. 70 pts had the opportunity to receive peg-asp intensification therapy (42 at the 2500 IU/m2 every 2 wks schedule and 28 on the 2000 IU/m2 every 3 wk schedule). Of the 42, 18 pts (43%; 80% CI, 32-54%) on the 2 wk schedule completed at least 13 of 15 doses of peg-asp (26 wks) and 22 of 28 pts (79%; 80% CI, 65-88%) on the 3 wk schedule completed at least 8 of 10 doses of peg-asp, which met the feasibility endpoint (lower bound CI 〉 60%). The median asp levels post the induction dose of peg-asp were 0.025, 0.78, 0.28, 0.10, at baseline, 7, 11 and 25 days and 〉 0.20 for each consolidation time point for both the 2 and 3 wk cohorts. Two deaths occurred during induction therapy (sepsis; CNS hemorrhage). Post-induction four pts developed pancreatitis, 14 pts had an allergic reaction to the asp, 12 pts developed osteonecrosis, 2 had a bone fracture, 13 pts had thrombosis/embolism and 32 pts had a grade 3-4 neutropenic infection. With a median follow-up time of 39 mos, the estimated 3-yr DFS is 73% for those who achieved a CR (n=90) and the estimated 3-yr OS is 75%. Conclusions: The administration of a dose intensified pediatric regimen with peg-asp to adults with ALL is feasible. However, the dose and schedule of peg-asp that is well-tolerated in adults is lower and less frequent as compared to that of pediatric pts. Although the DFS and OS are high for an adult cohort, longer follow up is needed. Pediatric-like therapies, including those using intensive peg-asp, are tolerable in young adults with ALL and represent a major therapeutic advance. Table 1. Outcome Summary n 3-yr % OS [95% CI] n 3-yr % DFS [95% CI] All Pts./CR Pts. 110 75 [66-82] 90 73 [62-81] Immunophenotype B cell 90 74 [64-82] 72 70 [58-80] T cell 20 78 [52-91] 18 83 [57-94] Ph- 89 80 [70-87] 78 75 [63-84] Figure 1. Figure 1. Disclosures DeAngelo: Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Storring:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Stone:Pfizer: Consultancy; Juno: Consultancy; AROG: Consultancy; Amgen: Consultancy; Agios: Consultancy; Celator: Consultancy; Novartis: Research Funding; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Merck: Consultancy; Roche/Genetech: Consultancy.