ALBERT

Description: Abstract 44 CALGB (now part of the Alliance for Clinical Trials in Oncology) performed a non-randomized phase II study testing one year (yr) of investigational maintenance therapy with decitabine for newly diagnosed adult AML patients (pts) 1 × 109/L, platelets 〉75 × 109/L, and be within 90 days after day 1 of the final consolidation. Decitabine 20mg/m2 was given IV over 1 hour for 4–5 days, every 6 weeks, for 8 cycles. 546 pts enrolled with a median age of 48 yrs (range, 17–60) and median presenting white blood count (WBC) of 12.6 × 109/L (range, 0.3–380 × 109/L). 75% achieved CR (412/546). Reasons for CR pts not receiving maintenance were mainly early relapse, alloHCT in 1st CR, inadequate count recovery, and patient refusal (Blum et al. ASH 2011). 33% of CR pts (134/412) received investigational maintenance. Of these, 46 (34%) were favorable risk; among the remaining 88 pts, 73 were consolidated with autoHCT, and 15 received HiDAC-based consolidation. The median time from initial study registration to initiation of maintenance therapy was 6.3 months. Pts receiving decitabine had a median age of 45 yrs (range, 18–60) and presenting WBC of 13.5 × 109/L (range, 0.4–221 × 109/L). Treatment with decitabine maintenance was feasible and reasonably well tolerated; the primary toxicity was myelosuppression. Preplanned dose reduction criteria for neutropenia were met after the first 20 pts had been treated. After this early timepoint, all subsequent pts who had been consolidated with autoHCT received only 4 days of decitabine per cycle (HiDAC consolidated pts continued to receive 5 days per cycle). The median number of cycles of decitabine received was 7 (range, 1–8); 46% of pts (62/134) received all 8 cycles, and 75% completed at least 4 cycles. Reasons for discontinuation of decitabine before completing 8 cycles included relapse (28%, 38/134), pt refusal (13%), adverse events (4%), and others. In this selected cohort of pts who received post-CR maintenance with decitabine, 1-yr and 3-yr overall survival (OS) were 96% and 66%; 1-yr and 3-yr disease-free survival (DFS) were 80% and 53%. 1-yr “failure-free survival” calculated from the time of registration to decitabine was 68% (70% for favorable risk, 68% for others). These results are similar to the outcomes for comparable pts enrolled on our prior CALGB study 19808 who received identical chemotherapy for induction and consolidation and then were randomized to observation or maintenance with interleukin-2 (3-yr OS 61% and 68%, 3-yr DFS 45% and 56%, for observation and IL-2 respectively). Post-consolidation maintenance with decitabine appears to provide only modest, if any, benefit overall. Correlative studies for CALGB 10503 are ongoing, including investigations into the impact of decitabine in unique molecular and cytogenetic subsets of disease, the prognostic/predictive value of aberrant methylation and other molecular markers, and assessment of minimal residual disease. Supported by CA33601 and CA128377. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Donor grafts with more naive T cells and plasmacytoid dendritic cells were associated with improved overall survival after unrelated donor bone marrow, but not peripheral blood stem cell (PBSC) transplants (Waller, E JCO 2014). Here we present results on influence of innate and adaptive immune subsets in G-CSF mobilized allografts on incidence of acute GVHD (aGVHD) and chronic GVHD (cGVHD) in 238 patients (pts). Methods: We analyzed the absolute numbers and percentages of T, NK, NKT and B cells along with an extensive immunophenotypic characterization of their activation status in consecutive PBSC allografts obtained from sibling and unrelated donors between 2010 - 2014 and studied their association with the incidence of aGVHD and cGVHD. Wilcoxon rank sum tests were used to screen differential marker expression between those who did vs. did not develop aGVHD and similarly for cGVHD. Significant markers were evaluated in the multivariable (m.v.) setting along with known prognostic factors, including: recipient age, related vs. unrelated donor, female donor vs. not, Anti-thymocyte globulin (ATG) use (yes vs. no), and Reduced-intensity conditioning (RIC) vs. not. Cutpoints for markers were generated using recursive partitioning algorithms and evaluated in m.v. models. Results: Of the 238 alloSCT pts evaluated, most (71%) had unrelated donors, 64% received ATG, where most pts with unrelated donors received ATG (83%), and 78% received RIC. The incidence of aGVHD and cGVHD was 58% and 38% respectively. A total of 107 pts had grade II-IV aGVHD reported (71 II, 28 III, 8 IV), and 92 of 192 evaluable for cGVHD (at least 100 days of f/u) had reported cGVHD. Median follow-up in living pts was 21 months (range: 1.4 to 41.1 months). Table 1 shows dichotomized markers most influential on aGVHD. Higher absolute numbers of T cells, activated T cells, CD8+ cells, CD8+ cells expressing IL-7 receptor and CD27 were associated with higher incidence of aGVHD. Higher number of Stage 4 NK cells expressing stem cell factor receptor, and T-regs were associated with a lower incidence of aGVHD. Similar analyses were done for cGVHD (Table 2). Higher absolute numbers of activated T lymphocytes, activated B lymphocytes, KIR expressing CD3+ cells, CD8+ lymphocytes and activated NK cells were associated with higher incidence of cGVHD. When the percent of these makers in relation to total lymphocytes was evaluated regarding association with aGVHD, higher percent of T-regs (OR: 0.204, p=0.0018), effector memory T cells (OR: 0.45, p=0.024) and NKG2D positive NK cells (OR: 0.38, p=0.0008) conferred protection from aGVHD . Similar analysis for cGVHD showed higher percent of naïve CD4+ T cells conferred protection from cGVHD (OR: 0.44; p=0.0062) while higher percent of CD8+ cells (OR: 3.93; p=0.0032) and activated NK cells (OR: 2.08; p=0.024) was associated with cGVHD. Conclusions: These results show a protective role of donor T-regs, CD4+ T cells and Stage 4 NK cells from aGVHD. Additionally, higher content of activated T cells, CD8+ cells and B lymphocytes are associated with higher incidence of cGVHD. Higher content of activated NK cells seems to protect from aGVHD, but not from cGVHD. Updated results including multivariable analyses will be presented. These findings showing the influence of specific subsets in the allograft on aGVHD and cGVHD may provide opportunities for therapeutic interventions for graft engineering or pharmacologic methods for targeting specific immune subsets to decrease incidence of aGVHD and cGVHD. Table 1 Univariate model results for aGVHD with dichotomized markers using cutpoints: Marker Absolute OR p-value CD3+/CD5616- (T lymphocytes) 3.07 0.0013 CD3+/HLA DR+ (Activated T lymphocytes) 3.26 0.012 CD8+/CD45RA- (CD 8+ lymphocytes) 2.56 0.012 CD8+/CD27+ (Effector Memory CD8 cells) 3.25 0.0082 CD8+/CD127+ ( CD8 cells expressing IL-7 receptor) 2.92 0.073 CD4+/CD25+/CD127-(T regs) 0.43 0.057 CD3-/CD16-/CD56+/CD117+ (Stage 4 NK cells expressing Stem cell factor receptor) 0.12 0.0007 Table 2 Univariate model results for cGVHD with dichotomized markers using cutpoints: Marker Absolute OR p-value CD3+/HLA DR+ (Activated T lymphocytes) 4.41

Description: Key Points High miR-10 family expression levels in AML patients are associated with achieving complete remission to induction chemotherapy. Functional experiments did not show any impact of miR-10a-5p in AML blast growth or survival at baseline conditions or after chemotherapy.

Description: Abstract 2693 Background: Aggressive B-cell NHL harboring a c-MYC rearrangement (myc+) with or without t(14;18) is associated with shortened PFS and overall survival (OS) (Savage, Blood 2009; Johnson, Blood 2009). Clinical presentation, risk-assessment, and therapies vary among pts and institutions. We reviewed pts with myc+ and double hit NHL treated at the Ohio State University (OSU) from Aug 2008-Jan 2012 to determine factors associated with prolonged PFS and OS. Methods: Pts with de-novo B-cell NHL who were myc+ by FISH break-apart probe were included. Pts with Burkitt's, follicular, and transformed NHL were excluded. Most pts were also evaluated for presence of t(14;18) by FISH, and those myc+ pts with t(14;18) were classified as double hit NHL. Response was determined by PET/CT at the completion of first-line therapy. Associations between myc+ and clinical characteristics were described. PFS and OS were defined from date of diagnosis to date of relapse or death. Univariable and multivariable Cox regression models were performed to assess relationships of selected clinical variables with PFS and OS. Results: Of 49 myc+ pts, 55% were male, and median age at diagnosis was 62 (range: 23–83). Morphologically, 30 pts had diffuse large B-cell lymphoma (DLBCL), 10 pts had B cell lymphoma unclassifiable with features intermediate between diffuse large B cell and Burkitt lymphoma (BCLU), and 9 pts had high grade NHL not otherwise specified. Twenty-eight pts had ECOG performance status ≤1, and 40 pts had stage III-IV disease. Twelve pts had bone marrow involvement, and 26 pts had bulky disease ≥5cm. IPI was ≥3 in 24 pts, and median Ki-67 was 90% (range: 45–100). Twenty-nine of 43 assessed pts (67%) were positive for t(14;18). Therapies included R-CHOP (N=17), R-EPOCH (N=17), Burkitt's-like (ie, R-HyperCVAD, R-CODOXM/IVAC, or R-CHOP with high dose methotrexate; N=11), or other (N=4). No pts underwent autologous transplant in first remission. Twenty-nine pts (59%) achieved a complete response (CR), 2 pts had a partial response, 1 pt had stable disease, 8 pts had progressive disease (PD), and 9 pts died before response assessment (5 pts after cycle 1, 3 pts after cycle 2, and 1 pt after cycle 3). With a median follow-up of 26.2 months (mos; range: 4.8–45.0), the median PFS for all pts was 16.6 mos (95%CI: 9.6 - not reached=NR), and median OS was 37.7 mos (95%CI: 15.7–NR). Median PFS was 3.9 mos for pts without CR vs. not yet reached in pts with CR (p

Description: Abstract 2955 Introduction: Deacetylase (DAC) inhibitors show promise as anti-neoplastic agents, the approved drugs are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have suboptimal activity or unacceptable toxicities. AR-42 is a class I/II DAC-I designed at OSU that demonstrates a 20,000-fold improvement in DAC inhibitory potency relative to the parent molecule (IC50=16 nM) with greater antiproliferative effects than Vorinostat in vitro and in vivo (Kulp et al, Clin Cancer Res, 2006 and Lucas et al, PLoS One, 2010). Methods: OSU 09102 (NCI 9119) is a first-in-man single agent, cohorts-of-3 phase I dose escalation study in adult patients with relapsed CLL, lymphoma (NHL), or multiple myeloma (MM) with normal kidney and liver function. Patients received AR-42 orally M-W-F in cycles of 28 days (3 weeks of 3-times-per-week dosing followed by a 7-day break). Moderate cell count suppression was allowed with an absolute neutrophil cutoff of 1000/μL, platelets 3 50,000/μL and hemoglobin 3 10 g/dL. In the first stage of dose escalation, each dose level increased by 100% until the first grade 2, drug-related toxicity was observed. Subsequent dose increases will be approximately 33% increase with accrual in cohorts of 3 patients. For pharmacokinetic analysis, plasma was obtained at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 24, and 48 hours after dosing on day 1 and day 19 (only up to 24 h), and then kept at –80°C until analysis. Results: We enrolled 3 patients at 20 mg (MM, MM, NHL), 3 patients at 40 mg (MM) with a transition to a slower dose escalation due to a grade 2 thrombocytopenia. Three more patients were enrolled at 40 mg (MM, MM, T-cell NHL), then 7 patients at 50 mg (MM × 4, follicular × 1, T-cell NHL × 2). One myeloma patient was enrolled at 70 mg. In the 40 mg cohort, related toxicities include 2 grade 3 and 2 grade 2 thrombocytopenia, 1 grade 3 neutropenia, 1 grade 2 vomiting, and 2 grade 1 QTc prolongation. In the 50 mg cohort 1 grade 4 and 3 grade 3 thrombocytopenia, 2 grade 3 neutropenia, 4 grade 2 fatigue, 2 grade 2 muscle spasm, 1 grade 2 blurred vision/dizziness, 3 grade 1 QTc prolongation, and 3 grade 1 nausea. Accrual was temporarily halted for a safety analysis Mar-2012 focused on the 50 mg cohort toxicities – one grade 4 thrombocytopenia considered a DLT, one patient found dead on cycle 2 day 10 without prior evidence of QTc prolongation, and one patient with reproducible dizziness and blurry vision. AR-42 was detected 15 mins after dose in 12 of 17 patients, suggesting rapid absorption. The time to reach the peak concentration in plasma (Tmax) varied from 1.5 hours to 4 hours. The Cmax (see chart) and AUC of AR-42 was not increased proportionally with doses, suggesting that the PK of AR-42 is not linear in the 20–50 mg range. Conclusion: The Cmax achieved at the 40 mg and 50 mg dose levels is adequate for HDAC inhibition in vitro and minor clinical responses were observed in myeloma and T-cell lymphoma as a single agent in the 40 mg cohort (see monoclonal proteins chart), hence 40 mg TIW 3-weeks-on and 1-week-off was declared the MTD. Complete pharmacokinetic, toxicity, and results from brief fatigue inventory will be presented at the meeting. AR-42 does not have the severe fatigue and gastrointestinal side effects of other broad DAC inhibitors and may be suitable for combination phase Ib trials in T-cell lymphoma and myeloma. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Emerging data are demonstrating that obesity continues to be an epidemic among the pediatric population. A number of studies in children and adults reported that obesity at diagnosis affects survival in some cancers. Some reports show that obesity is an independent prognostic factor in patients in APL.1,2 The impact of obesity and outcome has never been studied in pediatric patients with APL. Methods Patient data were collected and analyzed from APL patients treated on the North American Leukemia Intergroup C9710 study led by the Cancer and Leukemia Group B (Alliance), with participation by the Children’s Oncology Group (COG). Only patients with BMI data were included in these analyses (n=529) across all age groups. Children and adolescents (

Description: Abstract 1731 Background: Symptom burden in primary, post-ET and post-PV myelofibrosis (MF) is frequently severe and correlates with a poor prognosis. However, symptom manifestations are heterogeneous with variable presence of specific symptoms, splenomegaly and cytopenias. We sought to identify the spectrum and features of MF symptomatic phenotypes by cluster analysis of prospectively gathered information on MF symptoms and disease features. Methods: Data was collected among an international cohort of subjects with MF. Data included demographics, disease features and completion of the Brief Fatigue Inventory (BFI) and Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) (Blood 2011; 118:401–408). Surveyed symptoms addressed key disease features on a 0 (absent) to 10 (worst-imaginable) scale. Cluster development was based on consideration of r-squared in hierarchical clustering using Ward's linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 329 prospectively enrolled persons with MF was collected (Chinese 102, French 54, German 19, Italian 22, Dutch 45, English 51, Spanish 29, Swedish 7) including 223 PMF, 67 post-ET MF and 39 post-PV MF patients. Participants were of typical age (mean 59) and gender (47% F). Among all participants, four natural symptom clusters were identified (Figure 1). Among clusters, disease features including leukopenia, thrombocytopenia, and enlarged spleen varied significantly between clusters (P

Description: Abstract 1739 BACKGROUND: Differences in symptom burden characteristics between persons of European and non-European descent with BCR-ABL negative MPNs including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are not studied. We reported significant clinical and laboratory differences between these populations age at diagnosis and survivals (Blood 2011;119: 2469–73) which could affect symptom burden. Given China represents one-fifth of the global population, we aimed to evaluate MPN symptom burden among a cohort of Chinese MPN patients. METHODS: Data were collected from Chinese with MPNs and their physicians and compared these to a previously collected data from a cohort of subjects of predominately European descent (N=1488). Subject data included MPN-SAF (Blood 2011;118:401-8) and BFI score (Cancer 1999;85: 1186–96), demographics, and disease-related features. Statistical methods included ANOVA, chi-squared tests, and multiple regressions. RESULTS: Demographic and Disease Characteristics: 397 Chinese subjects were prospectively enrolled with a distribution of 172 (43%) ET, 102 (26%) PV, and 123 (31%) MF (of which 103 [84%] were PMF, 14 [11%] were post-ET MF, and 6 [5%] were post-PV MF). Median age (56.0 y) was younger in Chinese than in the European-descent cohort (63.0 y, p

Description: Abstract 1726 Background: We previously reported that symptom burden among persons with ET and PV can be severe and adversely affect QOL. The presence of severe symptoms is linked to poor prognosis. There is considerable inter-subject heterogeneity regarding which symptoms are present in which subjects. No studies have empirically evaluated whether disease characteristics can be grouped in related symptom clusters. Using our previously validated 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196), we sought to evaluate symptom burden by means of cluster analysis. Methods: Data was collected from an international cohort of subjects with MPNs including demographics, disease features and the completed BFI and MPN-SAF instruments. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual difficulties, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst-imaginable) scale. Development of symptom clusters was based on consideration of r-squared in hierarchical clustering using Ward linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 1,141 subjects with PV (N=519) and ET (N=622) was prospectively collected (Chinese 236, French 305, German 45, Italian 114, Dutch 191, English 56, Spanish 109, Swedish 85. Age (mean 59, range, 26–87) and gender (54% F) were typical. Five clusters were selected (Figure 1). Frequencies of prior bleeding, spleen size, anemia, presence of any lab abnormality, language, gender, and MPN type varied significantly between clusters (P

Description: Abstract 1736 Background: Histone deacetylase inhibition (HDACi) has shown a potent inhibitory activity on the autonomous proliferation of hematopoietic cells of PV and ET patients carrying the JAK2V617F mutation (Leukemia. 2008;22(4):740–7). Hematological responses have been recorded during treatment with the HDACi givinostat in patients with PV and myelofibrosis (Blood. 2011; 118:a1748). Additionally, combinational use of givinostat and hydroxyurea (HU) have shown encouraging clinical response in PV (Br J Haematol. 2010;150:446–55). Recent laboratory studies of vorinstat-treated JAK2V617F knock-in mice have observed normalization of peripheral blood counts, markedly reduced splenomegaly and decreased mutant allele burden (Blood 2012; 119, 3779–89). Despite this evidence of hematologic response, to date no studies have evaluated specific changes in symptom burden among PV and ET patients treated with HDACi. METHODS ET and PV patients from the UK were enrolled in a non-randomized, open-label phase II multicenter study of the HDACi vorinostat (Haematologica 2011;96(s2):a1023). Patients were asked to complete the 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408), 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196) and 30 item EORTC QLQ-C30 (J Natl Cancer Inst 1993; 85(5):365-76) at enrollment, week 12, week 24, and week 36. From weeks 1 through 24, participants were given 400mg of vorinostat daily and were observed from weeks 24 to 36. RESULTS Participant Demographics and Mutational Status: 15 PV and 10 ET patients were enrolled in the study. Median age of participants was 65 and 48% of participants were female. JAK2 mutations were present in 5/10 (50%) of ET and 14/15 (93%) of PV patients. Change in Symptom Severity with Vorinostat: Although most symptom severity changes did not reach statistical significance likely due to the small sample size, individual symptoms of headache (mean 1.6 baseline to 0.5 wk 36, mean maximum improvement 0.5 from baseline), dizziness (mean 1.6 baseline to 0.9 wk 36, mean maximum improvement 0.6 from baseline), sad mood (mean 2.6 baseline to 1.9 wk 36, mean max improvement 0.2 from baseline), and bone pain (mean 2.7 baseline to 0.8 wk 36, mean max improvement 0.7 from baseline) indicated consistent reductions in severity. Change in Symptom Incidence with Vorinostat: Non-sustained reductions in symptom incidence were seen with initiation of therapy for items of dizziness (50% baseline, 43% wk12, 55% wk 24, and 38% wk 36), numbness (65% baseline, 38% wk 12, 36% wk 24, 63% wk 36), sad mood (55% baseline, 47% wk 12, 40% wk 24, 50% wk 36), and itching (65% baseline, 50% wk 12, 40% wk 24, 75% wk 36). Change in MPN-SAF TSS Score with Vorinostat: Overall, MPN-SAF TSS did not vary significantly for the cohort over the course of the study (score change −.4 week 12, −0.5 week 24, −1.2 week 36, Figure 1). However, 9/17 participants who had a TSS of at least 6 at baseline had an overall improvement of at least 6 points (a moderate improvement) on at least one assessment after baseline. Of these, 5 of those 9 participants had an improvement of at least 10 points, which constitutes a large improvement in symptom burden based on a distributional definition of clinical significance using the standard deviation from a previous cohort. CONCLUSION This study represents the first analysis of symptom burden among PV and ET patients receiving vorinostat to date. In addition to previously identified changes in clinical and hematologic response, reductions in symptom burden including QOL and fatigue were observed in patients receiving vorinostat therapy which was most noticeable in patients with high baseline burden. The toxicity profile of vorinostat also suggests that better results might have observed if individualized assessment of clinicohematological responses including an integrated a marker for response into daily clinical practice and tailoring pharmacotherapy based on side effect profile (Leukemia. 2012;26(5):1148–9). Although further investigation among larger cohorts is needed, preliminary data is encouraging for successful therapeutic use of vorinostat in a clinical setting and with possible combinational therapy to reduce symptom burden among PV and ET patients. Disclosures: Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.