Rizzieri, David A.

Key Points Pinometostat demonstrates first evidence of DOT1L target inhibition and clinical responses in a subset of MLL-r advanced leukemia patients. The observed safety profile of pinometostat shows potential for exploration of combination therapies in leukemia.

Key Points Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.

BACKGROUNDTo evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.METHODSWe analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre‐HCT depression requiring treatment versus those without pre‐HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post‐HCT using Poisson models. We also compared the incidence of grade 2‐4 acute and chronic graft‐versus‐host disease (GVHD) in allogeneic HCT.RESULTSThe study included 1116 (15%) patients with pre‐transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre‐transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04‐1.23; P = 0.004) and a higher incidence of grade 2‐4 acute GVHD (HR, 1.25; 95% CI, 1.14‐1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre‐transplant depression was associated with fewer days‐alive‐and‐out‐of‐the hospital (means ratio [MR] = 0.97; 95% CI, 0.95‐0.99; P = 0.004). There were 512 (13.5%) patients with Pre‐transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre‐transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98‐1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97‐0.99; P = 0.002).CONCLUSIONPre‐transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre‐transplant depression represent a population that is at risk for post‐transplant complications. Cancer 2017;123:1828–1838. © 2017 American Cancer Society.

Abstract Pinometostat is a highly selective first in class DOT1L inhibitor currently in Phase 1 clinical trials in adult and pediatric leukemia patients (pts) with MLL rearrangements (MLL-r or MLL-PTD). Preliminary results of the adult trial have demonstrated clinical activity including complete remissions in a subset of patients (Stein, 2014). Investigation and identification of candidate molecular correlates of pinometostat response in both pt samples and cell lines are reported. RNA and DNA were isolated from PBMCs and/or bone marrow collected prior to treatment from 18 pts enrolled in the adult pinometostat Phase 1 study (CT.gov: NCT01684150), at the following doses 24 (n = 2), 36 (n = 3), 54 (n = 6), 80 (n = 3) and 90 mg/m2/day doses (n = 4). mRNA transcript abundance was assessed using whole genome RNASeq and DNA variants were determined using a 194 gene panel, MyAML (Genection Inc.). Correlations of transcript abundance and DNA variants detected with categorical (responder = CR or PR [n = 3], or no response [n = 16]) and continuous response parameters (time on study [TOS], mean = 59 days: range = 8-196 days) were performed. For cell lines, whole genome RNASeq data was generated from 14 cell lines (MLL-r or MLL-PTD) with a range of in vitro sensitivity to pinometostat (cell proliferation IC50 2 nM to &gt; 10 μM) and RNA transcripts identified as correlated with IC50 were submitted for pathway analysis. Univariate analyses revealed no DNA variants to be associated with either response category (FDR adjusted P &lt; 0.05), however, a statistical association (unadjusted P = 0.05) was identified between increased TOS and those pts harboring t(11:19). Indicating that specific MLL fusion partners may elicit differential sensitivity to pinometostat therapy (2/2 CR pts had t(11:19)). Analysis of the baseline PBMC RNASeq data revealed 201 genes as significantly correlated with TOS (FDR adjusted P&lt;0.05), these data were further analyzed using the Selventa causal modelling platform to identify pathways associated with TOS. Increased activity in pathways leading to differentiation, oxidative stress, inflammation, ras activation and decreased activities of PPAR-γ, DNA methylation and stem cell renewal were associated with increased TOS. Independent analysis of the cell line response data identified pathways that significantly overlapped with those observed in pt samples, with 4/7 of the pt derived mechanisms identified (PPAR-γ activity, inflammation, stem cell renewal and ras activation). In all cases directionality of pathway activity relative to pinometostat sensitivity were concordant between pt and cell line data. Based on these results the effect of a PPAR-γ agonist e.g. rosiglitazone, would be predicted to be antagonistic to pinometostat activity. Results of experiments investigating the effects of combination of rosiglitazone and pinometostat in MOLM-13 cell lines demonstrated that the combination was significantly less effective at inhibiting cell proliferation than pinometostat alone (IC50 shift of 2 fold (n = 2)). MLL-r fusion partner (e.g. t(11:19)) may influence clinical response to pinometostat. In addition RNASeq based characterization of patient samples and cell lines revealed candidate pathways that may cooperate with or antagonize pinometostat activity that warrant further investigation. Citation Format: Scott Daigle, Alice McDonald, Ty M. Thomson, David A. Drubin, Michael Maria, A. Carson, Brad Patay, Jeff Keats, Christine Klaus, Alejandra Raimondi, G. Garcia-Manero, D. A. Rizzieri, Raoul Tibes, Jesus Berdeja, Eytan M. Stein, Blythe Thomson, Stephen J. Blakemore. Identification of biomarkers and pathways associated with response to the DOT1L inhibitor Pinometostat (EPZ-5676) in MLL-r leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C12.

AbstractMyelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor‐alpha, interferon‐gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T‐cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells, and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS. These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor‐specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells.

Purpose To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). Patients and Methods We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. Results Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 109/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. Conclusion The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Abstract Background: SGI-110 (guadecitabine) is a novel HMA that prolongs in vivo exposure of the active moiety decitabine following subcutaneous (SC) administration. We previously reported guadecitabine clinical activity in previously untreated elderly AML with Overall Complete Response (CR+CRi+CRp) of 55% using a standard 5-day regimen (Yee et al, 2014). Here we report the first results of a more intensive 10-day regimen in the same patient population. Methods: Elderly AML patients (≥ 65y) with at least one of the following characteristics were enrolled: age ≥ 75y; poor Performance Status (PS) ≥ 2; significant comorbidities particularly cardiopulmonary dysfunction; poor risk cytogenetics; or secondary AML. Guadecitabine 60 mg/m2/d SC was administered for 10 days (Days 1-5; and 8-12) for the first 1-2 cycles followed by the 5-day regimen (Days 1-5) for subsequent cycles. Cycles were scheduled every 28 days. Primary endpoint was Overall Complete Response (Overall CR). Secondary endpoints included Overall Survival, Safety including all-cause 30-day and 60-day early mortality, and global maximum DNA demethylation from baseline by LINE-1 assay. Results: Fifty two patients were treated with median age 77 (range 66-92) including 40 (77%) ≥75y; 34 (65%) male; 21 (40%) PS ≥ 2; 19 (36%) poor risk cytogenetics; and 13 (25%) secondary AML. The median bone marrow blasts percentage was 49% (range 16-98%). All patients had a minimum follow up of 3 months; 26 (50%) patients remain on treatment at the time of the analysis. Overall CR was observed in 24 patients (46%):14 CR (27%), 8 CRi (15%), and 2 CRp (4%). There was no significant difference between median DNA demethylation in responders (- 27%) and non-responders (-28%). Early all-cause 30-day and 60-day mortality occurred in 2 (4%) and 10 (19%) patients respectively. The most common Grade ≥3 Adverse Events considered by investigators to be drug-related were febrile neutropenia (33%), thrombocytopenia (27%), neutropenia (21%), anemia (15%), bacteremia (10%), and pneumonia (6%). Conclusions: Administration of guadecitabine as a more intense 10-day regimen for the first 1-2 cycles was active with acceptable toxicity. However, and although it was not a randomized comparison, the 10-day regimen did not result in higher rate of Overall CR in previously untreated AML than what was previously reported for the 5-day regimen. A Phase III randomized clinical trial in previously untreated AML patients not considered candidates for intensive chemotherapy has been initiated with the 5-day regimen of guadecitabine. Reference: Yee K, Daver N, Kropf P, et al: European Hematology Association Meeting, June 12-15, 2104; Milan, Italy. Abstract S647. Citation Format: Gail Roboz, Hagop Kantarjian, Patricia Kropf, Ellen Richie, Nitin Jain, Elizabeth Griffiths, Nikola A. Podoltsev, Katherine Walsh, Casey O'Connell, Wendy Stock, David Rizzieri, Raoul Tibes, Todd Rosenblat, Woonbok Chung, Pietro Taverna, Xiang Yao Su, Sue Naim, Mohammad Azab, Jean-Pierre Issa. First results of a 10-day regimen of SGI-110 (guadecitabine), a second generation hypomethylating agent (HMA) in previously untreated elderly AML who are not candidates for intensive chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT321. doi:10.1158/1538-7445.AM2015-CT321

PurposeTo examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course.Patients and MethodsIn all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients.ResultsAuto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT.ConclusionFor patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

SummaryPre‐existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non‐Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS+) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS−). There were significant baseline differences between the cohorts. CNS+ patients were more likely to be younger, have lower performance scores, higher age‐adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression‐free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS+ group with a subset of CNS− patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS+ patients can achieve excellent long‐term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.

Abstract SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE's were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214