ALBERT

Description: Key Points Hundreds of lineage-specific lncRNAs are expressed during mouse and human erythropoiesis. Most mouse erythroid lncRNAs are not expressed in human erythroblasts and vice versa, yet some appear to be functional.

Description: Introduction Children and young adults with relapsed acute lymphoblastic leukemia (ALL) are at high risk for infectious complications, particularly invasive fungal infections, during their intensive re-induction therapy. We report results of a Pilot study investigating decitabine and vorinostat in combination with intensive re-induction chemotherapy for children and young adults with relapsed or refractory ALL. This study is currently open through the TACL Consortium [NCT01483690] and all patients and/or their parents or guardians signed informed consent to participate in this institutional review board approved therapeutic trial in accordance to the Declaration of Helsinki. Methods Patients 1-25 years of age with 2nd or greater relapse or refractory ALL are eligible. Seventeen patients have enrolled with a median age of 12 years (range, 19 months - 21 years). Patients received one course of therapy which included decitabine (15mg/m2 days 1-7; 15-21), vorinostat (180mg/m2 days 3-10; 17-24), vincristine (1.5mg/m2 days 10, 17, 24, 31), dexamethasone (10mg/m2/dose BID days 8-12; 22-26), mitoxantrone (10mg/m2 days 8, 9), PEG-asparaginase (2500 IU/m2 days 10, 24) and intrathecal methotrexate (dosed according to age and CNS status). Nine patients (53%) relapsed after a prior allogeneic hematopoietic cell transplant and 5 patients had refractory disease (29%) prior to enrolling on this study. Initial infection prophylaxis guidelines did not require anti-bacterial or anti-fungal therapy. Results The study was suspended after 5 patients enrolled due to 2 patients reporting a DLT [Grade 3 cholestasis/steatosis, Grade 4 bilirubin (n=1); Grade 3 delirium, Grade 4 seizure, Grade 4 somnolence (n=1)] and 4 of the 5 patients (80%) reporting non-albicans Candidemia [C. kruseii (n=2), C. lusitaniae (n=1), C. guillermondii (n=1)]. Based on this significant rate of fungal infection, despite all patients receiving prophylactic anti-fungal therapy (micafungin n=2, fluconazole n=1, amphotericin n=1), the study was amended to decrease the decitabine dose (15mg/m2 to 10mg/m2) and duration of decitabine (days 1-7; 15-21 to 1-5; 15-19) as well as require treatment dose non-azole class anti-fungal therapy (echinocandin or amphotericin) to be given to all patients on study. Twelve patients enrolled post-amendment; only 1 of 12 (8.3%) experienced a fungal infection (C. guillermondii). Of note, this infection occurred in a patient using fluconazole for prophylaxis in place of a protocol-specified agent. There have been no fungal infections reported to date for the 11 patients on study who have received echinocandin or amphotericin therapy at treatment doses. Treatment responses include 9 patients achieving a complete remission (CR) (53%), 5 with stable disease (29%), two treatment related deaths and 1 patient removed from protocol therapy on day 6 based on the physician’s decision. The median minimal residual disease (MRD) response in patients who achieved a CR and submitted bone marrow samples for end of therapy testing (n=5) was 0.056% (range, 0.00%-5%). Conclusions We report a substantial initial incidence of invasive Candida infections in patients treated with decitabine and vorinostat in combination with intensive chemotherapy despite anti-fungal prophylaxis which appears to be abrogated once the fungal prophylaxis was required at treatment doses using either an echinocandin or amphotericin class agent. As well, the lower dose and duration of decitabine may have contributed to this improvement, resulting in potentially shorter periods of neutropenia which may contribute to the risk of fungal disease. The mechanism for the unique propensity for non-albicans Candida infections in this study remains unclear. The initial response to this regimen incorporating epigenetic therapy is promising with correlative biology studies investigating methylation, acetylation and gene expression changes pending study completion. The study continues to accrue at a dose expansion cohort. Disclosures Off Label Use: Decitabine in relapse ALL Vorinostat in relapse ALL.

Description: Background: Although HMA (azacitidine [aza] or decitabine [dac]) are standard of care therapies for HR-MDS pts, responses may not be seen for 4-6 months and occur in

Description: Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood. Patients (pts) with relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) and/or multiple prior salvage therapies and/or refractory disease have a particularly poor prognosis. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects T cells to CD19+ B cells resulting in serial lysis. In phase 2 clinical studies, blinatumomab has demonstrated antitumor activity in adults with relapsed/refractory non-Hodgkin lymphoma and ALL. We evaluated efficacy and toxicity of blinatumomab in pediatric pts with relapsed/refractory ALL who have a particularly poor prognosis. Methods: Eligible pts were 2-18 years of age and had B-cell precursor ALL that was refractory, in ≥2nd bone marrow relapse, or in any marrow relapse after alloHSCT. This was a multicenter, open-label study using a Simon 2-stage design with a phase 1 and a phase 2 part. In the phase 1 part, a stepwise dose of 5→15 µg/m²/day was established as the recommended phase 2 dose (von Stackelberg et al. Blood. 2013;122:70). Blinatumomab was given by continuous intravenous infusion for 4 weeks (5 µg/m²/day for the first week and 15 µg/m²/day thereafter), followed by two treatment-free weeks (one cycle) for up to five cycles. The primary endpoint for the phase 2 part of the study was rate of complete remission (CR) within the first two cycles of treatment, including CR with incomplete hematologic recovery. Secondary endpoints included relapse-free survival (RFS), rate of advancement to alloHSCT, overall survival (OS), and incidence and severity of adverse events (AEs). Minimal residual disease (MRD) response (20% of pts were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%). The most common grade ≥3 AEs included anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%). Cytokine-release syndrome occurred in three (8%) pts, two of whom (5%) had grade 3 events. Conclusions: Blinatumomab showed promising antileukemia activity in heavily pretreated pediatric relapsed/refractory B-cell precursor ALL pts, with a median time from last relapse of 2.1 months. Half of the pts who responded within the first two cycles were able to receive alloHSCT following blinatumomab-induced remission, suggesting that blinatumomab may open a window for alloHSCT in those pts who are resistant to salvage chemotherapy. Disclosures Gore: Amgen Inc.: Travel Support Other. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. von Stackelberg:Amgen Inc.: Consultancy, Honoraria.

Description: Introduction: Blinatumomab, an investigational bispecific T-cell engager (BiTE®) antibody construct, has been shown to induce remission in adult patients with relapsed/refractory BCP-ALL. Medically important adverse events (AEs) related to blinatumomab treatment in adults are cytokine release syndrome (CRS) and neurological events. We report the primary analysis of the phase 1 portion of a multicenter phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods: In this continuing study, eligible patients are

Description: Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is dependent upon dysregulated signaling through the B-cell receptor (BCR) pathway. Bruton’s tyrosine kinase (BTK) mediates BCR signaling, and inhibition of BTK with ibrutinib, a selective, irreversible BTK inhibitor, is effective and well tolerated for patients (pts) with relapsed/refractory CLL/SLL. However, complete remissions (CRs) are infrequent, mechanisms of resistance to single-agent ibrutinib have been identified, and the duration of response beyond 3 years is unknown. Lenalidomide, a multi-functional immunomodulatory agent, is active in CLL/SLL, but limited by tumor flare reactions, which occur secondary to B-cell activation. Ibrutinib and lenalidomide modulate several key overlapping factors involving the CLL tumor microenvironment, and therefore a phase 1 combination study with lenalidomide dose escalation was undertaken. Methods: The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with ibrutinib. Secondary objectives included assessments of efficacy, PK/PD, and other mechanistic correlative studies. A 1-month (cycle 0) period of 420 mg of daily oral ibrutinib was administered as a single agent to decrease BCR signaling and mitigate lenalidomide-associated tumor flare. Beginning with the second month (cycle 1), ibrutinib was given concomitantly with lenalidomide. Four dose escalation cohorts of lenalidomide were planned using a 3+3 design; 2.5, 5, 7.5 and 10 mg. After the 2.5 mg cohort, intra-patient dose escalation was employed: in cohort 2, pts received 2.5 mg in week 1 followed by 5 mg subsequently; pts in cohort 3 received 2.5 mg in week 1, 5 mg in week 2 and 7.5 mg subsequently; pts in cohort 4 will receive 2.5 mg in week 1, 5 mg in week 2, 7.5 mg in week 3 and 10 mg subsequently. Ibrutinib was not dose escalated (420 mg). Pts receive 12 cycles of the combination, after which lenalidomide is discontinued and ibrutinib continues until unacceptable toxicity or disease progression. Eligible pts had relapsed/refractory CLL/SLL with adequate organ and bone marrow function. Pts who relapsed after stem cell transplantation were excluded. Results: To date, 11 pts were enrolled; 9 are evaluable (1 voluntarily withdrew consent prior to completing 3 cycles, the protocol-defined minimum to be evaluable, and 1 was a screen fail). The median age was 65 (49-81). Eight were male and 8 had CLL. Median Rai stage was 1 (1-4). The median number of prior therapies was 2 (range 1-8); 3 were purine analog resistant. Six had bulky (〉5 cm) disease. Two had del(17p13.1) and 4 had del(11q22.3). The median number of cycles completed was 8 (range 1-13). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. Possibly related grade 1/2 AEs that occurred in 〉1 patient included: rash (n=4), muscle cramps (n=3) and abdominal discomfort (n=2). Possibly related grade 3 AEs included neutropenia (n=4), lymphocytosis (n=2), neutropenic fever (n=1), anemia (n=1) and thrombocytopenia (n=1). There was 1 possibly related grade 4 AE, neutropenia, which was pre-defined as DLT, in the 7.5 mg lenalidomide cohort. One patient experienced grade 2 tumor pain, thought to be due to a lenalidomide-associated tumor flare reaction. Four pts required a lenalidomide dose reduction, for neutropenia (n=2) and fatigue (n=2). Six required a treatment hold, of either lenalidomide or both agents, for a median 7 days (2-28), for neutropenia (n=2), anemia (n=1), fatigue/diarrhea (n=1), atrial fibrillation (n=1) and to obtain a lymph node biopsy (n=1). Lymphocytosis was noted in 5 pts, peaking at a median of 22.5 days. The ORR is 100% (9/9), with all responders experiencing PRs. One progressed with Richter’s transformation during cycle 7, 4 months after achieving a PR. All 9 remain alive with a median follow up of 263 days (range 97-391). The 7.5 mg dose cohort is currently being expanded to 6 pts; after the MTD is determined, a 10 patient dose expansion cohort will commence. Conclusions: Ibrutinib with lenalidomide appears to be well tolerated, although lenalidomide dose reductions were common. Tumor flare reactions were rare. Response assessments at higher dose cohorts of lenalidomide are ongoing. Completed phase 1 data, preliminary data from the expansion cohort and correlative findings will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for CLL/SLL. Byrd:Genentech: Research Funding; Pharmacyclics: Research Funding.

Description: Introduction Children with relapsed T-ALL and T-LL have a dismal prognosis, with survival of less than 25% (Goldberg et al, J Clin Oncol 2003; Reismuller et al, Brit J Haematol 2009). Fewer than a third of children with relapsed T-ALL/LL attain a second remission with standard reinduction therapies (Raetz et al, J Clin Oncol 2008). Nelarabine (NEL) is a purine nucleoside analogue prodrug of AraG, which is resistant to cleavage by endogenous purine nucleoside phosphorylase and cytotoxic to T-lymphoblasts at micromolar concentrations. NEL has substantial single-agent activity in first and multiply relapsed T-ALL (Berg et al, J Clin Oncol 2005). In an effort to improve reinduction rates for children with T-ALL and T-lymphoblastic lymphoma (T-LL) in first relapse, we evaluated the safety and preliminary efficacy of NEL in combination with cyclophosphamide (CPM) and etoposide (ETOP) in this setting. Methods T2008-002: A Phase I trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse), is an investigator-initiated collaboration between the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium (TACL), the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC), and the Innovative Therapies for Children with Cancer consortium (ITCC). Eligible patients had first relapse or initial induction failure of T-ALL or T-LL, no CNS-3, no prior stem cell transplantation, and adequate performance status and organ function. The studyÕs primary objective was to establish the recommended phase 2 doses (RP2D) of NEL and CPM in combination with a fixed dose of ETOP. Subjects received a single course of NEL (325-650 mg/m2) and CPM (330-440 mg/m2) at 1 of 3 assigned dose levels in combination with a fixed ETOP dose (100 mg/m2), each for 5 consecutive days. Intrathecal therapy was administered no less than 7 days prior to or 21 days following the start of a course. Responding patients without dose-limiting toxicity (DLT) were eligible for a second course. The primary study endpoint was the occurrence of dose-limiting toxicity (DLT) during course 1. Secondary endpoints included rates of CR2, complete remission without platelet recovery (CRp), or partial response (PR), and minimal residual disease (MRD) levels at the end of each course. Results Of 19 children enrolled on T2008-002, 6 were enrolled at Dose Level (DL) 1 (NEL 325 mg/m2, CPM 330 mg/m2), 7 at DL2 (NEL 650 mg/m2, CPM 330 mg/m2), and 6 at DL3 (NEL 650 mg/m2, CPM 440 mg/m2). Two potential DLTs led to subject removal during course 1, but were later reversed upon committee review and those subjects replaced. 17 patients were evaluable for DLT and response. Confirmed DLTs occurred in 2 patients: 1 at DL2 (grade 2 (Gr2) motor neuropathy and Gr3 sensory neuropathy) and 1 at DL3 (Gr3 sensory neuropathy). Other ³ Gr3 non-hematologic adverse events are listed in the Table. Of 9 T-ALL patients evaluable for response, there were 2 CRs,1 CRp and 1 CR in the bone marrow/PR in an extramedullary site, with responses at all dose levels, for a response rate of 44% in the T-ALL cohort; at the RP2D, 2/4 evaluable T-ALL patients had a response. Of 8 T-LL patients evaluable for response, there were 2 CRs (1 each at DL1 and DL2), for an overall T-LL response rate of 25%. Eight patients received a second course of NECTAR; 9 subsequently underwent HSCT. MRD levels were available for 2 responding T-ALL patients, with 0.027% and 0.07% blasts after Course 1 and 0.07% and 5% of SubjectsToxicity (CTC3.0)Grade ³ 3 Anorexia3 (16%)Aspartate aminotransferase increased2 (11%)Diarrhoea NOS2 (11%)Febrile neutropenia6 (32%)Hyperkalemia2 (11%)Hypoalbuminaemia3 (16%)Hypocalcaemia4 (21%)Hypokalemia8 (42%)Hypotension NOS2 (11%)Nausea3 (16%)Pleural effusion3 (16%)Vomiting NOS2 (11%)Pain-Other2 (11%) Conclusions The recommended phase 2 doses (RP2D) for NECTAR are NEL 650 mg/m2, CPM 440 mg/m2 and ETOP 100 mg/m2, each given daily for 5 days. The activity and toxicity seen in this phase I dose escalation cohort compare favorably with established reinduction regimens in relapsed T-ALL/LL. An ongoing cohort expansion at the RP2D will better define the activity of NECTAR in first relapse of T-ALL and T-LL. Acknowledgments: Glaxo-Smith-Kline; Higgins Family Foundation; Women's Auxiliary Millennium Chair in Haematology/Oncology Disclosures Whitlock: Glaxo-Smith-Kline: Research Funding. Off Label Use: Nelarabine, cyclophosphamide and etoposide for relapsed T-ALL/T-LL are off-label drug uses.. Zwaan:GSK: Research Funding. Gore:GSK: Research Funding.

Description: Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts 〉5%) and CMML patients (pts) with 18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade 〉3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events 〉grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy 〉6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Description: Key Points CBFβ is not required for the emergence of nascent HSCs but is essential for a subsequent step before their release from the AGM. RUNX1 is able to drive the emergence of nascent HSCs in the AGM in the absence of its cofactor CBFβ.