ALBERT

Description: This volume summarizes the results of recent research on the Ontong Java Plateau (OJP) in the western Pacific Ocean (Fig. 1). The plateau is the most voluminous of the world's large igneous provinces (LIPs) and represents by far the largest known magmatic event on Earth. LIPs are formed through eruptions of basaltic magma on a scale not seen on Earth at the present time (e.g. Coffin & Eldholm 1994; Mahoney & Coffin 1997). Continental flood basalt provinces are the most obvious manifestation of LIP magmatism, but they have oceanic counterparts in volcanic rifted margins and giant submarine ocean plateaus. LIPs have also been identified on the Moon, Mars and Venus, and may represent the dominant form of volcanism in the solar system (Head & Coffin 1997). The high magma production rates (i.e. large eruption volume and high eruption frequency) involved in LIP magmatism cannot be accounted for by normal plate tectonic processes. Anomalously hot mantle often appears to be required, and this requirement has been a key consideration in the formulation of the currently favoured plume-head hypothesis in which LIPs are formed through rapid decompression and melting in the head of a newly ascended mantle plume (e.g. Richards et al. 1989; Campbell & Griffiths 1990). Eruption of enormous volumes of basaltic magma over short time intervals, especially in the subaerial environment, may have had significant effects on climate and the biosphere, and LIP formation has been proposed as one of the causes of mass extinctions (e.g. Wignall 2001). Several issues ... This 250-word extract was created in the absence of an abstract.

Description: Outcomes for elderly patients with AML are almost uniformly poor, and it has been shown (Wheatley et al., Blood2005, 106(11) 199a) that patients with adverse cytogenetics have a particularly poor prognosis. Additionally, a large proportion of such patients are considered not to be fit for intensive chemotherapy (Juliusson et al, Leukemia, 2006 (20): 42–7), and given best supportive care, or low-dose Ara-C. The NCRI AML14 trial observed no remissions in 18 patients with adverse cytogenetics treated with Ara-C, and no remissions in 20 patients treated with hydroxyurea. We present here a combined analysis of the BIOV-121 Study, and the UWCM-0001 study. Both studies were for untreated patients over 65 years of age who were not considered fit for chemotherapy. The treatment comprised clofarabine 30mg/m2 on days 1–5 repeated after 28–42 days for up to 3 courses. The primary endpoints were overall response (CR, CRi or PR) and safety. Patients: A total of 95 patients were recruited, of whom 95 received clofarabine 30mg/m2. Twenty-six patients (27%) had adverse cytogenetics. Results: 10/26 patients (38%) achieved either CR or CRi. With a median follow-up of 10 months (range 2–17 months), 1 year survival is 20%, with 19/26 patients having died. At most recent follow-up, 4/10 patients achieving CR or CRi are still alive in remission. Discussion: The remission rate of 38% seen with clofarabine compares favourably, not only with traditional non-intensive approaches (which have failed to induce any remissions in similar sized cohorts), but also to the 42% remission rate seen in patients treated with intensive daunorubicin/Ara-C based chemotherapy in the NCRI AML14 trial. One year survival rates are also encouraging, at 20% compared to 0%, 5% and 23% for patients treated with Ara-C, supportive care, and intensive chemotherapy respectively. Exploratory comparisons of survival between the 30mg clofarabine patients and the three treatment regimens give highly significant survival advantages compared to Ara-C and HU (p=0.0001, p=0.004 respectively) and no significant difference between clofarabine and DA (p=1.0), although confidence intervals in this case are wide. Conclusions: Clofarabine has the ability to induce remissions in patients with adverse cytogenetics, unlike Ara-C and supportive care, and survival in this group is improved. Remission rates and survival are similar to those seen for patients treated with intensive chemotherapy. Clofarabine is clearly worthy of further investigation, and may provide an important treatment option for high risk patients with AML.

Description: Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs 〉 grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)〉SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Description: Background: The treatment of older patients with AML is unsatisfactory and not improving. A substantial proportion of patients are not offered a standard intensive (“3+7”) chemotherapy approach because they are not considered medically fit (Juliusson et al, Leukemia, 2006 (20):42-7). Such patients are usually treated with best supportive care or low-dose Ara-C with a median survival of approximately 3 months. BIOV-121 is an open-label non-randomised multicentre international study of clofarabine, a next generation purine nucleoside analogue, in elderly patients (≥ 65 yrs) with previously untreated acute myeloid leukaemia (AML) who are unsuitable for standard (“3+7”) treatment. Methods: 66 patients aged ≥ 65 with untreated AML (WHO classification) were enrolled in study BIOV-121. Clofarabine was administered at a dose of 30mg/m2 for 5 days repeated every 28–42 days (1 course) for a maximum of 3 courses. All patients were considered unsuitable for standard intensive treatment based primarily on age, comorbidity and/or performance status. The primary endpoint of the study was overall response rate defined as the number of patients achieving a CR, CRi or PR according to the international working group guidelines. Results: 66 patients were recruited with a median age of 71 (range 64–81). 48 patients had de novo and 16 had secondary AML. 72% had an ECOG performance sore of

Description: Abstract 4625 CLL - Therapy, excluding Transplantation Acadesine induces cell death in B-cell chronic lymphocytic leukemia (CLL) cells in a dose-dependent manner. Acadesine enters B-cells where it is phosphorylated to ZMP, which induces apoptosis independently of ATM or p53. It is active in vitro against CLL cells from patients who have not responded to prior treatment with fludarabine and/or chlorambucil. A phase I/II open-labeled clinical study was designed to determine the safety and tolerability of acadesine given intravenously as a 4-hour infusion to patients with CLL. Part I is the dose escalation part of the study where patients receive a single dose of acadesine on Day 1 and are followed up to Day 22. In Part II, patients will receive up to 5 doses of acadesine at the maximum tolerated dose (MTD) identified in Part I over a period of up to 20 days. Patient population includes CLL patients with relapsed/refractory disease who have received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. A patient is defined as having refractory disease if they fail to achieve less than a partial response (PR) according to the NCI working group guidelines, or relapse within the first 6 months after treatment after achieving at least partial response. Primary endpoints of the study evaluate the safety and tolerability of acadesine. Secondary endpoints evaluate the pharmacokinetics of acadesine and ZMP, and B and T-cell counts in peripheral blood as efficacy biomarkers. Twenty-one patients have been included to date, eighteen in Part I at doses of 50, 83.5, 139.5, 210 or 315 mg/kg, and three in Part II, with two doses at 210 mg/kg at days 1 and 4. Pharmacokinetic data showed acadesine is rapidly converted into ZMP inside blood cells. In part I, at single acadesine dose, the Cmax levels for ZMP in whole blood obtained at 315 mg/kg were similar to the ones obtained at the previous dose (210 mg/kg), suggesting that the saturation plateau was reached, which was confirmed by the PK modeling. In 5 patients treated with acadesine at 210 mg/kg and 315 mg/kg a decrease in absolute B cell count was observed, ranging from 6% to 54% with respect to the B cell count prior to acadesine administration. Reversible asymptomatic hyperuricaemia was observed in four patients in cohorts 1 to 3, probably due the metabolism of acadesine to ZMP and uric acid. Prophylactic allopurinol was used in cohorts 4 and 5 and it has significantly reduced the incidence of hyperuricaemia. Acadesine 315 mg/kg was the dose limiting toxicity (DLT) dose with 2 of 3 patients having DLTs-Tumour Lysis Syndrome (TLS) and clinically significant acute renal failure (CTCAE V3.0 Grade 3-chronic dialysis not indicated). We started Part II of the study, with two consecutive doses at 210 mg/kg (Optimal Biological Dose). Three patients have been included to date. No DLT nor grade 3 or 4 Adverse Events related to acadesine were observed, and in all of treated patients a decrease in absolute B cell count was observed ranging from 6% to 35% with respect to the B cell count prior to acadesine administration. In the following cohort, we will administer 5 consecutive doses of acadesine at 210 mg/kg, at days 1, 4, 8, 11 and 15. In conclusion, a MTD was found at one single acadesine dose. Two consecutive doses have already been tested without safety concerns and 5 consecutive doses are currently planned in part II of this ongoing study. Results for this cohort and additional safety, pharmacokinetics and efficacy data will be presented at the meeting. Disclosures: Saunders: Advancell: Consultancy. de Frias:Advancell: Employment. Campàs:Advancell: Employment.