ALBERT

Description: Melt pond covered sea ice is a ubiquitous feature of the summertime Arctic Ocean when meltwater collects in lower-lying areas of ice surfaces. Horizontal transects were conducted during June 2008 above and below landfast sea ice with melt ponds to characterize surface and bottom topography together with variations in transmitted spectral irradiance. We captured a rapid progression from a highly flooded sea ice surface with lateral drainage toward flaws and seal breathing holes to the formation of distinct melt ponds with steep edges. As the mass of the ice cover decreased due to meltwater drainage and rose upward with respect to the seawater level, the high-scattering properties of ice above the water level (i.e., white ice) were continuously regenerated, while pond waters remained transparent compared to underlying ice. The relatively stable albedos observed throughout the study, even as ice thickness decreased, were directly related to these surface processes. Transmission through the ice cover of incident irradiance in the 400-700 nm wave band ranged from 38% to 67% and from 5% to 16% beneath ponded and white ice, respectively. Our results show that this transmission varied not only as a function of surface type (melt ponds or white ice) areal coverage but also in relation to ice thickness and proximity to other surface types through the influence of horizontal spreading of light. Thus, in contrast to albedo, this implies that regional transmittance estimates need to consider melt pond size and shape distributions and variations in optical properties and thickness of the ice cover.

Description: Background: Although daunorubicin/cytarabine ("3+7")-based chemotherapy (CT) regimens produce complete remission (CR) rates of approximately 70% in younger adults, about 30% require re-induction. Among those achieving CR, relapse after post-remission intensive CT or allogeneic transplant is common and limits cure. Venetoclax (VEN) is an orally available selective BCL-2 inhibitor that promotes mitochondrial-mediated apoptosis in myeloblasts during cytotoxic stress. VEN in combination with hypomethylating agents and low dose cytarabine in untreated unfit elderly AML patients (pts) elicits high response and led to drug approval in that setting. VEN in combination with standard '3+7" could lead to a higher rate of measurable residual disease (MRD)-negative CR, perhaps obviating the need for reinduction as well as limiting relapse after consolidation therapy without undue toxicity. Methods: The primary objective of this phase 1 study is to determine the maximum tolerated dose of VEN that can be given in combination with standard intensive induction (ind) and consolidation CT in previously untreated AML pts. Pt eligibility includes no prior treatment (rx) for AML, FLT3 wild type, non-inv16 or t(8; 21) AML, either de novo or secondary. Pts must not require strong CYP3A inhibitors/inducers, have normal organ function, have WBC=18 (study amended to include only those age 18-60 after the first 6 pts were treated). VEN is given during ind on days 1-11 in cohorts of 200, 400, and 600 mg/d/ (after 4 d ramp-up) with daunorubicin 60 mg/m2/d IVP days 2-4 and cytarabine 200 mg/m2/d by IVCI days 2-8. A day 15 marrow determines the need for a second ind consisting of the same doses of VEN, daunorubicin and cytarabine given on days 1-8, 2-3, and 2-6, respectively. VEN escalation is carried out in 3+3 fashion. Once the MTD for VEN during ind is determined pts will be treated at that dose during ind and remitting pts given escalating doses (cohorts of 200, 400, 600 mg) of VEN d1-8 in a 3+3 fashion (beginning at one dose level below the MTD (or 100 mg if 200 mg is determined to the ind MTD)) with a single cycle of cytarabine 3g/m2 over 3h q 12 h on days 1, 3, and 5. A 10 pt confirmation cohort will be accrued at the MTD. Dose-limiting toxicity (DLT) is defined as any death, delayed neutrophil recovery (failure to achieve absolute neutrophil count (ANC) ≥ 500/mL by day 42 in pts without residual AML), or any gr 4 non-heme non-resolving toxicity not clearly due to CT alone. A marrow exam, including an assessment of MRD by multiparameter flow cytometry with a sensitivity of 0.02%, is carried out at the time of count recovery during induction but no later than day 42. Correlative studies include flow cytometry-based BH3 profiling (Vo TT, Cell, 2012) on blasts obtained at enrollment and just prior to chemo and CyTof to characterize BCL-2-associated proteins. Results: The first pt treated (58 yo F with normal karyotype, and NGS panel showing a DNMT3A mutation, though subsequent PCR-based assay disclosed a FLT3 ITD) developed gr 4 DIC after the first dose of VEN 50 mg (required factor replacement for elevated INR, but had no bleeding). VEN was stopped and she achieved an MRD negative CR with standard ind, but the first cohort was expanded to 6 pts. 4 of the 5 additional pts achieved a CR, but a 73 year old man died of nadir sepsis at d 14. Given 2/6 DLT events, VEN 200 was considered unacceptable by protocol design. An amendment allowed further accrual at the starting dose of VEN 200 mg but restricted accrual to age 18-60. All 3 pts on the expanded cohort have responded, and none experienced a DLT, so accrual to the VEN 400 mg cohort is now beginning. None of the pts required a second ind course and no tumor lysis was seen. The median time to ANC and platelet recovery to 1K/ul and 100K/ul in the 7 pts who received all planned VEN is 36 d (range 24-43) and 27 d (range 24-55), respectively. The table lists the specific pt characteristics, adverse events and outcome. Conclusions: We have preliminarily shown that VEN 200 mg/d beginning one d prior and until three d after 3+7 ind can be given safely in pts age 18-60; escalation to VEN 400 mg is ongoing. Flow based MRD-negative remissions have been noted after a single ind cycle. Plans are underway to compare the VEN/3+7 ind regimen derived from this trial to 3+7 in non-favorable risk newly diagnosed AML pts ages 18-60 in the context of a North American Intergroup study. Table Disclosures Stone: Novartis: Consultancy, Research Funding; Macrogenics: Consultancy; Astra-Zeneca: Consultancy; Arog: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Otsuka: Consultancy; Agios: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Other: DSMB; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Otsuka: Consultancy; Biolinerx: Consultancy; Argenix: Other: DSMB; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenix: Other: DSMB; Stemline: Consultancy; Biosight: Consultancy; Roche: Consultancy; Takeda: Other: DSMB; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Consultancy; Trovagene: Consultancy; Biolinerx: Consultancy; Jazz: Consultancy; Trovagene: Consultancy. DeAngelo:Incyte: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Celgene: Consultancy; GlycoMimetics: Research Funding; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Shire: Consultancy; Takeda Pharmaceuticals: Consultancy; Abbvie: Research Funding. Galinsky:Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: Member on specialty oncology board. Letai:AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding; Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member. Konopleva:Kisoji: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. OffLabel Disclosure: Venetoclax is being used off label in combination with standard and induction and consolidation chemotherapy in AML

Description: Key Points Costimulatory blockade using abatacept represents a novel therapeutic approach for the treatment of cGVHD. Abatacept resulted in a clinical response in 44% of patients with both decreased prednisone use and T-cell PD-1 expression in responders.

Description: Introduction: Chronic graft versus host disease (cGVHD) remains a major source of morbidity and mortality following allogeneic transplantation. While corticosteroids remain first line therapy for cGVHD, they are associated with significant toxicity, and a substantial proportion of patients fail to completely respond. Treatments for steroid-refractory cGVHD are limited. While the pathophysiology of chronic GVHD is complex, activated T cells play a critical role, driven by allo-antigen stimulation. As such, inhibition of T cell activation via blockade of co-stimulation has potential as a therapeutic target in cGVHD. Abatacept is a recombinant fusion protein consisting of the extracellular domain of human CTLA-4 and a fragment of the Fc domain of human IgG1 that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is the first drug in a class of agents termed "selective co-stimulation modulators." The CTLA-4 moiety of Abatacept binds specifically to CD80 and CD86 and down-modulates the CD28-mediated co-stimulation of T cells. We conducted a phase I clinical trial was conducted to evaluate the safety, clinical and immune effects of Abatacept in patients with steroid-refractory cGVHD. Methods: The study followed a 3+3 design with two escalating doses of Abatacept to determine the maximum tolerated dose (MTD): 3 mg/kg and 10 mg/kg. Dose-limiting toxicities (DLTs) were defined as Grade 3 or 4 toxicities judged to be probably or definitely related to Abatacept. Infection was not considered a DLT. Abatacept was administered for a total of 6 doses. Doses 1-3 were administered at two-week intervals. One month following Dose 3, Abatacept was given at four-week intervals for three doses (Doses 4-6). Inclusion criteria included recipients of allogeneic bone marrow or stem cell transplantation with myeloablative or reduced intensity conditioning, with cGVHD defined by NIH consensus criteria. Patients must have had treatment with ≥ 0.5 mg/kg/day of prednisone for at least 4 weeks. Patients with active malignant disease relapse or other active malignancy and patients with uncontrolled infection were excluded. Peripheral blood was drawn prior to each dose of Abatacept and following completion of therapy to assess the effect of treatment on circulating T cells. PD-1 expression on circulating T cells, and T cell expression of interferon gamma versus IL-10 was assessed by multichannel FACS analysis. Results: 17 subjects were treated. Three patients were treated at a dose of 3 mg/kg without DLT. Three evaluable patients completed treatment on cohort 2, at a dose of 10mg/kg without DLT. A forth participant withdrew consent following one dose of treatment and therefore is not evaluable. Ten patients were treated on an expansion cohort at a dose of 10mg/kg. We observed one grade 4 pulmonary infection, and three grade 3 pulmonary infections which resolved. Other Abatacept related adverse events included grade 2 gastritis (n=1), grade 2 pain (n=1), and grade 1 diarrhea (n=2), fatigue (n=2), rash (n=1), and skin pain (n=1). Of the 16 evaluable patients, 7 (44%) achieved a clinical partial response as defined by improvement of two disease systems based on the 2011 NIH consensus criteria. Abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders with a mean baseline dose of 27mg compared to a mean dose of 14mg 1 month following the 6th dose of Abatacept (p = 0.01). PD-1 expression on circulating CD4+ and CD8+ T cells increased from a mean of 3.4% and 2.7% respectively at baseline to a mean of 8.9% and 7.6% respectively at one month following the 6thdose of Abatacept in clinical responders (n=3; p

Description: Background: Current chemotherapy regimens in children with acute lymphoblastic leukemia (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 40%, and less than 20% for patients over 60 years of age. The oral BCL2 inhibitor venetoclax has improved response rates in older patents with AML who are not candidates for standard induction chemotherapy. Furthermore, BH3 profiling and protein analysis has shown that ALL cell lines and primary cells exhibit BCL-2 dependence, supporting clinical trials of BCL-2 antagonists in ALL (Del Gaizo Moore et al Blood 2008; Benito et al Cell Rep 13:2715, 2015). This phase I trial was performed to determine if venetoclax can be safely added to a reduced intensity chemotherapy regimen for older adults with untreated ALL and in patients with R/R ALL. Methods: Patients (pts) over 60 yrs or older with untreated, Philadelphia chromosome negative ALL were eligible. After the first 6 pts were enrolled, the study was amended to allow enrollment of adults 18 yrs or older with R/R ALL. The primary objective of this study was to determine the feasibility of a 21-day schedule of venetoclax with the mini-hyper-CVD chemotherapy regimen. The therapeutic backbone of this protocol was based on a lower intensity version of hyper-CVAD with no anthracycline (Kantarjian et al Lancet Oncol 2018). Two dose levels of venetoclax were tested, 400 mg and 600 mg for 21 days of each cycle. The induction chemotherapy consisted of mini-hyper fractionated cyclophosphamide, vincristine, dexamethasone, alternating with cycles of methotrexate and cytarabine. Two doses of intrathecal chemotherapy were administered per cycle during the first four cycles. Upon completion of induction/consolidation chemotherapy, patients could receive an allogeneic stem cell transplant (SCT) or receive venetoclax plus POMP maintenance chemotherapy. Bone marrow and peripheral blood samples were collected for BH3 profiling and CyTOF to measure Bcl-2 family expression. The analysis is ongoing and will be reported. Results: To date 18 pts were enrolled. Three pts at dose level 1 (400 mg), 6 pts at dose level 2 (600 mg; the highest dose tested) and 9 pts in the expansion cohort (600 mg), which is the recommended phase II dose (RP2D). There has been no protocol defined DLTs. The median age was 65 yrs, (range, 23-82), 78% were male, 56% B-lineage, 56% were previously untreated. For the older de novo pts, 7 had B-ALL with 5 pts with haploid/near triploid cytogenetics and TP53 mutations. Two pts had ETP-ALL and 1 pt with mature T-ALL. In this group of untreated de novo pts, the overall response rate (ORR) rate was 100% with 9/10 (90%) achieving CR and 1 pt PR (Table 1 and Figure 1). All CR pts achieved an MRD negative status by multicolor flow cytometry with a sensitivity of 0.01%. Of the 10 pts with de novo ALL, 4 pts remain on treatment, and 6 pts went to SCT. The median follow up for the de novo pts was 11.3 mos (range, 2.0-17.8) and the median duration of response for these patients was 9.9 mos (range 0.9, 15.7). There have been no relapses thus far in the de novo ALL cohort. For the R/R pts, the median number of prior regimens was 2.5 (range 1-5) and the CR/CRp rate was 3/8 (37.5%) with 2 pts MRD negative (25%). Of the 8 pts with R/R ALL, 2 pts remain on treatment. For all 18 pts, the grade 3 adverse events included febrile neutropenia (39%), hyperglycemia (17%) and hypocalcemia (11%). There were two grade 4 events, pneumonia and sepsis, and no grade 5 events. Conclusions: The administration of venetoclax with a reduced intensity chemotherapy regimen (mini-hyper-CVD) was safe and well tolerated. The RP2D dose was 600 mg daily for 21 days per cycle. This regimen was particularly well tolerated in the older previously untreated ALL population. Although the CR and MRD negative rates were exceptionally high for the older adult cohort, longer follow up and larger studies are needed. The addition of venetoclax may represent a major therapeutic advance in older adults with ALL. Disclosures Jain: Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stevenson:Celgene: Research Funding. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Garcia:Genentech: Research Funding; Abbvie: Research Funding. Stone:Arog: Consultancy, Research Funding; Otsuka: Consultancy; Biolinerx: Consultancy; Takeda: Other: DSMB; Trovagene: Consultancy; Novartis: Consultancy, Research Funding; Biosight: Consultancy; Agios: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Argenix: Other: DSMB; Amgen: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Stemline: Consultancy; Agios: Consultancy, Research Funding; Otsuka: Consultancy; Argenix: Other: DSMB; Roche: Consultancy; Macrogenics: Consultancy; Astra-Zeneca: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Jazz: Consultancy; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Actinium: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Trovagene: Consultancy; Otsuka: Consultancy; Argenix: Other: DSMB; Novartis: Consultancy, Research Funding; Stemline: Consultancy; Takeda: Other: DSMB; Agios: Consultancy, Research Funding; Jazz: Consultancy; Astra-Zeneca: Consultancy; Arog: Consultancy, Research Funding; Roche: Consultancy; Macrogenics: Consultancy; Otsuka: Consultancy; Biosight: Consultancy; Abbvie: Consultancy, Research Funding; Biolinerx: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Argenix: Other: DSMB; Biolinerx: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Celgene: Consultancy, Other: DSMB; Actinium: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kantarjian:Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Letai:AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding; Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member. Konopleva:Agios: Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding. DeAngelo:Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. OffLabel Disclosure: Venetoclax for patients with acute lymphoblastic leukemia.