ALBERT

Description: Methane-rich gas occurs in the total organic carbon–rich Alum Shale (Furongian to Lower Ordovician) in southern Sweden. The lower part of the thermally immature Alum Shale was impregnated by bitumen locally generated by heating from magmatic intrusions from the Carboniferous to the Permian. Organic geochemical data indicate that the migrated bitumen is slightly degraded. In the upper Alum Shale, where methane is the main hydrocarbon in thermovaporization experiments, centimeter-size calcite crystals occur that contain fluid inclusions filled with oil, gas, or water. The Alum Shale is thus considered a mixed shale oil–biogenic shale gas play. The presented working hypothesis to explain the biogenic methane occurrence considers that water-soluble bitumen components of the Alum Shale were converted to methane. A hydrogeochemical modeling approach allows the quantitative retracing of inorganic reactions triggered by oil degradation. The modeling results reproduce the present-day gas and mineralogical composition. The conceptual model applied to explain the methane occurrence in the Alum Shale in southern Sweden resembles the formation of biogenic methane in the Antrim Shale (Michigan Basin, United States). In both models, melting water after the Pleistocene glaciation and modern meteoric water may have diluted the contents of total dissolved solids (TDS) in basinal brines. Such pore waters with low TDS contents create a subsurface aqueous environment favorable for microbes that have the potential to form biogenic methane. Today, biogenic methane production rates, with shale as the substrate using different hydrocarbon-degrading microbial enrichment cultures in incubation experiments, range from 10 to 620 nmol per gram and per day.

Description: Oil degradation in the Gullfaks field led to hydrogeochemical processes that caused high CO 2 partial pressure and a massive release of sodium into the formation water. Hydrogeochemical modeling of the inorganic equilibrium reactions of water-rock-gas interactions allows us to quantitatively analyze the pathways and consequences of these complex interconnected reactions. This approach considers interactions among mineral assemblages (anorthite, albite, K-feldspar, quartz, kaolinite, goethite, calcite, dolomite, siderite, dawsonite, and nahcolite), various aqueous solutions, and a multicomponent fixed-pressure gas phase (CO 2 , CH 4 , and H 2 ) at 4496-psi (31-mPa) reservoir pressure. The modeling concept is based on the anoxic degradation of crude oil (irreversible conversion of n-alkanes to CO 2 , CH 4 , H 2 , and acetic acid) at oil-water contacts. These water-soluble degradation products are the driving forces for inorganic reactions among mineral assemblages, components dissolved in the formation water, and a coexisting gas at equilibrium conditions. The modeling results quantitatively reproduce the proven alteration of mineral assemblages in the reservoir triggered by oil degradation, showing (1) nearly complete dissolution of plagioclase; (2) stability of K-feldspar; (3) massive precipitation of kaolinite and, to a lesser degree, of Ca-Mg-Fe carbonate; and (4) observed uncommonly high CO 2 partial pressure (61 psi [0.42 mPa] at maximum). The evolving composition of coexisting formation water is strongly influenced by the uptake of carbonate carbon from oil degradation and sodium released from dissolving albitic plagioclase. This causes supersaturation with regard to thermodynamically stable dawsonite. The modeling results also indicate that nahcolite may form as a CO 2 -sequestering sodium carbonate instead of dawsonite, likely controlling CO 2 partial pressure.

Description: A novel hydrogeochemical modeling approach is developed to unravel thermochemical sulfate reduction (TSR) in hydrocarbon reservoirs. Our numerical model couples a web of interconnected hydrogeochemical reactions to three-dimensional (3-D) and reservoir-wide diffusive mass transport. Our modeling approach simulates a semigeneric gas reservoir sealed by anhydrite. The calculated diagenetic processes fit the observations in reservoirs affected by TSR: formation of water, precipitation of calcite, metal (di-)sulfides, and elemental sulfur as replacements of dissolved anhydrite at the expense of CH 4(g) , as well as formation of hydrogen sulfide (H 2 S). By varying input parameters, the crucial factors controlling TSR have been identified. Our results highlight that reservoir-wide diffusive mass transport is one prerequisite for TSR. An increase in the rate constant of abiotic sulfate reduction (ASR) and in diffusive mass fluxes, as well as lack of precursor minerals for metal (di-)sulfide precipitation, can increase the souring intensity and accelerate H 2 S outgassing. In contrast, precipitation of elemental sulfur, which is stable according to the chemical thermodynamics, weakens H 2 S formation. Our modeling shows that TSR is complex and cannot be represented by the single reaction ASR and by simple correlations between the rate constant of ASR and the H 2 S gas content. The application of 3-D reactive transport modeling presented here, despite its semigeneric nature, provides a good example of how such an approach can be used ahead of drilling. Our modeling helps to investigate TSR in time and space to quantify the mass conversion of all reactants involved within this web and to predict the souring level.

Description: 〈span〉〈div〉ABSTRACT〈/div〉The nanometer-scale architecture of organic matter (OM) and associated pores in highly mature gas shales from the lower Silurian Longmaxi Formation in the upper Yangtze platform of south China were investigated using field emission scanning electron microscopy (SEM), focused ion beam SEM, and low-pressure gas (N〈sub〉2〈/sub〉 and CO〈sub〉2〈/sub〉) adsorption bulk pore characterization. The Longmaxi shale comprises fine-grained siliciclastic rocks deposited in a marine shelf environment, which was dominated by quartz and clay minerals. Four porous OM types were found in the Longmaxi shale on the basis of the chemical composition and spatial occurrence of OM, including (1) isolated original OM particles, (2) OM–clay mineral complexes, (3) OM–heavy mineral complexes, and (4) secondary migrated bituminous OM. The pores in the particulate OM are not homogeneously distributed, and the processes leading to different pores depend on the specific OM type. The nature of OM-hosted pores is a result of several factors, such as primary porous kerogen, mechanical compaction, organic–inorganic interactions, gaseous and liquid hydrocarbon generation, retention, and expulsion. Pore volumes and specific surface areas of the Longmaxi shale derived from low-pressure N〈sub〉2〈/sub〉 and CO〈sub〉2〈/sub〉 adsorption experiments reveal positive linear relationships with total organic carbon contents, which indicates that the pore systems in the highly mature Longmaxi shale are dominated by OM-hosted pores. Additionally, the OM-hosted pores appear connected compared to pores in the mineral matrix. Therefore, the OM-hosted pore systems offer the preferential storage space and primary migration pathways for natural gas in the Longmaxi shale reservoir.〈/span〉

Description: Purine analogs, particularly fludarabine (Fludara®), have a major impact on the management of chronic lymphocytic leukemia (CLL), having achieved overall response rates (ORR) of 60%–80% as a single agent in previously untreated patients. Despite these high response rates as compared with other agents, patients continue to have detectable minimal residual disease (MRD) and will eventually relapse. It has become clear that even with the most highly active combination regimens, chemotherapy alone cannot cure CLL. Monoclonal antibodies such as alemtuzumab (Campath®) that have been developed against antigens expressed on the surface of B-CLL cells act synergistically with fludarabine in vitro and also appear to have synergistic properties in vivo. We, therefore, evaluated the safety and efficacy of a new, 4-weekly combination regimen consisting of fludarabine and the anti-CD52 monoclonal antibody alemtuzumab (FluCam) for patients with CLL in a phase II study. Objectives of this study were to evaluate the feasibility, ORR, duration of response (DR), and the presence of MRD following treatment with FluCam. Patients received FluCam therapy after a short period of alemtuzumab dose escalation, with doses rising from 3 mg to 10 mg to 30 mg on consecutive days. The FluCam regimen consisted of fludarabine 30 mg/m2/day IV over 15–30 min (Days 1–3) immediately followed by alemtuzumab 30 mg IV over 2 h (Days 1–3). This combination was repeated on Day 29 for up to 6 cycles. MRD was measured by 4-color flow cytometry. Currently, 34 patients are eligible for evaluation out of a total of 37 patients included in this study. The median age of the patients was 61.0 years (range, 38–80), 26/34 (76%) were male, 26/34 (76%) had Binet stage C disease, and the median number of prior treatment regimens was 2 (range, 1–8). The ORR was 85%, with 10 (29%) patients achieving a complete response (CR) and 19 (56%) patients a partial response (PR). One (3%) patient had stable disease (SD), while 4 (12%) others had progression of their disease (PD). MRD negativity was achieved in the peripheral blood for 15/34 (44%) patients. CMV reactivation occurred in 2 patients: 1 patient had CMV confirmed by PCR and died due to E. coli sepsis, and 1 patient had subclinical CMV reactivation that was successfully treated with IV ganciclovir. Two patients with refractory disease developed fungal pneumonia. Notably, 7 patients had active autoimmune hemolytic anemia (AIHA) and/or autoimmune thrombocytopenia (AITP) when entering the trial and were successfully treated with FluCam. Moreover, 9 other patients with transfusion-dependent thrombocytopenia and/or anemia due to bone marrow infiltration prior to therapy were successfully treated with FluCam. In conclusion, results from the interim analysis of this new, 4-weekly dosing regimen of FluCam suggest that combination therapy with fludarabine and alemtuzumab is feasible, safe, and effective in treating patients with relapsed and refractory CLL, even in those patients with inherent poor prognostic factors, those who had received multiple prior therapies, or those who were refractory to fludarabine or alemtuzumab monotherapy. Based on these promising results, a prospective, randomized, phase III trial has been initiated comparing FluCam to fludarabine alone in patients with relapsed CLL.

Description: Combination chemoimmunotherapy regimens have shown substantial efficacy in the treatment of lymphoproliferative disorders, particularly in comparison to the efficacy of single-agent therapies. Fludarabine has become an established treatment regimen in CLL, and although overall response rates (ORR) in previously untreated patients range between 60% to 80%, patients who are refractory to fludarabine have poor outcomes. Alemtuzumab, the anti-CD52 monoclonal antibody, is the most effective single-agent therapy in CLL, and is capable of inducing minimal residual disease (MRD)-negative responses even among patients with fludarabine-refractory disease. Our previous clinical experience with the combination of alemtuzumab and fludarabine (FluCam) resulted in 83% ORR in 36 patients with relapsed/refractory CLL, with 30% achieving a complete response (CR; Elter et al J Clin Oncol2005;23:7024–7031). In addition, among 12 patients with fludarabine-refractory disease, 8 achieved responses (4 CRs), and median time-to-progression (TTP) for all patients was 13 months. In order to optimize the dose and schedule of the FluCam combination, we performed pharmacokinetic (PK) analysis of the previously reported 6-cycle regimen. PK data were collected for a 14-patient cohort that participated in the phase 2 FluCam trial. Median patient age was 60 years (range, 49–73), 9 patients had Binet C disease (5 were Binet B), and patients received a mean 2.5 prior therapies. Alemtuzumab 30 mg (after initial dose escalation) and fludarabine 30 mg/m2 were administered on days 1–3 of a 28-day cycle for up to 6 cycles. PK parameters were measured from samples collected before each subsequent cycle, and at days 1, 4, 7, 14, 21, 28, and 42, for a total of 158 patient samples, of which 120 were tested. Plasma concentration of alemtuzumab increased steadily from day 1 to day 4 of therapy to a median Cmax 1.55 mg/mL, but decreased to a median 0.145 mg/mL by 7 days after initiation of treatment. By day 21 of therapy, alemtuzumab plasma concentration decreased to undetectable levels. Because efficacy of alemtuzumab has been shown to correlate with serum levels of this antibody, significant improvement in progression free survival (PFS) may require a elevated plasma levels of alemtuzumab for the duration of the treatment cycle. Therefore, the significant responses seen in this trial can be attributed to documented synergistic activity between alemtuzumab and fludarabine, which has been demonstrated both in vitro and in vivo. Despite low CD4 counts through the duration of therapy, favorable safety results seen in the trial could be attributed to opportunity for hematologic recovery between treatment cycles. Detailed PK analysis is currently being completed and will be presented at the conference. Conclusions: Treatment with the FluCam immunotherapy combination yielded positive results among patients with fludarabine resistant/refractory CLL, a difficult-to-treat population. As shown previously, response rates correlate with higher alemtuzumab plasma concentrations. Therefore, longer PFS durations may require longer, more sustained alemtuzumab plasma levels, which may be achieved with either consolidation or maintenance.

Description: Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.