Brentuximab Vedotin In Patients Research Articles

A phase I study with an expansion cohort of the combination of ipilimumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: A trial of the ECOG-ACRIN Cancer Research Group (E4412).

TPS8602 Background: E4412 is a phase 1 study with an expansion cohort of the combination of brentuximab vedotin (BV) and ipilumumab in patients with relapsed and refractory Hodgkin lymphoma (HL). D...

Safety and efficacy of single-agent bendamustine after failure of brentuximab vedotin in patients with relapsed or refractory hodgkin's lymphoma: experience with 27 patients.

The optimal treatment of patients with heavily pretreated Hodgkin's lymphoma is controversial. Brentuximab vedotin is an active single agent in this context. Also, bendamustine can be regarded as a safe and effective alternative for patients with relapse after autologous transplantation and as an interesting cytoreductive strategy before allogeneic transplantation. An observational, multicenter, retrospective study is reported of single-agent bendamustine in 27 heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma, who had all received brentuximab vedotin as their last treatment and who showed disease progression, refractory disease, or early relapse. The primary study endpoint was the objective response rate, and the secondary endpoint was the safety of the bendamustine regimen. The overall response rate was 55.5%, with 10 of 27 patients (37.0%) obtaining a complete response. In comparison, the overall response rate previously observed with brentuximab vedotin in the same subset of patients was much lower (18.5%). Among the 10 patients with a complete response after bendamustine, only 1 had had a complete response to brentuximab, with 2 having a partial response and 7 stable or progressive disease. With a median duration of response of 8 months, all these patients had maintained a continuous response at the last follow-up examination. The treatment was well tolerated, with rather infrequent adverse events and transient and manageable toxicities. Albeit with the limits of an observational retrospective study, these data indicate that bendamustine shows its efficacy in patients already treated with brentuximab vedotin, regardless of their previously obtained response and without any significant toxicity.

Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma

AbstractWe present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N = 102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission (CR) on brentuximab vedotin, with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively, in this group (medians not reached). Of the 34 patients who obtained CR, 16 (47%) remain progression-free after a median of 53.3 months (range, 29.0 to 56.2 months) of observation; 12 patients remain progression-free without a consolidative allogeneic stem cell transplant. Younger age, good performance status, and lower disease burden at baseline were characteristic of patients who achieved a CR and were favorable prognostic factors for overall survival. These results suggest that a significant proportion of patients who respond to brentuximab vedotin can achieve prolonged disease control. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Brentuximab Vedotin in Patients With Hodgkin Lymphoma and a Failed Allogeneic Stem Cell Transplantation: Results From a Named Patient Program at Four Italian Centers

Brentuximab vedotin (BV) has demonstrated an extraordinary efficacy in heavily pretreated classical Hodgkin lymphoma (cHL) patients, targeting CD30-positive cells; however, limited data have been reported on the efficacy of BV in cHL patients failing allogeneic stem cell transplantation (allo-SCT). The aim of this study was to retrospectively evaluate the efficacy and safety of BV in a multicenter setting of cHL relapsing or progressing after allo-SCT. Sixteen BV-naïve patients with recurrent cHL after allo-SCT were included in a compassionate use program and treated with intravenous BV at the dose of 1.8 mg/kg of body weight every 3 weeks for a maximum of 16 cycles. The objective response rate was 69%. Five patients (31%) had complete remission, and 6 (37%) had partial remission. Stable disease was observed in 4 patients (25%), and progressive disease was observed in 1 (6%). After median follow-up of 26 months (range: 5-30 months), median progression-free survival (PFS), overall survival (OS), and duration of response were 7, 25, and 5 months, respectively. The 2-year PFS and OS were 20% and 61%, respectively. Grade 3-4 hematological adverse events included anemia (15%), thrombocytopenia (12%), and neutropenia (18%). Grade 3 peripheral sensory neuropathy occurred in 2 patients (12%). BV therapy is an effective and safe approach for achieving transient disease control in cHL patients with failed allo-SCT. To improve disease control, future studies should explore the combination of BV with targeted agents.

Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplant after Brentuximab Vedotin in Patients with Hodgkin Lymphoma Relapsed after Autologous Transplant

Purpose: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous stem cell transplantation (ASCT) is generally poor, because salvage chemo-radiotherapy is able to produce only short-lasting remissions. In a previous study on a large patients’ population (Sarina B et al, Blood 2010) was clearly demonstrated that the availability of a donor could significantly improve survival outcomes after allogeneic transplant, in particular for the subset of patients who reach a status of pre-transplant complete remission; however the application of this procedure is actually limited by a difficulty to obtain an objective response before alloSCT. It was recently shown that Brentuximab vedotin, a new generation antibody-drug conjugate, is able to induce nearly 30% of complete remission in HL patients relapsing after autologous transplant; therefore this agent could effectively work in relapses after ASCT as a platform to allow a better disease control in order to improve the outcome of the allografting procedure.Aims: Aim of this study was to retrospectively investigate if brentuximab vedotin administered as a salvage therapy in HL patients relapsing after ASCT could improve the efficacy of a subsequent reduced-intensity allogeneic transplant.Methods: Between August 2011 and September 2013, 11 patients underwent to allo-SCT at four hematologic Divisions of Northern Italy for HL relapse after ASCT, after brentuximab vedotin administered as a bridge to the allografting procedure. Median age was 32 years (range 21-61) and median number of prior regimens was 5, including ASCT. Patients received a median of 6 cycles (range 4-7) of brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion; median time between the last dose of brentuximab vedotin and the allo-SCT was 1 month (range 1-5 months). No patient experienced progression during treatment with brentuximab vedotin (4 complete remissions and 7 partial remission/stable disease). All but one patients did not have a HLA identical sibling, so they required a matched unrelated (6 patients), haploidentical donor (3 patients) or cord blood (1 patient); peripheral stem cells were the source in patients with HLA identical sibling or unrelated, whereas bone marrow was used in the haplo setting. Reduced-intensity was the conditioning regimen performed in all patients. Post transplant cyclophosphamide plus mycophenolate mofetil/tacrolimus was the graft-versus-host disease (GVHD) prophylaxis of the haplo setting, while Metotrexate/cyclosporine was administered in the other patients. Patients were monitored for engraftment and infectious complications per institutional standards; survival outcomes were defined according to the European Blood and Marrow Transplantation (EBMT) criteria for survival analysis.Results: One patient had primary graft failure with autologous reconstitution; she was a patient with a high body-mass index, in whom the drug’s doses of the conditioning regimen were underestimated in order to avoid excessive toxicity. All the other patients engrafted; median time to neutrophil recovery was 20 days (range 15-26). At a median follow-up of 12 months, the 2-year progression free survival was 51%, 2-year Overall Survival was 61%. There were 2 toxic deaths, one for EBV reactivation and one for leuko-encefalopathy disease, resulting in a 2-year non-relapse mortality of 18%.Conclusions: These data suggest that brentuximab vedotin represents a promising salvage therapy in HL patients relapsed after ASCT. Despite the bias concerning the differences in source of stem cells and pre-transplant conditioning regimens, we showed that brentuximab could be administered in patients who are candidates to a RIC allo-SCT, with encouraging survival outcomes. Further clinical trials with larger number of patients and longer follow-up are recommended to confirm the promising role of brentuximab as a bridge to alloSCT. DisclosuresNo relevant conflicts of interest to declare.

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Brentuximab Vedotin in Patients With CD30+ Mesothelioma: Mesothelioma, Thymic Malignancies, and Other Thoracic Malignancies

There is a clear need to develop new therapies for malignant mesothelioma. Surgical management is rarely curative and few chemotherapy regimens have activity in unresectable disease. A significant percentage of mesotheliomas express CD30. Brentuximab vedotin is an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Brentuximab vedotin (1.8 mg/kg q3wk) has induced objective response rates of 75% and 86% in patients (pts) with relapsed/refractory (r/r) Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), respectively.

Brentuximab vedotin for relapsed or refractory CD30+ Hodgkin lymphoma: a multicenter analysis from Asia.

IntroductionBrentuximab vedotin (SGN-35), an anti-cluster of differentiation (CD)-30 antibody conjugated to the anti-tubulin agent monomethyl auristatin E, has demonstrated promising efficacy and tolerability in relapsed and heavily treated Hodgkin lymphoma (HL). In this study, we report the Asian experience with brentuximab vedotin in patients with relapsed or refractory CD30-positive (CD30+) HL.MethodsThis is an observational, multicenter, retrospective study. Between October 2011 and June 2013, a total of 22 patients were treated with brentuximab vedotin under a named patient program in Asia. Patients received a 30 min infusion of brentuximab vedotin at a dose of 1.8 mg/kg of body weight every 3 weeks.ResultsFour patients (18.2%) showed a complete response, and the overall response rate was 72.7%. The median duration of response was 4.4 months (range 1.0–17.4). The median progression-free survival was 5.7 months, and the median overall survival has not yet been reached. The 1-year expected survival rate was 67.2%. The most common grade 3/4 adverse events were neutropenia (n=7; 31.8%). No patients experienced grade 3/4 sensory neuropathy.ConclusionsThese results confirm that brentuximab vedotin as a single agent is also effective and well tolerated when used in Asian patients with relapsed and refractory CD30+ HL.

Viral lymphomagenesis: from pathophysiology to the rationale for novel therapies

The association between viruses and lymphomas has long been recognized; however, the pathophysiological phenomena behind this relationship are unclear, and have been the object of intense research. Although our understanding of such mechanisms is slowly improving, much is still left to learn. With the recent advances in cancer biology, a diversity of biological pathways and novel targets and agents have been described in patients with haematological malignancies and successfully put into clinical practice. Clear examples are rituximab and brentuximab vedotin in patients with B cell lymphomas and Hodgkin lymphoma respectively. The main purpose of this review is not only to succinctly summarize what we know regarding the pathogenesis and pathophysiology of virally induced lymphomas and to describe the current practices in terms of diagnosis of treatment of such lymphomas, but also to provide a scientific rationale for the use of novel therapies that are likely to improve the outcomes of patients with these conditions.

Brentuximab Vedotin for Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma: A Review of Clinical Experience and Future Directions

SUMMARY Brentuximab vedotin is a novel agent indicated for the treatment of relapsed and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Brentuximab vedotin is an antibody–drug conjugate consisting of chimeric anti-CD30 antibody cAC10, linked to four molecules of monomethylauristatin E, a tubulin destabilizer. It was granted US FDA approval in 2011 following two pivotal Phase II studies showing objective responses of 75 and 86% in heavily pretreated relapsed and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. Brentuximab vedotin can be used as a bridge to more definitive stem cell transplant. There are currently over 30 open clinical studies involving the use of brentuximab vedotin used as single agent or combined with chemotherapy in both front-line and salvage settings. These studies include use in other CD30-positive B- and T-cell lymphomas, as well as in CD30-positive germ cell tumors. In clinical practice brentuximab vedotin has been associated with significant sensory and motor neuropathies and clinicians should be alert to the potential for significant neuropathy and the need for dose reduction. However, the potential for significant neuropathy must be balanced against the remarkable clinical benefit of brentuximab vedotin in patients with heavily pretreated relapsed and refractory lymphomas.

CD30-positive malignant lymphomas: time for a change of management?

In this issue of Haematologica, Zinzani et al. describe their experience with the anti-CD30 antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin’s lymphoma. A total of 65 heavily pretreated patients who had been treated in a named patient program in nine Italian

18-Fluorodeoxyglucose positron emission tomography/computed tomography for assessment of response to brentuximab vedotin treatment in relapsed and refractory Hodgkin lymphoma

Brentuximab vedotin has emerged as a possible treatment option in patients suffering from relapsed and refractory Hodgkin lymphoma (HL). We investigated the role of 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for monitoring treatment response to brentuximab vedotin in patients with relapsed and refractory HL. Twelve consecutive, heavily pretreated patients with relapsed and refractory HL treated with brentuximab vedotin were available for analysis. FDG-PET/CT studies were performed early during treatment after a median of 3 cycles (range, 2–5 cycles), and were analyzed visually using a 5-point scale (5PS) and quantitatively using the maximum standardized uptake value (SUVmax) and the three-dimensional (3D) isocontour at 50% of the maximum pixel value (SUV50) in the hottest single lesion. The median follow-up in our study cohort was 16 months (range, 5–30 months). The median progression-free survival (PFS) was 12.5 months and PFS at 12 months was 58%. Patients treated with brentuximab vedotin and negative interim FDG-PET/CT assessed by visual or quantitative analysis demonstrated a significantly prolonged PFS compared to patients with positive interim FDG-PET/CT. The 1-year PFS was 100% in patients with negative interim FDG-PET/CT assessed by visual analysis, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 38% (p = 0.033). The 1-year PFS was 75% in patients with negative interim FDG-PET/CT assessed by quantitative analysis using the SUV50, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 25% (p = 0.017) Interim FDG-PET/CT might be a suitable diagnostic approach to predict response to brentuximab vedotin in relapsed and refractory HL.

Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies

Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization. Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF). There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies. There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

Durable complete remission after brentuximab vedotin in a patient with relapsed and refractory Hodgkin lymphoma (HL)

We present a case of a 23-year-old female patient with relapsed classical Hodgkin lymphoma in reduced general condition. She was refractory after multiple lines of prior chemotherapy including autologous stem cell transplantation. By applying a targeted therapy concept using brentuximab vedotin (SGN-35), the patient experienced a rapid clinical improvement with loss of B symptoms immediately after the first treatment cycle. Elevated serum levels for C-reactive protein (CRP) and lactate dehydrogenase (LDH) returned to normal, and a significant improvement of hemoglobin levels were observed. Moreover, after administration of 16 cycles, the patient remains in complete remission, lasting now for > 15 months. Tolerability of treatment was excellent without evidence of infections or peripheral neuropathy. This case illustrates the clinical potential of brentuximab vedotin in patients with end-stage Hodgkin lymphoma who would otherwise have only limited treatment options.

Brentuximab Vedotin (SGN-35) in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies without Prior High-Dose Chemotherapy and Stem Cell Transplantation.

AbstractAbstract 2743 Background:Based on the impressive results of two pivotal phase II trials, the CD30 targeting antibody-drug conjugate brentuximab vedotin (SGN-35) was approved for the treatment of relapsed Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) by the Food and Drug Administration (FDA) in 2011. Recently, we reported the experience of the German Hodgkin Study Group (GHSG) with brentuximab vedotin as single agent in 45 patients suffering from refractory or relapsed CD30-positive HL. In this cohort with a median age of 35 years and a median number of four prior chemotherapy regimens, overall survival (OS) and progression-free survival (PFS) at 12 months were 83% (95%-CI: 72%-95%) and 43% (95%-CI: 28%-58%), respectively. Interestingly, 10 of 17 patients considered very high-risk (59%) who had primary refractory disease or early relapse and refractory disease prior to brentuximab vedotin treatment, achieved an objective response, which was comparable to the overall response rate of 60% for the whole cohort (Rothe et. al., Blood, July 2012). Since very limited data is available on relapsed or refractory HL patients who received brentuximab vedotin without prior high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), we have expanded our analysis. Methods:Since March 2010, the GHSG and associated centres have treated patients with refractory or relapsed HL or relapsed ALCL with brentuximab vedotin. In addition to six patients included in our previous analysis, we identified 10 further patients who had not undergone prior HDCT and SCT and were treated with brentuximab vedotin. All patients had histologically confirmed CD30-positive lymphoma and were treated within a named patient program (NPP). All participants gave written informed consent in accordance with the Declaration of Helsinki. Patients received a 30-minute infusion of brentuximab vedotin dosed at 1.8mg/kg body weight every three weeks. Response was defined according to the revised response criteria for malignant lymphoma. Overall survival (OS) was defined as the time from the initiation of therapy to death from any cause. Progression-free survival (PFS) was measured from initiation of therapy to progression, relapse, or death from any cause. Results:In total, 16 patients with HL (n=14) or ALCL (n=2) with a median age of 48.5 years and a median number of three prior chemotherapy regimens were analyzed. Reasons for ineligibility for HDCT and autologous SCT prior to treatment with brentuximab vedotin were refractory disease (n=11), comorbidity (n=4) and unknown reasons (n=1). Treatment with brentuximab vedotin resulted in an objective response in 11 patients (69%), including five complete remissions. Noteworthy, six of the 11 patients with chemotherapy refractory disease and all four patients with significant comorbidity achieved an response. Six patients received a consolidating HDCT followed by autologous (n=4) or allogeneic (n=2) SCT after brentuximab vedotin treatment. OS and PFS at 12 months were 68% (95%-CI: 40%-95%) and 22% (95%-CI: 0%-48%), respectively. Conclusion:This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in patients with heavily pre-treated CD30-positive malignancies. Moreover, we present the first data indicating therapeutic efficacy of brentuximab vedotin as reinduction therapy in chemotherapy-refractory HL and ALCL patients before HDCT and ASCT. Disclosures:Engert:Millenium The Takeda Oncology Company: Honoraria.

Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Retrospective Analysis of the Safety and Efficacy of Brentuximab Vedotin in Patients Aged 60 Years or Older with Relapsed or Refractory CD30+ Hematologic Malignancies

Retrospective Analysis of the Safety and Efficacy of Brentuximab Vedotin in Patients Aged 60 Years or Older with Relapsed or Refractory CD30+ Hematologic Malignancies

Brentuximab Vedotin Administered Concurrently with Multi-Agent Chemotherapy As Frontline Treatment of ALCL and Other CD30-Positive Mature T-Cell and NK-Cell Lymphomas

Brentuximab Vedotin Administered Concurrently with Multi-Agent Chemotherapy As Frontline Treatment of ALCL and Other CD30-Positive Mature T-Cell and NK-Cell Lymphomas

Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin

To build a multiscale mechanism based pharmacokinetic-pharmacodynamic (PK/PD) model for antibody drug conjugates (ADCs), using brentuximab-vedotin as an example, for preclinical to clinical translation of ADC efficacy. Brentuximab-vedotin experimental data, collected from diverse publications, were employed in the following steps to build and validate the model: (1) characterization of ADC and payload PK at the cellular level, (2) characterization of payload PK in plasma and tumor tissue of xenograft mouse, (3) characterization of ADC PK in mouse plasma, (4) prediction of the tumor payload concentrations in xenograft mouse by integrating parameters obtained from steps 1-3 with the novel tumor disposition model for ADC, (5) characterization of preclinical brentuximab-vedotin tumor growth inhibition data using the novel PK/PD model, (6) characterization of ADC and payload PK in cancer patients, and (7) prediction of clinical responses of brentuximab-vedotin using the PK/PD model, by integrating PK parameters obtained from step 6, and translated mouse parameters from step 5; and comparing them with clinical trial results. The tumor disposition model was able to accurately predict xenograft tumor and plasma payload concentrations. PK/PD model predicted progression free survival rates and complete response rates for brentuximab-vedotin in patients were comparable to the observed clinical results. It is essential to understand and characterize the disposition of ADC and payload, at the cellular and physiological level, to predict the clinical outcome of ADC. A first of its kind mechanistic model has been developed for ADCs, which can integrate preclinical biomeasures and PK/PD data, to predict clinical response.

Brentuximab Vedotin and Crizotinib in Anaplastic Large-Cell Lymphoma

Systemic anaplastic large-cell lymphoma (ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. Anaplastic large-cell lymphoma cells express the surface antigen CD30, and more than half express the anaplastic lymphoma kinase (ALK) protein. These 2 proteins provide unique therapeutic targets in ALCL. Remission rates in ALCL with combination chemotherapy are approximately 80%, but relapse after first-line therapy is common. Brentuximab vedotin is a US Food and Drug Administration-approved, antibody-drug conjugate that combines an anti-CD30 antibody with monomethylauristatin E, a potent antimicrotubule agent. Response rates to brentuximab vedotin in patients with relapsed/refractory ALK and ALK ALCL have exceeded 80% with frequent complete responses and a median duration of response greater than 1 year. Brentuximab vedotin in combination with chemotherapy is being explored as a first-line therapy in ALCL. Crizotinib is an inhibitor of ALK tyrosine kinase that has been approved for the treatment of ALK non-small cell lung cancer. Successful treatment of ALK ALCL with crizotinib has been reported in pediatric patients and small case series leading to ongoing trials in relapsed/refractory ALCL. Brentuximab vedotin and crizotinib represent major advances in the treatment of ALK and ALK ALCL and will likely result in marked improvement in prognosis for this subset of aggressive lymphomas.