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Real-World Evidence for Coverage and Payment Decisions
Published in Harry Yang, Binbing Yu, Real-World Evidence in Drug Development and Evaluation, 2021
Saurabh Aggarwal, Hui Huang, Ozlem Topaloglu, Ross Selby, Hui Huang, Saurabh (Rob) Aggarwal
More payers and other stakeholders are increasingly demanding evidence for a product's effectiveness in their coverage populations. Studies to generate this evidence can be conducted either by the product manufacturer, or payer, or as a joint collaboration from multiple stakeholders. A real-world study by Takeda Pharmaceuticals in Germany and the United Kingdom showed that brentuximab vedotin is effective in autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory Hodgkin lymphoma (rrHL)21. Kaiser Permanente Northern California has a viral hepatitis registry that includes administrative and clinical data for all patients with chronic hepatitis C22. Recently, many new joint collaborations between a product manufacturer and a payer/HTA were announced to align reimbursement to real-world outcomes in the payer/HTA's target population. For example, Merck and United Health's Optum have an initiative that involves the use of real-world data to co-develop and test advanced predictive models and co-design an outcome-based risk sharing agreement to reduce clinical and financial uncertainty23.
Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Dennis A. Eichenauer, Andreas Engert
Brentuximab vedotin is an antibody-drug conjugate targeting CD30. After the phase I study had indicated significant single-agent activity, a pivotal phase II study including 102 patients with HL recurrence after high-dose chemotherapy and ASCT was conducted.43 Patients received brentuximab vedotin at a dose of 1.8 mg/kg every 3 weeks for up to 16 cycles. The overall response rate was 75%. The median PFS was 5.6 months. However, the group of patients that achieved a complete remission had median PFS of 20.5 months.44 A recent follow-up analysis of the study revealed 5-year PFS and OS estimates of 22% and 41%, respectively. Of note, some patients had a durable remission without any additional therapy after the end of study treatment.45 Given the excellent activity in patients failing high-dose chemotherapy and ASCT, brentuximab vedotin either alone in combination with conventional chemotherapy was subsequently evaluated in patients who had disease recurrence after first-line treatment and in individuals with newly diagnosed HL.24,36,46,47 Final analyses of these studies are in part pending so that final conclusions with regard to the possible role of brentuximab vedotin in these situations cannot yet be drawn.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Ado-trastuzumab emtansine (Kadcyla) and brentuximab vedotin (Adcetris) are two ADCs that are being used for the treatment of hematological malignancies (Hodgkin lymphoma) and solid tumor (breast cancer), respectively (Beck and Reichert, 2014; Scott, 2017a). Brentuximab vedotin is a conjugate of a monoclonal antibody targeting CD30, which is expressed only during Hodgkin lymphoma. It is connected via cathepsin to anti-mitotic drug monomethyl auristatin E (Beck and Reichert, 2014; Scott, 2017a). Ado-trastuzumab emtansine is composed of anti-Her2-mAb Trastuzumab antibody linked to cytotoxic drug mertansine via thioether linkage (Beck and Reichert, 2014; Lambert and Chari, 2014). Variety of drugs can be conjugated at multiple locations in monoclonal antibody to further enhance their actions (Tobin et al., 2014).
Advances in Hodgkin’s lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors
Published in Expert Opinion on Pharmacotherapy, 2023
Thuy Ho, Cara Coleman, Palak Shah, Victor Yazbeck
Despite the excellent prognosis for the majority of patients with Hodgkin lymphoma, outcomes for patients with refractory or relapsed HL, especially after autologous or allogeneic stem cell transplantation, remain poor with traditional chemotherapy. More recently approved therapies, such as brentuximab vedotin and PD1 inhibitors, have shown promising results in this setting. However, drug resistance to chemotherapy, targeted and immunotherapy agents eventually arise, necessitating novel therapeutic approaches. Additionally, Hodgkin Reed Sternberg cells survive through multiple mechanisms, including escape from immune detection. Targeting the TME in addition to the primary tumor is also crucial for effective disease control. One strategy to overcome these resistance mechanisms and disrupt the tumorigenic niche is through epigenetic regulation, in which histone acetylation plays a major role. To date, a great number of histone deacetylase inhibitors have been developed. These agents have demonstrated a unique safety profile as monotherapy and as part of combination treatments in relapsed/refractory Hodgkin lymphoma and other hematologic and solid malignancies. The most frequent toxicity from HDAC inhibitors is thrombocytopenia, the severity of which varies depending on the individual HDACI and the nature of the synergizing agent(s). Overall, HDAC inhibitors appear to have a more tolerable safety profile than cytotoxic chemotherapy. In terms of efficacy in relapsed/refractory HL, the results have been variable, but with a promising signal of clinical activity based on disease control rate.
Relapse localization in Danish pediatric patients with Hodgkin lymphoma
Published in Acta Oncologica, 2021
Anni Young Lundgaard, Lisa Lyngsie Hjalgrim, Danijela Dejanovic, Anne Kiil Berthelsen, Eckhard Schomerus, Pernille Wendtland, Lena Specht, Maja Vestmoe Maraldo
Response assessment with PET/CT is now considered standard of care in HL treatment [15] and its ability to identify responders and non-responders is used to direct further treatment in pHL clinical trials. However, it has not been established that a CR after two series chemotherapy can predict EFS in low-risk patients [9], nor after three series, but a very early PET-response after one series may possibly do so [21]. Likewise, for adult patients with early stage HL, a negative response assessment PET/CT has not identified the patients for whom consolidating radiotherapy can be omitted without increasing the risk of relapse [22–24]. In our study, time to relapse or site of relapse did not seem to be associated with the outcome of the response assessment or the metabolic response on PET. A recent study in adult patients with early stage HL did not find a correlation between initial lymph node characteristics (nodal size, 2-[18F]FDG-uptake, or CT abnormalities after chemotherapy) and the risk of relapse [25]. Hence, irradiating metabolically active sites or bulky tumor sites only does not seem optimal and can only be recommended within clinical trials (currently investigated in AHOD1331 [NCT02166463], EuroNet-PHL C2 [NCT02684708] [11]). In patients with advanced disease, ISRT or INRT would still lead to large treatment volumes and other treatment strategies should be explored. Brentuximab vedotin is currently investigated in the high-risk group as first line treatment in the Children’s Oncology Group AHOD1331 trial (NCT02166463).
Current treatment of lymphoma in pregnancy
Published in Expert Review of Hematology, 2019
Anna Gurevich - Shapiro, Irit Avivi
Nivolumab and pembrolizumab, anti PD1 antibodies used in refractory or relapsed HL, have not been examined with respect to pregnancy, but have been associated with an increased risk of fetal loss [89,90]. The PD-1/PD-L1 pathway plays an important role in maintaining maternal immune tolerance to the fetus during pregnancy [91]. Inhibition of this pathway could cause an immune-mediated response to the fetus with detrimental effects. Nivolumab administration resulted in a non–dose-related increase in spontaneous abortion and increased neonatal death in monkeys [92]. A single case report exists of treatment with nivolumab and ipilimumab during the first trimester with a normal progression of the pregnancy until week 32, when a healthy preterm newborn was delivered due to signs of placental insufficiency [91]. As mentioned earlier, brentuximab vedotin, approved for relapsed and refractory HL outside pregnancy, is contraindicated during the gestational period.