AVM0703 Tumor Debulking Enhances Cy/Flu Efficacy

AVM0703 is a high concentration (24 mg/mL) dexamethasone phosphate drug product that permits the safe administration of the doses necessary to mobilize gamma delta+, bi-specific natural killer T (NKT) cells. AVM0703 is in clinical trials as a stand-alone treatment for relapsed/refractory (R/R) Non-Hodgkin's Lymphoma (NHL). Even more exciting is the potential combination of AVM0703 with standard chemotherapy to reduce the number of treatment cycles while maintaining efficacy. A therapeutic solution that reduces the number of chemotherapy cycles could lower the risk of secondary malignancies, decrease long-term toxicities, and limit costs associated with management of chemotherapy toxicities. AVM0703 has been well tolerated to date, with mild to moderate and self-limiting side effects. This indicates the use of AVM0703 in combination therapies may greatly improve quality of life for patients during treatment. AVM0703 has been tested in an aggressive mouse B-cell lymphoma model (A20) alone and in combination with cyclophosphamide/fludarabine (CyFlu). The tumor killing effect of AVM0703 on A20 cells in Matrigel TM embedded tumors is evident as early as 3 hours after dosing, assessed by flow cytometry. Maximum A20 cell death is observed 24 hours after treatment in blood (Figure 1) and between 3- and 24-hours in tumors (Figure 2). Treatment with AVM0703 alone was compared with Cy/Flu alone and with a combination of single dose AVM0703 followed by one Cy/Flu cycle. Tumor growth was monitored by caliper measurements and blood and tumors were analyzed by flow cytometry at the end point, 7-days after Cy/Flu dosing. AVM0703 alone was superior to one cycle of Cy/Flu and the combination of a dose of AVM0703 followed by Cy/Flu was the most effective (Figure 3). Of the mice treated with the combination, 33% had no visible tumor 7-days post-dose. We are currently testing AVM0703 administered between 6- and 24-hours before a single Cy/Flu dose and predict that A20 eradication should be more complete in all compartments. Acute 7 day studies will be followed by long-term studies to evaluate A20 tumor escape or recurrence. In previous studies with long term monitoring of tumor growth, AVM0703 administered 3 days before one cycle of Cy/Flu induced long-term stable disease up to 50 days in tumor bearing mice (Figure 4a) compared to two cycles of Cy/Flu where 33% of the tumors escaped (Figure 4b). Additional studies in combination with R-CHOP are underway. AVM0703 has the ability to debulk the tumor by mobilizing gamma delta+, bi-specific natural killer T (NKT) cells. When added to a chemotherapeutic regimen, the chemotherapy may be more effective due to the lower tumor burden in the body. As cancer survivors live longer, the late term consequences of chemotherapy have become apparent, which include secondary malignancies. The challenge for new treatments is to reduce toxicities without sacrificing efficacy. AVM0703 has the potential to be one solution when used in combination with chemotherapy. Future clinical trials will determine if debulking with AVM0703 results in a reduction of the number of necessary R-CHOP cycles while maintaining or enhancing the efficacy rate. Figure 1 Figure 1. Disclosures Deisher: AVM Biotechnology, LLC: Current Employment. Sawas: AVM Biotechnology, LLC: Current Employment. Suwito: AVM Biotechnology, LLC: Current Employment. Rylatt: AVM Biotechnology, LLC: Current Employment. Jarzyna: AVM Biotechnology, LLC: Current Employment. Zahid: AVM Biotechnology, LLC: Ended employment in the past 24 months. Parthasarathy: AVM Biotechnology, LLC: Consultancy, Ended employment in the past 24 months. Poulin: AVM Biotechnology, LLC: Current Employment. Lee-Diaz: AVM Biotechnology, LLC: Current Employment.

Evaluating Patients' Preferences Regarding Treatment Options for Waldenström's Macroglobulinemia, a Discrete-Choice-Experiment

Introduction The management of Waldenström's Macroglobulinemia (WM), a rare and incurable B-cell non-Hodgkin lymphoma, has evolved in recent years. Treatment options are increasing including more modern targeted therapies. Therefore there are currently several effective treatment options available for WM. There is no consensus on a preferred treatment. Widely used treatment options include rituximab combined with chemotherapy, proteasome inhibitors, and the oral BTK inhibitor ibrutinib. These treatments have varying properties in terms of efficacy, toxicity profile, duration (fixed-duration vs long-term maintenance), administration (oral vs intravenous/subcutaneous (IV/SC)), and type of agent (chemotherapy vs targeted therapy). A better understanding of patients' treatment preferences could aid physicians in developing an individualized treatment plan. Also, a better insight in patients' treatment views could help direct future clinical studies in WM. However, treatment preferences of WM patients have not been investigated. We aimed to evaluate treatment preferences of WM patients by means of a discrete choice experiment (DCE) and to assess the importance of different attributes describing the currently available treatment regimens. Methods A mixed-method approach, consisting of a literature review, qualitative interviews and expert discussions was utilized for identification and selection of attributes/levels. A DCE questionnaire was developed in Dutch and included 5 treatment-related attributes: 5-year progression-free survival (PFS), frequency/route of administration(IV/SC or oral)/setting (clinic or home) of treatment, adverse events (nausea & vomiting and fatigue, neuropathy and atrial fibrillation), risk of future secondary malignancies (low vs high), and type of treatment agent (chemotherapy or targeted therapy). Each respondent was presented with 16 choice cards and was asked to choose between two hypothetical but realistic treatment options (see Figure 1 for an example). A pilot DCE study was carried out in 5 patients to evaluate feasibility. Data were collected via a nationwide online questionnaire via the patient organizations' website and via paper-based questionnaires sent to the participants known at the outpatient clinic. An orthogonal design was used to construct the choice tasks and a mixed logit panel data model was used to assess patients' preferences and trade-offs between attributes/levels. Results A total of 330 online questionnaires and 17 paper-based questionnaires were returned. After excluding incomplete survey data, 214 (65%) questionnaires were included for data analysis, respondents characteristics are presented in Table 1. The 5-year PFS followed by the risk of secondary malignancies were the most important attributes for making treatment decisions. The probability of choosing a treatment option increased with 26% and 22% if the 5-year PFS increased from 50% to 70% and if the chance of future secondary malignancies was decreased from "high risk" to "low risk", respectively. Of the adverse events, patients disliked being at risk for neuropathy the most more than nausea, vomiting and extreme fatigue. Patients were willing to give up 7,2% treatment efficacy to avoid risk of neuropathy. The probability of choosing a treatment option increased with 8% for a fixed-duration treatment with IV/SC administration at the hospital compared to an ongoing daily oral regimen at home (Table 2). Socio-demographic characteristics such as age, gender and treatment status did not significantly influence patients' preferences with the exception of educational status. Lower 5-year PFS was more acceptable for patients with higher education (P<0.0001 ) and this subgroup of patients preferred a treatment with targeted therapy and low risk of secondary malignancy (P<0.0001). Conclusion These are the first data on WM patients' preferences on treatment characteristics. We found that Dutch WM patients find efficacy (high 5-year PFS rate) the most important attribute, followed by a low risk of future secondary malignancies. Neuropathy was the adverse event they most wanted to avoid. They preferred a fixed-duration IV/SC treatment over an ongoing oral regimen. These data can be used in discussions with individual patients about their treatment preference, and help direct future clinical trials that optimally connect to WM patients' preferences. Figure 1 Figure 1. Disclosures Minnema: Cilag: Consultancy; Janssen: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; BMS: Consultancy; Kite/Gilead: Consultancy. Kersten: Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Vos: Celgene: Other: Travel reimbursement; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Case Report: An Internal Mammary Rhabdomyosarcoma After Mastectomy and Systemic and Radiation Therapy in a Patient With Breast Cancer

Post-radiation soft tissue sarcomas (PRSTSs) are rare secondary malignancies. In this report, we describe the clinical presentation of a 52-year-old woman who underwent postmastectomy radiation therapy (PMRT) for left-sided breast cancer 2.7 years ago and presented with a left internal mammary mass and left interpectoral nodule on computed tomography. On further evaluation, she was diagnosed with internal mammary rhabdomyosarcoma and interpectoral nodal breast cancer relapse, and was treated with chemotherapy, followed by surgery and endocrine therapy. She developed left pleural metastases and is currently receiving targeted therapy. Internal mammary rhabdomyosarcomas are rare among PRSTSs and pose a diagnostic challenge for patients with breast cancer. Histological evaluation is important for the differential diagnosis of breast cancer relapses with secondary malignancies. The management of post-radiation thoracic rhabdomyosarcomas is challenging, and the prognosis is poor.

Extrahepatic Applications of Yttrium-90 Radioembolization

While initially described and now accepted as treatment for primary and secondary malignancies in the liver, radioembolization therapy has expanded to include treatment for other disease pathologies and other organ systems. Advantages and limitations for these treatments exist and must be compared against more traditional treatments for these processes. This article provides an overview of the current applications for radioembolization outside of the liver, for both malignant and nonmalignant disease.

Ruxolitinib-treated polycythemia vera patients and their risk of secondary malignancies

Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0–101.6). Within a median follow-up of 97 months (1.0–395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid “non-skin” malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The “SM-free survival” was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV.

Implications of inhibition of Rev1 interaction with Y family DNA polymerases for cisplatin chemotherapy

Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.

Total body irradiation as part of conditioning regimens in childhood leukemia—long-term outcome, toxicity, and secondary malignancies

Background Total body irradiation (TBI) is an established part of conditioning regimens prior to stem cell transplantation in childhood leukemia but is associated with long-term toxicity. We retrospectively analyzed survival, long-term toxicity, and secondary malignancies in a pooled cohort of pediatric patients (pts.) treated with the same TBI regimen. Methods Analyzed were 109 pts. treated between September 1996 and November 2015. Conditioning treatment according to EBMT guidelines and the ALL SCTped 2012 FORUM trial consisted of chemotherapy (CT) and TBI with 2 Gy b.i.d. on 3 consecutive days to a total dose of 12 Gy. Median follow-up was 97.9 months (2–228 months). Results Overall survival (OS) in our cohort at 2, 5, and 10 years was 86.1, 75.5, and 63.0%, respectively. Median survival was not reached. Long-term toxicity developed in 47 pts. After chronically abnormal liver and kidney parameters in 31 and 7 pts., respectively, growth retardation was the most frequent finding as seen in 13 pts. Secondary malignancies were rare (n = 3). Conclusion TBI-containing conditioning regimens in pediatric stem cell transplantation (SCT) are highly effective. Efforts to replace TBI- with CT-containing regimens have only been successful in subgroups of pts. Although we could show long-term toxicity in 43% of pts., overall survival was 63% at 10 years. Still, long-term effects such as growth retardation can permanently impact the pts.’ quality of life and functioning. Along with new substances, efforts should be undertaken to optimize TBI techniques and accompany the treatment by systematic follow-up programs beyond 5 years to improve detection of rare events.