Additional Systemic Therapy Research Articles

Outcomes of Cytoreductive Stereotactic Body Radiotherapy (SBRT) in Patients with Oligometastatic or Oligoprogressive Dominant Lung Metastases from Colorectal Primary

Oxaliplatin based systemic therapy regimens have improved the prognosis of patients with colorectal cancer (CRC) and with this, there has been increased interest in the integration of local therapies to oligometastatic and oligoprogressive sites. There is a vast body of literature exploring the benefits of cytoreduction with surgery and stereotactic body radiation therapy (SBRT) approaches. We report our rates of local control (LC) and overall survival (OS) for patients with oligometastatic/progressive CRC with lung metastases treated with SBRT. Single institution retrospective review of patients diagnosed with oligometastatic or oligoprogressive CRC with dominant metastases to the lungs who were treated with SBRT between September 2009 and December 2022. Oligometastatic disease was defined as newly diagnosed, untreated CRC with up to 5 metastases, up to 3 in one organ. Oligoprogressive disease was defined as CRC with 1 - 2 distant sites that continued to progress on active treatment while the primary site was controlled. Survival was estimated using Kaplan-Meier. Association between local control and patient factors was analyzed using log-rank test. A total of 84 patients with oligometastatic or oligoprogressive CRC were treated with SBRT to 124 lung lesions. Colon cancer was the primary site for 54 patients with a median age at time of SBRT of 66 years (IQR 57 - 73) and a median tumor diameter of 1.20 cm (IQR 0.93 - 1.90). Rectal cancer was the primary site for 30 patients, median age was 60 years (IQR 49 - 70) and median tumor diameter was 1.10 cm (IQR 0.80 - 1.48). Median dose for the entire cohort was 6000 cGy (range 5000 - 6000) with median number of fractions 5 (range 3 - 5). Median follow-up after SBRT was 24 months. Overall, there were 9 local failures at last follow-up. Almost half (n = 42) of the patients experienced distant recurrence. Median local control (LC) for the entire cohort was not reached, 2-yr LC and 5-yr LC were 94.6% and 85.7% respectively. There were no differences in LC between colon and rectal cancer (p = 0.29). Actuarial median overall survival was 71 months (95% CI 44.3 - 97.7) and 5-yr OS was 50.2%. Due to the small number of events, we were unable to identify patient factors associated with local failure on univariate or multivariate analysis. Cytoreductive SBRT is an effective treatment option for patients with oligometastatic or oligoprogressive CRC with dominant lung metastases offering excellent rates of LC. Most patients failed distantly highlighting the importance of additional systemic therapies.

Stereotactic Body Radiotherapy for Management of Pulmonary Oligometastases in Stage IV Colorectal Cancer: A Perspective

In pulmonary oligometastases from colorectal cancer (POM-CRC), metastasectomy is the primarily recommended treatment. Stereotactic body radiotherapy (SBRT) has been suggested as a viable alternative therapy. SBRT efficacy for POM-CRC is poorly delineated compared to selected non-CRC primaries. This perspective article aims to critically summarize the existing evidence regarding efficacy of SBRT in terms of overall survival (OS) and local control (LC), and factors modulating this, in the treatment of POM-CRC. Overall, reasonable LC and OS rates were observed. The wide range of expansions in planning target volume margins introduced variation in pretreatment protocols. Dose-fractionation schedules varied according to patient and tumor characteristics, though leverage of BED10 in select studies enabled standardization. An association between SBRT dose and improved OS and LC was observed across multiple studies. Prognostic factors that were associated with improved LC included: fewer oligometastases, absence of extra-pulmonary metastases, primary tumor histology, and smaller gross tumor volume. Differences in SBRT modality and techniques over time further confounded results. Many studies included patients receiving additional systemic therapies; preprotocol and adjuvant chemotherapies were identified as prognostic factors for LC. SBRT compared with metastasectomy showed no differences in short-term OS and LC outcomes. In conclusion, SBRT is an efficacious treatment for POM-CRC, in terms of OS and LC. Heterogeneity in study design, particularly pertaining to dose protocols, patient selection, and additional therapies should be controlled for future randomized studies to further validate SBRT efficacy.

A Real-World Evidence Study Using Alberta-Population-Based Data to Describe Treatment Patterns for Metastatic Castration-Sensitive Prostate Cancer Patients (AWARENESS).

Over the past decade, the treatment of metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly. Current guidelines suggest the use of androgen deprivation therapy (ADT) plus an additional systemic therapy, regardless of disease burden and risk, based on phase 1 evidence showing improved overall survival. We sought to describe treatment patterns of patients with mCSPC in the province of Alberta. This was a retrospective, population-based, cohort study of male patients aged ≥18 with mCSPC at the time of diagnosis and who initiated ADT between 1 January 2016 and 31 December 2020. Data were obtained from the Alberta Cancer Registry. Patients were assigned to an ADT-alone cohort or a treatment intensification cohort (cohorts 2-5). The primary objectives of this study were to describe baseline characteristics and the treatment of mCSPC patients who initiated ADT with or without treatment intensification. Overall survival between cohorts was a secondary objective. Descriptive statistics were used to describe differences in baseline characteristics of each cohort. Overall survival was calculated using the Kaplan-Meier method. All statistical tests were two-sided and are used to call out likely cohort differences descriptively. Between 1 January 2016 and 31 December 2020, we identified a total of 960 patients with mCSPC (median age 74 years, IQR 66-82). Most patients received ADT alone (67%), followed by ADT plus abiraterone (18%), ADT plus docetaxel (12%), and ADT plus enzalutamide or apalutamide (3%). Over the study period, we observed an increase in the utilization of treatment intensification over time, in particular, the increased use of androgen-receptor-axis-targeted (ARAT) therapies. Patients who received ADT alone were older, were more likely to have more than one comorbid condition, had fewer sites of metastatic disease, and were less likely to be on opioid medications. In this study, we show that patients who received ADT alone as treatment for mCSPC are older, have more comorbidities, and have less extensive disease. While there has been a decline over time in the number of patients treated with ADT alone, over 50% of all patients with mCSPC continue to receive ADT alone. Further work is needed to understand barriers to treatment intensification and for knowledge translation initiatives to improve the treatment of patients with mCSPC.

Magnetic resonance imaging for prospective assessment of local recurrence of non-small cell lung cancer after stereotactic body radiation therapy

ObjectivesTo evaluate multi-parametric MRI for distinguishing stereotactic body radiation therapy (SBRT) induced pulmonary fibrosis from local recurrence (LR). Materials and methodsSBRT treated non-small cell lung cancer (NSCLC) patients suspected of LR by conventional imaging underwent MRI: T2 weighted, diffusion weighted imaging, dynamic contrast enhancement (DCE) with a 5-minute delayed sequence. MRI was reported as high or low suspicion of LR. Follow-up imaging ≥12 months or biopsy defined LR status as proven LR, no-LR or not-verified. ResultsMRI was performed between 10/2017 and 12/2021, at a median interval of 22.5 (interquartile range 10.5–32.75) months after SBRT. Of the 20 lesions in 18 patients: 4 had proven LR, 10 did not have LR and 6 were not verified for LR due to subsequent additional local and/or systemic therapy. MRI correctly identified as high suspicion LR in all proven LR lesions and low suspicion LR in all confirmed no-LR lesions. All proven LR lesions (4/4) showed heterogeneous enhancement and heterogeneous T2 signal, as compared to the proven no-LR lesions in which 7/10 had homogeneous enhancement and homogeneous T2 signal. DCE kinetic curves could not predict LR status. Although lower apparent diffusion coefficient (ADC) values were seen in proven LR lesions, no absolute cut-off ADC value could determine LR status. ConclusionIn this pilot study of NSCLC patients after SBRT, multi-parametric chest MRI was able to correctly determine LR status, with no single parameter being diagnostic by itself. Further studies are warranted.

Longitudinal follow-up and outcomes of pediatric and adult patients with SDH-deficient GIST.

11542 Background: Gastrointestinal stromal tumor (GIST) are gastrointestinal non-epithelial neoplasms most commonly driven by somatic mutations in KIT or PDGFRA. Approximately ten percent of GIST are due to germline mutations in SDHx or epigenetic loss of expression of SDHC. While KIT and PDGFRa driven GIST respond to treatment with tyrosine kinase inhibitors, effective systemic therapies for SDH-deficient GIST have not yet been identified. SDH-deficient GIST are indolent tumors that typically progress slowly over time. A better understanding of the natural history of patients with these neoplasms is critical to identify effective treatments and improve patient care. A cohort of patients with SDH-deficient GIST is followed at the NIH Clinical Center and through the NIH Pediatric and Wild-type GIST Clinic. The aim of this study is to characterize the long-term outcome of this cohort of patients. Methods: Data from patients with SDH-deficient GIST enrolled in a study Natural History and Biospecimen Acquisition for Children and Adults with Rare Solid Tumors (NCT03739827) from January 2019 through January 2023 at the NIH were evaluated. In addition to review of medical records and imaging, when available, tumors were characterized by sequencing of SDH genes. Germline analysis of SDH genes was offered to consenting patients and families. Results: Clinical information and specimens were collected from 77 GIST patients (median age at diagnosis 21.5, [range 7-57] years; 72.7% (56) female, 21.3% (21) male) were classified by molecular subtypes: 33.8% SDHC epimutation, 28.6% SDHA, 22.1% SDHB, 14.3% SDHC and 1.3% SDHD. Median age at presentation of SDHC epimutation was younger (14.5 years, range: 8-56) when compared to SDHA (27.5 years, range: 7-55), SDHB (22 years, range: 8-54), SDHC (18 years, range: 10-57) and SDHD (39 years, N = 1). Most commonly, patients had at least one surgery (55.8%) while a lower proportion had four or more (7.8%). Primary tumors occurred in the stomach with 26% having metastases at presentation the most common location being the liver (10.4%). Overall, 64.9% of patients were treated with imatinib, 39% were treated with sunitinib and 15.6% received other additional systemic therapies. Within the cohort there were 13% of patients with paragangliomas and 6.5% with chondromas while only 9.1% had a family history of GIST. Conclusions: Longitudinal follow-up of an SDH-deficient GIST patient cohort will allow for better understanding of the natural history including treatment history and survival of patients with this rare disease and will help to optimize strategies for treatment and follow-up of these patients.

Topical treatment of psoriasis vulgaris.

Topical therapy plays an important role in the treatment of psoriasis. It is the gold standard in mild psoriasis cases and is also recommended in addition to UV and systemic therapy in cases of moderate to severe psoriasis. In this overview article we summarize the current therapeutic options, taking into account special localizations (scalp, facial, intertriginous/genital, or palmoplantar lesions) and situations (hyperkeratotic or inflammatory forms), as well as the therapy options during pregnancy and breastfeeding. In the initial phase, the combination of topical corticosteroids and vitamin D analogues has proven to be the therapy of choice, as well as monotherapy in each case. In maintenance therapy, fixed combination therapy is recommended once or twice a week. In addition to the right choice of active substances, the choice of the right formulation also plays an important role. To increase adherence, it is very important to consider the personal preferences and experiences of the patient. If topical therapy does not lead to a satisfactory result, additional UV therapy or systemic therapy should be considered.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

MP22-20 CONTEMPORARY TRENDS IN THE MANAGEMENT OF T1 BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP22-20 CONTEMPORARY TRENDS IN THE MANAGEMENT OF T1 BLADDER CANCER Michael Hung, Adithya Balasubramanian, and Douglas Scherr Michael HungMichael Hung More articles by this author , Adithya BalasubramanianAdithya Balasubramanian More articles by this author , and Douglas ScherrDouglas Scherr More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003247.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The current treatment strategy for T1 non muscle invasive bladder cancer is centered around bladder preservation with an emphasis on complete tumor resection and BCG therapy. However, the insidious nature of T1 bladder cancer lead many to offer early radical cystectomy with or without additional systemic therapy. We sought to examine the contemporary treatment patterns in the management of T1 bladder cancer in a nationwide cohort. METHODS: The National Cancer Database (NCDB) was queried to identify all cases of cT1 bladder cancer from 2004 to 2017. Demographic and clinical characteristics were compared and trended over the study period. We identified subsequent surgical therapy after initial diagnosis and stratified patients who underwent radical cystectomy and those who underwent bladder preserving surgery alone. Kaplan Meier curves were used to estimate survival in these cohorts, stratified by the treatment facility. RESULTS: The total of 128,400 patients were identified in the study period. The rate of radical cystectomy in patients with T1 bladder cancer increased from 4.6% in 2004 to 7.5% in 2017 (Figure 1a). In patients who underwent radical cystectomy, the overall rate of neoadjuvant and adjuvant chemotherapy was 11% and 17%, respectively. There was no significant difference in median OS among patients who received neoadjuvant chemotherapy compared to no systemic therapy (8.6 yrs vs 7.5 yrs, p=0.15), and no difference in rates of pathologic upgrade to T2-4 at cystectomy (36.7% vs 34.6%, p=0.42). Patients who underwent cystectomy had significantly longer median OS compared to those who had bladder preserving surgery alone (7.5 yrs vs 7 yrs, p=0.01). A majority (58%) of all radical cystectomies were performed at academic facilities and median OS was significantly higher at academic facilities versus community hospitals (8.1 yrs vs 6.1 yrs, p<0.01) (Figure 1b). CONCLUSIONS: Rates of radical cystectomy for the management of T1 bladder cancer have increased over time, congruent with evidence suggesting improved survival compared to local therapy alone. However, increased rates of neoadjuvant chemotherapy were observed despite the lack of clear guidelines or benefits for use. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e305 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Hung More articles by this author Adithya Balasubramanian More articles by this author Douglas Scherr More articles by this author Expand All Advertisement PDF downloadLoading ...

Impact of Postoperative Stereotactic Body Radiation Therapy on Survival of Patients with Spinal Metastases in the Context of Additional Systemic Adjuvant Therapy

Stereotactic body radiotherapy (SBRT) has been established as a safe and effective treatment modality for control of long-term pain and tumor growth. However, few studies have investigated the efficacy of postoperative SBRT versus conventional external beam radiation therapy (EBRT) in extending survival within the context of systemic therapy. A retrospective chart review of patients who underwent surgery for spinal metastasis at our institution was conducted. Demographic, treatment and outcome data were collected. SBRT was compared with EBRT and non-SBRT, and analyses were stratified by whether or not patients received systemic therapy. Survival analysis was conducted using propensity score matching. Bivariate analysis in the non-systemic therapy group revealed longer survival with SBRT compared to EBRT and non-SBRT. Further analysis also showed that primary cancer type and preoperative mRS significantly affected survival. Within patients who received systemic therapy, overall median survival for SBRT patients was 22.7 months (95% CI: 12.1 - 52.3) versus 16.1 months (95% CI: 12.7 - 44.0; p = 0.28) for EBRT patients and 16.1 months (95% CI: 12.2 - 21.9; p = 0.07) for non-SBRT patients. Within patients who did not receive systemic therapy, overall median survival for SBRT patients was 62.1 months (95% CI: 18.1 - unknown) versus 5.3 months (95% CI: 2.8 - unknown; p = 0.08) for EBRT patients and 6.9 months (95% CI: 5.0 - 45.6; p = 0.02) for non-SBRT patients. In patients who do not receive systemic therapy, treatment with postoperative SBRT may increase survival time compared to patients not receiving SBRT.

In brief: A new breast cancer indication for sacituzumab govitecan (Trodelvy).

Sacituzumab govitecan-hziy (Trodelvy – Gilead) has been approved for treatment of unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in adults who received prior endocrine therapy and ≥2 additional systemic therapies for metastatic disease. It was previously approved for treatment-refractory metastatic triplenegative breast cancer and for treatment of locally advanced or metastatic urothelial cancer in adults who received platinum-based chemotherapy and a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Underutilization of best systemic therapy in patients with metastatic prostate cancer.

111 Background: Advancement of treatment pathways in the management of metastatic prostate cancer (mPC) has identified newer systemic agents associated with survival advantage over androgen deprivation therapy (ADT) alone. Despite FDA approvals and guideline recommendations outlining standard of care (SOC) intensification of (ADT) with such additional systemic therapies such as docetaxel or novel hormonal therapies (NHT), these treatments are not being utilized uniformly by all practitioners. Our objective is to assess the utilization of such advanced therapies in patients with mPC and study differences in prescribing patterns. Methods: Between 2017 to present, we retrospectively identified all consecutive men with prostate cancer in a single health system. Electronic health record ICD code inquiries were used to identify patients. The population was further restricted utilizing diagnosis codes to include only those with metastatic prostate cancer and to exclude patients with second primary cancers. All treatment modalities and demographic information were analyzed to assess for prescribing patterns. Results: In total, 5,761 men had a diagnosis of prostate cancer. Exclusion criteria applied stepwise removed those with age &lt;18 years (2 patients) and secondary malignancies (1046 patients), resulting in 4,713 men for analysis. Of these, 665 men were found to have mPC and included in the final cohort. Mean patient age was 70.3 ± 9.6 years. We found no statistically significant difference in SOC prescribing pattern based on race, ethnicity, insurance type, zip code, 2020 United States census household median income, nor year of treatment. There was, however, overall low utilization of intensification of ADT with docetaxel or NHT at 42%, with 58% of patients still being treated with only first generation antiandrogens or luteinizing hormone releasing hormone agonists. Conclusions: In a large health system, we found that next generation care can be provided independent of insurance payor profile, race, ethnicity, and socioeconomic status. However, despite guidelines to support newer systemic agents for patients with mPC, we continue to observe that it is underused in clinical practice. Additional studies are needed to identify potential clinician and patient barriers, as well as prescribing pattern failures that are limiting the implementation of evidence-based treatment beneficial to overall survival.

Predictive Value of 18F-Fluorodeoxyglucose Positron-Emission Tomography Metabolic and Volumetric Parameters for Systemic Metastasis in Tonsillar Cancer.

Although the prognosis of tonsillar cancer (human papillomavirus-positive oropharyngeal squamous cell carcinoma) is improving, disease control failure (distant metastasis) still occurs in some cases. We explored whether several 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) parameters can predict metastasis. We retrospectively reviewed the medical records of 55 patients with tonsil squamous cell carcinoma who underwent pretreatment 18F-FDG positron-emission tomography/computed tomography (PET/CT) followed by primary surgery. During the follow-up period, systemic metastases were found in 7 of the 55 patients. The most common sites were the lungs (33%), bone (22%), brain/skull base (22%), small bowel (11%), and liver (11%). Pathologically, P53 mutation was less common in patients with systemic metastasis (41.7% vs. 14.3%, p = 0.054) than without systemic metastasis. In terms of PET parameters, the metabolic tumor volume (MTV2.5) and total lesion glycolysis (TLG2.5) values were lower in the primary tumor, and higher in the metastatic lymph nodes, of human papillomavirus (HPV)-positive compared to HPV-negative patients (all p &lt; 0.05). The MTV2.5, TLG2.5, and tumor-to-liver uptake ratio were 36.07 ± 54.24 cm3, 183.46 ± 298.62, and 4.90 ± 2.77, respectively, in the systemic metastasis group, respectively; all of these values were higher than those of the patients without systemic metastasis (all p &lt; 0.05). The MTV2.5 value was significantly different between the groups even when the values for the primary tumor and metastatic lymph nodes were summed (53.53 ± 57.78 cm3, p = 0.036). The cut-off value, area under the curve (95% confidence interval), sensitivity, and specificity of MTV2.5 for predicting systemic metastasis were 11.250 cm3, 0.584 (0.036-0.832), 0.571, and 0.565, respectively. The MTV2.5 of metastatic lymph nodes and summed MTV2.5 values of the primary tumor and metastatic lymph nodes were significantly higher in tonsillar cancer patients with than without systemic metastases. We suggest PET/CT scanning for pre-treatment cancer work-up and post-treatment surveillance to consider additional systemic therapy in patients with a high risk of disease control failure.

Analyzing the role of reoperation in recurrent glioblastoma: a 15-year retrospective study in a single institution

BackgroundMultiple treatment options at glioblastoma progression exist, including reintervention, reirradiation, additional systemic therapy, and novel strategies. No alternative has been proven to be superior in terms of postprogression survival (PPS). A second surgery has shown conflicting evidence in the literature regarding its prognostic impact, possibly affected by selection bias, and might benefit a sparse subset of patients with recurrent glioblastoma. The present study aims to determine the prognostic influence of salvage procedures in a cohort of patients treated in the same institution over 15 years.MethodsThree hundred and fifty patients with confirmed primary glioblastoma diagnosed and treated between 2005 and 2019 were selected. To examine the role of reoperation, we intended to create comparable groups, previously excluding all diagnostic biopsies and patients who were not actively treated after the first surgery or at disease progression. Uni- and multivariate Cox proportional hazards regression models were employed, considering reintervention as a time-fixed or time-dependent covariate. The endpoints of the study were overall survival (OS) and PPS.ResultsAt progression, 33 patients received a second surgery and 84 were treated with chemotherapy only. Clinical variables were similar among groups. OS, but not PPS, was superior in the reintervention group. Treatment modality had no impact in our multivariate Cox regression models considering OS or PPS as the endpoint.ConclusionsThe association of reoperation with improved prognosis in recurrent glioblastoma is unclear and may be influenced by selection bias. Regardless of our selective indications and high gross total resection rates in second procedures, we could not observe a survival advantage.

Effective Treatment of Low Risk Acute Gvhd with Itacitinib Monotherapy

Introduction The primary treatment of acute graft-versus-host disease (GVHD), prolonged courses of high dose systemic corticosteroids (SCS), cause significant morbidities, including an increased risk of serious infections. We used validated clinical (Minnesota standard [Minn std] risk) and biomarker (Ann Arbor [AA] 1) criteria to identify a group of patients with GVHD that is low risk (LR) for treatment failure and non-relapse mortality (NRM) and who might benefit from less toxic alternatives to SCS. Itacitinib (ita), a novel JAK1 inhibitor, blocks the inflammatory cytokine pathways key to target organ damage without the myelosuppression of JAK1/2 inhibitors such as ruxolitinib. We tested the hypothesis that ita monotherapy would be a safe and effective primary treatment of low risk GVHD in a multicenter phase II trial and compared outcomes to a matched control cohort of MAGIC pts with LR GVHD treated with SCS. Methods From February 2019 to April 2021, 70 pts with LR GVHD (Minn std risk/AA1) GVHD were treated with ita 200mg/day for 28 days; responders were allowed a second 28 day cycle. Ita was discontinued without tapering. Biomarker scores were available within 30 hours from sample collections, and treatment could be delayed up to 4 days after screening to accommodate a mostly outpatient population. A contemporaneous cohort of 140 control pts, matched for key characteristics, including target organ severity, donor type, HLA-match, and GVHD prophylaxis, was created from the Mount Sinai Acute GVHD International Consortium (MAGIC) database and biorepository. Control pts were treated with standard doses of SCS (median starting dose 1.1 mg/kg). ORR at 28 days of treatment was defined as the proportion of pts achieving complete or partial response of GVHD symptoms without additional systemic therapy. Infections required laboratory/imaging proof and were considered serious if they required systemic treatment. Results Both ita and SCS treatment produced excellent ORR (ita: 89%; SCS: 86%; p=0.67) including in pts with lower GI GVHD (86% vs 86%, p=1). Similarly high ORR was observed for both cohorts for all subgroup comparisons including by GVHD grade, target organ involvement, age, donor type, HLA-match, conditioning regimen, GVHD prophylaxis, and number of days post-BMT to treatment initiation. ORR was unaffected by the time from screening to initiation of ita (≤48 hours: 90%; >48 hours: 87%; p=1). Significantly more patients treated with itacitinib achieved a response by day 7 compared to those treated with SCS (81% vs 66%, p=0.02) and among responders, ORR were equally durable up to day 90 in both groups (89% vs 88%; p=1). There were no significant differences between ita and SCS pts for 1-year relapse (18% vs 21%, p=0.64), chronic GVHD (28% vs 32%, p=0.33), NRM (4% vs 11%, p=0.21), or survival (88% vs 80%, p=0.11). Regarding the safety data of ita monotherapy, the incidence of grade ≥3 non-hematologic and non-infectious TEAEs was similar to the SCS cohort with no event occurring in >10% of pts. The incidence of new or worsening grade ≥3 neutropenia, anemia, or thrombocytopenia was similar between ita and SCS cohorts. In fact, grade ≥3 leukopenia occurred less frequently in the ita group (16% vs 31%, p=0.02). Ita treatment resulted in an 91% lower cumulative steroid dose through day 28 compared to SCS (1.9 vs 22.0 mg/kg, p<0.001) and fewer pts developed at least one serious infection within 90 days (27% vs 42%, p=0.02; Fig 1). The mean number of infections per pt was also lower (0.43 vs 0.66; rate ratio 0.65 [0.43-0.97]), as was the likelihood of developing a severe (BMT CTN grade 2 or 3) infection (odds ratio 0.50 [95% CI: 0.27, 0.93]). The reduction in serious infections was driven by fewer viral infections in the ita group (Fig 2), particularly in the first 28 days and not explained by differences in letermovir use. Conclusion A short course of itacitinib monotherapy produced very high response rates that occurred faster than treatment with SCS, were equally durable and with a similar risk for cGVHD in patients treated for LR GVHD. Importantly, ita treatment resulted in significantly less severe leukopenia and a significantly lower incidence of serious infections than SCS, likely a result of dramatically less exposure to systemic steroids. Ita monotherapy should be further studied as primary treatment for LR GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mogamulizumab-Associated Rash (MAR) Correlates with Longer Progression Free Survival in Cutaneous T Cell Lymphoma (CTCL)

Background: Mogamulizumab-kpkc (mogamulizumab) is an anti-CCR4 monoclonal antibody approved for relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS). In the Phase III MAVORIC trial comparing mogamulizumab to vorinostat, mogamulizumab-associated rash (MAR) was reported in 25% of patients (pts) and was more common in responders than in non-responders. Since then, several small case series have suggested that MAR is associated with response to the drug and prolonged remission. Methods: We collected retrospective data from 8 academic centers on pts diagnosed with CTCL as defined by 2018 WHO-EORTC classification, who received at least one dose of mogamulizumab from 1/1/2000 to 1/31/2022. Primary endpoints were PFS and overall survival (OS) as calculated by Kaplan-Meier, compared with log rank test. Secondary endpoint was response to mogamulizumab in accordance with ISCL/EORTC 2011 criteria. MAR was graded with NCI CTCAE version 5.0. Categorical variables were compared between groups using Fisher test. Quantitative variables are presented with means and standard deviation or median and interquartile range (IQR). Univariate analysis was performed to calculate the hazard ratios (HR) for PFS. Results: A total of 159 pts were included in analysis: 80 (50%) pts had a diagnosis of MF, 67 (42%) had SS, and 11 (7%) had other CTCLs. Median age was 70 (IQR 59.5-76), 65 (41%) were female, 124 (78%) were non-Hispanic Caucasian, 22 (14%) were Black. Median of prior lines of therapy was 3 (0-14). ECOG was 0-1 in 80% of pts at start of mogamulizumab. Majority of pts (70%, n=111) had advanced stage disease (Stage III or IV). Extranodal disease other than skin was present in 111 (70%) and LDH was elevated in 80 (50%) of pts. MAR occurred in 72 (45%) pts. Majority of rash was grade 1-2 (76%, n=55) but 14% (n=10) developed grade 3 rash. Median time to onset was 3.7 months (mo) (IQR 2.1, 7.6) and median time to resolution was 4.3 mo (IQR 1.4, 7.5). Skin biopsy was obtained in 51 of 72 pts who developed MAR. Histologic patterns ranged from spongiotic/psoriasiform (40%, n=29), interface (19%, n=14), lichenoid (28%, n=20), granulomatous (7%, n=5) or a combination of patterns. Location of rash occurred in extremities (78%, n=56), trunk (69%, n=50), face/scalp (39%, n=28), buttocks/groin (8%, n=6) or combination of places. Of the pts who developed MAR, 24 (33%) were treated with topical steroids, 13 (18%) with systemic steroids, 16 (42%) with both topical and systemic steroids and 12 (17%) with other therapies, while 4 (6%) did not receive any treatment. Median follow up was 20.9 mo, IQR: (12.0, 38.4). Median PFS was 30.5 mo (95% CI: 27.0 mo to not reached) for pts who developed MAR vs. 8.6 mo (95% CI: 5.7-20.9) for those who did not (HR=0.38, 95% CI: 0.24-0.62, p<0.0001). Three-year OS for pts with MAR vs. those without was 84% vs 55% (HR 0.3, 95% CI: 0.14-0.63, p=0.0008). Complete remission (CR) was higher in pts with MAR (64%; n=46) than those who did not develop MAR (26%; n=23). Overall response rate (ORR) was also higher in those with MAR vs those without, 85% (n=61) vs. 54% (n=47), p<0.0001. Odds ratio of CR in pts with MAR was 4.64 (95% CI: 2.37-10.25), p<0.0001. CR and partial remission (PR) in the blood were the most predictive of longer PFS on univariate analysis with HR of 0.05 (95% CI: 0.02, 0.14, p<0.001) and 0.07 (95% CI: 0.03, 0.20, p<0.001), respectively. Advanced stage CTCL at the start of mogamulizumab was also associated with improved PFS compared with early stage, HR 0.61 (95% CI: 0.37, 1.00), p=0.05. At last follow-up, mogamulizumab had been discontinued in 114 pts due to rash (n=38), immune event (n=2), progression (n=56) or other adverse outcome (n=22). Mogamulizumab was held in 40 pts with drug rash. Of the pts who permanently discontinued mogamulizumab due to rash, 16 of 38 pts (42%) remain off systemic therapy at last follow up with ongoing response; median time off of systemic therapy for these pts was 7.8 mo (IQR: 6.1, 16.5). Conclusions: The development of MAR in patients with CTCL is associated with higher rates of CR and ORR and significantly longer PFS and OS. CR/PR response in blood were associated with improved PFS. Additionally, 40% of patients who developed MAR and discontinued mogamulizumab had ongoing responses without additional systemic therapy. Rash may be a surrogate marker of favorable outcome with mogamulizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ruxolitinib for Treatment of Steroid Refractory Sclerotic Chronic Graft-Versus-Host Disease (cGVHD): Results of a Multicenter Phase II Trial

Background: Sclerotic cGVHD is a highly morbid form of cGVHD, often refractory to standard and secondary therapies and associated with significant decline in patients' quality of life and functioning. We conducted a single-arm phase II multicenter trial to test the hypothesis that ruxolitinib is effective treatment for steroid refractory sclerotic cGVHD (ClinicalTrials.gov ID: NCT03616184). Methods: Eligibility criteria included adults with cGVHD and skin, joint and/or fascia sclerosis, who had received systemic corticosteroids for >12 months and at least one additional line of therapy, or systemic corticosteroids and at least two additional lines of therapy. Subjects received oral ruxolitinib 10 mg twice daily for 6 months, which was subsequently tapered over another month. Treatment could be extended up to 12 months in patients deriving clinical benefit. The primary objective was to determine the proportion of patients with an NIH-defined response in skin or joints at 6 months. A sample size of 47 patients (estimated 10% drop out) had α of 0.044 and a power of 84% to test the null hypothesis response rate of 25% (Clin Cancer Res. 2016; 22: 319-327) compared to an alternative of 45%. Other endpoints included overall response, non-relapse mortality (NRM), treatment failure (administration of additional systemic therapy, malignancy relapse or mortality), glucocorticoid dose reduction, and patient-reported outcomes (PROs) (Lee symptom scale and Scleroderma Health Assessment Questionnaire). Results: 49 patients were consented between November 2018- June 2021; 2 patients were screen failures. Baseline characteristics of 47 patients included a mean age of 58 (range 23-76) years, 40% female, and 91% white. 87% had peripheral blood as a graft source. 66% had matched unrelated donor transplant. 66% had prior acute GVHD. Median time from cGVHD diagnosis to enrollment was about 48 months. All patients had classic cGVHD at enrollment. Severity included mild (2%), moderate (13%) or severe (85%). Patients had received a mean of 3 prior lines of treatment. Patients received a mean of 8.6 cycles of ruxolitinib. 13% had missing data that precluded response assessment; these patients were considered non-responders. Partial responses (PR) in skin or joint (primary endpoint) were seen in 49% (95% CI 34-64%) at 6 months; other responses included stable disease (19%), progression (19%) and missing (13%) (Fig 1). No complete responses were observed in skin or joint. Overall cGVHD partial responses were seen in 47% (95% CI 32-61%); other responses included stable disease (13%), mixed responses/progression (27%) and missing (13%). PR/CR in individual organs (among those with organ involvement after excluding missing data) were as following: eye (12/32, 37%), mouth (9/17, 53%), esophagus (5/9, 55%), upper GI (2/3, 67%), lower GI (2/3, 67%), lung (1/9, 11%), and liver (5/14, 36%). 24% (95% CI 11.8-41.2%) had >50% reduction in glucocorticoid dose from baseline to 6 months. The cumulative incidences of treatment failure and NRM at 6 months were 15.2% (95% CI 6.6- 27.1%) and 2.2% (95% CI 0.2-10.3%). No patients have had relapse of malignancy. 6-month failure free survival was 84.8% (95% CI 70.7-92.4%) (Fig 2). Any grade and grade 3 or higher adverse events occurred in 55% (n=26) and 36% (n=17) of patients. 6 out of 17 grade 3 or higher adverse events were considered possibly or probably related to ruxolitinib. AE occurring in >10% of patients included dry eye, diarrhea, nausea, vomiting, infection, upper respiratory tract infection, weight gain, laboratory and other abnormalities. PRO analyses are ongoing and will be presented. Discussion: The trial met its primary endpoint with half of adults with moderate-severe sclerotic cGVHD achieving partial responses in skin or joint as well as overall cGVHD responses. The use of ruxolitinib was associated with high rates of failure-free survival. In conclusion, the use of ruxolitinib results in high rate of responses in highly morbid sclerotic form of cGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Versus Late Treatment with Ruxolitinib in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease: A Post Hoc Analysis from the Randomized, Phase 3 REACH3 Study

Background: Chronic graft-versus-host-disease (cGVHD) occurs in a relevant proportion of long-term survivors after allogeneic hematopoietic stem cell transplantation and is a leading cause of morbidity and nonrelapse mortality. Standard first-line treatment for cGVHD is systemic corticosteroids; however, approximately 40%-60% of patients either do not respond or become refractory and require additional systemic therapy. Ruxolitinib is an oral, selective Janus kinase (JAK)1/JAK2 inhibitor approved for steroid-refractory (SR)-cGVHD in adult and pediatric patients aged ≥12 years after failure of ≤2 lines of systemic therapy. In the phase 3 pivotal REACH3 trial, compared with best available therapy (BAT), ruxolitinib significantly improved response rates and allowed for steroid tapering among patients with SR-cGVHD. The impact of timing of ruxolitinib initiation on treatment response and patient outcomes needs further investigation. Methods: REACH3 (NCT03112603) was a phase 3 randomized, open-label, multicenter study in which SR-cGVHD patients aged ≥12 years with moderate or severe SR or steroid-dependent cGVHD were randomized to receive either ruxolitinib 10 mg twice daily or investigator-selected BAT. This post hoc analysis examined overall response rate (ORR [complete response (CR) + partial response (PR)]) at Week 24, best overall response (BOR) at any time, and duration of response (DOR) between early (≤14 days from SR-cGVHD), late (>14-28 days), very late (>28 days), or late and very late (>14 days) study treatment initiation. Subgroups were defined based on time from SR-cGVHD to randomization. DOR was measured as the time from first documented CR or PR among those with response at Week 24. Odds ratio (OR) and 95% CI for ORR and BOR were calculated using stratified Cochran-Mantel-Haenszel test or Wald confidence limits. DOR was analyzed with the Kaplan-Meier method. Results: Overall, 165 patients were randomized to ruxolitinib (n=88, 77, 47 for early, late-and-very-late [>14 days], and very late, respectively) and 164 to BAT (n=85, 79, 46). Median age ranged from 47-51 years between subgroups, and most patients were male (range between subgroups, 52.9%-66.2%). Approximately half of patients had experienced prior acute GVHD (range between subgroups, 47.8%-55.8%). Patients had moderate (42.9%) or severe (56.8%) SR-cGVHD at time of study entry; mean time from cGVHD diagnosis to randomization ranged from 154.3-346.0 days between subgroups. Ruxolitinib was superior to BAT in all time-to-treatment subgroups for ORR (early: OR, 2.83 [95% CI: 1.49, 5.37]; late-and-very-late: OR, 3.10 [95% CI: 1.51, 6.34]; very late: OR, 3.41 [95% CI: 1.30, 8.95]; Table). There was a trend toward higher rate of CR for ruxolitinib treatment vs BAT regardless of treatment delay. DOR represented as probability of loss of response over time is presented in the Figure. Ruxolitinib was superior to BAT for BOR of CR or PR up to Week 24 in late-and-very-late (OR, 2.92 [95% CI: 1.46, 5.87]) and very late subgroups (OR, 2.72 [95% CI: 1.13, 6.52]) and numerically greater in the early treatment subgroup (OR, 1.59 [95% CI: 0.80, 3.15]; Table). No differences in ORR, BOR (Table), or DOR were observed between ruxolitinib time-to-treatment subgroups. Conclusions: These data demonstrate that ruxolitinib provides clinical benefit compared with BAT regardless of time elapsing between onset of SR-cGVHD and treatment start. These findings confirm ruxolitinib as an effective treatment option compared with BAT that leads to durable responses in patients with cGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RADT-39. STAGED GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR LARGE INTACT AND RESECTED BRAIN TUMORS; THE MUSC EXPERIENCE

Abstract Stereotactic radiosurgery (SRS) is a well-established treatment modality for management of both benign and malignant central nervous tumors. One limiting factor in the use of SRS is tumor size. Staged radiosurgery treatment is an option to utilize this treatment modality while still limiting associated toxicity. This involves treating each target in 2 separate sessions, spaced apart by approximately 30 days. We describe a series of 17 patients with 20 unique lesions treated using this technique in our department from January of 2019 through December of 2021. 18 treated lesions were malignant brain metastases and 2 were meningiomas. For 13 lesions, SRS was the primary treatment, and for 7 lesions, SRS was adjuvant treatment after surgery. The median target size for fraction 1 was 18.40 cm^3 with a median dose of 12.65 Gy. The median target size for fraction 2 was 14.50 cm^3 with a median dose of 12.08 Gy. All but one target was prescribed to the 50% isodose line. Median follow up was 7.12 months. Local control at the site of treated lesions was 90%. 3 patients with local control at the site of the fractionated treatment were noted to have additional progression within the CNS. There were 2 patient deaths within 30 days of treatment. One death was due to respiratory failure. The other cause of death was unknown. Treatment was well tolerated with no grade 3 or higher acute toxicity. 50% of patients went on to receive additional systemic therapy. 55% of patients are known to have died at the time of latest follow up. Overall, staged gamma knife radiosurgery appears to be an effective option for treating both intact and resected tumors with an acceptable toxicity profile.

Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73–13.1, p = 7.8 × 10−6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

Radiosurgery for Primary and Metastatic CNS Malignancies in the Pediatric Population

<h3>Purpose/Objective(s)</h3> Safety and efficacy of stereotactic radiosurgery (SRS) are not well described for pediatric patients. This study presents disease control and toxicity outcomes after SRS for malignant CNS lesions in pediatric patients. <h3>Materials/Methods</h3> Retrospective chart review was performed for 31 pediatric patients treated at a single institution with a non-invasive stereotactic radiosurgery instrument for primary or metastatic CNS malignancies between 2000-2020. Analyses were performed with descriptive statistics, Kaplan-Meier, and proportional hazards modeling. <h3>Results</h3> Twenty-five patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the early adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4 at the time of diagnosis. Brain metastases were from non-germinomatous germ cell tumors (n=3), papillary thyroid cancer (n=1), and neuroblastoma (n=1). 71% of patients had prior involved-field external beam radiation to the brain (median dose 59.4 Gy in 33 fractions). Median age at SRS was 14 years (range 4-21). SRS was predominantly performed in a single fraction (median dose 17 Gy, range 15-20) to a total of 42 targets among 29 patients, with a median total gross target volume (GTV) of 1.3 cc. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger brain metastases (GTVs 8.5 cc & 23.2 cc). Median follow up after SRS was 44 months (interquartile range 20-72). The 3-year actuarial rates of local control, intracranial progression-free survival, and overall survival after SRS were 77.6%, 33.3%, and 74.6%, respectively. 9 patients (29%) had no evidence of intracranial disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at a median of 13 months after SRS. 16 patients (52%) developed distant brain recurrence without local failure at a median of 9 months after SRS. Among primary CNS tumors, there was no significant association of histology, grade, or dose with disease control outcomes on univariate analysis. All patients with subsequent CNS recurrence after SRS underwent salvage therapy, including additional radiosurgery (36%), systemic therapy (23%), resection (9%), or combined modality treatment (32%). In total, 4 patients developed CTCAE grade 2-3 toxicity from SRS, all of which were related to radiation treatment effect and occurred within 1 year of SRS. 2 patients received steroids alone, and 2 underwent invasive procedures (1 shunt revision, 1 resection of nonviable tumor). <h3>Conclusion</h3> SRS for malignant CNS lesions in the pediatric population provides effective local control and is generally well-tolerated. Although there remains a substantial risk of distant CNS failures, all patients were able to receive additional salvage therapy after SRS.