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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2060-2060
    Abstract: 2060 Background: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. This concept was explored in a phase I trial (NCT03514069), whose final report on toxicity is presented here. Methods: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3+3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. The primary study objective was the determination of the maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. The secondary objective was the determination of safety, overall survival (OS), and progression-free survival (PFS). The exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. Results: 60 patients were enrolled, with a median age of 60.5 years (range 22-78). 23 (38%) patients were female and 37 (62%) were male. 29 (48%) were MGMT unmethylated and received ruxolitinib with radiation of 60 Gy over 6 weeks. 31 (52%) patients were MGMT methylated and received ruxolitinib with 75 mg/m 2 of temozolomide (TMZ) with radiation of 60 Gy over 6 weeks. The 1-year OS rate was 77% for all GBM patients; 62% for arm 1 (unmethylated MGMT) and 93% for arm 2 (methylated MGMT). Median OS for arm 1 was 18.1 months (10.1, NA) and was not reached for arm 2. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Conclusions: Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical benchmarks for both MGMT methylated and MGMT unmethylated cohorts. A randomized phase 2 trial is planned. Clinical trial information: NCT03514069 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e13550-e13550
    Abstract: e13550 Background: It is known that in the setting of glioblastoma (GBM) having a methylated O6-Methylguanine Methyltransferase (MGMT) gene promoter confers a greater response to Temozolomide (TMZ) and an increased progression free survival (PFS) and overall survival (OS). Recent literature has uncovered interesting results when dichotomizing patients by demographics (i.e. age and gender) and analyzing response to the various available GBM therapies. Our primary objective is to analyze the effect of both age and MGMT status on OS and PFS in patients with newly diagnosed GBM. Understanding the role of MGMT on age in the setting of GBM can allow for a better understanding of disease course and treatment. Methods: 464 adult patients with newly diagnosed GBM and documented MGMT status were analyzed from a single major tertiary care institution between 2012 and 2018. Patients were stratified into four groups based on age (above or below 65 years) and MGMT status. A univariate Cox model was used to analyze the effect of age and MGMT status on PFS and OS, where our reference group was the group with the highest OS ( 〈 65/methylated). Results: The median age of the whole dataset was 63.4 years, and 65.2 years for patients who were MGMT methylated. Patients less than 65 years and were MGMT methylated had the best prognosis with a PFS and an OS of 10.9 months and 18.9 (Table), respectively. Patients above the age of 65 were more likely to be MGMT methylated (p = 0.002). There was an association between IDH1-mutant status and MGMT methylation (p = 0.006). Conclusions: Using MGMT status and age of the patient, our model predicts outcomes that can vary from 7.4 months to 18.9 months (HR = 3.41 p 〈 0.001).[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e13565-e13565
    Abstract: e13565 Background: Radiotherapy and concurrent chemotherapy with Temozolomide (TMZ) have myelosuppressive effect, and thrombocytopenia is commonly seen in this patient population seen in 5-10% of glioblastoma (GBM) patients. There is a lack of data analyzing the thrombocytopenia and it’s on the progression free survival (PFS) or overall survival (OS) of these patients. The primary objective of this study was to identify the degree of thrombocytopenia in newly diagnosed GBM patients receiving concurrent TMZ based chemoradiation (CRT). Secondary objectives included associations between thrombocytopenia PFS, and OS. Methods: We retrospectively reviewed 484 newly diagnosed GBM patients who underwent surgery followed by standard of care CRT. We also analyzed the association between platelet counts and age, sex, MGMT methylation status, and extent of surgical resection. Platelet count was collected at the time of surgery, CRT start date, and two, four, six, and ten weeks post-CRT start date. Patients were grouped into quartiles according to their platelets count. Results: Of the 484 patients collected, 308 were males, 139 had gross total resection of the tumor, 229 patients were older than 65 years, and 171 (42.1%) were MGMT methylated. In a univariate analysis, a platelet count less than 180,000 (lowest quartile) was associated with higher mortality (HR 1.63, P 〈 0.001) but had no significant association with PFS (HR 1.16, P = 0.48). Among the 118 patients who had platelet count lower than 180,000, 4 had platelets count less than 100,000 necessitating their TMZ to be stopped during CRT. In a multivariate analysis model adjusting for age, gender, MGMT status, and type of surgery, platelet counts less than 180,000 was also associated with significantly higher mortality (HR 1.60, P 〈 0.001). Conclusions: Our study concluded that patients who had platelet counts less than 180,000 at the time of surgery or CRT with TMZ had significantly higher mortality (HR 1.60, P 〈 0.001) but had no association with PFS (HR 1.16, P = 0.48).[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 4
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 10549-10549
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 10549-10549
    Abstract: 10549 Background: Treatment for pediatric low-grade glioma (LGG) is variable, depending on age and tumor location. Systemic therapy (ST) is often used to delay RT, but ST does not result in durable local control. The goal of this study was to evaluate event-free survival (EFS) and toxicities for pediatric LGG treated with RT over a 30-year period. Methods: All patients age ≤21 with intracranial pediatric LGG (WHO grade I-II) treated with RT at a single institution since May 1986 were included in this retrospective review. Patients with metastatic disease (M+) received craniospinal irradiation (CSI); otherwise, RT was conformal. EFS and overall survival (OS) were measured from the first day of RT. Events included death, progression, or secondary high-grade glioma. Results: 221 patients were eligible. Median follow-up was 11.3 yrs (range, 0.1-30.5). Median RT dose was 54 Gy. 10-yr EFS and OS were 67.9% (95% CI 60.4-74.3) and 91.1% (95% CI 85.8-94.5) for non-metastatic patients, respectively. For 12 M+ patients treated with CSI, 10-yr EFS and OS were 58.9% (95% CI 23.4-82.5) and 70.0% (32.9-89.2), respectively. 28.6% developed pseudoprogression (PP) with median time to onset and resolution of 6.1 months (IQR 3.6-14.6) and 6.4 months (IQR 3.5-11.7), respectively. Patients with PP had improved 10-yr EFS (83.4% vs. 61.0%, HR 0.40, p = .006). Patients with grade II tumors and who received pre-RT ST had lower EFS (Table). Sex, NF-1, tumor location, extent of surgery and CSI were not independently associated with EFS. 10-yr cumulative incidence of grade ≥2 vasculopathy was 7.5% (95% CI 4.9-11.4). There were 12 cases of secondary high-grade glioma, with a 20-yr cumulative incidence of 5.5% (95% CI 2.6-11.4). Conclusions: Irradiation provides long-term control of pediatric LGG in a majority of patients. Receipt of pre-RT systemic therapy was associated with reduced EFS; this association requires further investigation. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 9089-9089
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e14551-e14551
    Abstract: e14551 Background: In a retrospective study, we investigated the correlation between the molecular characteristics and treatment outcomes in pts with G2-3 glioma. Methods: Pts with G2-3 glioma and known IDH mutation status who were diagnosed between 1994 and 2017 were analyzed. In most of the pts, IDH mutation was determined by immunohistochemistry only. Overall survival (OS) was defined as the date of biopsy/surgical resection to the date of last follow up or death. OS was estimated by Kaplan-Meier method and compared by log rank test. Results: 606 pts with G2 (81%) or G3 (19%) glioma were included. The median age at diagnosis was 38 years (Interquartile range 27-52), 55% of the pts were male, 83% were white, 47% had IDH-mt tumor and 67% underwent surgical resection. The median follow-up was 55.6 months (mo). The median OS (mOS) in pts with IDH mutated (mt) and IDH wild type (wt) tumor were 201 and 128 mo, respectively. The predictors of worse OS in pts with IDH-mt tumor included G3, receipt of chemotherapy or radiation therapy (RT), bilateral disease and lack of 1p/19q codeletion. The determinants of worse OS in pts with IDH-wt tumor included male gender, receipt of chemotherapy or RT, history of prior malignancy, smoking, G3, astrocytoma histology, no surgical resection, EGFR amplification, and lack of 1p/19q codeletion. The mOS by IDH, 1p/19q, and MGMT status is summarized in the table. RT and chemotherapy were more commonly used among pts who had G3 glioma and those who underwent biopsy only. Conclusions: Tumor grade continues to be a determinant of pt outcomes in the setting of molecularly defined gliomas. Presence of 1p/19q codeletion is a predictor of favorable OS in pts with G2-3 glioma. Surgical resection is a determinant of OS in pts with IDH-wt G2-3 gliomas, but not in pts with IDH-mt tumor. The worse OS in pts who were treated with RT or chemotherapy is likely due to the use of these treatment modalities in more aggressive tumors and in those who only had biopsy. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2060-2060
    Abstract: 2060 Background: Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Methods: Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3+3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm 2 was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimate by Kaplan-Meier method and compared using log rank test. Results: 45 patients had survival data, 25 patients were Arm I and 20 arm II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p = 0.01 and p = 0.002), respectively. Conclusions: Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Clinical trial information: NCT03514069.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2030-2030
    Abstract: 2030 Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 9
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e14009-e14009
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e14009-e14009
    Abstract: e14009 Background: Breast cancer is the second most common cause of metastatic brain tumors. The presence of estrogen receptors (ER), and progesterone receptors (PR), and HER2 receptors have been used to guide both hormonal and targeted therapies for breast cancer. The presence or absence of these receptors may impact patient outcomes in breast cancer brain metastasis (BCBM). Methods: Patients with BCBM and known tumor marker status treated at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from diagnosis of BCBM to date of death or last follow up. Many of these patients received multiple lines of treatment including hormonal and targeted therapies at some point during their care. The Cox proportional hazard model was used to determine differences in OS. Results: 137 patients with BCBM were included. Of these, 48 were ER or ER/PR positive (ER+), 3 were PR positive (PR+), and 47 were HER2, HER2/PR, HER2/ER, or HER2/ER/PR positive (HER2+), and 37 were triple-negative. For ER+ tumors the median age at diagnosis was 60 years (Interquartile range (IQR) 31-87) and 86% were white. For PR+ tumors the median age at diagnosis was 67 years (IQR 66-74) and 75% were white. For HER2+ tumors the median age at diagnosis was 55 years (IQR 31-84) and 79% were white. For triple-negative tumors the median age at diagnosis was 56 years (IQR 34-91) and 83% were white. OS for ER+, PR+, HER2+, and triple-negative patients had a median of 57.7, 19.8, 137.4, and 54.6 months and a 2-year rate of 76%, 33%, 82%, and 73%, respectively. With ER+ patients as a reference, PR+ patients had an OS hazard ratio of 1.49 (95% CI = 0.35 - 6.23, p = 0.59), HER2+ patients had an OS hazard ratio of 0.62 (95% CI = 0.36 - 1.06, p = 0.082), and triple-negative patients had an OS hazard ratio of 0.92 (95% CI = 0.54 - 1.57, p = 0.77). Conclusions: HER2+ tumors were associated with an increase in OS when compared to ER+, PR+, and triple-negative tumors in patients with BCBM. The OS of the other three tumor marker groups was not significantly different from one another. Further studies need to be done within tumor marker cohorts to determine the most effective treatments within those cohorts.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. e13516-e13516
    Abstract: e13516 Background: Primary central nervous system lymphoma (PCNSL), a form of extranodal non-Hodgkin lymphoma represents 3% of primary CNS tumors. It is aggressive but typically confined to the CNS. Despite improvements in the management of PCNSL, more than 50% of patients eventually relapse. There are limited data on PCNSL from larger cohort studies. Methods: With IRB approval, the Cleveland Clinic Neuro-Oncology Center database was used to identify patients treated between 2006-2015 for PCNSL. Overall survival (OS) from the diagnosis of PCNSL and progression free survival (PFS) were the primary and secondary end points respectively. Cox proportional hazards models were used for data analysis. Results: 86 PCNSL patients were included in the analysis. Only 5% (4/76) were HIV positive. The median age of diagnosis was 63 (range 15 - 86) and 50% were males. 88% of patients presented only with brain lesion, 8% only in eye and 4% had both brain and eye involvement. 15% of patients (12/81) had positive CSF findings. Treatment included: chemotherapy (CT) alone (39% of patients); chemoimmunotherapy (CIT) (32%); CIT with radiotherapy (RT) (13%); RT alone (11%); CT with RT (4%); and immunotherapy (IT) alone (1%). Among 23 patients (31%) who received RT upfront, 74% had WBRT (n = 17). The most common upfront therapy was high dose methotrexate (HD MTX) (44%), followed by HD MTX with rituximab (23%), RTOG 0227 (12%), RTOG 1114 (11%) and rest 14% included rituximab or temozolomide or other cytotoxic chemotherapy alone or in combinations. The most common relapse site was brain (72%), followed by eyes (12%) and spine (8%). The median follow-up was 26 months. At last follow up, 41% had died and 93% of which were PCNSL-related. The median PFS and OS were 17.7 months and 84 months, respectively. There was a trend towards superior PFS in upfront IT vs. no IT (20 vs. 14 months, p 0.08). Better performance status (KPS 〉 80 vs. 〈 80, HR 0.42 (p = 0.033)) and PFS ≥ 24 months compared to ≤ 24 months (p = 0.0012) were associated with improved OS. Conclusions: We report a large single institution cohort of PCNSL patients treated in the era of immunotherapy. In our cohort, better KPS (≥80) and PFS ≥ 24 months had improved OS. Upfront IT showed a trend towards improved PFS.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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