scholarly journals Clinical benefit of high dose IL-2 (HD IL-2) therapy: evidence for improved overall survival in patients with stable disease

2013 ◽  
Vol 1 (S1) ◽  
Author(s):  
Tasha Hughes ◽  
Gail Iodice ◽  
Sanjib Basu ◽  
Steven Bines ◽  
Howard Kaufman
Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5489-5489
Author(s):  
Emilio P. Alessandrino ◽  
Letizia Zenone Bragotti ◽  
Anna A. Colombo ◽  
Alessandra Algarotti ◽  
Paolo Bernasconi ◽  
...  

Abstract From 1996 to 2003, 113 consecutive patients with multiple myeloma were treated with four different high dose approaches rescued by autologous peripheral blood progenitor cells (PBPC) after four cycles of VAD or other combinations. The median age was 53 years 31–68), 58% were male and 42% female, the median interval from diagnosis to transplant was 252 days (range 160–3116 days). Twenty-five patients received as preparative regimen Carmustine, Etoposide and Melphalan (BVM) at the total dose of 600 mg/m2, 900mg/m2 and 140–180 mg m2 respectively. Nineteen pts had as preparative regimen Thiotepa and Melphalan at the total dose of 10 mg/kg and 140–180 mg/m2 respectively, 38 pts received a double transplant with Melphalan given as a single agent at the dose of 200 mg/m2, while 31 pts received a single transplant with Melphalan 200 mg/m2. In patients with poor performance status at transplant or previous history of infection or renal impairment, the dose of melphalan was reduced by 20% respect to the standard planned dose. in the group of 25patients treated by BVM, 10 had progressive disease, 6 stable disease (SD), 7 partial remission (PR), 1 very good partial remission (VGPR). At day +90 from transplant, 17 patients were in CR or PR (68%). The actuarial probability of overall survival and event free survival at 5 years were 40% and 20%, respectively. One pt died of transplant, one developed a solid tumor 24 mos after transplant. in the group of 19 pts treated with TT and Mel (TT-Mel), 3 pts were with progressive disease, 3 with stable disease, 6 in partial remission, 3 with minimal response, 3 in VGPR, 1 in CR. At day +90, 15 pts were in CR or PR (78%). The actuarial probability of survival was 50% at 5 years, and event free survival 28%. in the group of 38 pts who received a double transplant, 7 pts were with progressive disease, 3 with stable disease, 14 in PR, 12 in VGPR or CR. At day +90 after the second transplant, 31 of 38 patients (81%) were in CR or PR. Overall survival and event free survival was respectively 48% and 20% at five years. in the group of 31 pts receiving a single transplant with Melphalan alone, 8 were with progressive disease, 1 with stable disease, 6 in VGPR, 1 in CR, 13 in PR. At day +90, 21 of 31 patients (67%) were in CR or PR. Overall survival and event free survival was respectively 45% and 22% at five years. In conclusion, double transplant seems better than one transplant with melphalan alone in terms of EFS and OS (p<0.03); the BVM combination produces high response rates, the regimen, however, is toxic with a high rate of life threatening mucositis. the addition of Carmustine and Vepeside or Thiotepa to Melphalan does not produce significant improvement of OS and EFS.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii174-ii175
Author(s):  
Priya Kumthekar ◽  
Solmaz Sahebjam ◽  
Mark Pegram ◽  
Nuhad Ibrahim ◽  
Jesse Sussell ◽  
...  

Abstract Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1875-1875 ◽  
Author(s):  
Basem M. William ◽  
Kaylee Brillhart ◽  
Manuel Afable ◽  
Kristen Bakalarz ◽  
Brenda Cooper ◽  
...  

Abstract B ackground: Current therapies for CLL/SLL have frequent toxicities, are non-curative, and several trials have demonstrated that early treatment of the disease doesn't result in longer overall survival. In high doses, both curcumin (CM), from turmeric, and vitamin D (VD) have been shown to be safe in multiple clinical trials of solid tumors. Curcumin was shown to disrupt CLL cell interactions with the microenvironment, induce apoptosis independent of DNA damage, and upregulate vitamin D receptor (VDR) in malignant lymphoid cells. We hypothesized that the combination of CM and VD is safe and active in CLL/SLL and would delay disease progression. Methods: This was an open-label phase II trial for previously untreated patients with asymptomatic,Rai stage 0-II CLL/SLL not currently meeting National CancerInstitute Working Group (NCI-WG) Criteria for treatment. All patients received 8 gm of CM and 10,000 IU of vitamin D3 (VD) orally daily. VD was started 1 week after CM and both agents were maintained for up to six 4-week cycles. The primary endpoint was the overall response rate (ORR) based on NCI-WG criteria. Secondary endpoints were event-free (EFS), overall survival (OS), and time to next treatment (TTNT). VD-25-OH and CM major metabolites; CM glucuronide (COG) and CM sulfate (COS), were measured in plasma by liquid chromatography-tandem mass spectrometry. Phosphorylated-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), a validated pharmacodynamic marker of CM activity, as well as VDR, were measured in CLL cells by flow cytometry. Results: A total of 35 patients (pts), 51% males, were accrued to the trial, 30 (86%) were evaluable for response. Median age was 60 years (range 45-80). Most had CLL (97%); 51% were Rai stage 0 and 49% were Rai stage 1. Cytogenetic abnormalities included del13q14 (37%), trisomy 12 (11%), del 11q22 (11%) and del 17p (3%); 20% had ZAP-70 levels >20%. Median number of cycles received was 5 (range 1-6) and treatment was well tolerated overall. The most frequent adverse effects (AE) were diarrhea/gastrointestinal upset in 69% of patients (14% were grade 3). No serious AEs were observed. Eighteen pts (51%) completed all 6 cycles of treatment; 10 (29%) withdrew consent, 4 (11%) discontinued treatment because of diarrhea, and 3 (9%) patients progressed on treatment. Best response was stable disease in 28/30 (93%) evaluable pts. After a median follow up of 29 months, EFS was 72.0% (95% CI 52.1 - 84.7%), 74.1% (95% CI 58.7-89.6%) had not started new CLL treatment, and OS was 100%. Median VD-25-OH levels were 28.75ng/ml (range 12.5-55.6) at baseline and 49.5 ng/ml (24.8-69) at 28 days. Median COG/COS levels were 15.8 (2.73-75)/6.71(0-33.5) and 18 (0-75.9)/7.21(0-35.2) ng/ml at 8 and 28 days, respectively. Flow cytometric analysis of CLL cells showed no significant change in VDR or Phosphorylated-NF-κB with CM-VD treatment. Conclusion: Curcumin and high-dose vitamin D combination is safe and well tolerated in patients with early stage CLL. Although no responses were seen, the majority of patients maintained stable disease on treatment. Longer follow up is planned on this study to determine long - term CLL progression rates of patients treated with CM-VD. Disclosures Afable: Eli Lilly: Employment. Lazarus:Pluristem Ltd.: Consultancy. Nagabhushanam:Sabinsa Corporation: Employment. Grote:BTR Group Inc: Employment. Kunati:Symrise AG: Employment.


2014 ◽  
Vol 2 (Suppl 3) ◽  
pp. P88
Author(s):  
Howard L Kaufman ◽  
Sandra Aung ◽  
Michael Morse ◽  
Michael Wong ◽  
James Lowder ◽  
...  

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 423-423 ◽  
Author(s):  
Sandra Aung ◽  
Michael A. Morse ◽  
Michael K.K. Wong ◽  
Howard Kaufman ◽  
Gregory A. Daniels ◽  
...  

423 Background: HD IL-2 has been reported to have a overall response rate (ORR) for mRCC of 15% and a median OS of 19 months (Fyfe, 1995), however, the studies that led to its regulatory approval are >15 years old and were performed in an era preceding targeted therapies. Methods: The PROCLAIM registry (www.proclaimregistry.com), a HD IL-2 observational database currently with over 30 participating sites, consists of a retrospective cohort (treated between 2007 and 2012) informing an ongoing prospective cohort (~600 patients). We report on the retrospective mRCC subjects (n=97, 13 sites) with survival status determined as of November 2013 and a median follow-up of 32 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least one dose of HD IL-2. Results: The ORR was 22% (8% CR and 14% PR). Of 97 subjects, 36 were confirmed deceased and 61 were known to be alive, none were lost to follow-up. The median OS was 51 months, compared to a median OS range of 5-35 months for FDA-approved targeted agents (Harrison, 2013). There was significant clinical benefit in patients with CR, PR, and stable disease (SD), none of which reached median OS compared to 37.9 months in patients with progressive disease (PD). There is a significant advantage in PROCLAIM for those patients treated 1st vs. 2nd line HD IL-2; the median OS was 61.8 months (n=82) vs. 15.3 months (n=15), respectively. The clinical benefit of HD IL-2 therapy as front line is consistent with published data (Birkhauser, 2013). No deaths due to IL-2 related toxicity were reported in the retrospective cohort. Conclusions: The PROCLAIM registry documents a vastly improved OS for HD IL-2 compared to historical results during a time interval marked by the advent of targeted therapy for advanced RCC. Response to IL-2 (CR or PR) is associated with prolonged survival, however, stable disease as well as front line use also appears to positively impact survival. Issues including patient selection characteristics and treatment sequencing are hypotheses currently being explored in the prospective database. Clinical trial information: NCT01415167.


2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Margaret L. Musser ◽  
Chad M. Johannes

Abstract Background Canine pancreatic carcinoma is a rare, aggressive tumour that is often diagnosed late in the course of disease. Effective treatment strategies have been elusive, and overall survival time is short. In humans, treatment with tyrosine kinase inhibitors alone, or in combination with IV gemcitabine, have been moderately effective. As canine and human pancreatic carcinomas share many clinical aspects, strategies that mimic human treatment regimens may confer a better outcome in canine patients. The aim of this study was to assess the role of the veterinary tyrosine kinase inhibitor, toceranib phosphate, in the treatment of cytologically or histologically confirmed canine pancreatic carcinomas. Results Retrospectively, medical records of dogs with confirmed pancreatic carcinoma treated with toceranib were reviewed. Eight dogs were identified that fit the inclusion criteria. Toceranib was well-tolerated by all patients. Six were treated in the gross disease setting. Four had image-based evaluation of clinical benefit (complete response, partial response, or stable disease of > 10 weeks). Of those patients, 1 achieved a partial response, 2 stable disease, and 1 had progressive disease, for an overall clinical benefit rate of 75 %. An additional dog had clinically stable disease that was not confirmed via imaging. The toceranib-specific median overall survival time was 89.5 days (range: 14–506 days). Conclusions Although limited in patient number, this small study suggests that toceranib may have biologic activity in dogs with pancreatic carcinoma. Larger, prospective studies are needed to confirm these preliminary results and define the use of toceranib in the microscopic disease setting.


Author(s):  
Pavani Chalasani ◽  
Kiah Farr ◽  
Vicky Wu ◽  
Isaac Jenkins ◽  
Alex Liu ◽  
...  

Abstract Background Treatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician’s choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile. Methods We conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy. Findings We consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients. Interpretation Metronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.


2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A339-A339
Author(s):  
Ahmad Tarhini ◽  
Ni Kang ◽  
Sandra Lee ◽  
F Stephen Hodi ◽  
Gary Cohen ◽  
...  

BackgroundSex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. Female sex hormones have been implicated in melanoma development and response to systemic therapy. We hypothesized a gender difference in response to adjuvant immunotherapy with ipilimumab (3 or 10 mg/kg; ipi3 or ipi10) versus high dose IFNα (HDI) as tested in the E1609 trial.MethodsE1609 demonstrated significant overall survival (OS) benefit with ipi3 versus HDI.1 We investigated treatment efficacy between ipi and HDI in the subgroups by sex (female, male), age (< 55 or ≥55), stage at study entry (IIIB, IIIC, M1a/1b), ECOG performance status (PS 0, 1), ulceration (yes, no), primary tumor (known, unknown), number of lymph nodes involved (0, 1, 2–3, 4+). Forest plots were created to compare OS and RFS with ipi3 vs. HDI and ipi10 vs. HDI using the concurrently randomized ITT populations. For the estimated HRs, 95% confidence intervals were created for all subgroups.ResultsThe subgroups of female, stage IIIC, PS=1, ulcerated, in-transit without lymph node involvement demonstrated significant improvement in overall survival (OS) and/or relapse free survival (RFS) with ipi3 versus HDI as summarized in table 1. Female sex was significant for both OS and RFS and was further explored. In investigating RFS with ipi3 versus HDI, a multivariate Cox regression model including sex, treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.026). Including sex, PS (0 vs. 1), age (<55 vs. 55+), ulceration (yes vs. no), stage (IIIB, IIIC, M1a, M1b), treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.024). While similar trends were seen, no significant interactions between sex and treatment effect were found in the OS multivariate analysis or in the comparison of ipi10 versus HDI. When exploring age, in the univariate analyses in the ipi3 versus HDI comparison older women appeared to drive most of the difference (age ≥55: OS, P=0.02 and RFS, P=0.08; differences non-significant for women <55). Table 1.Abstract 312 Table 1Treatment efficacy between ipi3 and HDI by subgroupConclusionsFemale sex was independently associated with RFS adjuvant immunotherapeutic benefit from ipi3, supporting a potentially important role for female related factors in the immune response against melanoma, and these warrant further investigation.Trial RegistrationNCT01274338Ethics ApprovalThe study protocol was approved by the institutional review board (IRB) of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. This study was monitored by the ECOG-ACRIN DataSafety Monitoring Committee and the NCI.ConsentAll patients provided IRB-approved written informed consent.ReferenceTarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. PMID: 31880964.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii276-iii276
Author(s):  
Alexis Judd ◽  
Erin Wright ◽  
Sarah Rush

Abstract Choroid plexus carcinoma (CPC) and Atypical teratoid/rhabdoid tumor (ATRT) are aggressive, malignant brain cancers most commonly arising in children less than 3 years of age. These tumors often have genetic alterations in the tumor suppressor gene SMARCB1/INI1. Rhabdoid predisposition syndrome (RTPS) categorizes patients with germline mutations in SMARCB1 or SMARCA4, leading to a markedly increased risk of developing rhabdoid tumors. Both CPC and ATRT have been demonstrated in patients with these rhabdoid predisposition syndromes. In general, these tumors tend to have a poor prognosis. However, with the presence of a SMARCB1 mutation they may have improved overall survival. We present two interesting cases of siblings with maternally inherited SMARCB1 mutations: one a 21-month-old male who presented with an ATRT and another a 10 month old female who presented with a CPC. The ATRT was treated as per the Children’s Oncology Group study ACNS0333 with high dose chemotherapy and stem cell rescue as well as cranial radiation. The CPC was treated as per CPT-SIOP 2009 with etoposide, cyclophosphamide and vincristine. Unlike other patients with these aggressive tumors, both of these patients are alive without evidence of disease recurrence 8 and 7 years post therapy, respectively. Additional genomic testing on both tumors is currently pending in order to potentially identify other mutations that may impact survival. These cases further illustrate the similar profile of two very different tumors with improved overall survival that may be secondary to mutations in SMARCB1 in RTPS.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuai Liu ◽  
Yanwei Liu ◽  
Guanzhang Li ◽  
Jin Feng ◽  
Li Chen ◽  
...  

Abstract Background As molecular advances have deepened the knowledge on low-grade glioma (LGG), we investigated the effect of higher radiation dose on the survival of IDH-wildtype (IDHwt) LGG. Methods In the current study, 52 IDHwt LGG patients who received radiotherapy were enrolled from the Chinese Glioma Genome Atlas dataset. Radiation doses > 54 Gy were defined as high-dose, whereas doses ≤ 54 Gy were defined as low-dose. We performed univariate and multivariate survival analyses to examine the prognostic role of high-dose radiotherapy. Results In total, the radiation dose ranged from 48.6 Gy to 61.2 Gy, with a median of 55.8 Gy, and 31 patients were grouped into high-dose radiation. Univariate survival analysis indicated that high-dose radiotherapy (p = 0.015), tumors located in the frontal lobe (p = 0.009), and pathology of astrocytoma (p = 0.037) were significantly prognostic factors for overall survival. In multivariate survival analysis, high-dose radiotherapy (p = 0.028) and tumors located in the frontal lobe (p = 0.016) were independently associated with better overall survival. Conclusions In conclusion, high-dose radiotherapy independently improved the survival of IDHwt LGG. This can guide treatments for glioma with known molecular characteristics.


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