CTNI-57. LOW-RISK MENINGIOMA: OUTCOMES FROM NRG ONCOLOGY/RTOG 0539

Abstract PURPOSE/OBJECTIVE(S) Outcomes of low-risk meningioma from NRG/RTOG-0539. MATERIALS/METHODS Outcomes of the intermediate and high-risk cohorts from this phase II trial have been previously reported. Low-risk (Group 1: new WHO grade 1) patients were observed after gross total (GTR) or subtotal resection (STR). Progression-free (PFS) and overall (OS) were estimated using Kaplan-Meier. CTCAE v3 AE grading was employed. RESULTS Group 1 enrolled 65 patients. 56/60 (93.4%) evaluable patients had investigator-reported GTR. Sufficient imaging for central confirmation was available for 48: GTR in 35 and STR in 13. Median follow-up for living patients was 9.1 years (y). For all evaluable patients 5 and 10 y PFS and OS rates were 89.4 and 85.0%, and 98.3 and 93.8%, respectively. For patients with centrally-confirmed STR, 5/10 y PFS rates were 72.7/72.7%, with 100% 10 y OS. For patients with centrally-confirmed GTR, 5/10 y PFS and OS rates were 94.3/87.6 and 97.1/90.4%, respectively. For combined study cohorts (Groups 1–3) with central-review (n=104), the median centrally-measured largest pre-operative tumor dimension was 4.3 cm (range 0.4 - 14.4); this was significantly associated with OS (hazard ratio [HR]=1.03, p=0.021) and PFS (HR=1.03, p=0.003). No grade 4 or 5 protocol-related adverse events were reported. There were 1 grade 3 (infection), 4 grade 2 (neurologic, pulmonary, gastrointestinal, and pain), and 5 grade 1 (3 neurologic, 1 occulovisual, 1 constitutional) events from 5 patients. CONCLUSION These results prospectively validate high OS and PFS outcomes for low-risk meningioma managed with surgery followed by observation, but raise questions regarding optimal management following STR (5 y PFS 72.7%), a subcohort that could potentially benefit from adjuvant therapy. However, we identified considerable discordance between local and central assessments of resection extent. Pre-operative tumor size has a significant impact on OS and PFS. Supported by: U10CA180868 and U10CA180822 from the National Cancer Institute (NCI)

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Cordotomy for patients with thoracic malignant astrocytoma

Journal of Neurosurgery Spine ◽

10.3171/2010.4.spine09901 ◽

2010 ◽

Vol 13 (4) ◽

pp. 418-423 ◽

Cited By ~ 8

Author(s):

Masaya Nakamura ◽

Osahiko Tsuji ◽

Kanehiro Fujiyoshi ◽

Kota Watanabe ◽

Takashi Tsuji ◽

...

Keyword(s):

Tumor Resection ◽

Radical Resection ◽

Subtotal Resection ◽

Optimal Management ◽

Malignant Astrocytoma ◽

Initial Operation ◽

Who Grade ◽

Kaplan Meier ◽

Malignant Astrocytomas ◽

Grade Ii

Object The optimal management of malignant astrocytomas remains controversial, and the prognosis of these lesions has been dismal regardless of the administered treatment. In this study the authors investigated the surgical outcomes of cordotomy in patients with thoracic malignant astrocytomas to determine the effectiveness of this procedure. Methods Cordotomy was performed in 5 patients with glioblastoma multiforme (GBM) and 2 with anaplastic astrocytoma (AA). A Kaplan-Meier survival analysis was performed, and the associations of the resection level with survival and postoperative complications were retrospectively examined. Results Cordotomy was performed in a single stage in 2 patients with GBM and in 2 stages in 3 patients with GBM and 2 patients with AA. In the 2 patients with GBM, cordotomy was performed 2 and 3 weeks after a partial tumor resection. In the 2 patients with AA, the initial treatment consisted of partial tumor resection and subtotal resection combined with radiotherapy, and rostral tumor growth and progressive paralysis necessitated cordotomy 2 and 28 months later. One patient with a secondary GBM underwent cordotomy; the GBM developed 1 year after subtotal resection and radiotherapy for a WHO Grade II astrocytoma. Four patients died 4, 5, 24, and 42 months after the initial operation due to CSF dissemination, and 3 patients (2 with GBM and 1 with AA) remain alive (16, 39, and 71 months). No metastasis to any other organs was noted. Conclusions One-stage cordotomy should be indicated for patients with thoracic GBM or AA presenting with complete paraplegia preoperatively. In patients with thoracic GBM, even if paralysis is incomplete, cordotomy should be performed before the tumor disseminates through the CSF. Radical resection should be attempted in patients with AA and incomplete paralysis. If the tumor persists, radiotherapy and chemotherapy are indicated, and cordotomy should be reserved for lesions growing progressively after such second-line treatments.

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Comparison of intermittent versus continuous methotrexate plus 6-mp in maintenance regimen for standard risk acute lymphoblastic leukemia in children (GBTLI ALL-99)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9512 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9512-9512 ◽

Cited By ~ 1

Author(s):

S. R. Brandalise

Keyword(s):

Maintenance Therapy ◽

Maintenance Treatment ◽

Risk Group ◽

Lymphoblastic Leukemia ◽

Treatment Schedule ◽

Group 2 ◽

Grade 3 ◽

Standard Risk ◽

Group 1

9512 Objectives: To compare by randomization the conventional use of 6-MP (50 mg/m2 daily) / MTX (25 mg/m2/wk) regimen with the intermittent use of MTX (200 mg/m2/IV 6 h infusion each 21 days)/ 6-MP (100 mg/m2/day × 10) in maintenance therapy. Methods: Newly diagnosed ALL children up to 18 yrs of age registered in the GBTLI ALL-99 Protocol. The eligibility criteria for standard-risk group were age >1 <9 years and WBC count at diagnosis <50,000/mm3 and good responders at D7/D14. Randomization was made after the late consolidation phase (week 42) prior to the maintenance treatment. Treatment Schedule: Induction: [DX(Pred), DNM, VCR, L-ASP, CICLO, Ara-C, 6-MP], Intensification: (MTX 2 g/m2 6 h inf. × 4, 6-MP) Late Consolidation: (DX, VCR, DOXO, L-ASP, CICLO, ARA-C, 6-TG) plus prolonged triple intratecal therapy, were done previously to maintenance therapy. Total treatment duration was two years. No CNS radiation was done. Toxicities were defined according to NCI-version 2001 criteria. Results: 560 pts were enrolled in the study. 22 slow responders pts (4.1%) moved to high risk group. The total number of analyzed pts was 512. Two hundred and thirty pts entered group 1 [continuous (conventional) 6MP-MTX] and 230 pts entered group 2 (Intermittent MTX/6-MP). Remission rate was 95.3%. 439 pts (87.9%) are in CCR. The mean follow up period is 2.2 years. The estimated 5 years OS rate for both groups is 88.1% ± 2.1%. The estimated 5 years EFS for both groups is 80% ± 2.9%. According to maintenance regimen, the 5 years EFS rate is 80.2% ± 4.5% and 88.3% ± 3.7% for group 1 and group 2, respectively (p=0.048). Grade 3 and 4 hepatic toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.019). Grade 3 CNS toxicities were 13 episodes (group 1) and 5 in group 2. Grade 4 hematological toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.003). Conclusions: Despite the short mean time follow-up (2.2 years) the patients with the intermittent regimen (Group 2) had better EFS rate (p = 0.048) and less hematological, CNS and hepatic toxicities, comparing with patients that received conventional maintenance treatment (group 1). No significant financial relationships to disclose.

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Carboplatin, ifosfamide, and mesna (CIM) for the treatment of gynecological carcinosarcoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16539 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16539-e16539

Author(s):

N. Walji ◽

A. Zachariah ◽

C. Yap ◽

S. A. Hussain ◽

C. J. Poole ◽

...

Keyword(s):

Complete Response ◽

Kaplan Meier ◽

Metastatic Setting ◽

The Common ◽

Group 2 ◽

Grade 3 ◽

Abdominal Irradiation ◽

Toxicity Criteria ◽

Group 1

e16539 Background: A GOG trial comparing cisplatin/ifosfamide/mesna chemotherapy versus whole abdominal irradiation for FIGO stages I-IV carcinosarcoma (CS) showed an estimated median survival (MS) of 50 months for chemotherapy but high toxicity. This study investigates the efficacy and tolerability of a novel regimen using carboplatin AUC 5, ifosfamide 3 g/m2 and mesna 1 g/m2 (CIM) in both the adjuvant and metastatic setting. Methods: Retrospective analysis of women with CS treated from May 1997-May 2007 with CIM (group 1) versus other chemotherapy regimens (group 2). Toxicity was graded according to the Common Toxicity Criteria and MS estimated using the Kaplan-Meier method. Results: Of 51 eligible women (median age 71 years) 35 (69%) had stage 3 or 4 disease. 35/51 (69%) received chemotherapy; 2 with stage 1c disease received pelvic radiotherapy (pRT) alone whilst the remaining 14 were unfit for any treatment. Median follow-up for the treated patients is 45 months. 11/35 patients (31%) received CIM as first-line chemotherapy. Other regimens included: carboplatin (n = 14); carboplatin/paclitaxel (n = 3); carboplatin/epirubicin (n = 3); carboplatin/doxorubicin (n = 2); doxorubicin/ifosfamide (n = 1); cisplatin/ifosfamide (n = 1). 20/35 (57%) received adjuvant chemotherapy (AC) of which 8 received CIM; 11/20 patients also received adjuvant pRT. MS in the CIM AC group is 54.7 months compared to 37.4 months for other regimens. 3/8 patients (37.5%) in the CIM arm developed recurrent disease compared to 9/12 (75%) for other regimens. 4/16 patients received CIM as first- or second-line palliative chemotherapy. All patients responded of whom 2 achieved clinical and radiological complete response (CR). One woman subsequently relapsed and achieved a second CR with CIM. MS for all chemotherapy-treated patients is 54.7 months (group 1) versus 20.6 months (group 2) (p = 0.07). No patients in group 1 experienced any grade 3/4 toxicity and all patients completed the prescribed treatment. There were 2 unexpected treatment-related deaths in group 2, one of whom received carboplatin/paclitaxel and the other carboplatin/epirubicin. Conclusions: CIM appears to be efficacious and well tolerated in the treatment of CS and merits further investigation in clinical trials. No significant financial relationships to disclose.

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Grade III meningioma: 10 year single centre case series

Neuro-Oncology ◽

10.1093/neuonc/noz167.080 ◽

2019 ◽

Vol 21 (Supplement_4) ◽

pp. iv18-iv18

Author(s):

Hari Mcgrath ◽

Jose Lavrador ◽

Ioannis Christodoulides ◽

Prajwal Ghimire ◽

Richard Gullan ◽

...

Keyword(s):

Case Series ◽

Extent Of Resection ◽

Tumour Recurrence ◽

Subtotal Resection ◽

Who Grade ◽

Surgical Interventions ◽

Grade 3 ◽

Oncology Centre ◽

Rhabdoid Features

Abstract Rationale WHO Grade 3 meningiomas are a rare, malignant subtype of meningioma. Few controlled case series detailing its treatment and follow-up are to be found in the literature. Methods Retrospective cohort study of patients treated in a single neuro-oncology centre in the period between September 2008 and March 2019 with an initial diagnosis of WHO Grade 3 meningioma. Demographic and clinical data has been collected from the available medical records. Results 9 patients were included in this series: 2 had convexity, 2 sphenoid wing, 2 parafalcine, 1 parasagittal with a further 3 multiple locations and 1 patient with parietal convexity meningioma. 3 tumours displayed rhabdoid features, whilst 4 displayed papillary features and a further 2 displayed epithelial structures. All patients underwent surgical intervention: 5 patients had a subtotal resection with 3 having total resection. 3/4 of reported Simpson Grading was grade 2, whilst the remaining 1/4 was grade 1. The extent of resection for 1 patient was uncertain. Post surgically, 6 received adjuvant radiotherapy, 2 had no further treatment and 1 received gamma knife therapy. No patient received chemotherapy. 5 patients saw no tumour recurrence at follow up appointments (mean 50 months). Within 2 years of their respective surgical interventions, 4 patients died due to tumour recurrence and associated complications (3 patients). Conclusion To establish a uniform approach to treatment of patients with WHO Grade 3 meningiomas is challenging. Management involves a patient-centred approach based on multidisciplinary meeting decisions. Multicentre registries may allow further conclusions.

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Real World Validation of VTE Risk Models in Newly Diagnosed Multiple Myeloma in a Community Setting

Blood ◽

10.1182/blood-2021-153953 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2971-2971

Author(s):

Shivani Kapur ◽

Kayla Feehan ◽

Samuel Mosiman ◽

Susan Frankki ◽

Lori J Rosenstein

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Risk Group ◽

Community Setting ◽

Low Risk ◽

Intermediate Risk ◽

Start Date ◽

Kaplan Meier ◽

Therapeutic Anticoagulation

Abstract Background: Multiple Myeloma (MM) is associated with increased risk for venous thromboembolism (VTE). Treatment, such as dexamethasone, immunomodulatory drugs (IMID), alkylating agents, and doxorubicin, alter hemostatic pathways and thus promote thrombogenesis 1. MM patients with VTE have a 3-fold increase in mortality compared to those without VTE, so identifying those at risk and aiming to prevent VTE events is important 2. Several clinical VTE risk prediction scores have been developed, including the SAVED score, IMPEDE VTE score, and more recently the PRISM score 2,4,5. The National Comprehensive Cancer Network suggests that patient with MM on IMID therapy should be on aspirin, or therapeutic anticoagulation for those at "high risk"3. However, it remains unclear which risk model, if any, should be used.Our objective was to validate the three published risk assessment tools in a community setting and assess the predictive ability of each. Methods: We conducted a retrospective chart review of all patients with newly diagnosed multiple myeloma who started chemotherapy at Gundersen Health System (La Crosse, WI) between 2010 and 2020 who had at least 6 months of follow up documented. Patients with prior indication for ongoing therapeutic anticoagulation or a diagnosis of VTE within 6 months prior to starting therapy were excluded. Total scores for IMPEDE VTE, SAVED and PRISM scores were calculated from the chemotherapy start date. Statistical analysis included Chi-square, Fisher's exact and Wilcoxon rank sum tests, and Kaplan Meier survival analysis. A p-value ≤ 0.05 was considered significant and all analysis was completed in SAS version 9.4. Results: Our cohort contained 123 patients diagnosed with MM. Average age was 68 years (SD 12.1, range 37-92). Our study included 68 (55%) males and 55 (45%) females with 121 (98%) being White/Caucasian. The mean BMI of patients was 29.4 kg/m2 (SD 7.0, range 18.6-54.4). Kaplan Meier survival analysis showed a 5-year survival rate of 53.1% (95% CI [42.7%, 63.4%]). In the entire cohort, 10 (8.1%) patients were diagnosed with VTE (as compared to 5.8% in IMPEDE study, 8.7% in SAVED study and 8.2% in PRISM study) with 80.0% occurring within 6 months of treatment start date. Aspirin was the most frequently used agent for thromboprophylaxis with 88 (86.3%) patients receiving either 81, 162, or 325 mg of aspirin. IMID therapy was given to 76 (61.8%) patients, 114 (92.7%) received dexamethasone and 114 (92.7%) received proteasome inhibitors. Amongst those on IMIDs, 72 (94.7%) patients received prophylaxis, most commonly aspirin. Abnormal metaphase cytogenetics were noted in 104 (85.4%) patients. Neither the IMPEDE VTE (p=0.6), SAVED (p=0.9) nor PRISM risk scores (p=0.3) were able to statistically predict VTE outcome in our patient population. Using the IMPEDE score, 7 patients in the intermediate risk group and 3 patients in the low-risk group had a VTE. In the SAVED model, 5 patients in the low-risk group and 5 patients in the high-risk group had a VTE. Using the PRISM risk score, all 10 of the patients with VTE were in the intermediate risk group. Most patients who were on IMID therapy fell into the intermediate risk group on the IMPEDE VTE and PRISM scoring systems, and the SAVED score had an approximately equal patient distribution between the high risk and low risk group. Conclusions: Our patients with multiple myeloma had similar rates of VTE as compared to the published models, with the majority occurring in the first 6 months of chemotherapy. In total, our patients on IMID therapy received appropriate prophylaxis with aspirin. Overall, 8.1% of our patients had a VTE event. However, none of the three risk models were able to predict the development of VTE. In fact, many of the VTE events occurred in patients who were felt to be low or intermediate risk. While the sample size is small and from a single health system, we had excellent follow up and ability to closely examine each chart for treatment and outcomes. Further efforts should focus on collaboration across institutions to increase the sample size, to validate and compare existing models. The majority of myeloma treatment occurs in the community; thus, it is important to ensure the findings are reproducible in that patient population. Disclosures No relevant conflicts of interest to declare.

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Patterns of recurrence in patients receiving conformal radiation for intracranial meningioma: a single-institution experience

Journal of Radiotherapy in Practice ◽

10.1017/s1460396920000539 ◽

2020 ◽

pp. 1-7

Author(s):

B. Rajkrishna ◽

Balakrishnan Rajesh ◽

Sebastian Patricia ◽

B. Selvamani

Keyword(s):

Conformal Radiotherapy ◽

Target Volume ◽

Tumour Resection ◽

Subtotal Resection ◽

Intracranial Meningioma ◽

Who Grade ◽

Time To Recurrence ◽

Grade 3 ◽

Patterns Of Recurrence

Abstract Aim: To evaluate the patterns of recurrence following postoperative conformal radiotherapy (RT) for intracranial meningioma. Materials and methods: Eighty-six patients who received conformal RT for intracranial meningiomas from 2014 to 2017 were retrospectively analysed. For documented recurrences, recurrence imaging was deformably co-registered to planning CT scan. In-field recurrence was defined as recurrence within the 90% isodose line, and out-of-field recurrences were those that occurred outside the 90% isodose line. We present the demographic details, surgical and RT details, outcomes and patterns of recurrence. Results: The median age was 46 years (range 17–72); 82·6% underwent surgery [46·5% had subtotal resection (STR), 43·7% gross tumour resection (GTR), 5·6% biopsy] and 17·4% had no surgery. Among these, 53·5% were WHO grade 2; 27·9% grade 1; and 1·2% grade 3 meningioma. Fifty per cent received stereotactic RT (SRT), 46·5% 3D conformal RT (3DCRT) and 3·5% intensity-modulated RT (IMRT). The mean clinical target volume (CTV) and planning target volume (PTV) margins were 4·5 mm (range 0–15) and 3·9 mm (range 1–5), respectively. The doses ranged from 54 to 59·4 Gy. The median follow-up after RT was 1·7 years (range 0·2–4·7). 17·4% were lost to follow-up, 5·4% had recurrence, and the median time to recurrence after completion of RT was 2 years (range 0·7–2·9). The 3-year recurrence-free rate was 81·5%. Three patients had in-field and two had in-field and out-of-field recurrence. Among the cases with recurrence, three received SRT, one 3DCRT and one IMRT. Four were grade 2 and one was grade 3 tumour, and the CTV margin ranged from 0 to 5 mm, and the PTV margin ranged from 3 to 5 mm. Conclusion: Local recurrence was seen in grade 2 and 3 meningiomas. SRT probably had more recurrence as they had lesser CTV margin. Increased CTV margin, escalated dose up to 59·4 Gy and 3DCRT/IMRT may be helpful in preventing local recurrences in grade 2 and grade 3 meningiomas.

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PATH-19. MOLECULAR, HISTOLOGIC AND CLINICAL CHARACTERISTICS OF OLIGODENDROGLIOMAS: A MULTI-INSTITUTIONAL RETROSPECTIVE STUDY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.701 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii168-ii168

Author(s):

Antonio Dono ◽

Kristin Alfaro-Munoz ◽

Yuanqing Yan ◽

Carlos Lopez-Garcia ◽

Zaid Soomro ◽

...

Keyword(s):

Health Science ◽

Cancer Center ◽

Subtotal Resection ◽

Adjuvant Radiation ◽

Science Center ◽

Who Grade ◽

Pik3ca Mutations ◽

Increased Risk ◽

Significant Difference ◽

Grade 3

Abstract In the 2016 WHO classification of CNS tumors, oligodendrogliomas are molecularly defined by IDH1 or IDH2 mutations and 1p/19q co-deletion. Some reports suggest that PI3K pathway alterations may confer increased risk of progression and poor prognosis in oligodendroglioma. However, factors that influence prognosis in molecularly defined oligodendroglioma (mOGD) have not been thoroughly studied. Also, the benefits of adjuvant radiation and temozolomide in mOGDs remain to be determined. 107 mOGDs diagnosed between 2008-2018 at the University of Texas Health Science Center at Houston (n= 39) and MD Anderson Cancer Center (n= 68) were included. A retrospective review of the demographic, clinical, histologic, molecular, and outcomes were performed. Median age at diagnosis was 37 years and 61 (57%) patients were male. There were 64 (60%) WHO Grade 2 and 43 (40%) WHO Grade 3 tumors. Ninety-five (88.8%) tumors were IDH1-mutant and 12 (11.2%) were IDH2-mutant. Eighty-two (77%) patients were stratified as high-risk: older than 40-years and/or subtotal resection (RTOG 9802). Gross-total resection was achieved in 47 (45%) patients. Treatment strategies included observation (n= 15), temozolomide (n= 11), radiation (n= 13), radiation with temozolomide (n= 62) and other (n= 6). Our results show a benefit of temozolomide vs. observation in progression-free survival (PFS). However, no benefit in PFS or overall survival (OS) was observed when comparing radiation vs. radiation with temozolomide. PIK3CA mutations were detected in 15 (14%) cases, and patients with PIK3CA-mutant mOGDs showed worse OS (10.7-years vs 15.1-years, p= 0.009). Patients with WHO Grade 3 tumors had shorter PFS but no significant difference in OS was observed compared to grade 2. Our findings suggest that mOGDs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS in temozolomide treated patients, adjuvant treatment with radiation or the combination of both, showed no significant advantage in terms of OS.

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Accuracy of the CARG chemotherapy toxicity risk prediction tool in older Indian patients with cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e24023 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e24023-e24023

Author(s):

Shreya Gattani ◽

Vanita Noronha ◽

Anant Ramaswamy ◽

Renita Castelino ◽

Vandhita Nair ◽

...

Keyword(s):

High Risk ◽

Cancer Patients ◽

Risk Prediction ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Chemotherapy Toxicity ◽

Patients With Cancer ◽

Indian Patients ◽

Grade 3

e24023 Background: Clinical judgement alone is inadequate in accurately predicting chemotherapy toxicity in older adult cancer patients. Hurria and colleagues developed and validated, the CARG score (range, 0–17) as a convenient and reliable tool for predicting chemotherapy toxicity in older cancer patients in America, however, its applicability in Indian patients is unknown. Methods: An observational retrospective and prospective study between 2018 and 2020 was conducted in the Department of Medical Oncology at Tata Memorial Hospital, Mumbai, India. The study was approved by the institutional ethics committee (IEC-III; Project No. 900596) and registered in the Clinical Trials Registry of India (CTRI/2020/04/024675). Written informed consent was obtained in the prospective part of the study. Patients aged ≥ 60 years and planned for systemic therapy were evaluated in the geriatric oncology clinic and their CARG score was calculated. Patients were stratified into low (0-4), intermediate (5-9) and high risk (10-17) based on the CARG scores. The CARG score was provided to the treating physicians, along with the results of the geriatric assessment. Chemotherapy-related toxicities were captured from the electronic medical record and graded as per the NCI CTCAE, version 4.0. Results: We assessed 130 patients, with a median age 69 years (IQR, 60 to 84); 72% patients were males. The common malignancies included gastrointestinal (52%) and lung (30%). Approximately 78% patients received polychemotherapy and 53% received full dose chemotherapy. Based on the CARG score, 28 (22%) patients belonged to low risk, 80 (61%) to intermediate risk and 22 (17%) to the high risk category. The AU-ROC of the CARG score in predicting grade 3-5 toxicities was 0.61 (95% CI, 0.51-0.71). The sensitivity and specificity of the CARG score in predicting grade 3-5 toxicities were 60.8% and 78.6%. Grade 3-5 toxicities occurred in 6/28 patients (21%) in the low risk group, compared to 62/102 patients (61%) in the intermediate /high risk group, p = 0.0002. There was also a significant difference in the time to development of grade 3-5 toxicities, which occurred at a median of 2.5 cycles (IQR, 1-3.8) in the intermediate /high risk group and at a median of 6 cycles (IQR, 3.5-8) in the low risk group, p = 0.0011. Conclusions: In older Indian patients with cancer, the CARG score reliably stratifies patients into low risk and intermediate/high risk categories, predicting both the occurrence and the time to occurrence of grade 3-5 toxicities from chemotherapy. The CARG score may aid the oncologist in estimating the risk-benefit ratio of chemotherapy. An important limitation was that we provided the CARG score to the treating oncologists prior to the start of chemotherapy, which may have resulted in alterations in the chemotherapy regimen and dose and may have impacted the CARG risk prediction model. Clinical trial information: CTRI/2020/04/024675.

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Identifying and Validating an Acidosis-Related Signature Associated with Prognosis and Tumor Immune Infiltration Characteristics in Pancreatic Carcinoma

Journal of Immunology Research ◽

10.1155/2021/3821055 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Pingfei Tang ◽

Weiming Qu ◽

Dajun Wu ◽

Shihua Chen ◽

Minji Liu ◽

...

Keyword(s):

Gene Expression ◽

High Risk ◽

Pancreatic Carcinoma ◽

Cox Regression ◽

Risk Group ◽

Immune Dysfunction ◽

Low Risk ◽

Excellent Performance ◽

Kaplan Meier ◽

Prognostic Prediction

Background. Acidosis in the tumor microenvironment (TME) is involved in tumor immune dysfunction and tumor progression. We attempted to develop an acidosis-related index (ARI) signature to improve the prognostic prediction of pancreatic carcinoma (PC). Methods. Differential gene expression analyses of two public datasets (GSE152345 and GSE62452) from the Gene Expression Omnibus database were performed to identify the acidosis-related genes. The Cancer Genome Atlas–pancreatic carcinoma (TCGA-PAAD) cohort in the TCGA database was set as the discovery dataset. Univariate Cox regression and the Kaplan–Meier method were applied to screen for prognostic genes. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish the optimal model. The tumor immune infiltrating pattern was characterized by the single-sample gene set enrichment analysis (ssGSEA) method, and the prediction of immunotherapy responsiveness was conducted using the tumor immune dysfunction and exclusion (TIDE) algorithm. Results. We identified 133 acidosis-related genes, of which 37 were identified as prognostic genes by univariate Cox analysis in combination with the Kaplan–Meier method ( p values of both methods < 0.05). An acidosis-related signature involving seven genes (ARNTL2, DKK1, CEP55, CTSV, MYEOV, DSG2, and GBP2) was developed in TCGA-PAAD and further validated in GSE62452. Patients in the acidosis-related high-risk group consistently showed poorer survival outcomes than those in the low-risk group. The 5-year AUCs (areas under the curve) for survival prediction were 0.738 for TCGA-PAAD and 0.889 for GSE62452, suggesting excellent performance. The low-risk group in TCGA-PAAD showed a higher abundance of CD8+ T cells and activated natural killer cells and was predicted to possess an elevated proportion of immunotherapeutic responders compared with the high-risk counterpart. Conclusions. We developed a reliable acidosis-related signature that showed excellent performance in prognostic prediction and correlated with tumor immune infiltration, providing a new direction for prognostic evaluation and immunotherapy management in PC.

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Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽

10.1182/blood-2020-133298 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Mats Jerkeman ◽

Martin Hutchings ◽

Riikka Räty ◽

Karin Fahl Wader ◽

Anna Laurell ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Molecular Remission ◽

Mantle Cell ◽

Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

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