De Novo Focal and Segmental Glomerulosclerosis After COVID-19 in a Patient With a Transplanted Kidney From a Donor With a High-risk APOL1 Variant

Background: Despite effective first-line (1L) treatment options for patients with NHL almost 40% of patients with diffuse large B cell lymphoma (DLBCL) will have a poor response or disease progression after 1L treatment. In follicular lymphoma (FL) 15-20% of patients experience early relapse, and almost 8% may develop transformation to more aggressive forms of the disease (such as DLBCL) after 1L treatment. More accurate identification of patients at high-risk for a poor prognosis with the standard of care could lead to improved outcomes. Although the International Prognostic Index (IPI) and its FL extension (FLIPI) are often used to stratify patients by prognosis, they have relatively modest sensitivity and specificity for predicting individualized risk. Radiomics is a promising approach to improve upon existing prognostic models because it provides a comprehensive quantification of tumor lesion morphology and texture derived from FDG-PET scans and may provide new and important information about disease biology and progression risk on an individual level. Methods: A collection of 107 radiomics features [pyradiomics v2.20] that describe shape, size or volume and texture of tumor lesions, including complex features that are believed to reflect the underlying biological tumor phenotype and microenvironment, were derived for n=1093 de novo DLBCL patients with available baseline FDG-PET scans from the Phase III GOYA study (NCT01287741) evaluating obinutuzumab plus CHOP chemotherapy (G-CHOP) versus rituximab plus CHOP chemotherapy (R-CHOP) (Vitolo, et al. J Clin Oncol 2017). The same set of features were also extracted from n=451 de novo FL patients with available baseline FDG-PET scans from the Phase III GALLIUM study (NCT01332968) comparing obinutuzumab plus chemotherapy with rituximab plus chemotherapy [Marcus, et al. N Engl J Med 2017]. To investigate the association between the derived radiomics features along with baseline clinical variables and progression-free survival (PFS), a Cox proportional hazard model with L1 regularization was trained and internally validated using the GOYA study. We used a nested Monte Carlo Cross Validation (nMCCV) strategy to train our model and provide high- and low-risk group predictions on held-out samples of data. This modeling strategy allows us to make a group prediction on all GOYA patients while reducing overfitting. To evaluate prognostic performance, we ported the final model trained using the GOYA study (called the Li prognostic model) to the fully independent GALLIUM study. Results: Using our nMCCV approach we identified 11 factors, with an inclusion probability of >50%, that are associated with PFS of DLBCL patients (Figure A). Included within the top features are several image-derived morphometric (i.e. metabolic tumor volume, surface area) and radiomics features (i.e. tumor elongation, NGTDM contrast, GLCM inverse variance). When stratifying patients on the predicted (via majority vote) low-risk vs high-risk groupings we found that our high-risk group had significantly worse prognosis vs the low-risk group (Figure B). In comparison, the high-risk group from the IPI model (defined as IPI > 2) had significantly worse prognosis vs the low-risk group, but the performance was slightly worse than our model (Figure C). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 72.7% [70.0-76.6] and 59.8% [54.8-65.2] (vs 74% [70.0-78.2] and 60.4% [55.1-66.2] for the IPI model). After training and testing in the DLBCL population, we evaluated the prognostic performance of our model in an independent set of FL patients. We found that high-risk FL patients had a significantly worse prognosis than the low-risk group (Figure D). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 77.4% [69.8-85.8] and 48.9% [39.5-60.5] (vs. 80% [0.748-0.856] and 58.3% [51.6-65.9] in the full group). Conclusions: Radiomics features are prognostic in DLBCL and provide a modest improvement in prognostic performance when combined with traditional IPI scores, clinical features, and lab values (vs IPI alone). Our prognostic signature, developed in DLBCL, has significant prognostic performance in an independent dataset of patients with FL. While these results are promising, our FL validation dataset was relatively small and further evidence is required to confirm our findings. Disclosures Li: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jemaa:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Carano:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bengtsson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Paulson:F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jansen:F. Hoffmann-La Roche: Current Employment; Molecular Health GmbH: Ended employment in the past 24 months; F. Hoffmann-La Roche, Abbvie, Alphabet, other (non-healthcare), indexed funds and ETFs: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Hibar:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.

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Cyclosporine therapy in steroid-dependent or steroid-resistant idiopathic focal and segmental glomerulosclerosis

Saudi Journal of Kidney Diseases and Transplantation ◽

10.4103/1319-2442.190864 ◽

2016 ◽

Vol 27 (5) ◽

pp. 958

Author(s):

Imen Gorsane ◽

I Helal ◽

I Yacoub ◽

FBen Hamida ◽

E Abderrahim ◽

...

Keyword(s):

Focal And Segmental Glomerulosclerosis ◽

Steroid Resistant ◽

Segmental Glomerulosclerosis ◽

Steroid Dependent ◽

Cyclosporine Therapy

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A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽

10.1182/blood-2018-99-111412 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5218-5218

Author(s):

Sonia Christian ◽

Kelley E. Kozma ◽

Stephanie Barath ◽

Ardaman Shergill ◽

Damiano Rondelli ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Level ◽

Dose Escalation ◽

De Novo ◽

Standard Of Care ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Induction Regimen ◽

Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

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