Souza, Cármino Antônio De

Background: To be useful across the broadest range of patients and clinical settings, clinical prediction models should be externally validated in different data sets and clinical settings and refined over time. In 2022, the HoLISTIC Consortium (www.hodgkinconsortium.org) developed and validated the A-HIPI model via TRIPOD guidelines for adults 18-65 with advanced stage classic Hodgkin Lymphoma (AS-HL) (Rodday et al., JCO 2023). The A-HIPI model, based on individual patient (pt) data from more than 5000 patients (pts) from North America, Europe, and Australia, predicts progression-free survival and overall survival within the first 5 years (PFS5 and OS5) based on pre-treatment pt and disease characteristics (www.qxmd.com/calculate/calculator_869/a-hipi). In collaboration with Brazilian clinical experts and researchers, we describe the performance of the A-HIPI in the Brazilian Prospective HL registry. Methods: The Brazilian Prospective HL registry (NCT02589548) was originally established in 2009 with the goal of evaluating risk factors, treatment, and disease outcomes. By 2022, 1357 pts with classic HL were registered with a median follow-up of 5 years for surviving patients (Biasoli I. HemaSphere 2022). 5-year PFS and OS were calculated using the Kaplan-Meier method. Using the methodology for validation and calibration outlined in by Rodday et al., calculated risk scores were calculated for PFS5 and OS5. Harrell c-statistic and the Uno c-statistic were calculated to evaluate discrimination (i.e., differentiation of those at higher risk of having an event from those at lower risk) and plots of deciles of predicted vs. observed outcomes were created to assess calibration (i.e., how similar the predicted absolute risk of the model is to the true (observed) risk in an external cohort). In the primary A-HIPI analysis, laboratory values outside of permitted range were excluded and not imputed. This was checked in sensitivity analysis using multiple imputation for missing values; no substantial differences were noted. Thus, in the current validation, out-of-range lab values were excluded. There were no exclusions in the current analysis for early death, defined as deaths that occurred from the onset of first treatment until 30 days after its end. Pts with HIV were excluded from the assembled cohort. Results: 694 patients with AS-HL with the inclusion criteria of the original study were included in the present study. The median age was 30.9 years (range, 18-65) at diagnosis with 46% of the pts being female. 230 (33%) patients were classified as Stage IIB, 190 with Stage III (27.4%), and 274 (39.5%) with Stage IV. Bulky disease (>10 cm) was present in 226 patients (33%). Median hemoglobin was 11.6 g/dL (8-16.3), median albumin 3.63 g/dL (1.41-5.46), and median lymphocyte count was 1.5 x 10 3 µL (0.10-4.76). The 5-y PFS (PFS5) in the A-HIPI Brazilian validation dataset was 68.4% (95% CI: 64.7-71.9%) and the 5-y OS (OS5) was 86.0% (95% CI: 82.8-88.6).Harrell c-statistics for the A-HIPI model were 0.60 (95% CI, .56-.64) for 5-year PFS and 0.69 (95%CI, .64-.74) for 5-year OS and Uno c-statistics for the A-HIPI model were 0.63 (95% CI, .58-.68) for 5-year PFS and 0.72 (95%CI, .65-.78) for 5-year OS. Calibration plots (see figures) show the predicted A-HIPI model estimates were well calibrated with the observed outcomes in the Brazilian HL registry. Conclusions: Despite important differences between the original development cohort for A-HIPI and the Brazilian registry in patient and clinical characteristics (e.g., younger age at diagnosis, greater proportion of Stage IV disease) and the well characterized impact of income maldistribution and socio-economic status on clinical outcomes (Biasoli et al., Int J Cancer 2018), the A-HIPI clinical prediction tool performed well in the Brazilian Prospective Registry. This included evidence of adequate discrimination and calibration. Future studies are planned, including the impact of treatment selection and response, use of interim imaging, and supportive care may underscore important differences in outcomes among adults with AS-HL.

Purpose The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI). Methods Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m 2 to 140 mg/m 2 ) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).