Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and ...others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.
In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). This study illustrates how different survival ...analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results.
We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non-small cell lung cancer, included in ten trials. We considered methods either used in the field of meta-analysis or in economic evaluation but never applied to assess the rmstD for economic evaluation using IPD meta-analysis. Methods were classified into two approaches. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial.
The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. The estimated rmstDs ranged from 1.7 month to 2.5 months, and mean ICERs ranged from € 24,299 to € 34,934 per life-year gained depending on the chosen method. At a ceiling ratio of € 25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%.
This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses.
Children with ependymoma may experience a relapse in up to 50% of cases depending on the extent of resection. Key biological events associated with recurrence are unknown.
To discover the biology ...behind the recurrence of ependymomas, we performed CGHarray and a dual-color gene expression microarray analysis of 17 tumors at diagnosis co-hybridized with the corresponding 27 first or subsequent relapses from the same patient. As treatment and location had only limited influence on specific gene expression changes at relapse, we established a common signature for relapse. Eighty-seven genes showed an absolute fold change ≥2 in at least 50% of relapses and were defined as the gene expression signature of ependymoma recurrence. The most frequently upregulated genes are involved in the kinetochore (ASPM, KIF11) or in neural development (CD133, Wnt and Notch pathways). Metallothionein (MT) genes were downregulated in up to 80% of the recurrences. Quantitative PCR for ASPM, KIF11 and MT3 plus immunohistochemistry for ASPM and MT3 confirmed the microarray results. Immunohistochemistry on an independent series of 24 tumor pairs at diagnosis and at relapse confirmed the decrease of MT3 expression at recurrence in 17/24 tumor pairs (p = 0.002). Conversely, ASPM expression was more frequently positive at relapse (87.5% vs 37.5%, p = 0.03). Loss or deletion of the MT genes cluster was never observed at relapse. Promoter sequencing after bisulfite treatment of DNA from primary tumors and recurrences as well as treatment of short-term ependymoma cells cultures with a demethylating agent showed that methylation was not involved in MT3 downregulation. However, in vitro treatment with a histone deacetylase inhibitor or zinc restored MT3 expression.
The most frequent molecular events associated with ependymoma recurrence were over-expression of kinetochore proteins and down-regulation of metallothioneins. Metallothionein-3 expression is epigenetically controlled and can be restored in vitro by histone deacetylase inhibitors.
During their follow-up, patients with cancer can experience several types of recurrent events and can also die. Over the last decades, several joint models have been proposed to deal with recurrent ...events with dependent terminal event. Most of them require the proportional hazard assumption. In the case of long follow-up, this assumption could be violated. We propose a joint frailty model for two types of recurrent events and a dependent terminal event to account for potential dependencies between events with potentially time-varying coefficients. For that, regression splines are used to model the time-varying coefficients. Baseline hazard functions (BHF) are estimated with piecewise constant functions or with cubic M-Splines functions. The maximum likelihood estimation method provides parameter estimates. Likelihood ratio tests are performed to test the time dependency and the statistical association of the covariates. This model was driven by breast cancer data where the maximum follow-up was close to 20 years.
Cancer relapses may be useful to predict the risk of death. To take into account relapse information, the Landmark approach is popular. As an alternative, we propose the joint frailty model for a ...recurrent event and a terminal event to derive dynamic predictions of the risk of death.
The proposed prediction settings can account for relapse history or not. In this work, predictions developed on a French hospital series of patients with breast cancer are externally validated on UK and Netherlands registry data. The performances in terms of prediction error and calibration are compared to those from a Landmark Cox model.
The error of prediction was reduced when relapse information was taken into account. The prediction was well-calibrated, although it was developed and validated on very different populations. Joint modelling and Landmark approaches had similar performances.
When predicting the risk of death, accounting for relapses led to better prediction performance. Joint modelling appeared to be suitable for such prediction. Performance was similar to the landmark Cox model, while directly quantifying the correlation between relapses and death.
The Lorenz curve is a graphical tool that is used widely in econometrics. It represents the spread of a probability distribution, and its traditional use has been to characterize population ...distributions of wealth or income, or more specifically, inequalities in wealth or income. However, its utility in public health research has not been broadly established. The purpose of this article is to explain its special usefulness for characterizing the population distribution of disease risks, and in particular for identifying the precise disease burden that can be predicted to occur in segments of the population that are known to have especially high (or low) risks, a feature that is important for evaluating the yield of screening or other disease prevention initiatives. We demonstrate that, although the Lorenz curve represents the distribution of predicted risks in a population at risk for the disease, in fact it can be estimated from a case–control study conducted in the population without the need for information on absolute risks. We explore two different estimation strategies and compare their statistical properties using simulations. The Lorenz curve is a statistical tool that deserves wider use in public health research.
Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile ...among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560).
One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates.
Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 IgG1 and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS.
GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.
10052 Background: N9 induction for high-risk neuroblastoma was designed to limit non-hematological toxicity (especially ototoxicity) and to prevent relapse in the central nervous system (CNS). N9 ...builds on 2 novel regimens: high-dose cyclophosphamide-topotecan-vincristine (CTV) and ifosfamide-carboplatin-etoposide (ICE), each with good penetration across the blood-brain barrier. Methods: N9 is a pilot study (Clinicaltrials.gov.NCT04947501) to assess feasibility and safety. Secondary/exploratory objectives include response, collection of peripheral blood stem cells (PBSCs; ≥5x10 6 /kg CD34(+) cells sufficient for ≥2 rescues), tumor resection, and assessment of central nervous system relapse. Early stopping rules centered on excessive delay in timing of chemotherapy. Eligibility criteria included age >1-to-<13 years; 1 prior chemotherapy cycle was allowed. CTCAE Version 5.0 and International Neuroblastoma Response Criteria are used.N9 comprises 4 cycles of chemotherapy. Cycles start after absolute neutrophil count is >500/μL, platelets >100,000/μL, and non-hematologic toxicities grade ≤2. Intervals of 21-28 days between start of cycles are foreseen. PBSC collection and surgery follow >3 cycles. Cycles #1 and #4 (CTV): cyclophosphamide 70mg/kg/day, days 1-2, topotecan 2mg/m 2 /day, days 1-4, and vincristine 0.067mg/kg, day 1. Cycle #2 (ICE): ifosfamide 1500mg/m 2 /day, days 1-5, carboplatin 400mg/m 2 /day, days 1-2, and etoposide 100mg/m 2 /day, days 1-5. Cycle #3: cyclophosphamide (as in CTV) and 72-hr infusions of doxorubicin 75mg/m 2 and vincristine 0.067mg/kg. Results: The target number of 15 patients were enrolled: 10/2021-9/2023; age 1.5–9.8 (median 3.3) years; 14 stage M, 1 stage L2; and 10 post-1 cycle of other chemotherapy. They completed N9 without undue toxicity: all cycles started on time, organ functions remained intact, 11/11 patients tested had no ototoxicity, and acute toxicities were typical for myelosuppression (including uncomplicated fever/neutropenia). Responses were complete (n=6), partial (n=5), and stable disease (n=4). The target number of PBSCs was collected in 12 patients (9-75, median 14 x10 6 /kg CD34(+) cells), 4x10 6 /kg in 2 patients, and pending in 1. All patients had gross total resections of the primary tumor. Post-N9, patients did not undergo transplant, but proceeded to immunotherapy (naxitamab) or chemoimmunotherapy (naxitamab+irinotecan-temozolomide). Of 9 with residual disease post-N9, 7 achieved CR (median of 5.6 months from study entry) and 1 achieved metabolic CR (16 months), though 3 subsequently relapsed (no CNS). Conclusions: N9 shows promise for reducing chemotherapy and long-term toxicity. Less chemotherapy without compromising survival is a realistic goal by virtue of the advances with anti-G D2 monoclonal antibodies which, in combination with GM-CSF+low-dose chemotherapy, are highly effective against chemo-resistant disease in bone/bone marrow. Clinical trial information: NCT04947501 .
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