Cost burden of chemotherapy for Indonesian healthcare insurance and social security/Jaminan Kesehatan Nasional (JKN) patients with non-Hodgkin lymphoma.

BACKGROUND: Cancer is among the leading causes of death globally, posing a significant economic burden on the healthcare sector. Among other types of cancer in Indonesia, non-Hodgkin lymphoma (NHL) ranks fifth in terms of prevalence. Chemotherapy for NHL patients is funded by a national health insurance scheme through the National Healthcare Insurance and Social Security/Jaminan Kesehatan Nasional (JKN). OBJECTIVE: This study aimed to analyze cost burden of chemotherapy for JKN patients with NHL. DATA SOURCE: A retrospective cross-sectional observational study was conducted among NHL patients receiving chemotherapy at a hospital in East Java, Indonesia in 2021. Data were collected from medical record documents and a total of 44 patient visits were recorded in this study. DATA SUMMARY: The result showed that patient visits were dominated by females (55%), a significant proportion were aged 31 to 40 years (32%), and the majority were JKN participants in the Contribution Assistance Recipients/Penerima Bantuan Iuran (PBI) category (64%). The most chemotherapy regimen given was R-CHOP (68%) and the mean total cost for NHL patients was Indonesian Rupiah (IDR) 5,178,146. The highest mean cost burden was on chemotherapy drugs with a value of IDR 6,333,315. Based on the regimen, the highest cost burden was R-CHOP-Bleo with a mean cost of IDR 8,764,091. CONCLUSION: Based on the results, the highest cost burden for chemotherapy among JKN patients with NHL in Indonesia was attributed to R-CHOP-Bleo regimen with a mean of IDR 8,764,091.

Quality of life assessment in diffuse large B-cell lymphoma (DLBCL) in REFLECT: a prospective, non-interventional, multicenter, German study, assessing Sandoz rituximab in combination with CHOP.

Health-related quality of life (HRQoL) data are important indicators of health status in patients with lymphoma. The objective of this analysis was to assess the impact of treatment with Sandoz rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on HRQoL in treatment-naïve adult patients with diffuse large B-cell lymphoma (DLBCL) included in the prospective, real-world REFLECT study. REFLECT is the first prospective study to assess HRQoL in patients with DLBCL treated with a rituximab biosimilar. HRQoL was assessed via the patient-reported European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire at baseline, mid-treatment (month 3), end of treatment (month 6), and follow-up (months 9 and 12). Subgroup analyses were performed to evaluate the influence of baseline characteristics on HRQoL, and associations between baseline HRQoL and treatment response. HRQoL was assessed in 169 patients. Mean global health status score remained stable from baseline (54.8) to mid-treatment (month 3; 54.7), before steadily improving through to end of treatment (month 6; 61.4), and follow-up month 9 (64.9) and month 12 (68.8). Similar trends were observed across most functional and symptom subscales. Higher cognitive, physical, or role functioning, and less appetite loss, diarrhea, fatigue, or pain at baseline, were all associated with an improved likelihood of reaching a complete versus partial response at the end of treatment. Overall, these findings confirm the HRQoL benefits of R-CHOP therapy in treatment-naïve adult patients with DLBCL, and suggest that baseline HRQoL may be predictive of treatment response.

Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Real-world total cost of care by line of therapy in relapsed/refractory diffuse large B-cell lymphoma.

AIMS: There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy. METHODS: Treatment costs and resources in the R/R setting were assessed by LoT. A sensitivity analysis identified any potential confounding of the results caused by the impact of the COVID-19 pandemic on healthcare utilization and costs. Overall, 310 patients receiving a second- or later-line treatment were included; baseline characteristics were similar across LoTs. Inpatient costs represented the highest percentage of total costs, followed by outpatient and pharmacy costs. RESULTS: Mean TCC per-patient-per-month generally increased by LoT ($40,604, $48,630, and $59,499 for second-, third- and fourth-line treatments, respectively). Costs were highest for fourth-line treatment for all healthcare resource utilization categories. Sensitivity analysis findings were consistent with the overall analysis, indicating results were not confounded by the COVID-19 pandemic. LIMITATIONS: There was potential misclassification of LoT; claims data were processed through an algorithm, possibly introducing errors. A low number of patients met the inclusion criteria. Patients who switched insurance plans, had insurance terminated, or whose enrollment period met the end of data availability may have had truncated follow-up, potentially resulting in underestimated costs. CONCLUSION: Total healthcare costs increased with each additional LoT in the R/R DLBCL setting. Further improvements of first-line treatments that reduce the need for subsequent LoTs would potentially lessen the economic burden of DLBCL.

Treatment patterns and costs among US patients with diffuse large B-cell lymphoma not treated with 2L stem cell transplantation.

Aim: To assess treatment patterns, healthcare resource utilization (HCRU), and costs for patients with diffuse large B-cell lymphoma (DLBCL) who did not receive stem cell transplantation in second-line. Patients & methods: An administrative MarketScan® database study to assess DLBCL claims from 01/01/2009-30/09/2020. Results: Most patients (n = 750) received rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in first-line (86.8%) and rituximab (39.5%) or bendamustine ± rituximab ± other (16.3%) in second-line. Over half were hospitalized (mean duration: 16.5 (standard deviation [SD]: 25.8) days per patient per year). Mean medical/pharmacy costs were US$141,532 per patient per year (SD: $189,579), driven by DLBCL-related claims. Conclusion: Healthcare resource utilization and costs for DLBCL-related claims were due to hospitalizations and outpatient visits. Novel therapies to reduce clinical and economic burdens are needed.

Pulmonary lesions in early response assessment in pediatric Hodgkin lymphoma: prevalence and possible implications for initial staging.

BACKGROUND: Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification. OBJECTIVE: This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging. MATERIALS AND METHODS: A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes. RESULTS: Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common. CONCLUSION: New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.

Real-world treatment patterns, healthcare resource utilization and costs among patients with peripheral T-cell lymphoma.

Objective: To evaluate treatment patterns, healthcare resource utilization (HRU) and costs among peripheral T-cell lymphoma (PTCL) patients in the USA. Methods: A retrospective cohort study, using the IQVIA PharMetrics® Plus claims database from 1 April 2011 to 30 November 2021, identified PTCL patients receiving systemic treatments. Three mutually exclusive subcohorts were created based on line of therapy (LOT): 1LOT, 2LOT and ≥3LOT. Common treatment regimens, median time on treatment, all-cause and PTCL-related HRU and costs were estimated. Results: Among 189 PTCL patients identified, 61.9% had 1LOT, 21.7% had 2LOT and 16.4% had ≥3LOT. The most common treatment regimens in the 1LOT were CHOP/CHOP-like, CHOEP/CHOEP-like and brentuximab vedotin; monotherapies were most common in the 2LOT and ≥3LOT. All-cause and PTCL-related hospitalizations and prescriptions PPPM increased with increasing LOT. Nearly 70% of total treatment costs were PTCL related. Conclusion: Higher utilization of combination therapies in the 1LOT and monotherapies in subsequent LOTs were observed, alongside high PTCL-related costs.

Peripheral T-cell lymphomas (PTCL) are a rare and fast-growing form of blood cancer. About 8000­12,000 people in the USA are diagnosed with PTCL every year. As it is a rare disease and has many types, and there is a limited understanding of the patients who have PTCL and the treatments they receive in the real world. The purpose of this study was to evaluate how these patients are treated, what are they treated with and what are the costs of these treatments in the USA. The data collected on these patients was divided into three groups based upon the number of lines of treatment/therapy (LOT) they received: 1LOT, 2LOT and ≥3LOT. This study researched different treatments and their duration in each line of therapy. Among 189 PTCL patients included in the study, the average age of patients was 55 years and 62% were male. Among these patients, 62% had 1LOT, 22% had 2LOT and 16% had ≥3LOT. The most common treatments in the 1LOT were traditional chemotherapy regimens followed by targeted therapies: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) or CHOEP-like, and brentuximab vedotin. Treatment regimens with only one drug were most common in the 2LOT and ≥3LOT. The total cost of PTCL treatment in the USA is very high; 70% of this cost is related to their treatment with various drugs. More research is needed to better understand the treatment and cost of this rare cancer.

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

BACKGROUND/AIM: This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. PATIENTS AND METHODS: To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. RESULTS: Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. CONCLUSION: ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

US cost-effectiveness analysis of polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma.

AIMS: We evaluated the pharmacoeconomic value of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) in previously untreated diffuse large B-cell lymphoma (DLBCL) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: A 3-state partitioned survival model was used to estimate life years (LYs), quality-adjusted LYs (QALYs), and cost impacts of Pola-R-CHP versus R-CHOP. Analyses utilized mixture-cure survival modelling, assessed a lifetime horizon, discounted all outcomes at 3% per year, and examined both payer and societal perspectives. Progression-free survival, overall survival (OS), drug utilization, treatment duration, adverse reactions, and subsequent treatment inputs were based on data from the POLARIX study (NCT03274492). Costs included drug acquisition/administration, adverse reaction management, routine care, subsequent treatments, end-of-life care, and work productivity. RESULTS: Incremental cost-effectiveness ratios of Pola-R-CHP versus R-CHOP were $70,719/QALY gained and $88,855/QALY gained from societal and payer perspectives, respectively. The $32,824 higher total cost of Pola-R-CHP versus R-CHOP was largely due to higher drug costs ($122,525 vs $27,694), with cost offsets including subsequent treatment (-$52,765), routine care (-$1,781), end-of-life care (-$383), and work productivity (-$8,418). Pola-R-CHP resulted in an increase of 0.47 LYs and 0.46 QALYs versus R-CHOP. Pola-R-CHP was cost-effective in 60.9% and 58.0% of simulations at a willingness-to-pay threshold of $150,000/QALY gained from societal and payer perspectives, respectively. LIMITATIONS: There was uncertainty around the OS extrapolation in the model, and costs were derived from different sources. Recommended prophylactic medications were not included; prophylactic use of granulocyte colony-stimulating factor for all patients was assumed to be equal across treatment arms in POLARIX. Work productivity loss was estimated from a general population and was not specific to patients with DLBCL. CONCLUSION: Pola-R-CHP was projected to be cost-effective versus R-CHOP in previously untreated DLBCL, suggesting that Pola-R-CHP represents good value relative to R-CHOP in this setting.

Cost-effectiveness of combination therapy of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone for previously untreated diffuse large B-cell lymphoma in Japan.

AIM: The POLARIX trial showed that Pola + R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone) prolongs progression-free survival (PFS) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), the conventional standard of care, with a similar safety profile. However, Pola + R-CHP has not been evaluated from the viewpoint of health economics in Japan. This study evaluates the cost-effectiveness of Pola + R-CHP for previously untreated DLBCL from a Japanese public healthcare payer's perspective. METHODS: A partitioned survival analysis model was constructed to estimate lifetime costs and effectiveness of Pola + R-CHP and R-CHOP in previously untreated DLBCL who had an International Prognostic Index score (IPI) score of ≥2. A parametric survival model was applied to data analyzed in the POLARIX trial to estimate the lifetime overall survival (OS) and PFS for each treatment. The parameters required for the model were based on the results of a literature search and expert opinion. RESULTS: The incremental cost-effectiveness ratio (ICER) of Pola + R-CHP vs. R-CHOP was JPY2,710,238 per quality-adjusted life year (QALY), less than the ICER of JPY7.5 million per QALY that is considered to be cost-effective based on the threshold of the Japanese cost-effectiveness evaluation system. One-way sensitivity analysis showed that the parameters influencing the results of the analysis were median PFS and the total cost per regimen of salvage chemotherapy, patient weight, and patient age. Probabilistic sensitivity analysis showed that the probability of Pola + R-CHP having superior cost-effectiveness was 99.2% when the reference value was JPY7.5 million. The results of scenario analysis suggested that prolongation of PFS was an important factor in the evaluation of cost-effectiveness in previously untreated DLBCL with or without prolongation of OS. CONCLUSIONS: This study suggests that Pola + R-CHP is a cost-effective treatment for previously untreated DLBCL in Japan under the public health insurance system.

Influence of treatment intensity and medical comorbidities in older adults with peripheral T cell lymphoma.

We conducted a population-based study of patients >65 years, diagnosed 2008-2017, with peripheral T-cell lymphoma (PTCL) using SEER-Medicare. Associations between PTCL subtype, treatment regimen, comorbidity, and mortality were assessed using the Kaplan-Meier method and multivariable Cox regression. Amongst the 2,546 patients, the median age was 77 years (interquartile range, 71-83). 5-year overall survival (OS) ranged from 22.2% to 37.3% depending on PTCL subtype. The most common frontline regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). 5-year OS rate was 47.0% for patients treated with etoposide + CHOP (N = 67; CHOEP), 33.7% for those treated with CHOP (N = 732), and 23.8% for patients treated with non-anthracycline-containing regimens (N = 105; p < 0.001). In patients without comorbidities, CHOEP remained independently associated with improved OS (HR 0.52, 95% CI,0.30-0.91). Median OS was 1.2 years from initiation of second-line therapy (N = 228) independent of treatment regimen. Frontline but not second-line treatment regimen is associated with OS in older patients with PTCL.

Cost of Disease Progression in Diffuse Large B-Cell Lymphoma After Frontline Treatment With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

BACKGROUND: In recent years, novel agents have become available to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL); the impact of such agents on treatment costs has not been formally studied. We present results from 2 independent, retrospective, real-world cohort analyses to determine the cost of disease progression after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: Analyses were conducted using the IQVIA PharMetricsⓇ Plus claims database and the Surveillance, Epidemiology, and End Results registry-Medicare-linked database (SEER-Medicare) and included patients ≥18 years and ≥66 years, respectively. "No progression" was defined as no second-line therapy for ≥2 years after the end of first-line R-CHOP and "treated progression" as initiating a second-line therapy within 2 years following the end of first-line R-CHOP. Analyses were adjusted for baseline covariates, and per-patient-per-month (PPPM) costs were compared between progressors and nonprogressors. RESULTS: The IQVIA PharMetrics Plus analysis (January 1, 2010-June 30, 2018) included 871 patients (nonprogressors, n = 725; progressors, n = 146), including 10 patients who received chimeric antigen receptor T-cell therapy (CAR-T). Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,554 vs. $1561, P < .001). The SEER-Medicare analysis (January 1, 2010-December 31, 2017) included 4099 patients (nonprogressors, n = 3389; progressors, n = 710), including 12 patients receiving CAR-T. Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,928 vs. $2902, P < .001). CONCLUSION: Treated progression of DLBCL increases adjusted PPPM costs by over $8000 compared with no progression.

Prospective assessment of vincristine-induced peripheral neuropathy in paediatric acute lymphoblastic leukemia.

OBJECTIVE: Vincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced peripheral neuropathy (VIPN). The present study comprehensively assessed VIPN outcomes in patients receiving vincristine treatment for ALL. METHODS: Children diagnosed with ALL commencing vincristine treatment were prospectively evaluated (baseline, post-induction, pre-reinduction, post-reinduction, follow-up). VIPN was examined clinically using the Balis sensory/motor scale, neurophysiologically using axonal excitability techniques and quality-of-life using Pediatric Quality of Life Inventory. RESULTS: Thirty-one patients were recruited to this study (age = 6.8 ± 4.4; 61.3% female). Incidence of motor VIPN (motor Balis grade > 0) symptoms were higher than sensory VIPN (sensory Balis grade > 0) at post-induction (92.0% vs 36.0%) and post-reinduction (81.8% vs 22.7%) vincristine treatment. Neurophysiological assessment also demonstrated greater change in motor axonal excitability parameters compared to sensory parameters including changes in depolarising threshold electrotonus (P < 0.0125), superexcitability and subexcitability parameters (all P < 0.0125). Follow-up assessment demonstrated persisting VIPN symptoms with reduced quality-of-life scores compared to baseline. CONCLUSIONS: Clinical and neurophysiological evaluation of VIPN suggests vincristine produces a motor-prominent sensorimotor neuropathy in children which persisted at follow-up. SIGNIFICANCE: VIPN signs and symptoms develop early in the treatment course, in line with axonal excitability profiles. Early detection of significant nerve changes may support timely implementation of neuroprotection strategies.

[Risk assessment and prophylactic treatment strategies for central nervous system relapse of diffuse large B-cell lymphoma].

Rituximab treatment significantly improved the outcomes of diffuse large B-cell lymphoma (DLBCL). A central nervous system (CNS) relapse remains a serious and fatal event for patients with DLBCL; therefore, the clinical question of the optimal treatment regimen for reducing the risk of CNS relapse remains unknown. The CNS-International Prognostic Index was identified as a predictive model for CNS relapse. No factors can completely predict CNS relapse although several reports regarding high-risk factors for CNS relapse have been reported. In practice, intrathecal methotrexate (MTX) and high-dose MTX therapy have been used for CNS prophylaxis. Unfortunately, evidence of the optimal therapy for CNS prophylaxis in patients with DLBCL remains lacking. This study aimed to review CNS relapse assessment and discuss study results with clinical impacts on CNS prophylaxis treatment strategies in DLBCL.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

Cost-Effectiveness Analysis of Frontline Polatuzumab-Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone and/or Second-Line Chimeric Antigen Receptor T-Cell Therapy Versus Standard of Care for Treatment of Patients With Intermediate- to High-Risk Diffuse Large B-Cell Lymphoma.

PURPOSE: Recent studies of polatuzumab vedotin and CD19 chimeric antigen receptor T-cell therapy (CAR-T) have shown significant improvements in progression-free survival over standard of care (SOC) for patients with diffuse large B-cell lymphoma. However, they are costly, and it is unclear whether these strategies, alone or combined, are cost-effective over SOC. METHODS: A Markov model was constructed to compare four strategies for patients with newly diagnosed intermediate- to high-risk diffuse large B-cell lymphoma: strategy 1: polatuzumab-rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) plus second-line CAR-T for early relapse (< 12 months); strategy 2: polatuzumab-R-CHP plus second-line salvage therapy ± autologous stem-cell transplant; strategy 3: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus second-line CAR-T for early relapse; strategy 4: SOC (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus second-line salvage therapy ± autologous stem-cell transplant). Transition probabilities were estimated from trial data. Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated from US and Canadian payer perspectives. Willingness-to-pay (WTP) thresholds of $150,000 US dollars (USD) or Canadian dollars (CAD)/QALY were used. RESULTS: In probabilistic analyses (10,000 simulations), each strategy was incrementally more effective than the previous strategy, but also more costly. Adding polatuzumab-R-CHP to the SOC had an ICER of $546,956 (338,797-1,199,923) USD/QALY and $245,381 (151,671-573,250) CAD/QALY. Adding second-line CAR-T to the SOC had an ICER of $309,813 (190,197-694,200) USD/QALY and $303,163 (221,300-1,063,864) CAD/QALY. Simultaneously adding both polatuzumab-R-CHP and second-line CAR-T to the SOC had an ICER of $488,284 (326,765-840,157) USD/QALY and $267,050 (182,832-520,922) CAD/QALY. CONCLUSION: Given uncertain incremental benefits in long-term survival and high costs, neither polatuzumab-R-CHP frontline, CAR-T second-line, nor a combination are likely to be cost-effective in the United States or Canada at current pricing compared with the SOC.

Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial.

BACKGROUND: Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies. METHODS: EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667. FINDINGS: Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]). INTERPRETATION: Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma. FUNDING: The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Mechanistic efficacy assessment of selected novel methanimine derivatives against vincristine induced Neuropathy: In-vivo, Ex-vivo and In-silico correlates.

Vincristine induced peripheral neuropathy (VIPN) is a serious untoward side effect suffered by cancer patients, which still lacks an adequate therapeutic approach. This study examined the alleviating potential of novel methanimine derivatives i.e. (E)-N-(4-nitrobenzylidene)-4-chloro-2-iodobenzamine (KB 9) and (E)-N-(2-methylbenzylidene)-4-chloro-2-iodobenzamine (KB 10) in VIPN. Vincristine was injected in BALB/c mice for 10 days to instigate nociceptive neuropathy. Dynamic and static allodynia, thermal (hot and cold) hyperalgesia were evaluated at 0, 5, 10 and 14 days using cotton brush, Von Frey filament application, hot plate test, acetone drop and cold water respectively. Tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), lipid peroxide (LPO), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and reactive oxygen species (ROS) assays were performed to assess the efficacy of KB9 and KB10 against neuroinflammation and oxidative stress utilizing ELISA, immunohistochemistry and western blot analysis in brain and sciatic nerve tissues. Computational studies were executed to determine the stable binding conformation of both compounds with respect to COX-2 and NF-κB. Interestingly, both compounds substantially reduced protein expression related to neuroinflammation, oxidative stress (LPO, GST, SOD, CAT) and pain (NF-κB, COX-2, IL-1ß and TNF-α). This molecular analysis suggested that the neuroprotective effect of KB9 and KB10 was mediated via regulation of inflammatory signaling pathways. Overall, this study demonstrated that KB9 and KB10 ameliorated vincristine induced neuropathy, through anti-inflammatory, anti-nociceptive and antioxidant mechanisms.

Carfilzomibe no tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia / Carfilzomib in the treatment of patients with relapsed or refractory multiple myeloma who have received prior therapy

INTRODUÇÃO: O mieloma múltiplo (MM) é uma neoplasia hematológica maligna caracterizada pela proliferação descontrolada de plasmócitos alterados na medula óssea, resultando na produção aumentada de imunoglobulinas não funcional (proteína monoclonal). O acúmulo destas imunoglobulinas e a interação dos plasmócitos com outras células da medula óssea resultam em anemia, lesões ósseas, infecções, hipercalcemia, injúria renal, fadiga e dor. A incidência mundial informada pelo Globocan é de 2,2 novos casos por 100.000 habitantes em homens e 1,5/100.000 em mulheres, com ocorrência, a nível mundial, de 176 mil novos casos e 117 mil mortes em 2020. Carfilzomibe é um agente antineoplásico, inibidor de proteassoma que se liga seletiva e irreversivelmente nos sítios ativos. Tem atividade antiproliferativa e pró-apoptóticas. PERGUNTA DE PESQUISA: Kyprolis® (carfilzomibe) em combinação com dexametasona é eficaz e seguro no tratamento de pacientes com mieloma múltiplo recidivado ou refratário que receberam uma terapia prévia quando em comparação a bortezomibe, ciclofosfamida, dexametasona, cisplatina, doxorrubicina, doxorrubicina lipossomal, etoposídeo, melfalana, vincristina ou talidomida? EVIDÊNCIAS CLÍNICAS: O demandante realizou as buscas na literatura utilizando as seguintes bases de dados: The Cochrane Library, Medline via PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Centre for Reviews and Dissemination (CRD), o que resultou na inclusão de 14 publicações. Na análise conduzida pela Secretaria Executiva foram consideradas 12 publicações referentes a um ensaio clínico randomizado e uma publicação de revisão sistemática. O estudo ENDEAVOR foi um ensaio clínico de fase III, multicêntrico, aberto, que incluiu 929 participantes randomizados para receber carfilzomibe+dexametasona ou bortezomibe+dexametasona. A mediana de SLP foi 18,7 meses (IC 95%, 15,6 a não estimável) no grupo que recebeu carfilzomibe comparado a 9,4 meses (IC 95%, 8,4 a 10,4) no grupo que recebeu bortezomibe, resultando em uma magnitude de benefício absoluto de 9,3 meses (HR 0,53 [IC95% 0,44 a 0,65]; p< 0,0001). A duração mediana de resposta foi 21,3 meses (IC95% 21,3 a não estimável) no grupo carfilzomibe e 10,4 meses (IC95% 9,3 a 13,8) no grupo bortezomibe. Em ambos os grupos, 98% dos participantes apresentaram eventos adversos (qualquer grau), sendo a anemia (43% versus 28%), diarreia (36,7% versus 40,6%) e febre (32,6% versus 15,4%) os eventos mais frequentes nos grupos carfilzomibe e bortezomibe, respectivamente. Os eventos adversos mais comuns grau 3 ou maior foram reportados em 81,9% dos participantes do grupo carfilzomibe (n=379) e 71,1% no grupo bortezomibe (n=324), sendo a anemia (17,3% no grupo carfilzomibe e 10,1% no grupo bortezomibe), hipertensão (14,9% versus 3,3%), trombocitopenia (12,5% versus 14,7%),os três eventos mais frequentes. Insuficiência cardíaca grau 3 ou superior, foi mais frequente no grupo carfilzomibe (6%) que no grupo bortezomibe (2%.). AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade. Na análise do cenário base, em um horizonte temporal de 30 anos, carfilzomibe acrescentou ganhos incrementais de 1,19 QALY, resultando em uma razão de custo utilidade incremental (RCEI) de R$ 195.310,00 por QALY. No cenário proposto pela Secretária-Executiva (horizonte temporal de 10 anos e valor de utilidade derivada do estudo ENDEAVOR), carfilzomibe gerou benefício de 0,63 QALY, com RCEI de R$ 365.830,00 por QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Com o desconto apresentado pelo demandante, a incorporação de carfilzomibe ao SUS implica em custos adicionais ao sistema de saúde no montante de aproximadamente R$ 365 milhões em cinco anos. A principal limitação da análise foi a estimativa da população. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 10 tecnologias potenciais para compor o esquema terapêutico de pacientes adultos com mieloma múltiplo recidivado ou refratário: Belantamabe mafodotin, Ciltacabtageno autoleucel, Elranatamab, Iberdomida, Idecabtagene vicleucel, Isatuximabe, nivolumabe, selinexor, teclistamab, venetoclax. Tais medicamentos são anticorpo monoclonal ligado a um antineoplásico, anticorpo biespecífico, anticorpo monoclonal, imumodulador, terapias baseadas em células T autólogas geneticamente modificadas (CAR-T), inibidor SINE, ou inibidor de Bcl-2. A maioria não possui registro na FDA, EMA ou Anvisa. CONSIDERAÇÕES FINAIS: Os resultados sugerem eficácia e segurança do carfilzomibe na população elegível, porém, no horizonte temporal de 10 anos, com QALY < 1, RCEI de R$ 365.830,00 por QALY e impacto orçamentário de aproximadamente R$ 17 milhões no primeiro ano de incorporação e R$ 131 milhões no 5º ano da incorporação, totalizando R$ 365 milhões em cinco anos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 109ª Reunião Ordinária da Conitec, realizada no dia 08 de junho de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação de carfilzomibe para o tratamento de mieloma múltiplo recidivado ou refratário no SUS. Os membros consideraram a evidência científica boa e favorável ao carfilzomibe, porém, a RCEI e o impacto orçamentário foram considerados muito altos para o tratamento de uma doença que já tem outras opções terapêuticas disponíveis no SUS. CONSULTA PÚBLICA: Entre os dias 08/07/2022 e 27/07/2022 foram recebidas 421 contribuições, sendo 152 pelo formulário para contribuições técnico-científicas e 269 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. A maioria foi a favor da incorporação de carfilzomibe no SUS (97% via formulário técnico-científico e 100%). O principal benefício apontado nas contribuições técnico-científicas foi sobre a eficácia, aumento da sobrevida e qualidade de vida, além da disponibilidade de mais uma opção terapêutica e promoção da igualdade no tratamento nos sistemas público e privado de saúde. A empresa detentora do registro do medicamento atualizou o preço do medicamento, e consequentemente os valores do impacto orçamentário e avaliação econômica. No impacto orçamentário o valor ficou em R$ 95,3 milhões em cinco anos. Nas contribuições de experiência e opinião, a totalidade dos respondentes discordou da recomendação preliminar da Conitec. No âmbito das opiniões e experiências positivas, foi mencionada a necessidade de garantir o acesso ao carfilzomibe, especialmente por representar uma alternativa para pacientes recidivados e refratários. Também foi citada a eficácia da tecnologia. Como dificuldades, destacou-se a falta de acesso pelo SUS. Em relação a outros medicamentos, foram mencionados benefícios, mas, também, a eficácia limitada no caso de pacientes recidivados. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec, em sua 112ª Reunião Ordinária, realizada no dia 31 de agosto de 2022, deliberaram por maioria simples, recomendar a não incorporação no SUS de carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia, no SUS. Não houve apresentação de dados clínicos adicionais. Com o preço do medicamento atualizado, ainda assim não se mostrou custo-efetivo. Foi assinado o Registro de Deliberação nº 765/2022. DECISÃO: Não incorporar, no âmbito do Sistema Único de Saúde - SUS, o carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, conforme a Portaria nº 107, publicada no Diário Oficial da União nº 184, seção 1, página 75, em 27 de setembro de 2022.

Evaluation of four chemotherapy regimens for treatment of advanced AIDS-associated Kaposi sarcoma in Kenya: a cost-effectiveness analysis.

BACKGROUND: The most effective treatment for advanced AIDS-associated Kaposi sarcoma is paclitaxel or pegylated liposomal doxorubicin (PLD); neither is routinely used in sub-Saharan Africa due to limited availability and high cost. We examined the clinical impact, costs, and cost-effectiveness of paclitaxel or PLD in Kenya, compared with etoposide or bleomycin-vincristine. METHODS: In this study, we use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International Model to project clinical outcomes and costs among people living with HIV and advanced Kaposi sarcoma on antiretroviral therapy. We compared four different treatment strategies: etoposide, bleomycin-vincristine, paclitaxel, or PLD. We derived cohort characteristics and costs from the Kenyan Academic Model for Providing Access to Healthcare network, and adverse events, efficacy, and mortality from clinical trials. We projected model outcomes over a lifetime and included life expectancy, per-person lifetime costs, and incremental cost-effectiveness ratios (ICERs). We conducted budget impact analysis for 5-year total costs and did deterministic and probabilistic sensitivity analyses to evaluate the effect of uncertainty in input parameters. FINDINGS: We found that paclitaxel would be more effective than bleomycin-vincristine and would increase life expectancy by 4·2 years per person. PLD would further increase life expectancy by 0·6 years per person. Paclitaxel would be the most cost-effective strategy (ICER US$380 per year-of-life-saved compared with bleomycin-vincristine) and would remain cost-effective across a range of scenarios. PLD would be cost-effective compared with paclitaxel if its price were reduced to $100 per cycle (base case $180 per cycle). Implementing paclitaxel instead of bleomycin-vincristine would save approximately 6400 life-years and would increase the overall 5-year Kenyan health-care costs by $3·7 million; increased costs would be primarily related to ongoing HIV care given improved survival. INTERPRETATION: Paclitaxel would substantially increase life expectancy and be cost-effective compared with bleomycin-vincristine for advanced AIDS-associated Kaposi sarcoma in Kenya and should be the standard of care. PLD would further improve survival and be cost-effective with a 44% price reduction. FUNDING: US National Institutes of Health and Massachusetts General Hospital. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.