bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and economic burden among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) receiving first-line (1L) chemoimmunotherapy (CIT) by risk status: A chart-linked claims analysis.
Authors: Leslie Lori A. , Gangan Nilesh , Tan Hiangkiat , Huang Qing
Published: June 2021

e19505

Background: In patients with CLL/SLL, high risk genetic abnormalities are associated with inferior responses to CIT, and the economic burden of this remains uncertain. This study aimed to compare real world clinical and economic outcomes in high risk and perceived non-high risk patients initiating 1L CIT. Methods: This retrospective cohort study identified patients with CLL/SLL from the HealthCore Integrated Research Database representing a national managed care population with over 58 million members. Medical records were obtained for eligible patients who initiated 1L CIT between 1/1/2007 and 7/31/2019 and underwent prognostic testing to classify them as high risk (HR: del17p, TP53 mutation, del11q or unmutated IGHV) or as non-high risk by FISH only (NHR: non-del17p and non-del11q). The first CIT claim date was the index date. Patients were required to have ≥12 months of pre-index and ≥30 days of post-index eligibility. Study outcomes included testing rate, time to next treatment (NT) or death, time to treatment failure (TF; defined as time to change of therapy, non-chemotherapy intervention, hospice care or death), and total plan paid costs (medical + pharmacy) per patient per month (PPPM) in the 1L period. Cox proportional hazard models and generalized linear models were used to calculate adjusted hazard ratio or rate ratio. Results: Among the 1,808 patients with CLL/SLL, 612 were FISH or IGHV tested and the rate of testing increased from 2007 to 2019 (30% to 44%), especially after adding ibrutinib for 1L CLL with del17p in NCCN guidelines v4.2014. Risk status was available for 253 patients (HR: 119; NHR: 134), with 80% of patients initiating 1L BR/FCR-based therapy in both cohorts. Median follow up was 26.4 vs. 25.8 months (HR vs NHR). HR patients had 65% higher risk of NT/death (median time: 2.4 vs 3.7 years), and 65% higher risk of TF (median time: 3.0 vs 4.9 years) compared to NHR patients (Table). The total costs PPPM were also significantly higher for HR patients in the 1L period ($12,194 vs $9,055, p=0.027; Rate Ratio=1.33, p<0.001). Conclusions: Initiating 1L CIT among HR patients with CLL/SLL was associated with increased risks of NT/death, TF, and higher costs compared to NHR patients identified by FISH only. Assessment of cytogenetic/molecular risk status for appropriate treatment is vital to optimize clinical and economic outcomes, especially in the novel agent era. Recent testing practices to assess genetic risk in CLL remains suboptimal.[Table: see text]
Safety and efficacy of chidamide in combination with decitabine plus anti-PD-1 camrelizumab after relapse or progression on decitabine-plus-camrelizumab in classical Hodgkin lymphoma.
Authors: Wang Chunmeng , Nie Jing , Liu Yang , Yang Qingming , Han Weidong
Published: June 2021

e19515

Background: The anti-PD-1 combination therapy significantly improves clinical outcomes in patients with relapsed/refractory classical Hodgkin lymphoma (cHL), and up to 71% of patients who receive decitabine-plus-anti-PD-1 camrelizumab could achieve a complete response. However, a subset of patients is recalcitrant to decitabine-plus-camrelizumab and half of patients might experience disease progression within three years. Effective treatment regimens for those with relapsed or progressive cHL who failed decitabine-plus-camrelizumab are needed. This Phase II study was designed to assess the safety and efficacy of the combination of decitabine-plus-camrelizumab and chidamide, a histone deacetylase inhibitor, in decitabine-plus-camrelizumab resistant cHL patients. Methods: Patients with relapsed/refractory cHL who had primary resistance or progressed/relapsed on decitabine-plus-camrelizumab were enrolled and administrated with chidamide at 10 mg (days 1 to 4) and 20 mg (days 8, 11,15 and 18); plus decitabine at 10 mg (days 1 to 5); and camrelizumab at 200 mg (day 6), every 3 weeks. Safety was assessed by CTCAEv5.0, and antitumor response by PET-CT according to the revised Lugano classification. The primary endpoint was objective response rate. Recruitment is ongoing. This trial is registered with ClinicalTrial.gov number, NCT04233294. Results: Between January 19, 2020, and January 31, 2021, nineteen patients with relapsed/refractory cHL after relapse or progression on decitabine-plus-camrelizumab were enrolled. A median of 20 cycles of prior decitabine-plus-camrelizumab was given (range, 4-28). Fourteen patients completed response evaluation with a median follow-up of 5.7 months. All eligible patients received this triplet-agent regimen with a median of 8 cycles (range, 3 to 12). Thirteen of the fourteen evaluated patients (93%) had an objective response, including six acquiring a complete remission (43%) and seven reaching a partial response (50%). The most common adverse events were leukocytopenia (58%; grade 3: 16%), nausea (53%) and hypertriglyceridemia (26%). No immune-related adverse events were observed. Conclusions: The preliminary result shows a high objective response rate with the combination of chidamide, decitabine and camrelizumab in patients with resistance to decitabine-plus-camrelizumab therapy. The addition of chidamide to decitabine-plus-camrelizumab has an acceptable safety profile, and does not trigger immune-related adverse events. Clinical trial information: NCT04233294.
Polatuzumab vedotin-bendamustine-rituximab (PBR) versus tafasitamab-lenalidomide (TafaL) in ASCT-transplant ineligible relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL): Economic evaluation including novel metrics.
Authors: Calamia Matthias , McBride Ali , Abraham Ivo
Published: June 2021

e19535

Background: PBR and TafaL are two recently regulatory approved regimens that offer treatment options for R/R DLBCL patients who are ASCT ineligible or choose not to undergo ASCT. PBR is administered over 6 cycles, whereas TafaL is sustained until disease progression or death. We report here on an independent, naïve comparative, pharmacoeconomic evaluation of both regimens. Methods: Cost effectiveness and cost utility analyses were performed using a Markov model with 3 health states (progression free survival (PFS), post progression survival (PPS), death) parametrically extrapolated over a 5-year (y) time horizon (US payer perspective; 2020 USD). Cost inputs included main treatment, premedication, drug administration, adverse event management, and physician and laboratory fees. Incremental cost effectiveness ratios (ICER) and cost-utility ratios (ICUR) estimated the incremental costs to gain 1 unadjusted (LY) or quality adjusted life years (QALY), respectively. A novel metric of the incremental cost per 1% gain in probability of achieving objective response (OR), PFS and overall survival (OS) at trial follow up (̃2y) and PFS and OS at 5y with TafaL over PBR were estimated. Deterministic (DSA) and probabilistic (PSA) sensitivity analyses complemented base case analyses (BCA). Willingness to pay (WTP) thresholds were estimated. Results: At trial follow up (̃2y), PFS and OS rates were 38% and 63% for TafaL vs rates of 18% and 27.5% for PBR. The corresponding 5y PFS and OS rates were 13% and 32.7% for TafaL vs 5.2% and 11.3% for PBR. In BCAs, 5y TafaL costs ($470,949) exceeded PBR’s ($251,615) by $219,334 for incremental gains of 0.71 LY and 0.32 QALY. This yielded BCA ICER of $307,840/LYg and ICUR of $689,314/QALYg attenuated in PSA estimates of ICER of $280,042/LYg and ICUR of $589,215/QALYg. In DSAs, TafaL PFS utility value and PBR treatment costs were the most influential parameters. In PSAs, TafaL had a 50% probability of being cost effective at WTPs of $278,050/LYg and $560,360/QALYg. The incremental cost per 1% gain in probability to achieve OR, PFS and OS at follow up were $7,714, $5,785 and $3,259; and $28,120 and $10,249 for PFS and OS at 5 years. Conclusions: Considering that economic evaluations are intended to inform (but not set) policy, this independent analysis demonstrated that sustained TafaL treatment is associated with better survival outcomes than PBR though at greater cost. The incremental costs to gain a 1% improvement in 2y and 5y survival outcomes with TafaL over PBR were modest, underscoring the longer-term benefit of TafaL over PBR in pts ineligible for or opting out of ASCT.
T-cell clonality in peripheral blood as a predictor of progression to systemic treatment in patients with stage IB mycosis fungoides (MF).
Authors: Raychaudhuri Suravi , Yann Charli-Joseph , Mintz Michelle , Pincus Laura , Huang Chiung-Yu , Ai Weiyun Z.
Published: June 2021

e19538

Background: A major unmet clinical need in the care of early-stage MF patients is the identification of those with a high risk of failing skin directed therapy or progressing to advanced disease. Herein, we inquired if the identification of a clonal T-cell receptor (TCR) gene rearrangement by PCR in peripheral blood could predict the clinical outcome, particularly the need for systemic treatment, in patients with stage IB MF. Methods: This is a retrospective cohort study of patients with stage IB MF who underwent peripheral blood TCR clonality analysis by PCR. The primary outcome of the study was time from diagnosis to initiation of systemic treatment. Secondary outcomes were: (1) time to progression to advanced-stage disease (stages IIB-IV) and (2) overall survival. Patients were censored at time of last clinical follow up. Log rank test was used to compare the survival distributions of the two groups; p value < 0.05 was considered significant. Results: From May 2014 to October 2019, 56 consecutive stage IB pts with > 6 months follow up were included in this analysis. Peripheral blood TCR clonality status was available in 42 patients: 18 pts had a positive TCR clone and 24 did not. Median follow up time was 36 months (range 8.5 – 198 months). At 3 years, 39% of patients with peripheral clone had progressed to systemic treatment versus 8% of those without a peripheral clone (log rank test, p-value = 0.003). For the secondary outcomes, at 3 years 17% of patients with peripheral clone had progressed to advanced stage versus 4% of those without (log rank test, p-value = 0.10); 5% of patients with peripheral clone had died versus 0% of those without (log rank test, p-value = 0.03). Conclusions: Detection of a predominant TCR clone by PCR in the peripheral blood is an important prognostic marker in the initial workup of MF, as its presence is highly correlated with subsequent progression to systemic treatment and death. If this finding is validated, it can be used to risk stratify and individualize therapy for MF patients.[Table: see text]
First-line treatment with Bendamustine plus Rituximab for patients with indolent non-Hodgkin’s lymphoma or Mantle cell lymphoma: Real-world experience.
Authors: Kotchetkov Rouslan , Susman David , Gerard Lauren , DiMaria Erica , Nay Derek Wayne
Published: June 2021

e19540

Background: Bendamustine plus rituximab (B+R) was established as a preferred first line therapy for patients with previously untreated indolent non-Hodgkin’s lymphoma based on the BRIGHT and STIL trials. However, only few reports on efficacy and safety data of this combination in the real-world setting are available to-date. Methods: We conducted a retrospective review of patients who received therapy with standard doses of B+R in our cancer center from June 2013 to January 2021. Patients with indolent non-Hodgkin’s lymphoma (iNHL) and mantle cell lymphoma (MCL) who received more than one cycle of B+R were evaluated. Results: Amongst a total of 201 patients 56% were males and 44% females. Median age at B+R initiation was 72 years (range 34-94). Follicular lymphoma (FL) (50.3%), marginal zone lymphoma (MZL) (19.4%), and lymphoplasmacytic lymphoma (LPL) (14.5%) were the most common iNHL. Stage 3 and 4 diseases represented 19.9% and 68.6% of patients. Extranodal disease was found in 35.8%. The proportion of patients with high risk disease was 48.5% for FL (FLIPI ≥3), 86.6% for LPL (WMISS score ≥2), and 80.5% for MCL (MIPI score ≥6.2). Prior history of secondary malignancy had 23.4% of patients; 11.4% patients had ECOG 3. Most common indications for B+R initiation were bulky symptomatic lymphadenopathy (69.1%), cytopenia (36.8%) and constitutional symptoms (36.8%). Fifty-eight percent of patients had more than one indication for therapy. Median number of B+R cycles delivered was 6 (range: 1-6), median dose of bendamustine was 90 mg/m2 (range 45-90). Full doses of treatment were given in 66.7% of patients, reduced in 33.3% with mean dose 78.3 mg/m2. A total of 50.8% completed 6 cycles with no delays, in 49.2% treatment was delayed (mean delay time 1.8 weeks). Overall response was 94.5%, with 77.6% complete and 16.9% partial remission. Median duration of follow-up was 35 months (range: 4-91). At the end of follow-up, event free survival (EFS) was 77.1% and overall survival (OS) was 79.6%. Six percent of patients relapsed, 8% developed secondary hematological malignancies, including 14 cases of aggressive B-cell lymphoma and 2 cases of MDS. 16.9% of patients required support with G-CSF. Grade 3-4 neutropenia was recorded in 22.4%, febrile neutropenia in 7.5%, grade 3-4 anemia in 7.9%, and grade 3-4 thrombocytopenia in 3.9% of patients. Rituximab-associated infusion reactions, skin rash, thrombophlebitis, and infection were the most common non-hematological adverse events. A total of 80.6% of patients proceeded to rituximab maintenance. Conclusions: B+R chemoimmunotherapy is feasible to administer in non-clinical trial setting. Despite more dose reduction as compared to STIL trial, B+R retained its efficacy with comparable EFS and OS. No new adverse events or increase in secondary malignancies were found.
Safety of same day HD-MTX with induction therapy for DLBCL with concurrent CNS disease or as prophylaxis for high risk of CNS relapse.
Authors: Barlow Brett , Hatic Haris , Bodine Charles Douglas , Mehta Amitkumar , Goyal Gaurav , Narkhede Mayur
Published: June 2021

e19545

Background: High-dose methotrexate (HD-MTX) at a dose between 2.5 to 5 gm/m2 is commonly administered in conjunction with standard induction chemotherapy to patients with Diffuse Large B Cell Lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse, as defined by the Lymphoma International Prognostic Index (CNS-IPI). Optimal timing of HD-MTX in relation to induction chemotherapy is unknown. A recent study suggested that HD-MTX intercalated with R-CHOP cycles was associated with increased toxicity and treatment delays without improvement in survival or CNS relapse compared with end of treatment MTX (Wilson et al 2020). This retrospective study evaluates the toxicities and treatment delays associated with HD-MTX administered on day 1 of cycles of chemo-immunotherapy. Methods: This single center retrospective cohort study included 45 patients (pts) with DLBCL with concurrent CNS disease or at high risk of CNS relapse who received HD MTX on day 1 of chemo-immunotherapy at our center. Data was abstracted from chart review and included variables describing clinical and treatment characteristics, time to MTX clearance, toxicities experienced and treatment delays. Results: 31 pts received HD-MTX on the day of R-CHOP chemotherapy, 6 pts received HD-MTX on the day of R-EPOCH (Rituximab, Etoposide, Doxorubicin, Vincristine, Cyclophosphamide, and Prednisone), and 8 pts received HD-MTX with R-MiniCHOP (dose reduced R-CHOP). Same day HD MTX with chemo-immunotherapy was associated with acute kidney injury (AKI; 17-25%), treatment delays >7 days (13-17%), and grade 2 mucositis (11-50%). The burden of toxicities was numerically higher in patients treated with R-EPOCH vs. R-CHOP (Table). Clinical outcomes are summarized in table below. Conclusions: In our heterogeneous population of pts, we describe that the incidence of toxicities and treatment delays experienced with same day HD-MTX are higher with R-EPOCH than with R-CHOP. Comparative studies with intercalated or end of treatment MTX will determine if the incidence of treatment delays, toxicities and de-escalations are higher with same day HD-MTX administration. [Table: see text]
The impact of body weight and body mass index on outcomes of diffuse large B-cell lymphoma treated with axicabtagene ciloleucel.
Authors: Wudhikarn Kitsada , Bansal Radhika , Khurana Arushi , Hathcock Matthew , Bennani N. Nora , Paludo Jonas , Villasboas Jose Caetano , Wang Yucai , Johnston Patrick B. , Ansell Stephen M. , Lin Yi
Published: June 2021

e19554

Background: Obesity is associated with a pro-inflammatory state and immune dysregulation. Retrospective studies indicate that obesity could affect toxicities and outcomes after immunotherapies including checkpoint inhibitors and allogeneic stem cell transplant. Currently, there are no data specifically on outcomes for obese patients who receive chimeric antigen receptor T (CAR-T) cells. We described the clinical outcome in obese patients with large B cell lymphoma (LBCL) who received axicabtagene ciloleucel (axi-cel). Methods: We analyzed the effect of body weight (BW) and body mass index (BMI) on toxicities and outcomes of 78 adults with LBCL who received axi-cel between June 2016 and October 2020 at Mayo Clinic. Obesity was defined as having BMI of 30 or higher. Results: Of 78 patients, 22 (28%) and 19 (24%) were classified as overweight (BMI 25-29.99 kg/m2) and obese (BMI ≥30 kg/m2), respectively. Baseline characteristics were not statistically significantly different between non-obese and obese patients. The median delivered dose of fludarabine was similar between non-obese and obese patients (89 [0-105] vs 88 [56-94] mg/m2, P=0.32) whereas the median delivered dose of cyclophosphamide was lower in non-obese patients (1503 [1077-1525] vs 1512 [1021-1660] mg/m2, P=0.01). The 30-days cumulative incidence of CRS and ICANS were similar between non-obese and obese patients. BW and BMI were not associated with CRS or ICANS. The overall response rate was 66% (CR 47%) and 68% (CR 53%) in non-obese and obese group, respectively ( P=0.83). The 1-year event free survival (EFS) and overall survival (OS) was 34.6% and 64.5%, neither were different between non-obese and obese patients (EFS 35.8% vs. 30.7%, P=0.60; OS 59.4% vs. 83.9%, P=0.18). The 1-year cumulative incidence of relapse and non-relapse mortality was comparable (60.8% vs. 69.0%, P=0.40 and 3.4% vs. 0%, P=0.42). In the Cox proportional hazards model, higher dose of fludarabine, but not cyclophosphamide, was associated with better EFS and OS; however, neither obesity nor BW were associated with toxicities and outcomes. Conclusions: In our study, Obesity was not associated with risk of toxicities or adverse survival outcomes. The effect of obesity on the pattern of LD chemotherapy dosing including toxicities and outcomes after CAR-T warrants further exploration. [Table: see text]
Prognostic factors of survival in patients with Burkitt lymphoma treated at the National Institute of Neoplastic Diseases in Peru: A 14-years’ experience.
Authors: Solf Rossana , Aliaga Rolig , Vallenas Francisco , Flores Claudio J. , Malpica Luis , Vasquez Chavez Jule Franve
Published: June 2021

e19570

Background: Burkitt lymphoma (BL) is one of the most aggressive B-cell lymphoma types. However, it has a high cure rate which varies depending on the different clinical pathological characteristics. We aimed to evaluate the prognostic factors for survival in patients with BL. Methods: We performed a retrospective study at the National Institute of Neoplastic Diseases in Peru from 2000 to 2014. We reviewed medical records of patients with BL aged 15 years and above. The data collected were based on clinical characteristics, treatment and survival. Patients with human immunodeficiency virus (HIV) infection were considered for analysis. The overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method, the survival curves according to the clinical characteristics were compared using the log-rank test. Prognostic factors were determined using Cox regression modeling. Results: A total of 55 patients had sufficient data for analysis. The median age was 34 years (range 15-73), 78% were male and 73% had B symptoms. Lymph node involvement (LNI) as primary site was present in 89% of patients, of which 43% and 39% were retroperitoneal and cervical LNI, respectively. Bulky mass ( > 10cm) was reported in 73% of the patients. Advanced disease was found in 78% (stage III 31%, IV 47%). Elevated serum LDH level was seen in 60% of cases; and 33% had HIV infection. Intensive chemotherapy was given to 80% (44) of patients, with 34% receiving multi-agent acute lymphoblastic leukemia protocol, 22.8% DA-EPOCH, 18% CODOX-M IVAC, and 11.4% Hyper-CVAD. No patient received rituximab in the front-line setting. The complete response rate was 39%. With a median follow-up of 9 years, the median OS for the entire cohort (N = 55) was 6.9 months (range 1.9-11.9) with a 5-year survival rate of 26.3%. The median OS for the treated patients (N = 44) was 11.3 months (range 3.2-19.4) with a 5-year survival rate of 30.6%. The median PFS was 7.3 months, and the 5-year OFS rate was 30.8%. 5-year OS rates were worse in those with B symptoms (66% vs. 12.5%, p = 0.003), elevated serum LDH level (44.1% vs. 15.2%, p = 0.043), albumin < 3.5 g/dL (36.5% vs. 15.4%, p = 0.023), beta-2 microglobulin > 2.5 mg/L (41.4% vs. 20%, p = 0.029), and HIV infection (31% vs. 16.7%, p = 0.006). In the multivariate analysis, the presence of B symptoms (HR 5.4 [2.2, 13.4], p < 0.001) and HIV infection (HR 2.8 [1.5, 5.4], p = 0.002) were both factors associated with worse survival. Conclusions: In our study, the 5-year OS rate of patients with BL treated with chemotherapy was shorter (30.6%) than in developed countries. The response rates were also lower than in other studies. Inclusion of rituximab is needed to improve response rates. Presence of B symptoms and HIV infection were associated to worse survival.
Clinical characteristics and outcome of mycosis fungoides among children, adolescents, and young adults: Single institution study.
Authors: Taylor Eric , Zhang Yumeng , Hooper Madeline , Seminario-Vidal Lucia , Sokol Lubomir
Published: June 2021

e19576

Background: Mycosis fungoides (MF) is the most common subtype of cutaneous T cell lymphoma (CTCL) [1]. MF is characterized by the skin infiltrate of small to medium size T lymphocytes with cerebriform nuclei. The incidence of MF increases significantly with age, with a median age at diagnosis of 60 years, and predominantly in white males [2]. The clinical outcome has not been evaluated among children, adolescents, and young adults. This study aimed to evaluate the characteristics and outcomes in this population. Methods: We retrospectively reviewed clinical data on 90 patients with MF at Moffitt Cancer Center between 2000 and 2020. Fifteen patients were diagnosed before the age of 20 years. Our cohort was compared to the largest US epidemiological report by Nath et al. using SEER database, which consists of 4892 patients from 1998-2008 [2]. The Chi-square test was used for comparison. Overall survival (OS) was calculated from diagnosis until death or last contact. OS between different groups was compared using the Kaplan-Meier curve. Hazard ratio and p-value were calculated using the log-rank test. Results: Of 90 patients, the median age at diagnosis was 32 years (range 6-39). The male to female ratio was 1.3:1. White and black races account for 57% and 27% of the patients. Compared to historical control, black patients were significantly higher in the current cohort (27% vs. 13%, p < 0.001). The difference widened in children and adolescents. More patients present with early stage MF in the current cohort (95.6% vs. 83%, p = 0.003). Clinical characteristics, including stage, LDH, WBC, ferritin level, were similar between children/adolescents and young adults. However, our cohort had significantly higher CD8 positive MF, and nearly half of children and adolescents were CD8 positive. Young adults had a higher rate of coexisting skin malignancy; however, this was not statistically significant due to small patient size. Time to diagnosis remained long, especially in children and adolescents’ group. However, the outcome is excellent. At a median follow-up of 4.9 years, four patients deceased, and the median OS was not reached. The prognosis remains poor in patients with advanced disease (HR = 39, p < 0.001) and large cell transformation (LCT) (HR = 8.5, p = 0.009). Conclusions: Compared to historical cohorts, higher proportion of black and female patients were noted in our young cohort with more early-stage and CD8 positive disease. This observation likely represents the different underlying biology of the disease [3]. Clinical outcome in young patients was excellent. However, patients with LCT or advanced stage carry a poor prognosis and need better therapies.
Economic evaluation of six and 12 month (m) treatment with isatuximab and carfilzomib and dexamethasone (IKd) versus daratumumab and carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory multiple myeloma (RRMM).
Authors: AlRawashdh Neda , Choi Briana , Obeng-Kusi Mavis , Calamia Matthias , McBride Ali , Abraham Ivo
Published: June 2021

e20010

Background: Isatuximab and daratumumab target the CD38 transmembrane glycoprotein on MM cells. IKd and DKd regimens have shown reductions of HR=0.53 (95%CI 0.32-0.89) and HR=0.63 (95%CI 0.46-0.85) resp. in progression or death risk compared to Kd in RRMM. In the absence of a direct IKd vs DKd trial, we performed an indirect treatment comparison on progression free survival (PFS) to enable cost-effectiveness analyses. Methods: A 3-state (pre-progression, progression, death) partitioned survival model was specified. NMA-adjusted transition probabilities were estimated from fitted exponential functions (time horizon of 6 and 12 m; cycle length 28 days). Inputs included the Wholesale Acquisition Cost of IKd, DKd, and premedications; cost of medication administration; and cost of adverse event management. Utility inputs for pre-progression (0.65) and progression (0.61) were per literature. Costs and utilities were discounted at 3.5%/y. A payer perspective was adopted. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Cost-effectiveness acceptability curves (CEAC) were generated. Results: As detailed in the Table, 6m of IKd treatment was associated with incremental gains of 0.01 (PSA 0.01) LYs but no gains in QALYs at cost savings of $24,188 ($23,762), yielding a dominant ICER of $ -2,418,800 ($-2,376,200) per LYg (ICUR not estimable). Further, 12m of IKd treatment was associated with incremental gains of 0.04 (PSA 0.04) LYs (or 0.48m) and 0.02 (0.03) QALYs at incremental cost of $1,585 ($2,239), yielding ICER of $39,625 ($55,975) per LYg and ICUR of $79,250 ($74,633) per QALYg. Per CEAC, IKd is the dominated strategy in the 6m model and had probability of 50% of being cost-effective at WTP of $100,000 in the 12m model. Conclusions: Clinically, compared to DKd, IKd is associated with slight incremental gains in LYs of 0.12m over 6m and 0.48m over 1y. The 6m clinical gain comes with cost savings of approximately $24,000 or about 15% of IKd therapy, while the 12m gain requires a minimal cost commitment of around $2,000 or 0.6% of DKd treatment. These findings imply a clinico-economic benefit of isatuximab compared to daratumumab containing regimens in RRMM. [Table: see text]
Single cell multiomic analysis and immune cell type profiling of multiple myeloma with t(4;14).
Authors: deMel Sanjay , Scolnick Jonathan , Huo Xiaojing , Soekojo Cinnie , Song Fangfang , Ooi Melissa , Chng Wee Joo
Published: June 2021

e20013

Background: Multiple Myeloma (MM) is an incurable plasma cell (PC) malignancy and high risk (HR) MM remains an unmet clinical need. Translocation 4;14 occurs in 15% of MM and is associated with an adverse prognosis. A deeper understanding of the biology and immune micro-environment of t(4;14) MM is necessary for the development of effective targeted therapies. Single Cell multi-omics provides a new tool for phenotypic characterization of MM. Here we used Proteona’s ESCAPE™ single cell multi-omics platform to study a cohort of patients with t(4;14) MM. Methods: Diagnostic bone marrow (BM) samples from 14 patients with t(4;14) MM were analysed using the ESCAPE platform from Proteona which simultaneously measures gene and cell surface protein expression in single cells. Cryopreserved BM samples were stained with 65 DNA barcoded antibodies and subsequently sorted on CD138 expression. The CD138 positive and negative fractions were recombined at a known ratio for analysis using the 10x Genomics 3’ RNAseq kit. Resulting data were analyzed with Seurat and MapCell. Results: The patients had a median age of 63 years. All received novel agent based induction. Median progression free and overall survival (PFS and OS) were 22 and 34 months respectively. MMSET was overexpressed in all PCs while FGFR3 expression could be categorized into zero cells expressing FGFR3, low expression (< 10% of cells expressing FGFR3) or high expression (> 80% of cells expressing FGFR3). We also found heterogeneity in the expression of cancer testis antigens (CTA) such as FA133A and CTAG2 between PC clusters across samples. Variation in the immune microenvironment of the BM was seen across all patient samples with no correlation between cell types and PFS or OS. However, an analysis of BM samples at diagnosis and relapse in one patient showed a shift in the ratio of T cells to CD14 monocytes with a ratio of 5.7 at diagnosis compared to 0.6 at relapse. Further analysis of PCs in this patient found 8 PC populations, each containing variable numbers of cells from both the diagnostic and relapse samples. This suggests that all populations present at relapse were also present at diagnosis, although at variable proportions. Increased expression of RCAN3 (associated with cereblon depletion) was detected at relapse. Conclusions: We present the first application of single cell multi-omics immune profiling in high risk MM. The heterogeneity in expression of CTA has implications for the application of immunotherapies, while the upregulation of RCAN3 may explain failure of immunomodulatory therapy. Our small sample size may explain the lack of correlation between gene or protein expression with clinical outcomes. We propose that t(4;14) MM is a genomically and immunologically heterogeneous disease. Single cell analysis of larger cohorts is required to build on our findings.
Patient-reported experience platform identifies discordance between guidelines and real-world practice: Maintenance therapy for high-risk multiple myeloma.
Authors: Sweeney Nathan W. , Goldsmith Scott Ryan , Crees Zachary , Molina Thomas H. , Ahlstrom Jenny
Published: June 2021

e20022

Background: Patient-reported data play a critical role in assessing clinical benefit from therapeutic interventions and are increasingly used in clinical trials. Internet-based platforms such as HealthTree Cure Hub for Multiple Myeloma ( www.healthtree.org ) provide the opportunity to obtain such real-world patient-reported data, while also providing valuable insights into high-yield areas to focus on quality-improvement efforts. For example, proteasome inhibitor (PI)-based maintenance after autologous stem cell transplantation (ASCT) is a consensus recommendation in many practice guidelines for high-risk multiple myeloma (MM) yet real-world adherence to this practice remains uncertain (PMID 23541011, 30932732). Methods: We examined post-ASCT maintenance therapy in patients with high-risk MM, as defined per mSMART criteria, using patient-reported treatment data from the HealthTree Cure Hub for Multiple Myeloma database. Patients who received an ASCT prior to 2014 were excluded. Results: Our analysis identified 110 MM patients with high-risk MM. Of those, only 48 (44%) received PI-based maintenance therapy. Additionally, 60 (55%) received IMiD (immunomodulatory imide drug) maintenance, 1 (< 1%) received ‘other’, and 1 (< 1%) did not report maintenance therapy. Conclusions: The benefits of PI-based maintenance in MM are well established for high-risk MM. However, analysis of patient-reported data using an online patient portal, HealthTree Cure Hub for Multiple Myeloma, suggests a disparity between practice recommendations and real-world practice patterns. These findings, and others from online patient portals, can serve as a springboard in helping investigators to identify areas for quality-improvement initiatives.
Thyroid hormone receptor α1 acts as a new squamous cell lung cancer diagnostic marker and poor prognosis predictor: Can it be a novel therapeutic target?
Authors: Mohamed Fatma El Zahraa Ammar , Abdelaziz Ali Omar , Kasem Ahmed Hussein , Ellethy Tarek , Gayyed Mariana Fathy
Published: June 2021

e20508

Background: Lung cancer is considered the first cause of cancer-related death worldwide. Unfortunately, all therapeutic regimens used in lung cancer treatment showed relatively equivalent efficacy. The search and subsequent testing of new therapeutic targets that can be used alternative to, after the failure of or in association with the currently used therapeutics to improve the prognosis is an urgent demand and consequently a very interesting era of oncological lung research. Up to date, it is known that Thyroid hormones and Thyroid hormone receptors (THRs) controls many tumors progression, nevertheless, its role in non-Small Cell Lung cancer (NSCLC) is not yet defineltly understood. This study investigated the expression of Thyroid hormone receptor alpha 1 (THRα1) in NSCLC cases. Methods: Immunohistochemistry using THRα1 antibody was performed on tissue sections collected from 80 patients diagnosed with NSCLC. We also analyzed the expression of THRα gene in Microarrays of squamous cell lung carcinoma (SCC) and adenocarcinoma (AC) patients by using GEO datasets on https://www.ncbi.nlm.nih.gov. Results: We showed, for the first time, the expression of THRa1 in NSCLC. Intermediate and high THRa1 expression was detected in (25% and 66.7%) of SCC cases respectively. High THRa1 expression was associated with shorter OS and poor prognosis. On the other hand, 86.7% of AC cases revealed low THRa1expression. By analyzing GEO data sets, a significant increase in THRa gene value was found in SCC compared to AC cases. Inflammatory cells in SCC cases showed high THRα1 expression. Conclusions: Our study is shedding a new light on the relevance of THRα1 in lung cancer not only as a possible prognostic marker but also as an innovative diagnostic additive tool for lung squamous cell carcinoma which could be tested as a therapeutic target as well.
Immune subtypes in LUAD identify novel tumor microenvironment profiles with prognostic and therapeutic implications.
Authors: Liu Shuoyan , Wang Feng , Gao Xuan , Wang Peiyuan , Chen Yujie , Chen Peng , He Hao , Chen Xiaofeng , Zhang Derong
Published: June 2021

e20512

Background: The incidence of lung adenocarcinoma (LUAD) is increasing year by year worldwide. Thorsson et al. identified six immune subtypes (ISs) (C1 - C6) in 33 diverse cancer types, including LUAD. The tumor microenvironment and lung cancer cells of 6 ISs have complex and different interplay, and the consequence of the interplay determines the growth of tumor cells and the prognosis of patients. Methods: Clinical and molecular information of TCGA LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) (N = 457). Kaplan-Meier survival analysis and Cox proportional-hazard analyses were performed in 4 independent GEO LUAD data sets (GSE31210, GSE37745, GSE50081, and GSE68465) and, where five immune subtypes C1-C4, C6 were stratified according to Thorsson et al.’s immune classification method. Results: Only 5 ISs were identified in the TCGA NSCLC cohort; the proportion of the C3 inflammatory IS (39.2%) was the most common IS observed in the TCGA LUAD cohort, whereas C1 was particularly dominant in LUSC (57.1%). The proportion of C3 was also the most common IS observed in GEO LUAD cohorts (GSE37745, GSE50081, GSE68465), except for one stage I-II lung adenocarcinomas cohort (GSE31210). The prognostic relevance of the C3 IS was associated with significantly longer overall survival and progression-free interval time of LUAD in the TCGA cohort. In contrast, the association was not significant in the TCGA LUSC cohort. C3 was also associated with significantly longer overall survival (p < 0.001) and disease-free interval time (p < 0.001) in the 4 GEO LUAD cohorts by multivariate analyses. To further evaluate prediction accuracies of C3, we compared the C3 model with the other 3 reported immune-related signatures. For all comparisons in these 4 GEO cohorts, C3 outperformed the other 3 signatures with superior overall survival and DFS predictive performances according to the time-dependent Concordance index. C3 presented higher levels of CD8 T, follicular helper T, M1 macrophage, CD4 memory resting, myeloid dendritic, neutrophils, and endothelial cells by using CIBERSORT and MCP counter. Low levels of M2 macrophages and cancer-associated fibroblast cells were also found in the C3 subtype. GSEA pathway analysis showed that the C3 subtype had a heightened activation in the antigen process and presenting pathway, interferon-gamma response pathway, T cell receptor signaling pathway, and neural killer cell-mediated cytotoxicity pathway than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, MMR repair DNA repair, and p53 signaling pathways than the C3 subtype. Conclusions: The robust prognostic relevance of the C3 IS allows a more precise categorization of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in LUAD patients.
Large cell neuroendocrine carcinoma of the lung: Prognostic factors to predict clinical outcomes.
Authors: Andrini Elisa , Tateo Valentina , De Biase Dario , Campana Davide , Lamberti Giuseppe
Published: June 2021

e20515

Background: Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare tumor, with clinical and molecular features between non-small cell and small-cell lung cancer (NSCLC and SCLC, respectively). To date, little is known about factors able to predict clinical outcome of these patients. We sought to identify prognostic factors in LCNEC. Methods: We retrospectively collected pathologically-confirmed LCNEC patients treated at the S. Orsola Malpighi Hospital of Bologna between 01/01/2009 and 31/12/2020. LCNEC was defined as tumor with neuroendocrine morphology, expression of ≥2 neuroendocrine markers (including chromogranin A, synaptophysin, or CD56) at immunohistochemistry and high tumor grade (defined as necrosis and high Ki67 ≥ 50% or high mitotic rate, ≥ 10 mitoses per 2 mm2). Clinical features, pathological features, and blood test values (including neuron-specific enolase [NSE], carcinoembryonic antigen [CEA], cytokeratin 19 fragment [cyfra 21-1]) were correlated with progression-free survival to first-line chemotherapy (PFS) and overall survival from the diagnosis of extensive disease (OS). Results: Eighty-one LCNEC patients (median age 69 years, range 63-76) were identified. Twenty-seven (33.3%) had limited-stage disease and 52 patients (67.5%) had Eastern cooperative oncology group performance status (ECOG PS) ≥ 1 at diagnosis. When extensive disease was found (ED-LCNEC, N = 67), 23 patients (34.3%) had liver metastases, 10 (14.9%) had brain metastases and 24 (35.8%) had bone metastases. Treatment in ED-LCNEC was platinum plus etoposide in 45 patients (81.9%) and platinum plus paclitaxel in 10 patients (18.1%). Among 55 patients treated with platinum-based chemotherapy, 5 patients (9.1%) received cisplatin, while 50 (90.9%) received carboplatin. Overall, OS was 9.17 months (95% confidence interval [95%CI]7.17-13.87), PFS was 4.87 months (95%CI 4.21-6.02) and ORR was 38.2% (95%CI 25.4-42.3, N = 21/56). At univariate analysis, ECOG PS ≥ 1 (P = 0.049), presence of liver (P = 0.004) and bone metastases (P = 0.009), ≥ 2 non-nodal metastatic sites (P < 0.001), elevated NSE (P = 0.009) and CEA level at diagnosis (P = 0.011) were associated with increased risk of death. At multivariate analysis, ECOG PS ≥ 1 (P = 0.020), ≥ 2 metastatic sites (P = 0.002), and elevated NSE level at diagnosis (P = 0.009) were independently associated with the risk of death. At univariate analysis brain metastases (P = 0.017), ≥2 metastatic sites (P = 0.006) and elevated value of CEA at baseline (P = 0.026) were associated with increased risk of progression. At multivariate analysis, only the presence of brain metastases (P = 0.043) retained its association with the risk of progression. Conclusions: In ED-LCNEC of the lung, ECOG PS, number of non-nodal sites of metastases and NSE at baseline are associated with worse survival, while the presence of brain metastases is associated with shorter PFS.
Analysis of genetic mutations associated with immune-activated microenvironment in lung adenocarcinoma.
Authors: Liang Zhen , Zhao Shuhua , Liu Danni , Mu Tianhao , Chen Jinfeng
Published: June 2021

e20520

Background: Tumor microenvironment plays an important role in suppressing or enhancing immune response. However, the relationship between genetic mutation and prognosis of lung adenocarcinoma (LUAD) patients, and the molecular mechanism of immune microenvironment are not completely clear. Methods: Expression matrix and somatic mutations of TCGA LUAD (n = 509) were downloaded from UCSC Xena. Immune-related gene list was downloaded from ImmPort. We applied R packages ESTIMATE and CIBERSORT to calculate the proportion of tumor-infiltrating immune cell by mRNA data. Samples were divided into ImmuneScore-High or ImmuneScore-Low depending on upper or lower quartiles of ESTIMATE immune infiltration score. Differential expression analysis between ImmuneScore-High and ImmuneScore-Low was performed with R package DESeq2. Results: Samples were divided into ImmuneScore-High (n = 127) and ImmuneScore-Low (n = 128). The immune cell components of these two groups presented different patterns. 10 most frequently mutated immune-related genes were significantly different between two groups (Chi-Squared test, p value < 0.05). 4,139 differentially expressed genes were obtained (|log2FC| > 1, FDR < 0.05). IL-7R, PIK3R5, TRBC2 and VCAM1 were identified with differential mutation frequency and presented differential expression between two groups. Kaplan-Meier plot in UALCAN cancer database showed IL-7R had a significant influence on the prognosis of patients (log rank test, p value = 0.045). Conclusions: ImmuneScore-High and ImmunScore-Low groups presented different genetic mutation frequency and gene expression. Moreover, mutation and different expression of IL-7R may be used as a potential biomarker in the treatment of patients with lung adenocarcinoma.
Real-world concordance between tumor mutational burden (TMB) from blood (circulating tumor DNA) and tissue in lung cancer.
Authors: Park Inae , Hwang Jin Young , Bae William , Lee Grace , Kim Leeseul , Choi Yoonhee , Jung Hojung , Chae Young Kwang
Published: June 2021

e20522

Background: Tumor mutational burden (TMB) level is associated with response to immunotherapy in lung cancer. However, tissue TMB can be difficult to obtain, as tissue samples obtained from biopsies may be insufficient. Circulating tumor DNA-based TMB has been developed in order to complement or replace tissue TMB, but there is limited real-world data on their concordance. Here, we investigate the landscape and concordance between blood and tissue TMB, along with clinical traits of the concordant and discordant groups. Methods: Tumor mutational burden (TMB) was calculated using Tempus (tissue) and Guardant Health (blood) next generation sequencing (NGS) platforms from October 2020 to January 2021. There were 33 patients who had both Tempus and Guardant TMB data. Under the assumption that tissue TMB (tTMB) correlates with blood TMB (bTMB) at a ratio of 1:1.6, the patients were divided into concordant and discordant groups. The concordant group patients had bTMB/tTMB ratios between 1.3 and 1.9. The discordant group was divided into two subgroups: over 1.9 (Group B) and less than 1.3 (Group C). Among the 33 patients, 9 patients were excluded due to their non-evaluable bTMB levels. Treatment response was evaluated using RECIST criteria. Results: Of the remaining 24 patients, 7 patients in the concordant group and 21 patients in the discordant group were analyzed according to their clinical manifestations [Blood TMB (n = 24): range [1.46, 44.01], median = 9.57], [Tissue TMB (n = 24), range [1.3, 18.4], median = 4.5]. We compared the clinical presentations (number of metastatic organs and metastatic sites) between the two discordant groups (Groups B and C). Among the 24 patients, 13% (n = 3) had small cell lung cancer, 50% (n = 12) had adenocarcinoma, and 29% (n = 7) had squamous cell lung carcinoma. Patients with higher bTMB than tTMB (Group B) had more squamous cell carcinoma cases (71%, n = 5) compared to remaining groups (Groups A and C) (29%, n = 2). Among the discordant group, 6% of the patients (n = 1) had small cell lung cancer, 47% (n = 8) had adenocarcinoma, and 35% (n = 6) had squamous cell carcinoma. Further, 58% (n = 14) of the patients had higher bTMB than tTMB levels. Among the concordant and discordant groups, tumor burden as reflected by the number of metastatic sites and metastatic lesions and the sum of the largest diameters of tumor lesions using RECIST had no significant difference (p = 0.10, 0.68, 0.54, respectively). The concordant and discordant groups showed no significant difference in objective response (33% vs. 20%, p = 0.60) or clinical benefit rate (100% vs. 60%, p = 0.33). Conclusions: The majority of the patients had higher blood TMB than tissue TMB (Group A), with a concordance rate as low as 28%. Further studies are warranted to understand the biology behind the difference between blood and tissue TMB, including intertumoral heterogeneity.
Dose-painting radiation with concurrent chemotherapy for locally advanced non-small cell lung cancer: A single-center observational study.
Authors: Lv Jiahua , Wang Junchao , Jia Hongyuan , Liang Long , Wu Lei , Wang Yi , Wang Qifeng , Li Tao
Published: June 2021

e20529

Background: Dose-painting radiotherapy is a promising technique which enables different dose distribution to different areas within the lung cancer. However, the efficacy and safety of this irradiation technique are still uncertain. In this study, we observed and analyzed the outcomes of dose-painting radiotherapy with chemotherapy for the locally advanced non-small cell lung cancer. Methods: Patients with stage III non-small cell lung cancer undergoing chemoradiotherapy were enrolled in this study. The dose-painting target was defined according to the distance between the tumor and the mediastinum (GTVwithin 2cm and GTVout-of 2cm). Doses of 60-80 Gy( 3-4Gy/fraction, bid) and 40-60 Gy (2-3Gy/fraction, bid) were prescribed to the GTVwithin 2cm and GTVout-of 2cm, respectively, in 20 fractions, using simultaneous integrated boost. All the patients received 2-4 cycles of chemotherapy using cisplatin plus paclitaxel or pemetrexed. Results: In total, 65 patients were included in this study. Median follow-up was 66.1 months (range 8.0-117.3months). The incidence of ≥Grade 2 radiation pneumonitis and esophagitis were was 30.8% and 38.5%, respectively. The 1, 3, 5-year OS and PFS were 78.4% and 58.5%, 32.3% and 26.1%, 18.5% and 13.8%, respectively. Late radiation esophagitis were seen in 3 patients and 2 patients were observed severe pulmonary fibrosis. None of the patients experienced fatal bronchopulmonary hemorrhage or tracheal fistula. Conclusions: Radiation dose painting with concurrent chemotherapy is feasible and well tolerated for locally advanced non-small cell lung cancer. It needs to be further confirmed by large randomized controlled clinical studies.