bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination therapy with arsenic trioxide (ATO), all-trans retinoic acid (ATRA), and gemtuzumab ozogamycin (GO) in relapsed acute promyelocytic leukemia (APL)
Authors: Aribi A. M. , Kantarjian H. , Estey E. , Freireich E. , Koller C. , Thomas D. , Kornblau S. , Faderl S. , Laddie N. , Garcia-Manero G. , Cortes J.
Published: March 2020

6558

Background: Relapse occurs in 20 to 30% of patients with APL treated with ATRA. ATO is an effective agent for salvage of APL relapse, and GO has shown activity in APL due to the high expression of CD33. Methods: We investigated the efficacy of a combination regimen of ATO, ATRA and mylotarg in 8 patients with APL in 1st relapse. All patients had been previously treated with regimens that included ATRA and chemotherapy. Patients received ATO 0.15 mg/kg intravenously until marrow complete remission (CR). Once in marrow CR patient was observed until CR. Once CR was achieved or 60 days from the start of induction therapy, consolidation therapy was initiated with 1) ATO 0.15 mg/kg intravenously for 5 days per week for 4 weeks, repeated every 8 weeks for total of 5 courses, 2) ATRA 45mg/m2 orally twice daily 10 days per month for 10 months, and 3) GO 9 mg/m2 intravenously monthly for 10 months. Patients then received maintenance with 1) idarubicin 8mg/m2daily on day 1 and 2 every month for 3 months, 2) ATRA 45mg/m2orally daily 10 days per month for 14 months, 3) 6-MP 50 mg orally 3 times per day for 11 months and methotrexate 15mg/m2 orally once a week for 11 months. Results: The median age is 51years (range, 18–68 years), median WBC count 1.9 ×109/L (range 0.9–7.7 ×109/L), platelets 71 ×109/L (range, 6–164 ×109/L). The median duration of 1st CR was 7 months (range, 3 to 17 months). Seven patients achieved CR with median time to remission of 8 weeks (range 3–15 weeks). One patient achieved marrow CR after 3 weeks of therapy but is too early to evaluate for CR. All 7 are still in CR after a median follow up of 36+ months (range, 1+ to 51+ months). All seven patients achieved molecular remission. All patients had myelosuppression but there was no grade 3–4 extramedullary toxicity. Two patients died, one died secondary to complication related to metastatic lung adenocarcinoma, and the other patient died of sepsis. Conclusions: We concluded that the combination of ATO, ATRA and mylotarg is effective and may achieve durable remissions in many patients with APL in first relapse. It should be considered as an effective alternative to allogeneic or autologous transplant.

No significant financial relationships to disclose.
The financial impact of trastuzumab in metastatic breast cancer: The experience of the Institut Curie
Authors: Doz M. A. , Le Tourneau C. D. , Guilhaume M. S. , Dieras V. , Vincent-Salomon A. , Courbard M. , Le Vu B. , Buron C. C. , Livartowski A.
Published: March 2020

663

Purpose: To estimate, in term of public health on the scale of a region, the cost of trastuzumab and to point out the financial impact of this new targeted therapy in the adjuvant setting. Methods: To understand the consequences of the spending on of trastuzumab at a macroeconomic level in the French hospital financing system, we decided to focus on an establishment in particular, and to analyze the increasing spending of trastuzumab at a micro-economic level, to provide a cost analysis of patients treated with trastuzumab for HER2-overexpressing metastatic breast cancer. We retrospectively reviewed 137 medical reports of patients who received trastuzumab either in combination with chemotherapy or as a single agent and in maintenance therapy. Median age of the patients was 52 years (range 32- to 79+). Eighty five percent had 3+ HER2 overexpression and fifteen percent had 2+ HER2 (FISH amplified). Results: Median survival from first treatment with trastuzumab was 38.5 months (range 0,04–53,06+). The cost of the first year treatment is in average €43,435.58 per patient, for the second year €36,419.01 and for the third year €37,198.94. Drugs cost represents 78% of the hospital stays cost for a patient and 2.9% of the budget of Institut Curie. Conclusions: This retrospective analysis showed the very high level of expenses of trastuzumab to treat metastatic breast cancers. With the adjuvant use of trastuzumab, it is expected that these expenses are going to increase exponentially.

No significant financial relationships to disclose.
Biomarkers detected by proteomic analysis predicts breast cancer response to neoadjuvant chemotherapy
Authors: Shen D. , He J. , Gornbein J. , Chen Z. , Faull K. F. , Whitelegge J. P. , Chang H. R.
Published: March 2020

669

Background: Neoadjuvant chemotherapy provides an excellent opportunity for objective assessment of treatment-induced tumor response and for studying biomarkers characteristic of therapy-induced tumor responses. Methods: Proteomic analysis of T3/T4 breast cancer was performed in patients with locally advanced breast cancer in a phase II clinical trial. The breast cancer specimen was obtained before and after four cycles of Taxotere/Carboplatin/±Herceptin treatment. Two proteomic approaches, SELDI mass spectrometry and Clontech Ab Microarray 500, were used to screen for protein biomarkers that predict response of breast cancer to chemotherapy. Results: Five tumors with pathologically complete response (pCR) and 29 tumors with various amounts of residual tumors (Non-pCR) were analyzed by SELDI-TOF using the NP 20 chip. The normalized mass signals were compared between pCR vs Non-pCR at each aligned location by Wilcoxon rank sum test. Statistically significant differences were found at 22 m/z locations using a liberal p <0.20 criterion. The best univariate predictor occurred at m/z 14960 (p=0.004), which correctly classified 5/5 pCR spectra (100%) and 24/29 Non-pCR spectra (83%). A multivariate classification tree developed using m/z 14960 and m/z 12138 intensities correctly classified all 34 spectra. Ab microarray analysis was performed on five pCR tumors and in five tumors with the largest residual cancer. The Internal Normalization Ratio (INR) was calculated and used to compare the difference of protein expression between the two groups. Eight differentially expressed protein biomarkers were selected with the criteria of a statistically significant (Student t, p<0.05) expression change of <0.77 or >1.3 fold. Three proteins (Tat-SF1, PYK2 and PTP1B) were higher, and five (E2F2, IL1b, FEN1, CDC37 and ACM1) were lower in tumors with pCR. The unsupervised hierarchical clustering of the 10 samples by these eight proteins completely separated the pCR tumors from the poor responders. Conclusions: Our study suggests that bothSELDImass spectrometry and antibody microarray may be used to predict the tumor response to neoadjuvant chemotherapy. Proteomic analysis may be useful in developing tailored chemotherapy for breast cancer.

[Table: see text]
Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial
Authors: Mehta M. P. , Gervais R. , Chabot P. , Shapiro W. R. , Patchell R. A. , Glantz M. J. , Recht L. , Phan S. , Smith J. A. , Renschler M. F.
Published: March 2020

7014

Background: In a previous randomized study, RT plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM) (p=0.048). Methods: This Phase 3 trial randomized pts with BM from NSCLC and KPS ≥70 to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10. A sample size of 550 was based on α=0.001, β=0.8, hazard ratio (HR)=0.65, with a primary endpoint of TNP determined by a blinded events review committee. Results: 554 pts received RT (N=275) or RT+MGd (N=279), 348 in North America (NA), 206 in Europe and Australia (EA). Treatment arms were balanced for factors of known prognostic importance. Most pts had multiple BM (81%), extracranial metastases (51%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with >92% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4%), ALT increase (3%), and fatigue (3%). TNP improved from 10 months (mo) for RT to 15.4 mo for RT+MGd, p=0.12, HR=0.78. Time to neurocognitive progression was also improved, p=0.089, HR=0.79. More RT pts required salvage brain surgery or radiosurgery than RT+MGd pts (41 RT, 19 RT+MGd). In NA pts, statistically significant prolongation of both TNP, from 8.8 mo for RT to 24.2 mo for RT+MGd, p=0.004, HR=0.53, and time to neurocognitive progression, p=0.04, HR=0.69, were observed. In NA, RT was started sooner after the diagnosis of BM than in EA (median/mean 1.6/2.2 weeks NA vs. 3.0/6.5 weeks EA). There was a significant interaction between earlier RT and MGd benefit, p=0.017. When RT was initiated within 3 weeks of BM diagnosis, regardless of region, TNP was significantly prolonged by addition of MGd (N=378, p=0.006, HR=0.59). When initiation of RT was delayed beyond 3 weeks after BM diagnosis (N=176, 21% of NA pts, 50% of EA pts), MGd benefit was lost. A major reason for RT delay was use of chemotherapy as initial treatment for BM in 41 pts, 17% NA, 83% EA. Conclusions: MGd significantly prolonged TNP in NSCLC patients with BM receiving prompt RT in this randomized Phase 3 trial. The majority of patients in NA received prompt RT (79%), leading to a statistically and clinically significant benefit when combined with MGd.

[Table: see text]
Excision cross-complementing group 1 (ERCC1) single nucleotide polymorphisms (SNPs) and survival in cisplatin (cis)/docetaxel (doc)-treated stage IV non-small cell lung cancer (NSCLC) patients (p): A Spanish Lung Cancer Group study
Authors: Taron M. , Alberola V. , Lopez Vivanco G. , Camps C. , De Las Peñas R. , Alonso G. , Provencio M. , Salvatierra A. , Sanchez J. , Rosell R.
Published: March 2020

7053

Background: SNPs are the result of historical errors in DNA replication or repair that have been inherited through generations and are now shared among individuals. ERCC1 belongs to the nucleotide excision repair pathway. We examined whether ERCC1 SNPs 118 C/T and C8092A affect the repair of cis DNA lesions and thereby influence survival in cis-treated NSCLC p. Methods: SNP genotyping of ERCC1 118C/T and C8092A was performed by the TaqMan assay, and results were correlated with median survival (MS) in 706 cis/doc-treated stage IV NSCLC p. Results: Characteristics: 590 male, 116 female; performance status (PS) 0: 216 p (30.6%), PS 1: 480 p (68%), PS 2: 10 p (1.4%); adenocarcinoma, 371 p (53%). Overall response rate: 30%. After a median follow-up of 7.8 months (m) (range, 1–47 m), overall MS was 8.9 m. SNP frequencies: 118 T/T, 40.2%; C/T, 45.4%; C/C, 14.4%; C8092A C/C, 57.6%; C/A, 36%; A/A, 6.4%. MS according to 118 C/T SNP: T/T, 8.9 m; C/T, 9.5 m; C/C, 10 m (P = 0.51). MS according to C8092A SNP: C/C, 9.3 m; C/A, 10.2 m; A/A, 7.2 m (P = 0.05). When stratified by PS, the association between C8092A and MS is stronger for p with PS 0: C/C, 15.9 m; C/A, 13.8 m; A/A, 8.7 m (P = 0.04). Conclusions: This is the largest study to date reporting the effect of ERCC1 C8092A SNP on MS in stage IV NSCLC p treated with a single regimen. The uncommon A/A genotype predicts poor survival in p treated with dis/doc.

No significant financial relationships to disclose.
Cisplatin(P)-including triplets versus P-free doublets in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC): SICOG 0101 randomized trial
Authors: Comella P. , Palmeri S. , De Cataldis G. , Filippelli G. , Cioffi R. , Farris A. , Maiorino L. , Massidda B. , Roselli M. , Gambardella A.
Published: March 2020

7103

Background: We previously reported that triplets with P-gemcitabine (G) plus vinorelbine (V) (PGV) or paclitaxel (T) (PGT) prolonged the survival (S) of advanced NSCLC patients (pts) in comparison with P-based doublets (PG or PV). Aims of the present study were: (1) to compare (log-rank test) the S of P-based triplets vs P-free doublets, and (2) to compare (Fisher test) safety and response rate (RR) of T- and V-regimens. Methods: A 2x2 factorial design was adopted. Pts aged ≤ 70 years, with PS (ECOG) < 2, inoperable stage IIIA, IIIB, or IV NSCLC were randomly treated with: GV = G 1,000 mg/m2 + V 25 mg/m2 on day (D) 1 and 8; GT = G 1,000 mg/m2 + T 125 mg/m2 on D 1 and 8; PGV = P 50 mg/m2 on D 1 and 8 + GV; PGT = P 50 mg/m2 on D 1 and 8 + GT. In all arms, cycles were repeated Q 3 weeks. Only responder pts after 3 cycles received further chemotherapy (CT). Thoracic RT was delivered after CT to pts with intra-thoracic disease. 330 events were required to have a 90% power to demonstrate (two-sided P < 0.05) a 30% reduction of hazard of death. Results: From April 2001 to December 2005, 431 pts were recruited in the 4 arms. Characteristics in % were well balanced in P-based triplets and P-free doublets: males, 84/91; PS 0, 25/23; squamous cell carcinoma, 38/42; weight loss, 22/29; stage IV, 66/65; CNS metastases, 5/8; ≥ 2 metastatic sites, 29/30. So far, 411 pts were assessed for response: RR of triplets vs doublets was 88/204 (43%) vs 68/207 (33%) (P = 0.020), and of T-based vs V-based regimens was 40% vs 36% (P = 0.218). To date, 313 deaths were registered: median and 1-year S were 10.6 mo. and 41% for pts treated with triplets, and 10.4 mo. and 39% for pts treated with doublets (P = 0.786). Over initial 3 courses, occurrence of grade ≥ 3 toxicity (T vs V, % pts) was: neutropenia, 18% vs 30% (P < 0.004); febrile neutropenia, 4% vs 7%; platelets, 7% vs 12% (P = 0.056); anemia, 5% vs 7%; vomiting, 1% vs 2%; diarrhea, 6% vs 3%; stomatitis, 3% vs 0.5%. Grade ≥ 2 neurotoxicity occurred in 1% of both groups. Conclusions: Activity was significantly higher with P-based triplets, but they did not affect the OS. T-based regimens were equally active and less toxic than V-based regimens. Therefore, the GT regimen may represent a new standard of care for advanced NSCLC pts.

No significant financial relationships to disclose.
Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided cisplatin-based two-drug chemotherapy in unresectable non-small cell lung cancer
Authors: Moon Y. W. , Kim Y. T. , Sohn J. H. , Chang J. , Kim S. K. , Park M. S. , Chung K. Y. , Choi S. H. , Yang J. Y. , Kim J. H.
Published: March 2020

7118

Background: Heterogeneity of tumor response to chemotherapy is a big obstacle in cancer treatment. The aim of this study was to investigate correlations of ATP-CRA and clinical outcome after ATP-TCA-guided cisplatin-based chemotherapy in unresectable NSCLC. Methods: From Sep. 2003 to Oct. 2005, ATP-CRA was done in tumor tissue specimen obtained from patients with suspected lung malignancy. ATP-CRA tested sensitivities of anticancer drugs used widely in advanced NSCLC such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabin, and vinorelbine. The cell death rate was determined by measuring the intracellular ATP levels of untreated controls and drug exposed cells. A sensitive drug was defined as a drug producing 30% or more reduction of ATP compared to untreated controls. Test-guided cisplatin-based two-drug chemotherapy was given to pathologically confirmed NSCLC. Results: 31 patients were enrolled and their median follow-up duration was 13.3 months. Response rate was 48.3%. Median progression-free and overall survivals were 4.4 months and 11.2 months, respectively. Patients were dichotomized into platinum-sensitive (S) and resistant (R) groups. S-group (19) contained cases sensitive to platinum alone (6) or both drugs (13). R-group (12) contained cases sensitive to none (9) or the other drug alone (3). Clinical response rate was higher in S-group (75.0% vs 35.3% in R-group; p = 0.0635). Considering correlations of test results and clinical response, positive/negative predictive values were 64.7% / 75.0% with the predictive accuracy of 69.0%. Although without significant differences in histology, stage, and performance status, S-group had longer progression-free (5.0 vs 2.4 months in R-group; p = 0.056) and overall (21.8 vs 9.7 months in R-group; p = 0.018) survivals. Conclusions: In vitro chemosensitivity test, ATP-CRA results and clinical outcome were correlated well after test-guided cisplatin-based two-drug chemotherapy in unresectable NSCLC, presenting favorable response and survival in platinum-sensitive versus resistant group.

[Table: see text]
Identifying patients with non-small cell lung cancer (NSCLC) unlikely to benefit from erlotinib: An exploratory analysis of National Cancer of Institute of Canada Clinical Trials Group BR.21
Authors: Florescu M. , Hasan B. , Shepherd F. A. , Seymour L. , Ding K. , Pater J.
Published: March 2020

7161

Background: Despite a 9% response rate, BR.21 demonstrated significant survival benefit for patients receiving erlotinib as 2nd/3rd line therapy for NSCLC. We undertook to characterize, by exploratory subset analysis, patients less likely to benefit from erlotinib. To identify factors for consideration, we first identified baseline characteristics associated with early progression by eight wks and early death by 3 mos. Methods: Using stratification factors and potential prognostic factors from BR.21, the Cox regression model with stepwise selection was used to establish a prognostic model to separate erlotinib patients into 4 risk categories based on the 10th, 50th & 90th percentiles of prognostic index scores. 7 variables (smoking history, PS, weight loss, anemia, high LDH, response to prior chemo and time from diagnosis to randomization) were used in the final model. The hypothesis was that the characteristics of the treated patients in the highest risk group would also be predictive of lack of benefit from erlotinib when erlotinib and placebo patients with the same characteristics were compared. Results: Factors associated with PD by 8 wks were: PS2–3 (p = 0.009), weight loss (p = 0.0004), anemia (p = 0.008), PD to prior chemo (p = 0.006), non-Asian (p = 0.047), EGFR IHC-negative (p = 0.005), Factors associated with survival < 3 mos were: PS2–3 (p < 0.0001), weight loss (p < 0.0001), anemia (p < 0.0001), PD to prior chemo (p < 0.0001), non-Asian (p = 0.008), high LDH (p < 0.0001), time to randomization <12 mos (p = 0.0003). Comparison of overall survival for the 4 risk groups derived from prognostic index score as follows: high benefit (HR = 0.41, p = 0.007), 2 intermediate benefit (HR 0.79, p = 0.09; HR 0.80; p = 0.09); no benefit (HR 1.23; p = 0.42). Median survivals for erlotinib (placebo) patients in each group were 17.3 (8.3), 9.7 (7.5), 4.1 (3.7), 1.9 (2.7) mos. Conclusions: By establishing a prognostic model, we identified a small group of patients who are unlikely to benefit from 2nd/3rd line erlotinib therapy. This model requires prospective validation to confirm that it is both prognostic and predictive of outcome from treatment.

[Table: see text]
Erlotinib as first-line treatment for untreated advance stage NSCLC with good prognosis
Authors: Akerley W. L.
Published: March 2020

7178

Background: Erlotinib demonstrated improved survival in previously treated NSCLC, but did not affect survival in untreated NSCLC when used with concurrent chemotherapy. A potential hypothesis for this paradox is erlotinib may be more effective for patients with less aggressive tumors (i.e. those still surviving after multiple chemotherapy treatments). The current trial was designed to evaluate erlotinib before initial chemotherapy in a population of patients with less aggressive tumors based on clinical criteria. Methods: Eligibility criteria included stage IIIB/IV or recurrent NSCLC, no prior chemotherapy for systemic disease, PS = 0–1, weight loss less than 10%, and no urgent symptoms. Patients received erlotinib 150 mg po/day until objective or symptomatic progression before they were switched to chemotherapy. The 10 endpoint was time-to-progression after 1st chemotherapy. Results: 40 patients have been accrued. The median age was 65, 35 had PS = 1, 8 were never-smoker, and 23 were former smokers. Histologies were: Adeno 20, BAC 2, Sq 6, NSCLC 11, Other 1. The major toxicity was rash (Gr0 in 4, Gr1in 15, Gr2 in 14, Gr3 in 3, 4 too early. Other toxicity included liver (Gr 1 in 2, Gr2 in 1), mucositis (Gr1 in 1, Gr2 in 1) and diarrhea (liver (Gr1 in 10, Gr2 in 1, Gr3 in 2). 34 have been followed long enough for response evaluation, which identified 4 (12%) with PR (median 37 wks), 8 with stable (median 20 wk) and 22 with progression. At progression only 2 patients were too ill to start chemotherapy due to inadequate performance status. The median time on erlotinib was 8 wks overall: for rash Gr 0–1 8 wks, Gr 2–3=43 wks (p = 0.03). The median and 6-month PFS for chemotherapy are 22 wks and 45% with17 still on treatment. The median and 1-yr survivals are 50 wks and 47% with 24 pts still alive. Conclusions: Mid-term safety analyses exceeded expectations. Rash predicts duration of erlotinib effectiveness. Preliminary results suggest single agent, erlotinib may be as effective (PFS and survival) as initial chemotherapy with less toxicity and merits randomized testing as first treatment for advanced lung cancer.

No significant financial relationships to disclose.
Elevated osteopontin (OPN) plasma levels are highly prognostic in advanced non-small cell lung cancer (NSCLC): Analysis of SWOG S0003
Authors: Mack P. C. , Redman M. W. , Chansky K. , Williamson S. K. , Farneth N. , Lara P. N. , Le Q. , Gumerlock P. H. , Crowley J. J. , Gandara D. R.
Published: March 2020

7198

Background: OPN is a secreted glycoprotein with a diverse array of functions, including induction of uPA & increased cell migration. OPN has been shown to be elevated in a number of tumor types, & its downregulation reduces tumorigenicity & metastasis in tumor models. High levels have also been associated with tumor hypoxia/angiogenesis, as are vascular endothelial growth factor (VEGF) & plasminogen activator inhibitor (PAI-1). We hypothesized that secreted levels of these biomarkers would correlate with clinical outcome after treatment. Methods: Plasma concentrations of OPN, VEGF & PAI-1 were measured by ELISA in 160 NSCLC patients enrolled on the Southwest Oncology Group (SWOG) trial S0003 (paclitaxel/carboplatin ± the hypoxic cytotoxin tirapazamine). Post-treatment plasma samples were available in 56 patients. Results: Baseline OPN plasma levels correlated significantly with patient overall survival (OS). High interpatient variability was observed, with levels ranging from undetectable to 2560 ng/ml, (median: 606.5 ng/ml). When dichotomized, median OS was 11 months for patients below median OPN levels & 7 months for those above (p = 0.004). Survival decreases with increasing OPN concentration. Furthermore, OPN levels correlated with response rate (RR) (median responders: 497; median non-responders: 698 ng/ml. Wilcoxon rank-sum p = 0.03). No association between baseline levels of either VEGF or PAI-1 with RR or OS was observed. However, plasma levels of both PAI-1 & VEGF were significantly inter-related & trended together (p < 0.0001), & both decreased significantly after treatment (p = 0.0004 & 0.04, respectively). Median decrease: OPN: 17%, PAI: 44%, VEGF: 42%. No significant differences were observed between study arms, suggesting that OPN is prognostic in NSCLC, but not predictive for response to tirapazamine. Conclusions: 1) There is a great need for development of tumor biomarkers which can be serially assessed pre- & post-therapy. 2) High OPN plasma levels were significantly associated with reduced RR & OS for patients on this trial. OPN is a strong candidate for inclusion in a panel of prognostic (& perhaps predictive) markers for NSCLC. Supported by the Hope Foundation & R01-CA107228.

No significant financial relationships to disclose.
The impact of FLIPI on outcome of frontline treatment with single-agent I-131 tositumomab for follicular lymphoma (FL)
Authors: Kaminski M. S. , Hamstra D. , Estes J. , Wahl R.
Published: March 2020

7509

Background: The FLIPI is potentially useful in predicting clinical outcome and comparing treatment results among clinical studies in FL. We recently reported the results of I-131 tositumomab as frontline treatment in 76 pts with advanced-stage FL (NEJM 325:441, 2005). A single 1-week course resulted in a 95% and a 75% overall and complete response (CR) rate, respectively, and at a median follow-up of 5.1 years median progression-free survival (PFS) was 6.1 yrs. In multivariate analyses, bone marrow involvement was the only baseline variable that had a significant effect on PFS. Methods: To evaluate whether baseline FLIPI scores in this study could predict outcome and to compare this pt population with that in other frontline studies, the records of all 76 patients were reviewed. Results: FLIPI scores were available for 74 of the 76 pts: 11 pts (15%) low risk, 37 (50%) intermediate risk, and 26 (35%) high risk. CR rates for each risk group were 82%, 73%, and 73%, respectively. 5-yr PFS were 63% (35–92%, 95% CI), 63% (47–78%), and 52% (33–71%), respectively, p = 0.322. Grouping low + intermediate risk vs. high for PFS: p = 0.134. 5-yr overall survival (OS) rates were 100%, 95% (87–100%), 78% (62– 93%), respectively, p = 0.072, but grouping low + intermediate risk vs. high p = 0.028. A comparison to other frontline studies is below. Conclusions: The FLIPI did not predict for PFS or OS in FL pts treated with single-agent I-131 Tositumomab. However, an OS difference was seen when low + intermediate risk pts were grouped and compared with high risk pts. The distribution of FLIPI scores amongst pts in this study is similar to that observed in other front-line FL studies. Further studies exploring single-agent radioimmunotherapy vs. chemo/radioimmunotherapy combinations are warranted.

[Table: see text]

[Table: see text]
Incidence of secondary leukemia/myelodysplasia (AML/MDS) in Hodgkin’s disease (HD) with three generations of therapy at Stanford University
Authors: Advani R. H. , Hoppe R. T. , Rosenberg S. A. , Horning S. J.
Published: March 2020

7516

Background: Long term HD survivors have an increased risk of therapy-related AML/MDS that peaks about 5 years (yr) after alkylating agent (AA)-based chemotherapy (CT). Successive generations of Stanford studies limited AA exposure to address this risk. Methods: Patients (pt) treated with CT from 1974–2003 (RT only excluded) were retrospectively analyzed. S study pt received AA-based CT (MOPP or PAVE) alone (6%), with involved (IF) (21%) or extended field (EF) radiotherapy (RT) (73%); C pt received AA-based CT alone (26%) or with RT (37%) or non-AA-based CT (VBM or ABVD) + IFRT (37%); G pt received VBM + IFRT (12%) or the Stanford V + RT regimen (88%). Results: 21 (3.3%) of 639 pt developed AML/MDS: 13 after primary and 8 after secondary CT. AML/MDS incidence was significantly less in G pt (0.3%) compared to S (6.7%) and C pt (4.5%), p < 0.0001 and remained significant when pt followed <5 yr (18%) were excluded, p = 0.001. Secondary therapy was required more often for S (29%) and C (28%) pt than G (11%) pt. Number and Percent of AML/MDS in Three Eras Conclusion: AML/MDS was rare in the current Stanford V regimen era, indicating that limiting the cumulative dose of AA CT in combination with lesser RT volumes have significantly reduced the incidence of leukemia and the need for secondary CT. Longer follow-up is required to assess the impact of the Stanford V regimen on solid tumor and cardio-vascular risks.

[Table: see text]

No significant financial relationships to disclose.
Stanford V regimen in 59 patients (pts) with HD and HIV Infection (HD-HIV): A very effective approach in the long-term analysis
Authors: Spina M. , Gabarre J. , Fasan M. , Re A. , Schiantarelli C. , Talamini R. , Talamini R. , Vaccher E. , Tirelli U.
Published: March 2020

7583

Background: The introduction of HAART has significantly improved the outcome of pts with HD-HIV. However there are no data on the long-term follow-up of HD-HIV pts treated with conventional chemotherapy (CT) regimens and concomitant HAART. In 2002, we reported the results of a prospective phase II study with the intensive 12-week CT with adjuvant radiotherapy (Stanford V) and concomitant HAART in 59 pts with HD-HIV, a well-known unfavorable subgroup of HD (Spina et al. Blood 2002; 100:1984–1988). Methods: To analyze the long-term outcome of patients included in the Stanford V and HAART protocol. Results: The median follow-up is 53 months (range 3–104 months The overall survival (OS) is 59%, the freedom from progression (FFP) is 62% and the disease free survival (DFS) is 72%. The 5-year probability of OS was significantly different in pts with an international prognostic score (IPS) <3 in comparison to that of pts with an IPS >2 (84% vs 36%, p = 0.001). Similarly, the percentages of FFP at 5 years in these groups were 72% and 45% (p = 0.03). No significant side effects have been observed so far. Conclusions: After a median follow-up of 4.5 years, 72% of pts with this unfavorable subgroup and IPS <3 is free from progression, superimposable to that observed in the general population with comparable adverse prognostic factors. Therefore, Stanford V is a very effective regimen in pts with HD-HIV in the long-term analysis. Supported by AIRC and ISS grants.

No significant financial relationships to disclose.
Anti-CD74-doxorubicin immunoconjugate (IMMU-110) is cytotoxic in non-Hodgkin’s lymphoma (NHL) models and overcomes MDR
Authors: Blumenthal R. , Stein R. , Michell R. , Goldenberg D. M.
Published: March 2020

7598

Background: The internalizing LL1 anti-CD74 antibody is an optimal agent for delivering drugs, toxins, or radionuclides to CD74+ cancer cells. Here, we investigated the efficacy of IMMU-110 (Immunomedics, Inc.) in common follicular and aggressive types of NHL cells and in two disseminated non-Burkitt NHL models. Methods: CD74, MDR and MRP expression on NHL cell lines was determined by flow cytometry. In vitro cytotoxicity was assessed by cell cycle analysis of propidium iodide (PI)-stained cells and by measuring apoptotic cells using FITC-Annexin V and PI. In vivo therapy of a single 350-μg dose of IMMU-110 was evaluated in disseminated SUDHL4 and FSCCL. Results: Raji and Daudi Burkitt lines express similar amounts of CD74 (>93% positive cells and a MCF=35), yet a 3-day treatment with 0.8 μg/ml of IMMU-110 results is 18.4% of Raji and 67.9% of Daudi cells in Sub-Go. Aside from Daudi cells that respond with cells shifting into Sub-Go, most other NHL cell lines experience a G2/M block (44%-82% of cells) in response to a 3-day exposure to IMMU-110. Both MDR- and MDR+ NHL cells responded to IMMU-110. Kaplan Meier analysis showed a significant increase in survival of both SUDHL4 (MDR-/MRP-)- and FSCCL (MDR+/MRP+)-bearing SCID mice (P < 0.025) with 100% survival of treated mice vs. 38% survival of untreated mice at 70–77 days post cell implantation. Conclusions: IMMU-110 is cytotoxic in non-Burkitt and in Burkitt NHL cell lines. The magnitude of the cytotoxic response is not related to the amount of CD74 expressed on the cell surface. IMMU-110 is therapeutic in drug-sensitive (SUDHL4) and drug-resistant (FSCCL) NHL models, suggesting that antibody targeting can bypass the MDR drug efflux system that prevents free doxorubicin from being therapeutic.

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Lenalidomide (Len) in combination with dexamethasone (Dex) is more effective than Dex alone at first relapse and provides better outcomes when used early rather than as later salvage therapy in relapsed multiple myeloma (MM)
Authors: Stadtmauer E. A. , Weber D. , Dimopoulos M. A. , Borrello I. , San-Miguel J. F. , Hellmann A. , Marta Olesnyckyj M. , Yu Z. , Zeldis J. B. , Knight R. D.
Published: March 2020

7600

Background: High-dose Dex remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, oral, immunomodulatory drug (IMiD) that has activity against MM with additive effects when combined with Dex. At the interim analysis of MM-009/010, Len/Dex achieved a significant benefit over Dex, providing a longer median TTP, higher response rates, and higher CR rates. Aim: This prospective subgroup analysis was performed to determine the potential benefit of starting Len/Dex at first relapse by analyzing outcomes versus Dex among patients (pts) who had received only 1 versus >1 prior line of therapy. Methods: Pts who had received 1–3 prior treatments and were not refractory to Dex were randomized to either oral lenalidomide (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. The EBMT criteria were used for response. Randomization was stratified at entry by number of prior therapies (1 versus > 1). Results: Of 692 randomized pts, 241 pts (34%) received only 1 prior therapy. Those receiving 2nd-line Len/Dex had a significantly longer median TTP (66 vs. 20 wks) and a higher RR (CR + PR); (63% vs. 26%) versus those receiving 2nd-line Dex. After a median follow-up of 12.1 mos for all pts, 2nd-line Len/Dex provided significantly improved overall survival (OS) (hazard ratio 1.85, P = 0.03) versus 2nd-line Dex. Among the 451 pts who had received > 1 prior line of therapy, the median TTP (44 vs. 20 wks), RR (57% vs. 20%), and OS (hazard ratio 1.50, P = 0.03) were higher with Len/Dex vs. Dex. Response to Len/Dex was superior to that of Dex regardless of the type of prior therapy. Comparing pts who received Len/Dex as 2nd-line versus later salvage therapy, the median TTP was longer and response rates higher in pts treated in second-line. Conclusions: Len/Dex provided higher response rates and improved TTP compared with Dex at first relapse and beyond. TTP and response rates were superior when Len/Dex was administered earlier at first relapse compared with its use as later salvage therapy. These data support the use of Len/Dex for pts as 2nd-line therapy for relapsed MM.

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Pharmacodynamic relationships between asparagine INPUT (Imax) post asparaginase (ASNase) therapy and outcome in SR ALL patients (CCG-1962)
Authors: Avramis V. I. , Panosyan E. H. , Avramis I. A. , Dorey F. , Gaynon P.
Published: March 2020

9025

Background: ASNase is an important agent in the treatment of childhood acute lymphoblastic leukemia. Most other chemotherapeutic agents require entry into cells and some variety of activation. ASNase acts unmodulated and totally outside of cells, targeting extracellular ASN and glutamine. Several investigators have described a relationship between ASNase activity and ASN. In vivo, the equilibrium asparagine level depends on the input rate of ASN derived from the nutrients plus the de novo biosynthesis minus its deamination from the serum ASNase activity. Imax is a pharmacodynamic (PD) parameter developed in 1980’s representing the cumulative input of ASN from nutrients and de novo biosynthesis. Of note, glutamine is the amino group source for the synthesis of ASN from aspartate. In Enzyme-substrate relationships a sigmoid relationship exists that reaches a maximum product formation (Imax). We reported a link between Day 14 ASN depletion - not ASNase activity - and response for children with ALL in first marrow relapse (Jarrar et al, 2006). Methods: On CCG-1962, 117 children with standard risk ALL were randomly allocated to native or pegylated ASNase. Relevant PK-PD parameters have been reported (Avramis et al, Blood 2002). ASNase activity was not predictive of EFS. Induction (IND) Day 3 - 24 serum ASN levels were fitted into a PD model and the Imax values were evaluated for 112 patients. Results: The median Imax values were 1E-6 nmoles/ml/min in all 112 (range 2.0E-2 to 1.0E-7) and in the native or PEG-ASNase randomized patients. The mean values were 1.1E-3.1±3E-3 in 112 patients and 1.5E-3±4.0E-3 & 1.1E-3±3.0E-3 nmoles/ml/min in the native or PEG-ASNase randomized patients. We examined EFS by Imax values in lifetable analyses. High Imax values predicted statistically poorer outcome (p<0.00001) with various cut-off values (e.g., Imax ≥1x 10−3 or Imax ≥5 × 10−4 nmoles/ml/min. The effect was similar in the native and pegylated ASNase subsets. ASNase activity was not prognostic. Conclusions: Hence, ASN Imax in serum is a treatment-independent PD prognostic factor in a subset of children with standard risk ALL. Strategies to provide uniform therapeutic effect among patients with differing Imax are under consideration.

No significant financial relationships to disclose.
Serum vascular endothelial growth factor as a significant marker of treatment response in Hodgkin disease
Authors: Weyl Ben Arush M. , Ben Barak A. , Shenzer P. , Maurice S. , Livne E.
Published: March 2020

9033

Background: The aim of this pilot study was to determine VEGF serum levels (S-VEGF) at diagnosis and at restaging in children diagnosed with Hodgkin’s disease, and to investigate whether this parameter provides prognostic information for remission after 2 courses of chemotherapy Methods: S-VEGF levels of 9 consecutive pediatric patients (pts) with Hodgkin’s disease were assayed at diagnosis and at restaging. Levels of VEGF were determined using a commercially available ELISA anti-human VEGF immunoassay kit. PET-CT fusion was performed for each child at diagnosis and after 2 courses of chemotherapy in order to assess response to treatment. Results: 8 children went into complete remission or very good partial response after 2 courses of chemotherapy according to the protocol, one child developed tumor progression and respond to second line chemotherapy. At diagnosis average S-VEGF level was 655.7pg/ml (range, 1078.7–29.22 pg/ml) and at restaging decreased to 237.6 pg/ml (range, 0–453 pg/ml). (p=0.0039). One child with Hodgkin’s disease who had a higher level at first restaging and developed progressive disease responded to reinduction therapy and had a significantly lower level at the second restaging. The comparison between the levels of S-VEGF at diagnosis and at restaging showed a significant difference for the pts who responded to treatment with decreased S-VEGF and the pt who developed tumor progression with increased S-VEGF. Conclusions: Changes in S-VEGF levels correlated with response to treatment for most of the children diagnosed with Hodgkin’s disease. This provides a rationale for exploring clinical interest in S-VEGF measurements of a larger group of children with Hodgkin, and using the test for clinical trials of antiangiogenic therapies.

No significant financial relationships to disclose.
Risk factors associated to invasive infection in children and adolescents with cancer during febrile neutropenia episodes
Authors: Carlesse F. A. , Petrilli A. , Weckx L. Y. , Cypriano M. S. , Pereira C. A.
Published: March 2020

9046

Background: Febrile neutropenia (FN) after chemotherapy requires prompt introduction of empiric antimicrobial therapy. It has been demonstrated that FN patients do not represent a homogeneous group, and the stratification of infectious risk leads to changes in therapy. Our objectives were to evaluated the efficacy of the antimicrobial regimens used according to the FN institutional protocol and to identify risk factors related to invasive infection in children and adolescents during episodes of FN. Methods: We conducted a prospective study in the Pediatric Oncology Institute (IOP-GRAACC-UNIFESP/SP-Brazil) from March/2003 to June/2004. We analyzed 448 FN episodes in 200 patients, they were classified in high and low risk of invasive infection according to the underling disease and comorbities. Low risk patients (solid tumors, ALL and lymphomas in remission, without comorbities) were treated with oral gatifloxacin as outpatient; whereas high risk (AML, solid tumors, Lymphomas and ALL with comorbities or activity) were treated with cefepime as inpatient. Invasive infection was considered when a culture obtained from a sterile site resulted positive for bacterial and/or fungus or there were clinical and laboratory findings that strongly suggest sepsis. Results: Of 204 (45.5%) episodes treated with gatifloxacin, 72.1% obtained success without modification. Of 206 (46.0%) episodes treated with cefepime, 34.5% obtained success without modification, 38 (8.5%) patients were treated with distinct antibiotic regimen. Invasive infection was observed in 133 episodes (29.6%); 16 (3.6%) deaths occurred, all of them in the high risk group and the overall success was 84.3%. In the logistic regression analysis remained as independent risk factors: age ≤3 ys (OR: 2.3), temperature ≥38.5ºC (OR:1.6), central venous catheter (OR:1.7), underlying active disease (OR:1.6), mucositis (OR:2.4) and diarrhea (OR:2.4). Conclusions: Applying a institutional protocol, it is possible to predict the infectious risk and treat the patients individually .The observed overall success (84.3%), confirms that the therapy based in the protocol was adequate. There was no toxicity associated with gatifloxacin in this study, and no deaths in the low risk group.

No significant financial relationships to disclose.
Expression of erythropoietin and its receptor in neuroblastomas
Authors: Sartelet H. , Fabre M. , Castaing M. , Bosq J. , Racu I. , Lagonotte E. , Scott V. , Michiels S. , Patte C. , Vassal G.
Published: March 2020

9054

Background: Children with neuroblastomas (NB) may potentially benefit from treatment with recombinant human erythropoietin (Epo). Epo is a specific stimulator of erythropoiesis, acting via its specific receptor (EpoR). The aim of this study was to evaluate the expression of Epo and EpoR in NB and in normal tissues and their action in the proliferation of tumor cells. Methods: A tissue microarrays study was performed on 101 patients with NB from 3 hospitals (16 stage I; 7, II; 22, III; 48, IV and 8, IVS). Four blocks were constructed and contained 101 primary tumors, 39 paired metastases (35 lymph nodes), 56 paired control normal tissues and 6 cell lines of NB. Immunohistochemical staining was performed on sections using antibodies against Epo and EpoR. Immunostaining intensity was evaluated by a semi-quantitative score based on the percentage of positive cells. The wilcoxon signed rank test was applied for the comparison of paired data. For overall survival analysis, the expression was dichotomized at the median value and cox regression models were used stratified by hospital. An in vitro study of cell proliferation in presence of recombinant Epo was carried out with two of the 6 cell lines, one expressing EpoR, the other not. Results: Median follow-up was 64 months. The expression of EpoR was significantly higher in tumors than in paired control tissues (p<0.0001) but not for Epo (p=0.06). When restricted to the lymph nodes metastases, the level of expression of EpoR was significantly more expressed in the metastases than in primary tumors (p=0.02), contrary to Epo (p=0.99). Survival analysis showed that patients who expressed more EpoR had a statistically significant better overall survival than those who did not (p=0.03). Furthermore, the expression of EpoR was an independent prognostic factor from induction chemotherapy, tumor stage and age (p=0.02). No significant differences were found in Epo analyses. EpoR was expressed in only three cell lines and Epo not in any of them. In the in vitro study, recombinant Epo did not modify the proliferation of both cell lines. Conclusions: Epo and EpoR were expressed in NB but did not modify cells proliferation. The use of Epo in children with NB could be proposed but its benefit should be confirmed in a clinical trials.

No significant financial relationships to disclose.
Non cutaneous AIDS-associated Kaposi’s sarcoma
Authors: Stebbing J. , Mazhar D. , Palmieri C. , Thirlwell C. , Powles T. , Nelson M. , Gazzard B. , Bower M.
Published: March 2020

9555

Background: Acquired immune deficiency syndrome related Kaposi’s sarcoma (AIDS-KS) remains a significant cause of morbidity and mortality. We describe for the first time a proportion of patients with AIDS-KS who presented with no evidence of cutaneous disease. Methods: From our cohort of 5,932 individuals infected with the human immunodeficiency virus (HIV-1) treated in the HAART era, 319 were identified with KS. Of these, 11 patients (5.4%) were diagnosed with KS without the presence of any cutaneous disease. We compared their survival, clinical, immunologic and virologic characteristics to other individuals with KS. Results: There were no statistically significant differences in survival, CD4 count or HIV viral load at KS presentation. We observed that tumour-associated edema (p=0.046) and non-oral gastro-intestinal KS (p=0.042) were significantly more common in patients with non-cutaneous KS. Only 1 case of non-cutaneous KS was observed prior to the era of highly active anti-retroviral therapy (HAART). Conclusions: Non-cutaneous KS is a recognisable condition; patients should be treated with the standard of care as their prognosis is not inferior. This is likely to reflect a strong immune response, in the era of HAART.

No significant financial relationships to disclose.
Indication for neoadjuvant chemotherapy in adult patients with high-risk soft-tissue sarcomas
Authors: Kasper B. , Kuehl E. , Wuchter P. , Bernd L. , Ho A. D. , Egerer G.
Published: March 2020

9578

Background: To determine the efficacy and safety of neoadjuvant chemotherapy for local tumour control and overall survival in patients with high-risk soft-tissue sarcomas (tumour size ≥ 5 cm, G II/III, extracompartimental and deep localisation) we have analyzed the clinical outcome in 25 patients. Methods: Patients with high-risk soft-tissue sarcomas were treated with four cycles of etoposide 125 mg/m2/day 1+4, ifosfamide 1500 mg/m2/day 1–4 and doxorubicin 50 mg/m2/day 1 (EIA regimen) followed by definitive surgery with or without postoperative radiotherapy and adjuvant chemotherapy. 21 patients received chemotherapy in a combined neoadjuvant/adjuvant clinical setting; eighteen of them completed adjuvant chemotherapy. Four patients received chemotherapy in an adjuvant setting only. Results: The objective response rate of neoadjuvant chemotherapy assessable in 21 patients was 43%. Including NED (n = 7) and partial remissions (n = 3), the radiographic response rate was 47.6% with additional 42.9% stable diseases (n = 9). Surgery was performed in two patients before completing the four neoadjuvant chemotherapy cycles because of disease progression. Median overall survival for all patients from the time of first diagnosis was 21.6+ months [range: 8 - 50] and from the start of treatment 20.5+ months [range: 8 - 49]; median progression-free survival after start of treatment was 18.6+ months [range: 1 - 49]. After completion of chemotherapy, R0-resection could be performed in 13 of 21 patients (60%). At completion of entire treatment, 21 of 25 patients (84%) had NED after R0- and R1-resection. Two patients showed no disease progression after R2-resection and are alive with disease (AWD) 21 and 18 months after start of treatment. Two patients died of disease (DOD) ten and eight months after first diagnosis due to metastases. Conclusions: The high proportion of R0-resections supports the idea of a tumour downstaging after neoadjuvant treatment. Our data support the hypothesis that neoadjuvant chemotherapy might be beneficial as an integral part in the treatment strategy of high-risk soft-tissue sarcoma patients.

No significant financial relationships to disclose.