bluuebunny/crossref_metadata_2025 huggingface dataset:
Routine detection of EGFR mutations in patients with NSCLC: A comparative study of three alternative methods in 105 patients
Authors: Zalcman G. , Richard N. , Hardouin A. , Gervais R. , Antoine M. , Mittre H. , Baumann J. J. , Galateau-Salle F. , Cadranel J. , Kottler M.
Published: March 2020

7184

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has been reported in lung adenocarcinoma patients with tumoral EGFR mutations. Those mutations were found mainly by direct genomic sequencing on snap-frozen surgical specimens. Conversely, TKIs are used in metastatic patients who do not undergo tumor resection. In these patients, there is a need for routine sensitive molecular procedures, to overcome the small size of non-surgical bronchoscopy paraffin-embedded biopsy samples. Methods: Patients were selected on clinical and pathological characteristics: never (n = 43) or former smokers, patients with non-squamous NSCLC (n = 105) or patients with bronchioloalveolar adenocarcinoma (n = 34). Direct genomic sequencing assay was performed as reported elsewhere. Denaturing, high-performance, liquid chromatography (DHPLC) assay was performed with EGFR-specific primers that amplify exons 18, 19, and 21. A multiplex, allele-specific, oligonucleotide PCR (MASO-PCR) assay was carried out with a set of primers that identify the 14 most frequent molecular events described for the EGFR gene, which covers 90% of EGFR gain-of-function mutations described to date. Results: 123 samples were screened from 105 non-squamous NSCLC patients (female/male ratio = 0.84). Non-surgical biopsy specimens were available in 38 patients. EGFR mutations were detected by at least two of three procedures in 18/105 patients (17%). In paraffin-embedded specimens with low tumor content, EGFR heterozygous mutations were found either by MASO-PCR alone (n = 2, confirmed in the matched surgical sample by another procedure), or both by MASO-PCR and DHPLC (n = 16); they were missed by nucleotidic sequencing in 6 samples. 18 patients received TKI. 6 dramatic responses were achieved in patients with EGFR mutation, while no mutation could be found in non-responsive patients. Overall disease control was obtained in 8/18 patients (44%). Conclusions: MASO-PCR and DHPLC appear more sensitive than direct sequencing in non-surgical paraffin-embedded biopsies, which represent the bulk of samples in lung cancer patients. We propose that the cost-effective MASO-PCR be used for routine screening of EGFR mutations in NSCLC patients.

No significant financial relationships to disclose.
Phase II open-label study to investigate efficacy and safety of PTK787/ZK 222584 orally administered once daily at 1,250 mg as second-line monotherapy in patients (pts) with stage IIIB or stage IV non-small cell lung cancer (NSCLC)
Authors: Gauler T. C. , Fischer B. , Soria J. , Gounant V. , Griesinger F. , Krissel H. , Laurent D. , Eberhardt W. E.
Published: March 2020

7195

Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R 1–3) in NSCLC is associated with poor prognosis and shorter overall survival. PTK787/ZK 222584 (PTK/ZK), a novel, oral, anti-angiogenic compound blocks tyrosine kinase signaling from all VEGF receptors. Methods: A prospective, single-arm, multi-center, proof-of-principle phase-II study to investigate both efficacy and safety of PTK/ ZK in patients with stage IIIB/IV NSCLC who received prior first line treatment with a platinum based chemotherapy regimen. All pts were relapsed/refractory as determined by available imaging. All pts were planned to receive 1,250 mg of PTK/ZK once daily (qd) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation is based on RECIST criteria. Disease stabilization of at least 12 weeks based on CT/MRI-imaging was defined as clinically relevant drug activity. All pts had dynamic contrast enhanced MRI investigations for additional efficacy analysis and serum asservations for serum proteomic analysis. Results: To date, 56 pts have been enrolled. PTK/ZK is generally well tolerated. Most frequent adverse events (AEs) are nausea and vomiting. One pt developed interstitial lung disease (ILD) and in one pt with tracheal stent a fatal lung bleeding occurred. No other unexpected serious AEs have been reported. Maximum response for 48 evaluated pts include one pt with a partial response (PR) (2%), 27 pts with stable disease (SD) (56%), (disease control rate 58%), and 20 pts with progressive disease (PD) (42%). The pt with PR has responded for over 20 weeks. 15 pts have SD for at least 12 weeks; 5 pts of these had SD for at least 28 weeks. Conclusions: These preliminary results suggest that second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In pts with refractory disease in stage IIIB/IV NSCLC, a considerably high rate of disease control could be achieved in this study. The study is currently recruiting for twice daily (bid) treatment.

[Table: see text]
C/EBPα expression by immunohistochemistry lacks prognostic or predictive significance in primary resected non-small cell lung cancer
Authors: Costa D. B. , Stephenson P. , Kocher O. , Tenen D. G. , Feins R. H. , Keller S. M. , Schiller J. H. , Johnson D. H. , Halmos B.
Published: March 2020

7202

Background: The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is down-regulated in a majority of lung cancers. We sought to determine if C/EBPα could be a prognostic or predictive factor in non-small-cell lung cancer (NSCLC). Methods: Our cohort originated from ECOG 3590/4592 (randomized trial of postoperative adjuvant therapy with thoracic radiation or cisplatin and etoposide plus thoracic radiation in patients with completely resected stages II and IIIA NSCLC; and its laboratorial study). 166 tumor samples contained material for immunohistochemical (IHC) analysis of C/EBPα expression. We used a scoring system comparing tumor staining to that of basal bronchial cells (3+). 0 or 1+ (weak) staining suggested lack of, while 2 or 3+ (strong) suggested C/EBPα expression. Our primary outcomes were differences in progression-free and overall survival between the groups with weak or strong staining. Results: Among the 166 patients analyzed for C/EBPα IHC, the median progression free and overall survival were 30.7 and 40.3 months, respectively; which do not differ from the complete E4592 cohort. 92 patient samples (55%) had 0 or 1+ staining, and the remaining 74 (45%) 2 or 3+. The median progression free survival for patients with weak and strong C/EBPα IHC expression was 31.5 and 30.2 months, respectively (p = 0.84). The median overall survival between the weak and strong groups was 47.5 and 38.3 months, respectively (p = 0.54). 10 years after enrollment, 27% (25/92) of patients were alive in the weak, and 24% (18/74) in the strong C/EBPα IHC group. No difference between our primary outcomes by C/EBPα expression was identified. There was no difference in outcome by treatment arm, tumor histology, stage, or patient’s characteristics. There was a trend towards loss of C/EBPα and less differentiated tumor samples (p = 0.07). Conclusions: C/EBPα is a novel tumor suppressor gene in lung cancer with loss of expression in over 50% of NSCLC. However, our data demonstrate that in a subset of patients with resected NSCLC, C/EBPα IHC status is neither a prognostic nor a predictive marker. Further studies are needed to establish the molecular mechanisms of C/EBPα inactivation in lung cancer and its possible role as a new therapeutic target.

No significant financial relationships to disclose.
Long-term survival differences for bronchioloalveolar carcinoma (BAC) patients with ipsilateral intrapulmonary metastasis at diagnosis
Authors: Zell J. A. , Ou S. I. , Ziogas A. , Anton-Culver H.
Published: March 2020

7207

Background: It has been suggested that survival for BAC patients with stage IIIB disease due to multiple lesions in the same lobe is improved over other stage IIIB patients, and that patients with multicentric BAC have improved survival over BAC patients with distant metastasis. To determine the prognostic implications of these various subsets of advanced stage BAC patients, we compared survival rates using a large population-based cohort. Methods: A case-only analysis of data from the U.S. SEER database during 1998–2002 was conducted. The primary outcome measured was overall survival (OS). OS and lung cancer-specific survival (LCSS) univariate analyses were conducted using the Kaplan-Meier method; multivariate survival analyses were performed using Cox proportional hazards ratios. Results: 2653 incident cases of BAC were analyzed with a 5-year follow-up duration, including 831 patients with advanced (i.e. stage IIIB or IV) BAC. Patients with stage IIIB BAC due to multiple lesions in the same lobe (n = 96) had significantly improved median OS (46 months) and LCSS (not reached at >58 months) compared to other stage IIIB BAC patients on univariate analysis (n = 133; OS = 8 months, LCSS = 9 months) (P < 0.0001). Stage IV BAC patients with intrapulmonary metastasis (n = 320) had significantly improved median OS (13 months) and LCSS (15 months) compared to those with stage IV BAC due to distant spread on univariate analysis (n = 282; OS = 7 months, LCSS = 7 months) (P < 0.0001). These observed survival differences remained after adjustment for age, gender, ethnicity, and surgical treatment status (Table). Conclusions: Patients with stage IIIB BAC due to tumors in the same lobe have significantly better outcomes than other stage IIIB BAC patients. Stage IV BAC patients due to intrapulmonary spread have significantly improved outcomes over stage IV BAC patients with distant metastasis. These results add further support for modification to the current NSCLC staging system.

[Table: see text]

No significant financial relationships to disclose.
Predicting gene promoter methylation in lung tumors through examination of sputum and serum
Authors: Belinsky S. A. , Grimes M. , Johnson D. , Levy D. , Schiller J.
Published: March 2020

7208

Background: Personalized medicine may be a key approach in improving survival for advanced lung cancer. Success for this approach is seen with the response of cancer patients with an activating mutation within the epidermal growth factor receptor to the growth fact inhibitor, gefitinib. Genes involved in all types of normal cell function are targeted for inactivation by promoter hypermethylation during lung cancer development. This makes gene-specific promoter hypermethylation an attractive target for novel treatment strategies. One obstacle to targeted therapy is accessibility of tissue from peripheral tumors for methylation analysis. The purpose of this study was to determine the predictive power of sputum and serum to detect NSCLC through analysis for methylation of genes in these fluids. Methods: Tissue, serum, and sputum were obtained from 72 stage III NSCLC patients participating in a Phase III trial of Carboplatin, Paclitaxel and Radiotherapy, With or Without Thalidomide (ECOG 3598). Methylation specific PCR assessed methylation of the p16, MGMT, DAPK, RASSF1A, PAX5-α, PAX5-β, H-cadherin, and GATA5 genes. Results: At least one gene was methylated in 89% of tumors. Prevalence for methylation ranged from 15–47% and did not differ between gender. Methylation of ≥ 3 genes was seen in ∼50% of tumors. The agreement between sputum or serum in classifying methylation status of any gene in the tumor ranged from 54– 69%. The reduced sensitivity was presumably due in part to absence of tumor DNA in the biological fluids of methylation positive tumors. Logistic regression models revealed 3.1 (CI, 1.2, 8.2) and 4.2 (1.1, 16.1) increased odds for methylation of the p16 and MGMT gene, respectively in tumors if the serum or sputum was positive for methylation. The effect of tumor histology for predicting methylation using sputum and serum is being examined. Conclusion: These studies demonstrate for genes such as p16 and MGMT the possibility of interrogating biological fluids to predict for methylation in the primary tumor. (Supported by CA-89551).

No significant financial relationships to disclose.
Rituximab maintenance improves progression-free and overall survival rates after combined immuno-chemotherapy (R-FCM) in patients with relapsed follicular and mantle cell lymphoma: Final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)
Authors: Dreyling M. , Forstpointner R. , Gramatzki M. , Böck H. , Hänel M. , Seymour J. , Planker M. , Dührsen U. , Wilms K. , Unterhalt M. , Hiddemann W.
Published: March 2020

7502

Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m2/d days 1–3), Cyclophosphamide (200 mg/m2/d days 1–3) and Mitoxantrone (8 mg/m2/d day 1) (FCM) ± Rituximab (375 mg/m2/d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m2/d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL.

[Table: see text]
Survival in patients with multiple myeloma receiving zoledronic acid: Stratification by baseline bone alkaline phosphatase levels
Authors: Berenson J. , Shirina N. , Chen Y. M. , Dimopoulos M.
Published: March 2020

7505

Background: Zoledronic acid is indicated for the treatment of bone metastases in patients with multiple myeloma and has been demonstrated to reduce the risk of skeletal morbidity. However, it is unknown whether there is a survival benefit secondary to the reduction in skeletal complications. To assess the effect of zoledronic acid on survival in patients with multiple myeloma, we conducted a retrospective analysis of a subset of patients in a large, randomized, controlled trial. Methods: Survival data were analyzed for multiple myeloma patients (n = 209) treated with zoledronic acid 4 mg (n = 107) or pamidronate 90 mg (n = 102) who had at least 1 post-baseline safety evaluation and information on baseline bone alkaline phosphatase (BALP) levels (a marker of bone metabolism). Patients were retrospectively stratified by baseline BALP levels according to the following criteria: low BALP (< 146 U/L) and high BALP (≥ 146 U/L). Survival data were analyzed over 25 months on study. Results: The overall survival rate at 25 months was significantly higher in patients treated with zoledronic acid compared with pamidronate (76% versus 63%; P = .038, Cox regression). Among patients who had a low baseline BALP level, the survival rates were similar for both treatment groups. However, among patients with a high baseline BALP level, zoledronic acid treatment significantly improved survival at study end compared with pamidronate (82% versus 55%; P = .048, log-rank test). Conclusions: This exploratory analysis suggests that zoledronic acid treatment may improve survival compared with pamidronate, and this effect was observed primarily in patients who had a high baseline BALP level, indicating more aggressive osteolytic disease.

[Table: see text]
Estimating the impact of rituximab on bcl-2-associated resistance to CHOP using competing risks in elderly patients with diffuse large B-cell lymphoma (DLBCL)
Authors: Mounier N. , Briere J. , Gisselbrecht C. , Lederlin P. , Berger F. , Bosly A. , Tilly H. , Reyes F. , Gaulard P. , Coiffier B.
Published: March 2020

7514

Background: In diffuse large B-cell lymphoma, the combination of rituximab and CHOP (R-CHOP) has been proved to reduce bcl-2-associated treatment failure in elderly patients. However, some deaths could be due to age-associated morbidity such as cardio-vascular events. Patients and Methods: We therefore, addressed the question of its long-term impact by a competing risks analysis of 292 patients from the previously updated LNH-98–5 trial by the Groupe d’Etude des Lymphomes de l’Adulte (GELA) (Feugier et al, J Clin Oncol 2005). Using the competing risk formulation of Cox model regression, we investigated the effect of the explanatory variables on different competing events during the disease’s course such as progression, relapse, or death. Results: With a median follow-up of 5 years, R-CHOP was associated with a better survival than CHOP in 193 bcl-2-positive patients (56 ± 9% vs 42 ± 11%, P = 0.01), whereas in 99 bcl-2-negative patients there was no difference (58 ± 14% vs 52 ± 15% vs, P = 0.6). Results of competing risks analysis are given in table. Of particular interest, R-CHOP significantly decreased the risk of progression or relapse in both bcl-2-positive (RR = 2.6, P < 0.001) and bcl-2 negative (RR = 2.2, P = 0.01) and had no impact on the risk of death in complete remission patients (age over 70 remained an adverse factor). After relapse, aa-IPI 2–3 (RR = 2.9, P < 0.0001) and bcl-2 overexpression (RR = 1.5, P = 0.03) had still a significant effect on the risk of death but not front-line R-CHOP and age above 70. Conclusion: These findings highlight the role of rituximab in the sensitization to drug-induced apoptosis without inducing long-term sequel. However, Bcl2 positive patients failed to salvage treatment after relapse.

[Table: see text]

No significant financial relationships to disclose.
Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: A phase II trial in the North Central Cancer Treatment Group
Authors: Ansell S. M. , Geyer S. M. , Kurtin P. J. , Inwards D. J. , Kaufmann S. H. , Flynn P. J. , Morton R. F. , Luyun R. F. , Dakhil S. R. , Gross H. , Witzig T. E.
Published: March 2020

7532

Background: Mantle Cell Lymphoma (MCL) is characterized by t(11;14) resulting in over expression of cyclin D1, a member of the phosphatidylinosital 3-kinase (PI3K) pathway. Temsirolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) kinase. Previous studies with weekly temsirolimus at a dose of 250mg demonstrated a 38% overall response rate in 35 patients (JCO 23 (23); 5347–56, 2005). Thrombocytopenia was frequently observed and was dose limiting. The current study tested whether low-doses (25mg) of temsirolimus could produce a similar overall response rate (ORR) with less toxicity. Methods: Eligible patients had biopsy proven cyclin D1 positive MCL and had relapsed or were refractory to therapy. Patients received temsirolimus 25mg IV weekly as a single agent. Patients were restaged after 1 cycle (4 doses), after 3 cycles, and every 3 cycles thereafter. Patients with a tumor response after 6 cycles were eligible to continue drug for a total of 12 or 2 cycles after complete remission (CR) and then were observed without maintenance. The goal was to achieve an ORR of at least 20%. Results: Twenty-nine patients were enrolled between March and August 2005. Twenty-two patients have completed therapy. One patient with a major protocol violation on cycle-1 and one ineligible patient were excluded, leaving 27 evaluable patients. The ORR was 41% (11/27), with 1 CR and 10 PRs. Early evaluation of TTP showed a median of 5.5 months (95% CI: 3.3–7.7) and the duration of response for the 11 responders was 6.2 months (95% CI: 3.6 to not yet reached). These results compare favorably with the 6.5 months and 6.9 months, respectively, found in previous trials that used 250 mg. The median dose delivered per month was 80 mg (range, 10–100 mg). Sixteen (59%) of patients required a dose reduction. The median time on treatment was 4.4 months (95% CI, 3.3–7.7). The incidence of grade 3 and 4 thrombocytopenia was 12% and 0%, respectively. One patient experienced grade 5 infection without neutropenia, which was considered unrelated to CCI-779. Conclusions: Single agent CCI-779 at a dose of 25mg has anti-tumor activity in relapsed MCL similar to the 250 mg dose. This study indicates that combinations of temsirolimus with other agents should be feasible.

[Table: see text]
Long term outcome of 135 high grade non-Hodgkin’s lymphoma of the head and neck (HN NHL) treated with high dose CHOP regimen and involved field radiotherapy
Authors: Laccourreye L. , Desablens B. , Le Maignan C. , Le Mevel A. , Berthou C. , Lamy T. , Gandour C. , Guilhot F. , Ifrah N. , Colombat P. , Goelams
Published: March 2020

7550

Background: We present the results of a prospective study conducted by the GOELAMS group and evaluating long-term clinical outcome in a series of 135 patients with a HN NHL undergoing chemotherapy and radiotherapy. Methods: From 1986 through 1998, 135 patients aged from 17 to 69 years were enrolled in a prospective multicenter study for primary treatment of HN localized stage I/II high-grade NHL. Treatment regimen consisted in 3 VCAP + 40 Gy locoregional irradiation. Results: The median age was 48.5 years (17–69) with 36 patients being 60 or over. The main localization was Waldeyer’s ring (57) including tonsil (35), nasopharynx (14), whole Waldeyer (8), neck (49), nasal cavities (14), thyroid (8) salivary gland (5), mandibular bone (2). According to the WFC, histological subtype were as F (21%), G (57%) and H (20%) and unclassified (2%). Ann Harbor classification included 80 stage 1 and 55 stage II. The IPI score was 0 (49.7%), 1 (22.3%), 2 (10.4%), 3 (2.3%) undetermined (16.3%). PS>2 and bulk (≥ 5 cm) were observed in 7.5% and 43% of patients respectively. 94% achieved CR. 2 patients died during treatment. Relapses occurred in 23/127 (18.1%) at a median time of 31 months (5.5–80). 16 of these relapses occurred before 3 years of CR, 5 between 3 and 6 years and 2 after 6 years of CR. With a median follow up of 65 month (7–146) OS and EFS were 81.5% and 77% respectively. In univariate analysis age≥ 60, extension, PS≥2, Bulk≥5 cm, erythrocyte sedimentation rate≥ 40, high serum LDH,IPI≥2 and salivary gland or panwaldeyer localization significantly decrease EFS (P = 0.055, 0.017, 0.006, 0.0001, 0.04, 0.028, 0.014 and 0.043 or 0.0001 respectively). In multivariate analysis only the bulk≥5 cm, the erythrocyte sedimentation rate≥40 and the localization to salivary gland significantly decrease EFS (P = 0.004, 0.004 and 0.033 respectively). Conclusions: This study underlines the high efficiency of this protocol in treating HN NHL. HN NHL localized to the salivary glands or with a bulk ≥ 5 cm should be included in new therapeutic trials in order to improve their outcome.

No significant financial relationships to disclose.
Influence of parent age and gender on anticipation in familial B-cell malignancies
Authors: Alexandrescu D. T. , Brown K. , Dutcher J. P. , Wiernik P. H.
Published: March 2020

7553

Background: Anticipation (A) occurs when a disease manifests at an earlier age or with increased severity in the next generation. Dependence of A on parent age and sex has not been previously investigated in B-cell malignancies. Methods: 144 pairs [45 mixed Hodgkin’s/non-Hodgkin’s (HD/NHL) and NHL/HD, 44 NHL, 24 HD and 31 CLL] were analyzed retrospectively for presence of anticipation in overall, paternal (PT) and maternal transmission (MT). 90 pairs belong to our familial hematological malignancies database, and 54 were pooled from the literature. A among diseases, as well as PT and MT were compared by t-test. Parent age at conception was correlated with A by Pearson correlation (PC). Results: Age at conception was similar among all malignancies, and overall anticipation varied between −18.93 and −26.61 yr, with no significant difference among diseases, except between CLL and mixed HD/NHL-NHL/HD (−18.93 vs. −26.61 yr, mean difference −7.68 yr, p = 0.03, 95% CI −14.74 to −0.62). A significant PC between the parent age at conception and A was found for all malignancies, with the exception of borderline significance in the case of mixed HD/NHL-NHL/HD MT. No difference in overall A was observed between PT and MT, except for HD (−27.25 vs. −14.25 yr, mean difference −13.00 years, P = 0.02, 95% CI −23.68 to −2.32). However, higher PCs were observed with PT than MT for all diseases (Table). Conclusions: A is present in all familial B-cell malignancies analyzed and it correlates with parent age of conception. Although mean absolute A was more prominent with PT than MT only in the case of HD, all diseases showed a tendency towards a higher PC with PT. Although less prominent than with neurological disease, this phenomenon points towards a germline inheritance of B-cell malignancies and a common genetic basis for HD and NHL.

[Table: see text]

No significant financial relationships to disclose.
Prediction of outcome using positron emission tomography (PET) compared to standard response criteria and potential role in treatment decisions in diffuse large B-cell lymphoma (DLBCL) patients
Authors: Trneny M. , Jaeger U. , Belohlavek O. , Skrabs C. , Koren J. , Hanswirth A. , Pytlik R. , Klener P.
Published: March 2020

7565

Background: PET has been demonstrated to give valid information about viable tumor residua. There are however only limited data regarding the combination of classical response criteria with PET and there is a lack of information on the impact of additional therapy (add-Th) on the outcome of PET neg. or PET pos. pts. Methods: One hundred thirty-nine pts (median age 50y) with newly diagnosed DLBCL who were examined by PET during (after 2–4 cycles CHT - ‘early PET’) or/and at the end of therapy (‘end PET’) were analyzed retrospectively. IPI risk distribution were as follows: L 28%, LI 24%, IH 33% and H 15% pts. All pts were treated with anthracyclin based CHT. “Early PET” was performed in 84 pts. and “end PET” in 103 pts before add-Th, PET at both time points was performed in 48 pts. Add-Th (HDT with ASCT or/and radiotherapy), was given as planned or as a result of response evaluation (conventional methods - CT, trephine biopsy). No treatment modification was made on PET result only, except for 2 cases when planned RT was skipped because of PET neg. RT was performed in 59 pts (42.4%) and HDT with ASCT as consolidation in 54 pts (38.8%). Median follow up was 30 m. Results: CR or CRu was achieved after CHT in 102 (74%) pts, PR in 24 (17%) pts, stable or progress dis. in 13 (9%). ‘Early PET’ was neg. in 60% pts and ‘end PET’ was neg in 67% pts. PET neg. was achieved at least once in 97 (70%) pts, and PET pos. at least once was found in 50 pts (36%). The PFS at 30 m according to the combination of conventional and PET response was as follows: for CR PET-neg. pts 89%, for PR PET-neg. pts 90%, for CR PET-pos. pts 45% and for PR PET-pos. pts 64% (p=0.0001). OS was 93%, 63%, 90% and 83%, respect.(p=0.004). The analysis of impact of add-Th showed PFS at 30 m: for PET-neg pts with Add-Th 96%, for PET-neg. pts without Add-Th 82%. PET-pos. pts without Add-Th had a PFS of only 10% and PET-pos. pts with add-Th had PFS 58% (p=0.0001). The OS was 92%, 98%, 38% and 74% respect. (p=0.0001). Conclusions: Our data demonstrate that PET give more powerful information than standard response criteria. The second analysis support the the idea that pts with DLBCL in CR who remain PET pos. should undergo the additional therapy. Partial support: Grant MSM 0021620808

No significant financial relationships to disclose.
A multi-center, open-label study to evaluate the safety and efficacy of pentostatin, cytoxan, and rituxan (PCR) in the treatment of previously untreated or treated, stage III or IV, low-grade B-Cell NHL
Authors: Mena R. R. , Christiansen N. P. , Nyman D. W. , Markan Y. , Chowhan N. M.
Published: March 2020

7591

Background: The decision to treat indolent B-cell NHL is often based on progressive disease, worsening symptoms, and increasing hematological derangement. When treatment is indicated, these lymphoproliferative disorders are very sensitive to combination chemotherapies. Combination therapy with these agents, pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, represents a promising approach in the treatment of these patients. Most regimens have utilized fludarabine (F) as the purine analog but the myelosuppression and immunosuppression of (F) combinations frequently results in severe infections. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with low-grade stage III/IV NHL (REAL classification) to be enrolled. Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of 8 cycles. Clinical evaluation was performed after cycles 2, 4, 6 and 8. Patients were stratified by disease and by prior treatment status. Results: The intent-to-treat (ITT) population consisted of 54 NHL patients (median age 65, range 30–86) who received a total of 330 cycles (median 6 per patient). The ECOG status was 0 (31%), 1 (58%) and 2 (12%). The overall objective response rate was 71% (CR 15%, Cru 13%, PR 43%). Eight grade 4 neutropenias were documented along with a single grade 4 leukopenia. There were a total of 3 deaths which occurred within 30 days of the last dose. The first death was due to a second primary, NSCLC, diagnosed after treatment began. The second death occurred in an 81 year-old female, who had achieved PR, and her death was due to CHF. The last death, due to MI/CAD, occurred in an 84 year-old woman with SD. Conclusions: This immunochemotherapeutic regimen is active in indolent Grade III/IV NHL and the incidence of significant toxicities was low. Updated trial results will be presented at the ASCO annual meeting. Future trials evaluating the use of R as maintenance therapy following this PCR regimen may also be warranted with an eye toward increasing the overall survival of patients with NHL.

No significant financial relationships to disclose.
Effect of complete response pre- and post- autologous stem cell transplantation in multiple myeloma
Authors: Sayani F. , Stewart D. , Kmet L. , Faris P. , Savoie M. L. , Chaudhry A. , Brown C. , Russell J. , Bahlis N.
Published: March 2020

7604

Background: The value of achieving a complete response (CR) pre or post high dose therapy and autologous stem cell transplant (HDT-ASCT) in multiple myeloma is still uncertain. Knowing the impact of achieving a CR prior to HDT-ASCT on survival, may lead to the incorporation of novel therapeutic agents into the front line treatment of this disease. The aim of our study was to determine whether achieving a CR before or after HDT-ASCT affects overall survival (OS) in multiple myeloma patients. Methods: We performed a retrospective analysis of 88 consecutive myeloma patients receiving HDT-ASCT at our center from 1993 to 2004. The OS of patients achieving at least 90% reduction in their M-protein, i.e. complete response and very good partial response (CR/VGPR), pre or post HDT-ASCT, was compared to that of patients achieving a partial response or less (<90% reduction in M-protein). OS, defined as the number of months from HDT-ASCT to death or last follow up, was estimated by the Kaplan-Meier method. Response status was evaluated pre and at 100 days post HDT-ASCT. Results: Prior to HDT-ASCT, twenty-two (25%) patients achieved a CR/VGPR. Median follow-up time was 39 months for patients in CR/VGPR and 18 months for non-CR/VGPR group. OS at 5 years was 58% (95% CI: 21%-82%) for patients in CR/VGPR, compared to 69% (95% CI: 51%-81%) for all patients in PR or less prior to stem cell collection. Post HDT-ASCT, 48 (55%) patients achieved a CR/VGPR. Their OS estimate at 5 years was 67% (95% CI: 44%-82%) compared to 71% (95% CI: 27%-92%) for all other patients. Overall, 30% more patients achieved CR/VGPR post HDT-ASCT. However, the survival curves did not differ by response status pre or post HDT-ASCT (log-rank test p=0.58 and 0.57 respectively). Conclusions: Our results suggest that achieving a clinical CR/VGPR pre or post HDT-ASCT does not appear to impact OS. These results might have been influenced by the small sample size and the possible need for a longer follow-up time. A more robust definition of CR at the molecular level, plus the use of novel therapeutic agents in front-line treatment, may better define the impact of achieving CR in multiple myeloma.

No significant financial relationships to disclose.
Extended follow-up of outcome measures and analysis of prognostic factors in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin
Authors: Biehn S. E. , Moore D. T. , Voorhees P. M. , Garcia R. A. , Lehman M. J. , Dees E. C. , Orlowski R. Z.
Published: March 2020

7617

Background: Preclinical studies of bortezomib (bort) with pegylated liposomal doxorubicin (PLD) showed enhanced anti-tumor efficacy compared with either single agent. This led to a phase I trial in patients (pts) with advanced hematologic malignancies who received bort on days 1, 4, 8 and 11 at 0.9–1.5 mg/m2, and PLD on day 4 at 30 mg/m2, every three weeks (Blood 105:3058, 2005). Significant activity was seen, with 36% of relapsed/refractory multiple myeloma (MM) pts achieving a complete or near-complete response, while 73% attained at least a partial response. It was therefore of interest to define time to progression (TTP) and overall survival (OS) with this regimen. Methods: Additional follow-up was obtained on all 22 evaluable MM pts. TTP and OS were determined from day 1 of bort/PLD, and the Kaplan-Meier method was used to calculate time-to-event estimators. The log-rank test was used to compare TTP and time to retreatment (TTR) on bort/PLD vs. the prior therapy. Cox regression was used to evaluate covariates for association with TTP and OS. Results: Median TTP with bort/PLD was 9.3 months (mos)(95% confidence interval (CI) 8.3–22.4) versus 3.8 mos (95% CI 2.3–10.0) on the pt’s prior therapy (p=0.04). Similarly, the median TTR after bort/PLD was prolonged (p=0.04) compared with TTR after the prior regimen, with 3 pts having not yet received their next therapy. With a median follow-up of 36 mos, 13 of these patients (59%) remain alive, and the median OS has not yet been reached. Karnofsky performance status was significantly associated with TTP (p=0.02), while the hematocrit (hct; p=0.06) and IgA subtype (p=0.08) had borderline significance. Hct was significantly associated with OS (p=0.03), while the number of prior regimens (p=0.07) and the platelet count (p=0.06) had borderline significance. Conclusions: Bort alone induced a median TTP of 6.6 mos and OS of 16 mos in MM (N Engl J Med 348: 2609, 2003). The current results support the possibility that the bort/PLD regimen may improve upon TTP, and especially OS, compared with bort alone. This hypothesis is being studied in a randomized, international phase 3 trial ( NCT00103506 ) comparing bort and bort/PLD.

No significant financial relationships to disclose.
FDG-PET predicts disease burden in multiple myeloma
Authors: Kostakoglu L. , Niesvizky R. , Liu M. , Goldsmith S. J. , Christos P. , Jayabalan D. S. , Coleman M.
Published: March 2020

7619

Background: Because of the clinical and biologic heterogeneity of multiple myeloma, staging systems have been developed based on recognition of various prognostic factors. The recent integration of FDG-PET into the diagnostic algorithm may also have prognostic implications. Our aim was to evaluate the value of FDG-PET in determining the extent of disease as a staging tool in MM and to compare PET results with the established staging systems and laboratory data. Methods: Thirty seven patients with MM (mean age: 62±12) underwent a whole body FDG-PET scan at initial staging prior to therapy. FDG uptake was qualitatively scored in the following patterns: minimally diffuse (score 1), focal (score 2), multifocal (score 3), diffuse (score 4) and extramedullary (score 5). Standardized uptake values (SUVmax) were obtained in 780 osseous and extramedullary sites for quantitative evaluation. Additionally, mean SUVmax was calculated in 14 representative anatomic sites in the axial and appendicular skeleton in 20 age-matched control patients with no osseous malignancy. Ratios of the mean lesion SUVmax to the mean SUVmax of corresponding osseous sections from the control group were calculated. A score was obtained for each patient to reflect disease severity by adding the ratio for each lesion. Qualitative and quantitative results were correlated with the tumor burden (paraproteins, free light chains in the serum) and staging scores of Durie-Salmon (D-S) and the international staging systems (ISS). Results: There was good correlation between the quantitative score and both D-S staging and the ISS. However, correlation was stronger with the D-S system compared to that with ISS (r=0.44, p=0.007 vs. r=0.33, p=0.06). There was also good correlation between the quantitative score and the tumor burden (r=0.37, p<0.05). The qualitative scoring system produced a good correlation with the tumor burden (r=0.35, p<0.05). There was no correlation between the qualitative scoring system and D-S staging or ISS (P>0.05). Conclusions: FDG-PET is useful in assessing the extent of disease as a staging tool at initial diagnosis in MM. The scoring system we have developed appears to correlate with the established staging systems and the level of free light chains which may contribute to the prognostic evaluation of patients with MM.

No significant financial relationships to disclose.
Outcome of clear cell sarcoma of the kidney (CCSK) treated on the National Wilms Tumor Study-5 (NWTS)
Authors: Seibel N. L. , Sun J. , Anderson J. R. , Breslow N. E. , Perlman E. J. , Ritchey M. L. , Thomas P. R. , Coppes M. J. , Grundy P. E. , Green D. M.
Published: March 2020

9000

Background: CCSK was initially described by its bone metastasizing tendencies and propensity for late recurrences. Outcome for patients with CCSK has improved from NWTS 1–4. On NWTS 4 patients were randomized to treatment for 15 months vs 6 months. Their overall 8 year relapse free survival was 88% vs 61%, respectively. NWTS-5 was designed to improve the event free survival (EFS) and overall survival (S) for patients with CCSK by incorporating cyclophosphamide and etoposide. Methods: Prospective single-arm study conducted between August, 1995 and June, 2002. Patients less than 16 years of age with a centrally confirmed pathological diagnosis of CCSK were eligible. Staging consisted of CT scans of chest, abdomen, pelvis, bone scan, skeletal survey, and CT or MRI of head. Patients were treated with vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide for 24 weeks and XRT (10.8 cGy). Results: 110 eligible patients were enrolled on study. Median age was 22 months, 69% were males, and 63% white. Stage distribution was: stage I, 14; II, 41; III, 46; IV, 9 [metastatic sites: lung (3), bone (1), brain (1), liver (1), bone and bilateral lung (1) and other (2)] Median follow-up is 4.6 years. 5-year EFS and S were 79% (95% CI, 69% to 86%) and 89% (95% CI, 80% to 94%). All but one of 21 recurrences occurred within 3 years of initial treatment. The most common site of recurrence was brain (11/21). 5-year EFS for Stage I-IV was 100%, 87%, 74% and 36% respectively. Adverse prognostic factors for patients with Stage II/III disease were white race, and lymph node involvement. Conclusions: Outcome for patients with CCSK treated on NWTS-5 is similar to that seen on NWTS-4 and recent SIOP and UKCCSG trials. Stage is highly predictive of outcome. Brain recurrence was higher than that seen on NWTS-4; lung recurrences were lower. The next Childrens Oncology Group (COG) protocol will use the same treatment for patients with Stages I-III; therapy for patients with Stage IV disease will incorporate carboplatin. The role of XRT in CCSK needs to be evaluated.

No significant financial relationships to disclose.
Site of metastases does not influence the clinical outcome of children with metastatic Germ Cell Tumors (GCT). A report from the Childrens Oncology Group (COG)
Authors: Malogolowkin M. H. , London W. B. , Cushing B. , Giller R. , Davis M. , Cullen J. , Olson T. A.
Published: March 2020

9002

Background: To describe the clinical outcome of children with metastatic GCT (stage IV) at diagnosis according to the primary metastatic site(s). Methods: From March 1990 to February 1996, 299 children and adolescents with stage III/IV gonadal and stage I-IV extragonadal GCT were eligible for a Pediatric Intergroup high-risk (HR) GCT trial. Patients were randomized to receive 4–6 courses of cisplatin (P) standard dose [ 20 mg/m2/day (d) × 5] or high-dose (HDP) [40 mg/m2/d × 5] with etoposide (E) 100 mg/m2/d × 5 and bleomycin (B) 15 mg/m2 on d1. We retrospectively investigated the outcome of patients with stage IV and compared their outcome according to metastatic site(s). Results: There were 133 patients with stage IV disease. The median age was 2.6 years (y) [range, 3 d-19.3 y], 70 were female. Primary sites included: 43 testicular, 14 ovarian, 76 extragonadal (45 sacroccocygeal, 28 mediastinal, 3 other). Histologies included: 66 pure yolk sac tumors, 21 immature teratomas and yolk sac tumors, 26 mixed germ cell tumors, 7 pure germinoma/seminoma/dysgerminomas, 1 immature teratoma with a non-classic germ cell tumor, 2 mixed germ cell tumor admixed with a nonclassic germ cell tumor, 5 pure choriocarcinomas, and 5 patients with unknown histology. There were no statistically significant differences in the 5-year EFS or OS rates by site of metastases. Of the 19 patients with either bone or brain involvement, 17 patients had bone and 3 had brain metastases. Conclusion: The outcome for patients with metastatic GCT is excellent with contemporary cisplatin-based regimes and is independent of the site of metastatic disease.

[Table: see text]

No significant financial relationships to disclose.
A topotecan-containing induction regimen for treatment of high risk neuroblastoma
Authors: Park J. R. , Stewart C. F. , London W. B. , Santana V. M. , Shaw P. J. , Cohn S. L. , Matthay K. K.
Published: March 2020

9013

Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and cyclophosphamide to a multi-agent chemotherapy induction regimen for treatment of newly diagnosed high-risk neuroblastoma. Methods: Patients received 2 cycles of topotecan (starting dose 1.2 mg/m2/day for 5 days) and cyclophosphamide (400 mg/m2/day for 5 days) (T/C) followed by an additional 4 cycles of chemotherapy; cisplatin, etoposide alternating with vincristine, doxorubicin, cyclophosphamide. Pharmacokinetically guided topotecan dosing (target systemic exposure of AUC 50 - 70 ng/ml*hr determined by single day topotecan lactone levels) was performed. Chemotherapy cycles were scheduled every 21 days, PBSC harvest occurred after T/C cycles and surgical resection of residual primary tumor after cycle 5. Results: Thirty-one patients, 3 with INSS Stage 3 and 28 with Stage 4, were enrolled between April 2004 and November 2005. Median age at diagnosis was 2.5 years (range 0.9 - 9.35 years). Ten of 25 patients had tumor cell MYCN amplification and 21 of 22 tumors were classified as unfavorable Shimada histology by central review. Targeted topotecan systemic exposure was achieved in 87% (27/31) of patients during T/C cycle 1 and in 85% (23/27) of patients during T/C cycle 2. PBSC collections occurred as intended in 95% of patients (21/22 patients), median harvest 30.8 × 106 CD34+cells cell/kg (range 2.24 - 542). No dose limiting toxicities occurred. All patients experienced Grade 3 or 4 hematopoietic toxicity. Febrile neutropenia occurred in 79% (19/24) of patients during T/C cycles and 78% (18/23) of patients during subsequent cycles of induction therapy. Documented infection occurred in 12.5% (3/24) patients during T/C cycles and 26% (6/23) during subsequent induction cycles. Dose intensity of all chemotherapy agents was maintained in 95.8% (23/24) of patients. Conclusions: This pilot induction regimen was well tolerated with expected and reversible toxicities. Dose intensity of standard induction chemotherapy agents was not limited by the addition of dose-intensive topotecan. These data support investigation of efficacy in a Phase III clinical trial for newly diagnosed high-risk neuroblastoma.

[Table: see text]
Oral out-patient chemotherapy medication errors in children with acute lymphoblastic leukemia
Authors: Hawkins D. S. , Taylor J. , Winter L. , Geyer L.
Published: March 2020

9028

Background: Oral out-patient chemotherapy medications (OOCMs) compromise the majority of therapy for children with acute lymphoblastic leukemia (ALL). OOCM are administered at the patient’s home, usually by parents with limited medical training. The frequency of errors in OOCM dose or schedule is unknown in children with ALL. Methods: We conducted a prospective case series. After providing informed consent, parents were interviewed during an ambulatory clinic visit to determine the dose and frequency of OOCMs administered since the last ambulatory clinic visit or hospitalization. Parents also completed a questionnaire regarding their understanding of the child’s OOCMs. Patient medical records were reviewed to determine the appropriate OOCM doses and schedules and then compared to the parent report. Pharmacy records were reviewed to determine how OOCMs were prescribed. OOCM errors included omission of any OOCM, use of an incorrect OOCM, > 10% deviation from the intended OOCM dose, or incorrect OOCM schedule. Results: 69 children (median age 6.4 years, range 1.3–17.9 years) participated, with a total of 171 OOCMs assessed. Fifteen (8.7%) OOCMs were given incorrectly, including 10 OOCMs administered incorrectly by parents, and five prescribed incorrectly. Eight errors involved under- or over-dosing within 10–20% of the intended OOCM dose. There were no errors in pharmacy dispensing. Errors were more common with glucocorticoids (9/60 OOCMs evaluated) than anti-metabolites (6/111 OOCMs evaluated). Conclusions: OOCM errors are unusual in children with ALL. Both administration and prescription errors were observed. Efforts to improve optimal use of OOCMs should include prevention of errors, potentially by identifying patients at higher risk for OOCM errors.

No significant financial relationships to disclose.