bluuebunny/crossref_metadata_2025 huggingface dataset:
An international multi-center study to assess the clinical accuracy of the molecular subclassification of leukemia by gene expression profiling
Authors: Haferlach T. , Mills K. , Kern W. , Hofmann W. , Te Kronnie T. , Hernandez Rivas J. , Downing J. , De Vos J. , Kipps T. , Foa R.
Published: March 2020

6522

Background: Microarray analysis can identify differentially expressed genes of pediatric and adult leukemias. Recently, the MILE (Microarray Innovations in Leukemia) study has started in 11 centers (European Leukemia Network: 7, USA: 3, Singapore: 1). MILE compares the accuracy of gene expression profiles of 16 acute and chronic leukemia subclasses, MDS, and non-leukemia as control group to routine diagnostic workup. Methods: In a pre-phase each center was trained on the identical microarray protocol (HG-U133 Plus 2.0 microarrays). 2 cell lines (MCF-7, HEPG2) and cell lysates of three leukemia patients (AML t(8;21), CML, CLL) were tested. After proficiency testing, centers started to analyze 2000 leukemia samples. Results: The pre-phase demonstrated a very high intra- and inter-laboratory comparability among centers. Using principal component analysis each sample type was clustered with no observable sub-grouping of the different centers. Replicates of leukemia samples demonstrated squared correlation coefficients between 0.930–0.997 for CML, 0.936–0.998 for CLL, and 0.940–0.999 for AML t(8;21).Here we present classification results of the first series of 607 pts. that were included prospectively in a training data set (total n=1,049) to form linear classifiers for all 153 class pairs. The average cross-validation accuracy is 89.4%. In first independent cohort (HG-U133 Plus 2.0, n=105) 89.5% classification accuracy were achieved. In a second independent cohort (n=1,094), analyzed previously in two centers on HG-U133A/B microarrays, 83.5% classification accuracy were achieved. In detail, 136 out of 139 (97.8%) chronic leukemia samples (CML or CLL) were classified fully in agreement with standard diagnostic procedures. For acute leukemia subtypes 767 out of 904 (84.8%) were classified correctly. Interestingly, an AML-like signature can be found in MDS samples with IPSS >1.5. Conclusions: This international multi-center study demonstrates a very high inter- and intralaboratory reproducibility of microarray analyses. Data will be used to design a new custom format microarray dedicated to further develop the application of gene expression profiling for diagnosis and subclassification of leukemia.

No significant financial relationships to disclose.
Targeted immune depletion prior to reduced-intensity allogeneic stem cell transplantation results in rapid and complete donor chimerism with low treatment-related mortality
Authors: Dean R. M. , Fowler D. H. , Steinberg S. M. , Odom J. , Gea-Banacloche J. , Sportes C. , Hardy N. , Pavletic S. , Gress R. E. , Bishop M. R.
Published: March 2020

6540

Background: Significant variation in host immune status may influence outcomes after reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT). We have investigated a strategy of targeted immune depletion (TID) with conventional chemotherapy to deplete host T cells and achieve a minimal disease state prior to RI alloSCT. The aim of TID is to rapidly establish complete donor chimerism after RI alloSCT in order to potentiate a graft-versus-tumor (GVT) effect. In a prospective phase II trial (NIH 03-C-0077), we evaluated the effect of TID on donor chimerism, acute graft-versus-host disease (GVHD), and clinical outcome. Methods: Thirty-one patients (pts) with relapsed and refractory hematologic malignancies (NHL = 16; HL = 4; CLL/PLL = 4; MDS/AML = 3; other = 4) were enrolled. Median age was 57 years (range: 31–71). All pts received EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine) ± rituximab (R) as TID to deplete host CD4+ cells <100/μL. All pts then received a RI conditioning regimen consisting of fludarabine and cyclophosphamide followed by a T-cell replete allograft from HLA-matched siblings. GVHD prophylaxis consisted of cyclosporine plus short-course mini-methotrexate. Results: EPOCH-F(R) achieved the target host T-cell level in 74% of pts. All 31 pts engrafted after RI alloSCT. Complete donor chimerism (> 95%) was observed in 74% and 81% of pts at day +14 and +28 post-transplant, respectively. The incidence of grade II-III acute GVHD was 42% with no cases of grade IV acute GVHD. The median potential follow-up from transplant is 25 months. Actuarial treatment-related mortality at 1 and 2 years was 3% and 8%, respectively. Event-free survival probabilities at 1 and 2 years post-transplant are 65% and 49%, respectively. Ten pts are alive and event-free >24 months post-transplant. The overall survival probabilities at 1 and 2 years are 84% and 64%, respectively. Conclusions: TID prior to RI alloSCT results in rapid, complete donor engraftment and may potentiate GVT effects. This treatment strategy was associated with very low TRM and favorable outcomes in an older patient population with advanced hematologic malignancies.

No significant financial relationships to disclose.
Reduced intensity allogeneic stem cell transplantation in patients with myelodysplastic syndrome: Does the conditioning matter? A retrospective study of the SFGM-TC on 61 patients
Authors: Terriou L. , Chir Z. , Esperou H. , Boiron J. , Gratecos N. , Vernant J. , Michallet M. , Milpied N. , Jouet J. , Yakoub-Agha I.
Published: March 2020

6547

Background: Reduced-intensity allogeneic stem cell transplantation (RIT) has emerged as an alternative to myeloablative transplantation in pts with myelodysplastic syndrome (MDS). Given the uncertainty regarding the appropriate conditioning, SFGM-TC conducted a retrospective multicenter study with the attempt to evaluate the impact of conditioning on pts’ outcome. Methods: The record of 61 pts (37 males) with MDS who received a RIT between 1998 and 2003, from 22 French transplantation centres, were reviewed. According to the FAB classification, 11 pts had RA at diagnosis, of whom one had progressed to REAB and one to AML before transplantation. Thirty-two pts had REAB, of whom 2 had progressed to REAB-T and 7 to AML. Twelve pts had REAB-T and 6 CMML, of whom 8 progressed to AML. The median time from diagnosis to RIT was 12 months (6–129). Conditioning regimen consisted of fludarabin (Flu) plus busulfan ( n=29), Flu plus 2-Gy TBI ( n=20) and idarubicin plus aracytine and Flu (n=12). Donors were HLA-identical siblings (n=52) and HLA-matched unrelated (n=9). All pts received peripheral blood stem cells. The median of CD34+ infused cell dose was 5 × 106/kg (0.5–17.3). Results: At the reference date of 1 July 2005, median follow-up was 44.7 months (21–85). Estimated 3-year overall survival (OS), progression free survival (PFS), relapse and transplant-relapse mortality (TRM) were 35%, 27%, 66% and 30%, respectively. Neither of the 3 conditioning regimens used had impact on pts’ outcome. In multivariable analyses, while acute III/IV grade GVHD development was the only factor found to adversely influencing OS (HR=3.6; 95% CI: 1.1–12.2), chronic GVHD development was the only favourably influencing PFS and relapse ratios (HR=0.3; 95% CI: 0.1–0.7 and HR=0.2; 95% CI: 0.1–0.6, respectively). TRM was adversely influenced by male sex of pt (HR=9.2; 95% CI: 1.5–66.6). Conclusions: RIT seems to be an effective treatment in MDS pts irrespective of conditioning type. While acute III/IV grade GVHD appeared to be detrimental, the benefit effect of chronic GVHD was to be bound to GVL effect. New approaches with focus on immunosuppressive treatment are needed to enhance the GVL effect with an acceptable risk of GVHD.

No significant financial relationships to disclose.
Human leukocyte antigen (HLA) DR4 is not associated with differences in overall survival (OS), progression free survival (PFS), or graft-vs-host-disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo HSCT) for myeloid malignancies
Authors: Gupta S. , Aggarwal C. , Hahn T. , Padmanabhan S. , McCarthy P. , Battiwalla M.
Published: March 2020

6552

Background: HLA DR4 is associated with autoimmune disorders and with response to cyclosporine immunosuppression in T-cell Large Granular Lymphoproliferative Disorder (BJH 2003;123(3)). We have earlier reported association of DR 15 positivity with decreased acute GVHD (aGVHD) in patients undergoing allo HSCT for myeloid malignancies (Blood, 2005 Nov 10;Epub). Therefore we investigated the role of HLA DR4 on graft-versus-leukemia effect and GVHD in HLA-matched allo HSCT performed for myeloid malignancies. Methods: A retrospective review of 119 consecutive related and 48 consecutive unrelated allo HSCT patients (pts) treated between 1992 and 2003 at RPCI was performed to investigate the influence of HLA DR4 on OS, PFS and the incidence of grade 2–4 aGVHD and chronic GVHD (cGVHD). HLA DR B1 locus typing was determined by either molecular (n=108) or serologic (n=59) methods. The proportion of patients with one or two HLA DR4 antigens was 26% (43/167) which is similar to the range seen in general Caucasian population. Pt characteristics included: AML (n=84), CML (n=63), and MDS (n=20); median age 43 years (range 11–66); Male (n=104), Female (n=63); Caucasian (>95%); Total Body Irradiation (TBI) conditioning regimens (n=124); Busulfan (Bu)/Cyclophosphamide (Cy) (n=22), Bu/TBI (n=27), Cy/TBI (n=13), Etoposide/Cy/TBI (n=84), or other combinations (n=21). Results: There was no difference in OS and the PFS between the HLA DR4 positive vs negative groups in any disease or donor subgroups (p=0.4 and 0.6). GVHD prophylaxis was similar in the two groups but aGVHD and cGVHD incidence was not different in the two groups (p=0.8 and 0.9) Conclusions: HLA DR 4 is not associated with differences in GVHD or outcomes unlike the previous finding that HLA DR15 is associated with decreased acute GVHD in myeloid malignancies. These results suggest that there are differential effects of HLA DR antigens on the incidence of GVHD and outcomes in myeloid and lymphoid malignancies. Understanding these differences may facilitate the design of pt specific GVHD prophylaxis following allo HSCT.

No significant financial relationships to disclose.
Fatigue in older adults with acute myeloid leukemia (AML): Predictors and impact on quality of life (QOL) and functional status
Authors: Alibhai S. M. , Leach M. , Brandwein J. , Minden M. D.
Published: March 2020

6565

Background: Fatigue is one of the most common and important symptoms in patients with cancer, yet little is known about predictors of fatigue or its impact on either QOL or functional status in older adults with AML. Methods: Patients aged 60 or older presenting with AML to an AML referral centre were enrolled at diagnosis. Fatigue and QOL were evaluated at baseline and at 1, 4, and 6 months. Questionnaires included the Functional Assessment of Cancer Therapy Anemia and Fatigue subscale (FACT-An) and the European Organization for the Research and Treatment of Cancer QLQ-C30. Correlations between FACT-An scores, predictor variables, and QOL domains were examined with Pearson correlation. Mixed effects modeling was used to examine changes in fatigue over time. Results: Between June 2003 and December 2005, 63 patients (mean age 72) were enrolled. Fatigue was the most common symptom and was of moderate severity in the majority of patients. Fatigue scores at baseline did not correlate with age, hemoglobin level, white blood cell count, or bone marrow blast percentage but correlated positively with depression scores. There were strong correlations (r=0.56 to 0.70, p<0.01) between fatigue scores and depression scores over time, and moderate to strong correlations (r=0.36 to 0.67, p<0.01) with both global QOL and all 5 QOL domains of the QLQ-C30 over time. Correlations were slightly weaker with functional status measures (r=0.25 to 0.76). There was a weak but inconsistent relationship between fatigue scores and change in hemoglobin over time. Fatigue scores did not improve over time regardless of treatment intent and were not better by 6 months among those achieving complete remission. Conclusions: Fatigue is the most common symptom in older adults with AML and is negatively correlated with QOL and functional status. There is a weak relationship with anemia but not with other markers of disease severity. Fatigue does not improve by 6 months even in those who achieve remission. Further studies are needed to identify potential intervention targets to improve fatigue in this population.

No significant financial relationships to disclose.
Diptheria toxin-interleukin 3 fusion protein therapy of patients with elderly or relapsed/refractory acute myeloid leukemia (AML)
Authors: Frankel A. E. , Weir M. A. , Hall P. D. , Hogge D. E. , Rizzieri D. A.
Published: March 2020

6569

Background: To target myleoid leukemic stem cells in relapsed/refractory patients, we produced a recombinant protein composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin 3 (IL3). DT388IL3 binds to IL3 receptors on leukemic progenitors; the toxin is internalized and enzymatically inactivates protein synthesis leading to programmed cell death. We prepared a clinical batch of DT388IL3 and obtained FDA approval for a phase I study. Patients and Methods: Relapsed/refractory or elderly (≥70 years) AML patients with normal organ function and low anti-DT antibody titers were consented and given 15 minute infusions of DT388IL3 on a M-W-F for two weeks schedule. Premedication was hydrocortisone, acetaminophen, and diphenhydramine. Inter-patient dose escalation was done. Five patients at 4 ug/kg, 6 patients at 5.32 ug/kg, and 2 patients at 7.07 ug/kg received all 6 planned doses. Results: Eighteen patients have been treated as of 1/06. Median age was 58 years (25–81). There were 9 males and 9 females. One patient had de novo AML; 7 patients were in second relapse; 6 patients were in third relapse and 4 patients had refractory AML. One patient each received an autologous stem cell transplant (SCT), and an allogeneic SCT. Cytogenetics were unfavorable in 3, intermediate in 10 and not done in 5 patients. One patient each had MDS-related AML and treatment-related AML. Drug-related side effects were mild and transient including grade 3 fever, grade 2 hypotension, chills and hypoalbuminemia. Responses seen to date have been transient including a reduction in bone marrow blast index (% cellularity × fraction blasts) of pretreatment 40%, 70%, 36% and 40% converting to 8%, 4%, 4% and 4% on day 15. Conclusions: The preliminary data suggests mild toxicity with biological activity. Dose escalation is planned as per protocol.

No significant financial relationships to disclose.
Pharmacokinetics of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B Study 10105
Authors: Gupta P. , Miller A. A. , Owzar K. , Murry D. J. , Sanford B. L. , Vij R. , Yu D. , Hasserjian R. P. , Larson R. A. , Ratain M. J.
Published: March 2020

6573

Background: Angiogenesis may contribute to the pathophysiology of myelodysplastic syndromes (MDS). PTK787/ZK222584 (PTK/ZK; Novartis and Schering AG) inhibits vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and c-kit receptor tyrosine kinases. Methods: We evaluated early toxicity and pharmacokinetics in a Phase II trial of PTK/ZK in patients with MDS. Patients received PTK/ZK 1,250 mg orally once daily on 28-day courses until disease progression or unacceptable toxicity. A two compartment model with first order absorption and an inducible clearance was fit to serial concentration time data using a MAP Bayesian algorithm as implemented in ADAPT II software. Results: We report preliminary toxicity and pharmacokinetics on 56 of 80 pts enrolled between March 2004 and January 2005. The most common CTC grade ≥2 non-hematological toxicities observed were fatigue, nausea, vomiting, dizziness and ataxia. The initial area under the concentration-time curve (AUCinit) ranged from 25.5–423.1 mg*h/L (mean, 105 mg*h/L). The induced AUC (AUCind) ranged from 8.2–265.3 mg*h/L (mean, 56.2 mg*h/L). There was a significant decrease in drug exposure (Hodges-Lehmann Estimate 45.2 mg*h/L [95% CI=30.5,60.0]; Wilcoxon signed rank test p <0.0001), likely due to CYP3A4 auto-induction. However, there was no statistical correlation between AUCinit and AUCind for individual patients. Because of marked inter-individual heterogeneity observed in AUCinit and AUCind, we examined if drug exposure correlated with toxicity during the first 2 courses. On exploratory analyses, there was no relationship between pharmacokinetic parameters (AUCinit, AUCind or a function of both AUCs) and the occurrence or grade of non-hematological toxicities. Conclusions: Drug exposure declined significantly within 7–14 days after starting treatment with PTK/ZK. In this sample, there was no statistical evidence suggesting that variability in drug exposure was associated with non-hematological toxicities of PTK/ZK in patients with MDS.

No significant financial relationships to disclose.
Serial changes in bone marrow cellularity, reticulin fibrosis and microvessel density in patients with chronic myeloid leukemia (CML) in chronic phase treated with imatinib
Authors: Lokeshwar N. M. , Kumar L. , Vijayaraghavan M. , Dawar R. , Sharma A. , Kochupillai V.
Published: March 2020

6596

Background: Imatinib Mesylate, a BCR-ABL tyrosine kinase inhibitor produces sustained complete hematological response (CHR) in CML patients in chronic phase. There is a paucity of information on the effects of imatinib on the bone marrow (BM) morphology and angiogenesis. We evaluated the sequential changes in these parameters in 22 CML chronic phase patients treated with first line imatinib (400 mg) and compared with 10 controls (non-hematological malignancies). Methods: Trephine BM biopsies were evaluated by means of morphology, morphometry, Gomori’s stain and CD 34 staining. Reticulin fibrosis was graded from grade 1 to grade 4. Microvessel density (MVD) was calculated by counting the microvessels in hot spots (400 ×). Final value was mean of 10 fields. Total vascular area (TVA) was calculated by image analysis and expressed as percentage of the total area. Results: 22 patients were included in the study. Median age was 34 years (range 20–58 years). All patients attained a CHR at a median of 18 days. Major cytogenetic response was seen in 64%, minor response in 27% and no response in 9% of patients. Baseline BM cellularity was increased in all patents as compared to controls. The median cellularity at 6 months and 1 year was decreased to 60% and 50% respectively. The median grade of reticulin fibrosis at baseline was grade 3 as compared to controls (median grade 1). There was a significant decrease in reticulin fibrosis at 6 months and 1 year (median-grade 1, p=0.04). The median MVD at baseline was 8.25 (range 6–26) and was increased as compared to controls (median MVD-3.6). There was a significant decrease in MVD at 6 months and 1 year (median MVD-4.0, p=0.04). Similarly the TVA decreased from 6.2% at baseline to 4.3% at 1 year. These changes correlated with the cytogenetic responses. Two patients who had disease progression during therapy showed reversal in the bone marrow changes. Conclusions: Imatinib Mesylate produces significant effects on bone marrow morphometry and angiogenesis in patients with CML in chronic phase. There is a consistent decrease in bone marrow cellularity, reticulin fibrosis and microvessel density during therapy.

No significant financial relationships to disclose.
Randomized trial of high-dose chemotherapy with autologous haematopoietic stem cell support vs. standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: Overall survival after 6 years of follow up
Authors: Zander A. R. , Kroeger N. , Schmoor C. , Krueger W. , Moebus V. , Frickhofen N. , Metzner B. , Schultze W. , Berdel W. , Koenigsmann M. , Thiel E.
Published: March 2020

672

Background: Investigation of high dose chemotherapy (HD-CT) supported by autologous hematopoietic stem cell transplantation compared with standard dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more axillary lymph nodes. Methods: Between November 1993 and September 2000 307 patients were randomized to receive the following cycles of Epirubicin (90 mg/m2), Cyclophosphamide (600 mg/m2) intervenously (every 21 days) either HD-CT of Cyclophosphamide (1500 mg/m2), Thiotepa (150 mg/m2) and Mitoxantrone (10 mg/m2) intervenously for 4 consecutive days followed by stem cell transplantation or standard dose chemotherapy SDCT in 3 cycles of Cyclophosphamide (500 mg/m2), Methotrexate (40 mg/m2) and Fluoruracil (600 mg/m2) intervenously on days 1 and 8 every 28 days. The primary end points were event-free survival and overall survival. Results: After a median follow-up of 6.1 years 166 events with respect to event-free survival (SD-CT: 91, HD-CT: 75) and 123 with respect to overall survival (SD-CT: 66 and HD-CT: 57) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0,80, p = 0,15. The hazard ratio for overall survival for high dose chemotherapy versus standard dose chemotherapy is estimated as 0,84, p = 0,33. Analysing the effect of treatment on event-free survival premenopausal patients, patients with tumor grade III and ER-positive patients had a better outcome with HD-CT with an interactive effect of 2.5 and 1.4. The significance was only shown in grade III patients in favour of HD-CT, (p = 0,049). The interactive effect of HD-CT with prognostic factors did not reach significance for overall survival. Conclusion: Even with a follow-up of 6.1 years there was only a trend in favour of high dose chemotherapy with respect to overall survival but without a statistical significance. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients which might benefit from this treatment approach.

No significant financial relationships to disclose.
Effect of zoledronic acid (Zol) compared with pamidronate (Pam) on disease progression in breast cancer (BC) patients with bone metastases stratified by baseline characteristics
Authors: Hei Y. , Lipton A. , Shirina N. , Chen Y. M. , Xie T.
Published: March 2020

678

Background: Zol has been shown to significantly reduce the risk of skeletal complications compared with Pam in BC pts with bone metastases. Zol has also demonstrated antitumor effects in animal models of human BC and significantly delayed bone lesion progression in pts with renal cancer. To assess whether Zol may reduce the risk of overall disease progression compared with Pam, we conducted a retrospective analysis of BC pts enrolled in a large randomized, controlled trial. Methods: Patients treated with Zol or Pam were retrospectively stratified by baseline characteristics, including Brief Pain Inventory (BPI) composite pain score, time from initial cancer diagnosis to development of bone metastases, and duration of cancer. The relative risk of overall disease progression during 25 months on study was analyzed using the Cox proportional hazards model. Results: Median BPI pain score at baseline was 2.75, median time to development of bone metastases was 44 months, and median time with cancer was 58 months for all patients. In the subset of pts with a baseline BPI score ≥ 2.75 (n = 556), treatment with Zol significantly reduced the risk of disease progression by 21% compared with Pam (hazard ratio [HR] = 0.793; P = .018). Similarly, among pts who developed bone metastases < 44 months from initial diagnosis of cancer (n = 564) and pts with cancer for < 58 months (n = 563), treatment with Zol reduced the risk of disease progression by approximately 20% compared with Pam (HR = 0.805; P = .026 and HR = 0.800; P = .023, respectively). Conclusions: Zol significantly reduced the risk of overall disease progression compared to Pam in specific subsets of pts with higher pain scores and shorter time to development of bone metastases. This exploratory analysis suggests that Zol has potential antitumor effects that may reduce the risk of disease progression in this patient population. These results are consistent with published reports and provide the initiative for further investigations with additional clinical studies.

[Table: see text]
EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC): Results of a prospective phase II trial
Authors: Miller V. A. , Zakowski M. , Riely G. J. , Pao W. , Ladanyi M. , Tsao A. S. , Sandler A. , Herbst R. , Kris M. G. , Johnson D. H.
Published: March 2020

7003

Background: Erlotinib produces dramatic responses in a subset of patients with NSCLC. Mutations in the EGFR tyrosine kinase domain, EGFR amplification or polysomy and EGFR overexpression on immunohistochemistry have all been associated with sensitivity and benefit; pts with KRAS mutation are commonly resistant to this agent. These correlative studies were prospectively undertaken to characterize the ability of these markers to predict response rate, time to progression and survival in pts with BAC treated with the EGFR-TKI, erlotinib. Methods: One hundred and two patients received erlotinib as part of a phase II trial in BAC (Kris, Proc ASCO 2005); 84 had one or more correlative studies completed. Analysis of EGFR exons 19 and 21 (n=82) (Pao, et al PNAS 2004), EGFR IHC (n=62) (DAKO) was performed and EGFR copy number was determined by chromogenic in situ hybridization (CISH) (n=74) (Zymed); detection of ≥ 4 signals per cell was considered evidence of amplified copy number. KRAS exon 2 (n=79) testing was performed by direct sequencing. Fisher’s exact test was used to study the association of each feature in pts with partial response or no partial response. Time to progression and survival were analyzed with log-rank test. Results: See table below. Conclusions: 1) EGFR exon 19 or 21 mutation is a powerful predictor of response and TTP but not OS in pts with BAC treated with erlotinib. 2) CISH ≥4 is associated with response and improved TTP but not OS. 3) Patients with both EGFR mutation and amplification fare well supporting the concept of “oncogene addiction”; erlotinib should be considered as initial therapy in this population. 4) EGFR amplification without mutation is uncommon. 5) There is no clear utility of EGFR IHC in clinical decision making. 6) The presence of KRAS mutation predicts resistance to erlotinib. Supported, in part, by Genentech.

[Table: see text]

[Table: see text]
Phase III randomized study of vinorelbine (V), gemcitabine (G) followed by docetaxel (D) (VGD) versus paclitaxel (P) and carboplatin (C) (PC) in patients (pts) with advanced non-small cell lung cancer (NSCLC) (Japan Multinational Trial Organization LC00–03)
Authors: Kawahara M. , Ogawara M. , Nishiwaki Y. , Kubota K. , Komuta K. , Minato K. , Fujita Y. , Origasa H. , Fukushima M. , Furuse K.
Published: March 2020

7013

Background: Our phase II study of non-platinum VGD for advanced NSCLC demonstrated excellent results with the median survival time (MST) of 15.7 mos and a 1-year survival rate of 59% (Brit J Cancer 88:42,2003). A phase III trial was performed to determine the survival benefit of VGD compared with PC for advanced NSCLC as a Japan-SWOG Lung Cancer Common Arm Trial. Methods: Between Mar 2001 and Apr 2005, 401 chemo-naïve NSCLC pts with Stage IIIB with pleural effusion or Stage IV without brain metastasis, who had ECOG PS 0–1, were randomized to VGD; V 25 mg/m2 iv and G 1000 mg/m2 iv, days 1, 8, every 21 days for 3 cycles followed by D 60 mg/m2 iv, d1, every 21 days for 3 cycles or PC; C AUC=6 iv and P 225 mg/m2 iv, day 1, every 21 days for 6 cycles. The primary endpoint was overall survival (OS). For a two-sided test at the 5% level of significance and power of 85%, the number of pts required to detect a 40% difference in MST was 400. Results: 393 pts (196 VGD, 197 PC) were evaluable for response, OS and toxicity. Baseline demographics were balanced (VGD vs PC): median age 65 yrs(both arms);male(74 vs 69%); PS 0 40%(both arms);Stage IIIB (17 vs 18%); Ad/Sq (66%/23% vs 76%/15%). There were 238 deaths with a median follow-up of 23 mos. 49% in VGD and 29% in PC arm completed 6 cycles (p=0.00005). Response rates in arms VGD/PC were 23% vs 36% (p= 0.008). There were no significant differences in progression free survival, OS, 1- and 2-yr survivals between VGD and PC arms: 5.9 vs 6.0 mos (p=0.95, Log rank), 13.1 vs 13.8 mos (MST, p=0.28, Log rank), 55.6 vs 55.5%, and 27.6 vs 31.8%. Grade 3/4 toxicities in arms VGD/PC were: neutropenia (G4) (30 vs 54%, p<0.00001), thrombocytopenia (4 vs 6%), febrile neutropenia (20 vs 19%), neuropathy (2 vs 21%, p<0.00001), pulmonary (9 vs 2%, p=0.0006). There were 2 treatment-related deaths (pneumonitis) in VGD arm. Conclusions: Non-platinum triplet chemotherapy had comparable activity in pts with advanced NSCLC. The VGD had significantly less myelosuppression, but more pulmonary toxicity than PC.

No significant financial relationships to disclose.
Updated report of a phase III study of induction therapy with gemcitabine + carboplatin (GC) followed by either delayed vs. immediate second-line therapy with docetaxel (D) in advanced non-small cell lung cancer (NSCLC)
Authors: Fidias P. , Dakhil S. R. , Lyss A. P. , Loesch D. M. , Waterhouse D. , Cunneen J. , Ye Z. , Tai F. , Obasaju C. K. , Schiller J. H.
Published: March 2020

7032

Background: GC is an active regimen in patients with advanced NSCLC. For non-progressors after induction treatment, optimal timing of sequential therapy is unclear. Is it best to sequence immediately to an active non-cross resistant agent or delay the introduction of this agent until time of disease progression (PD)? This trial was designed to answer this question. Methods: Pts with Stage IIIB or IV NSCLC were enrolled. G 1000mg/m2 was administered on day 1,8 followed by C at AUC 5.0 on day 1. After 4 cycles, non-progressers were then randomized to immediate D (75mg/m2 administered on day 1 every 3 wks) or delayed D (pts were observed until first evidence of PD). Conclusions: This study confirms that it is possible to deliver docetaxel immediately following four cycles of GC without significantly increasing toxicity. The response rate of 42.1% and clinical benefit rate (CR+PR+SD) of 88.2% observed in the immediate D arm compares favorably with the rates of 6.1% and 60.6% of the delayed D arm. Additional toxicity and response information will be available at the time of the meeting.

[Table: see text]

[Table: see text]
Comparison of docetaxel and vinca alkaloid, alone or in combination with other chemotherapy agents, in the first-line treatment of advanced non-small cell lung cancer (NSCLC): A meta-analysis
Authors: Douillard J. Y. , Fossela F. , Georgoulias V. , Pujol J. L. , Kubota K. , Monnier A. , Takeda K. , Cucherat M. , Laporte S.
Published: March 2020

7034

Background: Taxanes and vinca alkaloids are commonly used agents, in first-line therapy of advanced NSCLC. As some data in comparative studies have suggested possible differences in survival and safety, we performed a meta-analysis in order to assess the potential benefit of docetaxel-based regimens in comparison with vinca alkaloid-based regimens, in terms of overall survival (OS) and toxicity. Methods: MEDLINE, CANCERLIT and Cochrane Library searches were supplemented by information from clinical study reports and by manual searching of relevant meeting proceedings. Only randomized trials comparing docetaxel-based chemotherapy to vinorelbine- or vindesine-based chemotherapy were included. Outcomes recorded were OS and neutropenia. Fixed-effects and random-effects models were used to estimate the pooled hazard ratio (HR) of OS and the odds ratio (OR) of neutropenia. A HR or OR less than 1 indicates that docetaxel is superior to vinca alkaloids. Heterogeneity was assessed using the Cochran Q-test. Results: The seven selected trials (six using vinorelbine as vinca alkaloid) yielded a total of 2,867 patients (docetaxel regimens: 1,638; vinca alkaloid regimens: 1,229). Docetaxel was combined with a platinum compound in three trials, with gemcitabine in two trials and used as monotherapy in two trials. The vinca alkaloid was combined with a platinum compound in six trials, and used alone (vinorelbine) in one. The pooled estimate of the OS shows a significant improvement in favor of docetaxel (HR=0.89, 95%CI [0.82;0.96], p=0.03), this benefit persisting after exclusion of the vindesine study (HR=0.90 [0.83;0.98]) and also after excluding monotherapy regimens (HR=0.89 [0.82;0.97]. While neutropenia was common, it was significantly less frequent with docetaxel (OR=0.60 [0.39;0.92], p=0.019), as was febrile neutropenia (OR=0.60 [0.39;0.96], p=0.034). Conclusions: The results of this meta-analysis support the superior efficacy (OS) and safety (neutropenia and febrile neutropenia) of docetaxel in first-line therapy of advanced NSCLC as compared with vindesine or vinorelbine. Detailed results, as well as subgroup analyses, will be presented at the meeting.

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Analysis of prognostic factors in patients with advanced relapsed/refractory NSCLC: Cox regression analysis of a randomized phase III trial comparing docetaxel and paclitaxel poliglumex (PPX)
Authors: Bonomi P. , Langer C. , O’Brien M. , O’Byrne K. , Bandstra B. , Paz-Ares L. , Ross H. , Sandler A. , Socinski M.
Published: March 2020

7040

Background: A phase III trial compared PPX to docetaxel as 2nd-line treatment in pts with relapsed/refractory advanced NSCLC (STELLAR 2). While overall survival was similar between arms, the need for supportive measures to manage the effects of myelosuppression was significantly reduced in the PPX arm. The current analysis was performed to evaluate determinants of survival in the 2nd-line treatment of NSCLC. Methods: STELLAR 2 enrolled 849 pts, 427 on PPX and 422 on docetaxel; all patients were included in the analysis. Randomization between the study arms was stratified by tumor stage, performance status (PS), start of frontline chemotherapy (< 4 mo vs more than 4 mo), gender, and prior taxane therapy. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of baseline characteristics on overall survival (OS). Results: At randomization, 29% of pts had received prior taxane, 14% were PS2, 80% had stage IV disease, and 31% had started frontline therapy within the prior 4 months. Risk factors significantly affecting survival as determined by multivariate analysis are listed in the table . These factors were consistent when treatment was added to the model. Prior exposure to taxane was not predictive of survival; tumor stage was a significant univariate predictor (p=0.0349), but had relatively less impact in the multivariate model. Conclusion: These analyses identified several factors associated with reduced survival benefit from standard second line therapy. Consequently, alternative treatment strategies may be necessary in patients with poor prognosis. For example, more tolerable agents may enhance the benefit/toxicity ratio in these patients.

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Differences in primary care clinicians’ approach to non-small cell lung cancer (NSCLC) patients compared to breast cancer (BrCa)
Authors: Wassenaar T. R. , Eickhoff J. C. , Jarzemsky D. R. , Smith S. S. , Larson M. L. , Schiller J. H.
Published: March 2020

7041

Background: Lung cancer is a disease associated with a stigma of being primarily self-induced via smoking and therefore avoidable. It is unclear if this stigma results in feelings of guilt and shame on the part of the patient, and a difference in care on the part of primary care physicians (MDs), both of which could lead to differences in treatment and patient self-advocacy, and ultimately poorer outcomes. Methods: We conducted a prospective survey study of 1,132 MDs who were randomized into 4 groups. Each group received a questionnaire representing a clinical scenario (smoker/NSCLC; nonsmoker/NSCLC; smoker/BrCa; nonsmoker/BrCa). The scenarios were identical in terms of stage, gender and outcome; but varied in the disease and smoking history (smoker (S) vs. nonsmoker (NS)). The primary objective was to collect preliminary data to determine if these MDs approached the care and referral of patients (pts) with NSCLC or BrCa differently. A secondary objective was to determine whether or not tobacco use influenced the MD’s approach to the cancer pts. Comparisons of response patterns between the groups were evaluated by Chi-square analysis. Results: 672 questionnaires were completed: 175 in the NS/BrCa, 177 in the S/BrCa, 166 in the NS/NSCLC and 154 in the S/NSCLC scenarios. We observed that MDs were less likely to refer pts with advanced NSCLC to an oncologist than BrCa pts (p=<0.001). More MDs knew that chemotherapy improved survival in pts with advanced BrCa than did MDs regarding chemotherapy use in advanced NSCLC (p=0.0145). In addition, more MDs stated they did not know the benefit of adjuvant therapy for NSCLC than for BrCa (p= <0.001). As a result, more pts with advanced BrCa were referred for further therapy vs. NSCLC pts, who were more likely to be referred only for symptom control (p=0.0092). BrCa pts also had more aggressive follow up than did pts with NSCLC (p=0.0256). There was no statistical significant difference when comparing smoking vs. non-smoking pts. Conclusions: We conclude that there is a significant lack of knowledge in the primary care physician regarding the treatment of pts with advanced stage NSCLC, and the role and benefit of adjuvant therapy. This might lead to a less aggressive referral pattern in these pts to clinical oncologists.

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Induction (Ind) plus concurrent (Con) chemotherapy with high-dose (74 Gy) 3-dimensional (3-D) thoracic radiotherapy (TRT) in stage III non-small cell lung cancer (NSCLC): Preliminary report of Cancer and Leukemia Group B (CALGB) 30105
Authors: Blackstock A. W. , Socinski M. A. , Bogart J. , Gu L. , Wang X. , Green M. , Vokes E. E.
Published: March 2020

7042

Background: Combined chemoradiotherapy is the standard of care in stage III NSCLC. At standard TRT doses, local failures remain problematic and strategies exploiting the dose-response aspect of TRT are warranted. 3-D TRT allows escalation of TRT dose with acceptable toxicity (Socinski et al, J Clin Oncol 22:4341, 2004) and may enhance survival by improving loco-regional control. Methods: This is a two-arm randomized phase II trial evaluating 74 Gy with Con chemotherapy: Arm A- 2 cycles of Ind carboplatin (C) (AUC 6) and paclitaxel (P) (225 mg/m2) followed by weekly Con C (AUC 2/wk) and P (45 mg/m2) and 74 Gy; Arm B- 2 cycles of Ind C (AUC 5) and gemcitabine (G) (1000 mg/m2 d1,8) followed by Con G (35 mg/m2 twice weekly) and 74 Gy. The primary endpoint was a survival rate of ≥50% at 18 months after treatment initiation or med survival time (MST) of ≥18 mos. Results: 69 pts were entered (43 Arm A, 26 Arm B)- med age 61 yrs (39–77), 77% male, PS 0:1 42%:58%, stage IIIA:B 52%:48%. Ind therapy on both arms was well tolerated with no pts experiencing disease progression. ARM A- Overall response rate (RR) to all therapy was 61.9%. Gr 3–4 toxicities during Con therapy were anemia (15%), neutropenia (26%), esophagitis (9%), fatigue (9%), neuropathy (3%) and pulmonary (12%). There was 1 (3%) Gr 5 cardiac event. With med follow-up of 16.4 mos, the med progression-free survival (PFS) is 15.2 mos. The MST is not mature enough to estimate as only 15 deaths have occurred. ARM B- Closed early due to 3 (13%) Gr 5 pulmonary events. Overall RR to all therapy was 66.6%. Gr 3–4 toxicities during Con therapy were anemia (13%), fatigue (35%), esophagitis (35%), hemoptysis (4%), pulmonary (26% plus the 3 Gr 5 events). With med follow-up of 22 mos, the med PFS is 7.7 mos and the MST is 13.9 mos. There was a correlation between Gr 3–5 pulmonary toxicity and V20 ≥ 38% (p<0.05). Conclusions: 1) High dose 3-D TRT is feasible within CALGB, 2) the details of TRT (V20) are important with regard to toxicity, 3) the survival of pts on Arm A appears promising.

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Does downstaging in patients (pts) with IIIA-N2 non-small cell lung cancer (NSCLC) and a response to induction chemotherapy (ICT) influence outcome with surgery (S) or radiotherapy (RT)? An exploratory analysis of EORTC 08941
Authors: Van Meerbeeck J. P. , Kramer G. W. , Legrand C. , Smit E. F. , Passioukov A. , Giaccone G. , Van Zandwijk N. , Van Schil P. E.
Published: March 2020

7047

Background: In EORTC 08941, no difference in overall and progression free survival was observed in 332 pts with irresectable stage IIIA-N2 NSCLC, treated with either S or RT after a response to platinum-based ICT (van Meerbeeck, JCO 2005; 23, 1095s). Postoperative radiotherapy (PORT) was given to 40% of pts. In the S-pts, non-randomized exploratory comparisons showed a statistically significant benefit in outcome for (bi-)lobectomy vs. pneumonectomy (p = 0.0088) and for mediastinal lymphnodes (MLN) downstaged vs.non-downstaged pts (p = 0.0009). No difference was observed between S-pts treated with/without PORT. By randomizing after response to ICT, MLN-downstaging is assumed to be equally distributed among both treatment groups but cannot be formally retrieved in RT-pts. In order to compare the influence of MLN-downstaging in each treatment arm, we estimated in an exploratory analysis the outcome in subsets of S-pts and matched paired subsets of RT-pts. Methods: The subsets of 129 actually resected S-pts are defined as follows: (i) pts with MLN-downstaging at resection, (ii) pts without MLN-downstaging. Each subset was compared to a randomly selected subset of 154 actually irradiated RT-pts, matched on 4 baseline factors: histological subtype, gender, T stage, response to ICT. Kaplan-Meier estimates for overall survival (OS) and logrank p-values were then computed. Results: A match was feasible for 54/61 downstaged, 59/68 non-downstaged pts. Estimated OS (with 95% CI) for each S-subset and RT-matched pair subset is in the table . Conclusions: From these exploratory analyses, it appears that: 1. RT improves OS in MLN-non-downstaged pts; 2. S does not improve OS in MLN-downstaged patients. This should however be prospectively assessed.

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No significant financial relationships to disclose.
Pemetrexed in patients (pts) with relapsed small cell lung cancer (SCLC): A phase II study from the Hoosier Oncology Group
Authors: Hanna N. H. , Ansari R. , Bhatia S. , Govindan R. , Bruetman D. , Hosford M. , Fisher W. , White A. , Breen T. , Juliar B.
Published: March 2020

7063

Background: Patients with relapsed SCLC have a dismal prognosis. Pemetrexed is a well tolerated agent, which is active against non-small cell lung cancer. We postulated that Pemetrexed may also be active and well tolerated in pts with relapsed SCLC, for whom few effective options exist. Methods: Eligible pts had small cell or a poorly differentiated neuroendocrine cancer, received 1 or 2 prior chemotherapy regimens and had an ECOG PS 0–2. Pts received Pemetrexed 500 mg/m2 iv once every 3 weeks along with vitamin B12, folic acid, and dexamethasone for up to 6 cycles or progressive disease or intolerable side effects. Chemosensitive (S) pts (relapse > 90 days following 1st line chemo) and chemoresistant (R) pts (PD ≤ 90 days following 1st line chemo) were analyzed separately. The primary objective of this phase II study was to estimate the clinical benefit rate [partial response (PR) or stable disease (SD)] in the 2 populations. Pts were to be accrued in 2 stages. If 8 of 18 and 3 of 21 pts achieved a PR or SD in the S and R populations, respectively, accrual would have continued to a total of 46 (S arm) and 50 (R arm) pts in each arm. Results: From 1/05 to 9/05, 43 pts were enrolled. Criteria to proceed to stage II were not met for either arm. S arm (n = 20): M/F 12/8; median age 63 (range, 45–79), PS 0/1/2 7/8/5. R arm (n = 23): M/F 17/6; median age 65 (range, 42–79), PS 0/1/2 7/10/6. Select grade 3/4 toxicities (combined group): 4 pts with neutropenia; 2 pts each with anemia, AST/ALT, bilirubin elevation; 1 pt each with thrombocytopenia, febrile neutropenia, infection with neutropenia, and rash. S arm: 1 PR and 1 SD were confirmed. R arm: 1 PR and 1 SD were confirmed. Conclusions: Pemetrexed 500 mg/m2 has minimal single agent activity in pts with relapsed SCLC.

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A phase II trial of pemetrexed in patients with recurrent thymoma or thymic carcinoma
Authors: Loehrer P. J. , Yiannoutsos C. T. , Dropcho S. , Burns M. , Helft P. , Chiorean E. G. , Nelson R. P.
Published: March 2020

7079

Background: Few prospective trials have been conducted in patients with advance thymic malignancies. Pemetrexed a multi-targeted antifolate with a broad range of clinical activity, but previously untested in thymic malignancies. As a result, a phase II trial was initiated to evaluate the clinical activity of pemetrexed in previously treated patients with thymoma (THY) and thymic carcinoma (TC). Methods: From February, 2005 to November, 2005, twenty-seven previously treated patients with unresectable stage IVA (n = 16) or stage IVB (n =11) disease were treated with pemetrexed at a dosage of 500 mg/m2 every three weeks for a maximum of 6 cycles or until undue toxicity or progressive disease. All patients received folic acid, vitamin B12 and steroid prophylaxis. Profile of patients include: median age = 52 years (range 26–84); M: F = 13:14; PS 0/1= 17/10; median number of prior therapies = 2 (range 1–6); 21 had prior radiation therapy; and histology (THY = 16, TC = 11). Results: The median number of cycles administered was 5 (range 1–6). Eleven patients had grade 3 toxicities including: dyspnea, infections, fatigue, abnormal chemistries and neutropenia. No Grade 4 toxicities were noted. Accrual was completed in November, 2005 with four patients still on therapy. In 23 fully evaluable patients, two complete and two partial responses (RECIST) were noted. All four responding patients had had stage IVA thymoma. Five patients progressed on therapy and two patients discontinued therapy for intolerance to chemotherapy (constipation, dyspnea) and 1 patient for progressive Morvan’s Syndrome. The median time to progression for all patients was 45 weeks (THY = 45.4 weeks vs. TC = 5.1 weeks). With three deaths thus far, the median overall survival has not been reached. Conclusions: Pemetrexed is an active agent in a heavily pretreated population of patients with recurrent thymoma. Patients with recurrent thymic carcinoma appear to have a much more aggressive clinical course than thymoma.

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