bluuebunny/crossref_metadata_2025 huggingface dataset:
Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): Results of the CA180006 ‘START-B’ study
Authors: Cortes J. E. , Kim D. W. , Rosti G. , Rousselot P. , Bleickardt E. , Zink R. , Sawyers C.
Published: March 2020

6529

Background: Dasatinib (D) (BMS-354825) is an oral, multitargeted tyrosine kinase inhibitor of Bcr-Abl and SRC with activity against IM-R cell lines. In a phase I study, there was preliminary evidence that D was active in MBC-CML patients (pts). Methods: START B is an open-label study of D in IM-R or IM-I MBC carried out in 46 sites worldwide. From December 2004 to May 2005, 124 MBC pts were accrued. D was given orally at 70 mg twice a day (BID) with dose escalation to 100 mg BID for poor initial response or dose reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow evaluations, including cytogenetics. The primary endpoint was confirmed (minimum 4 weeks duration) major hematologic response (MaHR). Results: Data are currently available on the first 74 pts (68 IM-R, 6 IM-I). Median age was 55 years, 55% were male. Other prior therapy included interferon in 55% of pts and bone marrow transplant (BMT) in 12%. Prior IM dose was >600 mg/day in 49% of pts and 47% of pts received IM for > 3 years. At baseline, the WBC count was ≥20 × 103/mm3 in 46%, the platelet count was < 100 × 103/mm3 in 72% of pts and 35% of pts had ≥ 50% bone marrow blasts. Mutations in the BCR-ABL domain were found in 27/63 (43%) pts. Median duration of therapy was 3.5 months. D doses were reduced in 35% pts, temporarily interrupted in 58% pts, and escalated in 41% pts. With a minimum of 6-month follow-up, hematologic response was seen in 39 (53%) pts: confirmed MaHR in 24 (32%) pts, Complete in 18 (24%) and No Evidence of Leukemia in 6 (8%). Major cytogenetic responses were documented in 22 (30%) pts and was complete in 20 (27%). The median time to MaHR was 56 days. There was no loss of response in pts with MaHR; the duration of MaHR ranged from 1.2+ to 7.8+ months. The median PFS had not been reached. Severe myelosuppression was very common. Non-hematologic toxicities were usually mild to moderate. Most common Grade 3–4 toxicities included diarrhea in (7%), pleural effusion (9%), nausea (4%). Peripheral edema was reported in 14% of pts (0% Grade 3–4), and rash in 11% of the pts (0% Grade 3–4). Conclusions: Dasatinib was highly effective in IM-R pts with MBC with durable MaHR. Data on all 124 pts will be presented at the meeting.

[Table: see text]
A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib resistant and intolerant patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP)
Authors: Kantarjian H. M. , Gattermann N. , O’Brien S. G. , Bhalla K. , Hochhaus A. , Cervantes F. , Alland L. , Ottmann O. , Giles F. , Le Coutre P.
Published: March 2020

6534

Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: This open-label study was designed to evaluate the safety and efficacy of AMN107 (400 mg bid) defined by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant or intolerant CP pts. Results: For this study which remains open to enrollment, preliminary data are reported for 67 pts including 39 (58%) with imatinib-resistant and 27 (40%) imatinib-intolerant CML (1 pt unknown). The median age was 62 (range 31–80) yrs and the median time from first diagnosis to treatment was 52 (range 5–279) mos. BCR-ABL mutations associated with imatinib resistance were detected in 11/17 (65%) pts at baseline. The median duration of AMN107 exposure was 129 (range 3–225) days. Treatment is ongoing for 50 (75%) pts with 17 (25%) pts discontinued (9 adverse events, 2 disease progression, 6 other). Major CyR was observed in 13 (19%) pts (6 complete, 7 partial), minor CyR was observed in 4 (17%) pts, and minimal CyR in 5 (7%) pts. Complete HR was reported in 35 of 42 (83%) pts without a baseline CHR. AE’s in ≥ 10% of pts were headache in 24 (36%) pts, fatigue in 21 (31%) pts (Gr 3/4 in 2 (3%)), pruritus in 19 (28.4%) pts (Gr 3/4 in 1 (2%)), rash in 18 (27%) pts (Gr 3/4 in 2 (3%)), nausea in 18 (27%) pts, diarrhea in 18 (27%) pts (Gr 3/4 in 1 (2%)), constipation in 11 (16%) pts, vomiting in 10 (15%) pts, thrombocytopenia in 10 (15%) pts (Gr 3/4 in 9 (13%)), anemia in 10 (14.9%) pts (Gr 3/4, 1 (2%)), neutropenia in 9 (13%) pts (Gr 3/4 in 8 (12%)), bone pain, muscle spasms, arthralgia, peripheral edema in 8 (12%) pts each, abdominal pain and myalgia in 7 (10%) pts each (Gr 3/4 in 1 (2%) each), and dyspnea in 7 (10%) pts. No deaths occurred. Conclusions: AMN107 has clinical activity and an acceptable safety and tolerability in pts with imatinib-resistant or intolerant CML-CP.

[Table: see text]
High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up
Authors: Aoki E. , Kantarjian H. , O’Brien S. , Talpaz M. , Giles F. , Garcia-Manero G. , Wierda W. , Verstovsek S. , Jones D. , Luthra R. , Cortes J.
Published: March 2020

6535

Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated.

[Table: see text]
Ibritumomab tiuxetan combined with high-dose chemotherapy and autologous stem-cell transplantation (SCT) in patients with chemo-refractory aggressive non-Hodgkin’s lymphoma
Authors: Shimoni A. , Zwass T. , Oksman Y. , Hardan I. , Shem-Tov N. , Yerushalmi R. , Nagler A.
Published: March 2020

6538

Background: High-dose chemotherapy and autologous SCT have an established role in the treatment of patients with first chemo-sensitive relapse of aggressive lymphoma. However, autologous SCT has only limited success when performed in refractory or progressive stage of the disease and the expected 1-year progression-free survival (PFS) in this setting is < 20%. Methods: This study was designed to explore the safety and outcome following inclusion of ibritumomab tiuxetan (IT) in the conditioning regimen given prior to autologous SCT. Patients were eligible for this study only if they had refractory lymphoma and a positive PET-CT prior to SCT. The primary end-point was 1-year PFS. Rituximab 250 mg/m2 followed by IT 0.4 mCi/kg were given on day -14. Chemotherapy according to standard BEAM was started on day -6. Results: The study included 20 pts, median age 55 years (range, 35–66). Histology was diffuse large cell (n=14), transformed follicular (n=5) and mantle cell lymphoma (n=1). Patients had active lymphoma at SCT, either primary refractory (n=11) or refractory relapse (n=9) and 12 had bulky disease at SCT. The median number of prior therapies was 3 (range, 1–6). There were no early infusion reactions associated with IT. Fourteen patients achieved CR, 4 achieved PR and 2 died early after SCT. With a median follow-up of 9 months (range, 1–20), 14 patients are alive and 6 have died with an estimated 1-year survival of 58% (95% C.I., 31–85). All surviving patients are progression-free. Only 2 patients relapsed with a 1-year cumulative incidence of only 14% (5–51). Two patients died of multi-organ toxicities and 2 of late occurring infections. These rates of non-relapse mortality are expected in heavily pretreated patients with refractory lymphoma and there was no additional toxicity related to IT. Conclusions: The inclusion of IT in the conditioning regimens given prior to autologous SCT may reduce the risk of relapse following autologous SCT and improve the poor outcome of patients with refractory lymphoma given SCT with standard conditioning regimens. This observation merits further study in larger comparative trials.

No significant financial relationships to disclose.
Outcome of salvage therapy for relapsed or refractory peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), and diffuse large B-cell lymphoma (DLBCL)
Authors: Wu G. , Kuruvilla J. , Nagy T. , Keating A. , Crump M.
Published: March 2020

6544

Background: Compared to patients with ALCL and DLBCL, PTCL patients have a lower response and higher relapse rate following anthracycline-based chemotherapy. However, in the case of relapsed or primary refractory disease, it is unclear if response to salvage treatment and survival are similarly inferior. Methods: Between 01/01/1995 and 12/30/2004, 45 patients with PTCL, 21 with ALCL, and 171 with DLBCL were referred to our institution for consideration of ASCT. The majority of patients (70%) received a platinum-based salvage regimen. Responding patients then received high-dose etoposide and melphalan followed by autologous stem cell transplant (ASCT). Results: The three groups were similar in age (median 53, range: 19–66), but PTCL patients had more advanced stage disease (III or IV) at salvage than ALCL and DLBCL (71 vs. 61 vs. 48%, p=0.03). Response rates to salvage chemotherapy were similar: 53% for PTCL, 57% for ALCL, and 53% for DLBCL (p=0.94). For T-cell (PTCL and ALCL) patients, there was a trend to better response if a platinum-based regimen was given (61 vs. 35%, p=0.06). Post-transplant, 9/21 PTCL, 3/11 ALCL, and 41/88 DLBCL patients relapsed (43 vs. 27 vs. 46%, p=0.47). Two-year event-free survival (EFS) rates were 28% (95% CI: 14–42%) for PTCL, 45% (23–67%) for ALCL, and 45% (37–53%) for DLBCL (p=0.068). Event-free and overall survival for all patients, and for those who proceeded to ASCT, are shown in the table . Conclusions: Two-year EFS is inferior for patients with relapsed/refractory PTCL treated with the intention of proceeding to ASCT, compared to ALCL and DLBCL, as is 2-year OS rate. However, PTCL patients had similar response to primarily platinum-based salvage chemotherapy, and achieved similar outcome post-ASCT. These findings suggest that strategies to improve the outcome of PTCL patients may include changes to first-line treatment and salvage regimens.

[Table: see text]

No significant financial relationships to disclose.
Correlation of CD3 and CD34 cell dose with incidence of acute GVHD in myeloablative stem cell transplantation
Authors: Saad A. , Visweshwar N. , Sehbai A. , Cumpston A. , Watkins K. , Buckhalter R. , Hobbs G. , Abraham J. , Ericson S.
Published: March 2020

6553

Background: Allogeneic stem cell transplantation is used to treat different types of hematologic malignancies. The target stem cell dose typically is based on the recipient’s ideal body weight (IBW) with CD34 dose of 2.0–5.0 ×106/Kg. The dose of CD3 in the infusate is typically not taken into account in a stem cell product, except in T-depleted transplantation. The dose of T-cells in peripheral blood stem cell collections has been found to be at least 10-fold more than that in a bone marrow harvest product. Combined CD4+ and CD25+ cells infused have been directly correlated with increased incidence of GVHD. Methods: This is a retrospective study reporting the correlation of the CD34 and CD3 doses of stem cell transplant with incidence of acute GVHD in 67 consecutive patients who were treated between 2003 and 2005. All patients were followed up for at least 100 days following the stem cell transplant. Results: Among the 67 patients, 35 patients developed acute GVHD, while 32 patients had no evidence of acute GVHD. The CD3 and CD34 doses did not correlate. The correlation coefficient was 0.14 (P value: 0.27). Using t-test, there was NO statistical difference between the mean CD34 dose when comparing the group of patients who developed acute GVHD with the group that did not develop acute GVHD (P value: 0.31). Those who developed acute GVHD (n = 35) received a mean CD3 dose of 41.9 × 107/kg IBW (95% CI: 35.9–47.9). Those who did NOT develop acute GVHD (n= 32) received a mean CD3 dose of 33.5 × 107/kg IBW (95% CI: 27.3–39.8). By using the t-test, the P value for the different means was 0.0575. However, using a CD3 dose cutoff value of 30 × 107/kg IBW, the incidence of acute GVHD was statistically significantly less among those who received CD3 dose < 30 × 107/kg IBW. The Chi Square P value was 0.04. Conclusions: In our series, CD3 dose less than 30 × 107/kg IBW was associated with reduced risk of acute GVHD (P value: 0.04). There was no correlation between CD3 and CD34 counts in peripheral stem cell product. In addition, the CD34 dose did not influence the incidence of acute GVHD. These data suggest that, in addition to considering CD34 dose required for engraftment in allogeneic transplant, the CD3 dose will need to be considered to try to minimize the risk of acute GVHD.

No significant financial relationships to disclose.
A multicenter randomized study comparing vinorelbine plus gemcitabine versus capecitabine monotherapy as salvage treatment in patients with advanced breast cancer pretreated with taxane and anthracycline chemotherapy: A preliminary report
Authors: Mavroudis D. , Ardavanis A. , Boukovinas I. , Varthalitis I. , Syrigos K. , Potamianou A. , Kouroussis C. , Georgoulias V.
Published: March 2020

658

Background: Both Vinorelbine plus Gemcitabine (VG) regimen and Capecitabine (C) monotherapy are active salvage treatments in patients (pts) with advanced breast cancer (ABC). In this multicenter study we compared the efficacy and tolerability of the two regimens as salvage treatment in pts with ABC pretreated with taxane and anthracycline chemotherapy. Methods: Pts were randomized to receive either vinorelbine 25 mg/m2 plus gemcitabine 1000 mg/m2 (VG) both on day 1 in cycles every 2 weeks or capecitabine 1250 mg/m2 (C) twice a day on days 1–14 in cycles every 3 weeks. The primary end point of the study was to compare the time to disease progression (TTP). Results: A total of 114 pts were randomized to VG (n=60) and C (n=54). All pts were evaluable for toxicity and 58 VG and 54 C pts for response. Seven (VG) vs 9 (C) pts had stage IIIB disease and 6 vs 5 pts had PS 2. We observed one complete response on each arm and 14(24%) vs 12(22%) partial responses for an overall response rate of 25.8% vs 24.1% (p=0.8) in VG vs C pts, respectively. The median duration of response was 5 vs 12 months (p=0.02) and the median TTP 3.7 vs 5.8 months (p=0.4) for VG and C pts, respectively. A total of 339 VG and 270 C cycles were administered with no toxic deaths. Both regimens were overall well tolerated; grade 3–4 neutropenia 17% vs 4% (p=0.02), anemia 4% vs 2% (p=0.6), grade 3 thrombocytopenia 2% vs 2%, neurotoxicity 3% vs 2%, grade 2–4 hand-foot syndrome 2% vs 15% (p=0.009) for VG and C pts, respectively. Conclusions: In this preliminary analysis the VG and C regimens showed similar activity but different although rarely severe toxicity. Updated results will be presented at the meeting.

No significant financial relationships to disclose.
Early results of modified fludarabine, cyclophosphamide, and rituximab (mFCR) for patients with previously untreated advanced chronic lymphocytic leukemia (CLL)
Authors: Tarhini A. A. , Land S. , Lim F. , Kiefer G. J. , Pietragallo L. , Pinkerton R. A. , Sulecki M. , Meisner D. , Schaefer P. M. , Foon K. A.
Published: March 2020

6599

Background: Recent data reporting results of FCR therapy in previously untreated advanced CLL patients (F-25 mg/m2 d1–3 q 4wk; C-250 mg/m2 d 1–3 q 4wk; R-500 mg/m2 d1 q 4wk for 6 cycles) demonstrated complete remission (CR) of 70% and overall response (OR) of 95% (J Clin Oncol 2005;23:4079). The major toxicity was grade 3/4 neutropenia during 52% of courses. One approach to decrease neutropenia without compromising efficacy could be by reducing the doses of F and C and increasing the dose of R as high-dose R has been reported to be more efficacious in CLL. Methods: We conducted a phase II study for previously untreated advanced CLL patients treated with mFCR (F-20mg/m2 d1–3 q 4 wk; C-150 mg/m2 d1–3 q 4 wk; R-500mg/m2 d1 and d14 q 4wks; maintenance R-500 mg/m2 q 3 months until progression). A Simon two-stage design was used where 15 patients were accrued in the first stage and because of acceptable toxicity and response rate in stage I an additional 35 patients will be treated. The primary endpoint was response rate. Results: Twenty patients (13 male, 7 female), age 36–85 years (median 59) were treated with a total of 105 mFCR courses. All 20 patients were evaluable for toxicity. Grade 3/4 neutropenia occurred during 11(10.5%) courses. There were no episodes of neutropenic fever. Grade 3/4 thrombocytopenia occurred during 4 (3.8%) courses. Two patients are currently on study and not evaluable for response and among the 18 evaluable patients, the CR was 68%, PR was 32% with an OR of 100%. Eleven of the 12 CR patients had no evidence of CD5+/CD19+ coexpressing cells in their bone marrow after therapy and one had <1%; all 12 were NED by CT scan. Conclusions: Our preliminary results suggest mFCR is highly effective with considerably less grade 3/4 neutropenia than standard FCR. Complete responders had minimal residual disease in their bone marrow following mFCR.

[Table: see text]
Pooled safety analysis of oblimersen alone or with fludarabine and cyclophosphamide in patients with advanced chronic lymphocytic leukemia
Authors: Koziner B. , O’Brien S. , Boyd T. , Larratt L. , Moore J. , Chanan-Khan A.
Published: March 2020

6611

Background: Bcl-2 is an antiapoptotic protein linked to chemotherapy resistance and poor prognosis in chronic lymphocytic leukemia (CLL) patients (pts). Oblimersen (Obl), an anti-Bcl-2 oligonucleotide, has been shown to enhance apoptosis induced by fludarabine (Flu) + cyclophosphamide (Cy) in pts with relapsed CLL. We combined safety results from 2 CLL clinical trials to determine the relative effect of Obl on treatment-emergent adverse events (TEAEs) in Obl+Flu+Cy therapy. Methods: This analysis included 30 pts who received Obl 3mg/kg/d alone by continuous IV on days 5–7 and 230 pts who received Flu 25mg/m2/d + Cy 250mg/m2/d on days 5–7, every 28th day, either with (n=115) or without (n=115) Obl 3mg/kg/d on days 1–7. Mean number of cycles initiated were 3.3, 3.6, and 4.0 for Obl, Obl+Flu+Cy, and Flu+Cy, respectively. Results: The most frequent (>2% patients) grade 4 TEAEs were mainly hematologic: neutropenia (Obl alone, 0.0%; Flu+Cy, 11.3%; Obl+Flu+Cy 7.0%), thrombocytopenia (3.3%, 1.7%, 4.3%), anemia (0.0%, 5.2%, 3.5%), febrile neutropenia (0.0%, 0.9%, 2.6%), hypotension (0.0%, 0.0%, 2.6%), and leukopenia (0.0%, 2.6%, 0.0%). Thrombocytopenic events with Obl-Flu-Cy were reversible and were not associated with clinically significant bleeding events. The most frequent non-hematologic grade 3–4 TEAEs (>5%) were nausea (0.0%, 1.7%, 7.8%), vomiting (0.0%, 0.9%, 6.1%), fatigue (3.3%, 4.3%, 6.1%), and dyspnea (3.3%, 1.7%, 5.2%). Serious TEAEs occurred at a rate of 23.3%, 32.2%, and 57.4%, respectively. TEAEs resulting in death occurred in 2 pts (Obl alone), 5 pts (Flu+Cy), and 9 pts (Obl+Flu+Cy). One Obl+Flu+Cy death was due to cytokine release reaction and one to tumor lysis syndrome. Discontinuation due to TEAEs occurred in 20.0% of pts who received Obl alone, in 34.8% of Flu+Cy pts, and in 34.8% of Obl+Flu+Cy pts. Conclusions: The addition of Obl to Flu+Cy was well tolerated, with similar low frequencies of grade 3+4 TEAEs, primarily the same type observed with Flu+Cy alone. Despite an increased incidence of serious TEAEs observed with Obl+Flu+Cy, the percentage of patients who discontinued protocol therapy due to a TEAE was the same in each group. First cycle reactions mandate close observation when initiating combination therapy.

[Table: see text]
Retrospective analysis of WSG AM01 tandem high dose chemotherapy trial in high risk primary breast cancer: A hypothesis generating study
Authors: Nitz U. A. , Gluz O. , Herr A. , Ting E. , Mohrmann S. , Frick M. , Jackisch C. , Poremba C. , Lindemann W. , Diallo-Danebrock R.
Published: March 2020

665

Background: The WSG AM 01 trial is the first one to report superiority of HDC in terms of DFS and OS in patients with >9 positive axillary lymph nodes. Retrospectively we tried to identify patient subgroups with maximum benefit from HDC. Methods: 403 patients were randomized to tandem HDC or to dose-dense conventional chemotherapy (DD). 236 tumors were available for central pathologic review (117/119). A panel of 34 markers were determined by IHC in TMA. Kaplan-Meier, Log rank and Cox proportional hazard models were used for uni- and multivariate analysis. We choose K-means clustering with K=5 and using Manhattan distance as similarity measure. Results: Pts: n=236 (HDC/DD): mean age 47.3/47.4 yrs, mean tumor sizes 3.5/3.4cm, mean positive lymph nodes 17.2/17.0, HR+ 55%/53%, G3 44%/35%. HDC was superior to DD (p=0.02). Multivariate analysis demonstrated a significant correlation for grading, tumor size, PR+. HR > 2 were reported for the following markers: Her2neu+, p53+, bcl2−, Ck 5/6 and 17+, Ck8−, c-kit+, vimentin+, ETR 1/2, BCRP+. Triple negative tumors (TN) (31%) had a large benefit from HDC (HR DD vs. HD: 3.06, 95%CI:1.41–6.06). Groups identified by K-means clustering could be attributed to luminal-A-(31%), luminal-B-(27%), her2-(11%), basal like-(11%) type and a so far undefined proliferative group (20%) characterized mainly by the absence of specifying markers. Interestingly, the proportion of the above mentioned molecular subtypes within of high risk populations very similar to those reported for less selected populations. Her2, basal-like and the undefined proliferative group had significantly worse outcome when compared to luminal tumors (p<0.01). Very poor prognosis if treated by conventional CT was observed in basal like (HR DD vs HD=2.66 95%CI: 0.9–7.9) und the undefined group (HR=1,72, 95%CI:0.92–3.21), where most of the TN tumors were found. Conclusions: Tandem HDC is superior to DD conventional CT for treatment of HRBC. The largest benefit from high dose chemotherapy was reported for younger patients with TN poor differentiated tumors, >2cm. Negative hormone receptor status, p53+, bcl2−, MIB/p16+ and BCRP+ predicted benefit from dose intensification. Subgroups are small and may help to generate further hypothesises.

No significant financial relationships to disclose.
Impact of chemotherapy dose-related factors on survival in breast cancer patients treated with adjuvant anthracycline-based chemotherapy
Authors: Chirivella I. , Bermejo B. , Insa A. , Perez-Fidalgo A. , Magro A. , Rosello S. , Garcia-Garre E. , Martin P. , Bosch A. , Lluch A.
Published: March 2020

668

Background: The relationship between chemotherapy (CT) dose intensity and patient (pt) outcome in the management of early stage breast cancer (EBC) is still controversial. Although randomised clinical trials have provided evidence that supports the delivery of full standard doses of CT on schedule, precise thresholds for CT dose-related factors and their impact on survival-related endpoints have not yet been fully defined. The objective of this project is to assess the impact of CT dose-related factors on event-free and overall survival in a large group of EBC pts treated with anthracycline-based chemotherapy. Methods: A total of 1056 EBC (stage I-II-IIIA) cases diagnosed and treated from January 1980 to December 2000 were retrospectively studied. All of them received adjuvant anthracycline non-taxanes-based CT. Consecutive charts from 793 pts that were fully completed were included in the analysis. Survival-related endpoints were analysed through Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards models. Results: With a median follow-up of 10.0 years, pts exposed to either > 2 cycle-delay (delay at any cycle defined as ≥ 3 days vs. plan), or ≥ 15 day-delay across the whole CT regimen, or < 95% relative dose intensity (RDI) showed significantly worse 10-year Event-Free Survival (EFS) and Overall Survival (OS) as compared to pts with no dose delay/reduction (data shown below). Controlling for age at diagnosis, disease stage, histological grade, menopausal status and year of treatment did not modify these results. Conclusions: Based on this preliminary analysis, CT dose delays and reductions in EBC pts treated with adjuvant anthracycline-based regimens have a significantly negative impact on EFS and OS.

[Table: see text]

No significant financial relationships to disclose.
Urinary n-telopeptide (NTX) predicts palliative pain response in metastatic breast cancer patients receiving second-line zoledronic acid
Authors: Dranitsaris G. , Clemons M. , Ooi W. , Cole D.
Published: March 2020

679

Background: A substantial number of breast cancer patients will have bony progression or develop skeletal related events (SRE) despite treatment with a bisphosphonate (BP) such as clodronate or pamidronate. What could be of use to the practicing oncologist is a marker for predicting which patients will derive palliative benefit with the second-line use of a more potent BP such as zoledronic acid. In this study, we assessed the clinical utility of using early changes in urinary NTX as a predictor of palliative response to second-line zoledronic acid. Methods: 30 patients with either a documented SRE or bony progression while on either clodronate or pamidronate were switched to infusions of zoledronic acid (4 mg) every 4 weeks for 12 weeks. Urinary NTX and worst pain score using the Brief Pain Inventory were evaluated weekly for the first 4 weeks & again at week 8. No change in systemic anti-cancer treatment was allowed in the month before or after commencing study treatment. A palliative response was defined as a reduction of at least two units in the worst pain score. Logistic regression analysis was used to determine if a decrease in urinary NTX at week 1 relative to baseline was a significant predictor of palliative response to zoledronic acid when measured at week 8. Results: At week 1, 23 of 30 (76.7%) had a drop in their urinary NTX excretion relative to baseline. At week 8, these 23 patients experienced a 2.4 unit decline in their worst pain score, compared to only a 0.28 unit reduction in the 7 patients whose week 1 urinary NTX increased relative to baseline (P=0.11). A week 1 drop in urinary NTX was identified as an important predictor for palliative response to zoledronic acid when measured at week 8 (OR=9.4; 95%CI: 2.28 to 79.8, P=0.014). Conclusions: Our findings imply that a decline in urinary NTX at week 1 is a useful marker for identifying which patients will derive palliative benefits from second-line zoledronic acid. Additional data on a larger sample of patients is needed to validate the clinical utility of using early changes in urinary NTX as a rapid predictor of patient benefit.

[Table: see text]
An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer
Authors: Tsao M. , Zhu C. , Sakurada A. , Zhang T. , Whitehead M. , Kamel-Reid S. , Ding K. , Seymour L. , Shepherd F.
Published: March 2020

7005

Background: BR.21 demonstrated a significant survival benefit for patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib vs. placebo (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58–0.85, p<0.001). Tyrosine kinase (TK) domain mutations and high EGFR gene copy number by fluorescent in situ hybridization (FISH) have been associated with significantly higher response rates to erlotinib, while high gene copy number is a better predictor of survival benefit than mutations. K-ras mutation has been associated with non-responsiveness to EGFR TK inhibitors and poorer outcome for patients treated with erlotinib and chemotherapy. The survival impact of K-ras mutation on single agent erlotinib therapy in NSCLC patients remains unknown. Methods: 731 patients were randomized to BR.21 (488 erlotinib, 243 placebo). K-ras mutation analysis was conducted by sequencing in 246 patient samples. Results: K-ras analysis was successful in 206 patients; 30 (14.6%) demonstrated oncogenic mis-sense mutations on codon 12 or 13 (22 on the erlotinib arm and 8 on the placebo arm). For all 206 patients with known K-ras genotype, the HR for erlotinib was 0.77 (95% CI 0.57–1.06, p=0.06). For the 176 K-ras wild type patients, the univariate HR for erlotinib was 0.69 (95% CI 0.49–0.97, p=0.03). In contrast, the HR for the thirty K-ras mutant patients was 1.67 (95% CI 0.62–4.5, p=0.31), with an interaction p value of 0.09. Overall response rates were 5% (1/20) in K-ras mutant patients, and 10.2% (10/98) in K-ras wild type patients. In patients with K-ras genotype known, the multivariate Cox regression model showed that K-ras mutation was significantly associated with shorter survival (HR 1.63, 95% CI 1.06–2.51, p=0.03). Conclusion: In BR.21, patients with K-ras mutation do not appear to derive any survival benefit from erlotinib therapy. However, the numbers of patients are small and results need to be confirmed in other studies. (Supported by the Canadian Cancer Society, Ontario Cancer Research Network, the Jacqueline Seroussi Memorial Foundation for Cancer Research and OSI Pharmaceuticals).

[Table: see text]
CISCA (cisplatin vs. carboplatin) meta-analysis: An individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC)
Authors: Ardizzoni A. , Tiseo M. , Boni L. , Rosell R. , Fossella F. V. , Schiller J. H. , Paesmans M. , Radosavljevic D. , Paccagnella A. , Mazzanti P. , Bisset D.
Published: March 2020

7011

Background: The issue of the equivalence between carboplatin and cisplatin in the treatment of advanced NSCLC is still controversial. To answer this question, we conducted an individual patient (pt) data meta-analysis of randomized trials comparing cisplatin- and carboplatin-based chemotherapy (CT) in first-line treatment of advanced NSCLC. Methods: A literature search was performed to identify randomized trials investigating the substitution of carboplatin for cisplatin, combined with the same agent/s, in the first-line CT of advanced NSCLC. The primary end-point was overall survival (OS) and the secondary end-points were response rate (RR) and toxicity. For each end-point the analysis was based on a fixed-effects model. For the study of the effect on OS, Cox proportional hazards model was used. The probability to have an objective response or an adverse event was studied using a logistic regression model. Results: Nine trials were identified and the relative databases obtained. In total, 2,968 pts were randomized to receive CT with cisplatin (1,489) or with carboplatin (1,479), respectively. The RR was 30% and 24% for cisplatin- and carboplatin-based CT, respectively, with an OR of 1.37 (95% C.I.: 1.16–1.62; p < 0.001). Concerning the OS, carboplatin was associated with a relative risk of death 7% higher compared with cisplatin, even if this difference was not statistically significant (HR = 1.07; 95% C.I.: 0.99–1.15; p = 0.101). Patients on cisplatin-based CT had more nausea-vomiting and nephro-toxicity while thrombocytopenia was more frequent during carboplatin-based CT. Subgroup analyses revealed that cisplatin-based CT led to statistically significant advantage in survival in the subgroups of pts with non-squamous tumours and in those treated with third generation CT. Conclusions: CISCA is the first individual pt data meta-analysis on this subject. We found that cisplatin-based is superior to carboplatin-based CT in terms of RR; however, the increased RR does not translate into an OS benefit. Nevertheless, selected pts with advanced NSCLC may obtain slightly more benefit from cisplatin-based third generation CT.

No significant financial relationships to disclose.
A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR)
Authors: Paz-Ares L. , Sanchez J. M. , García-Velasco A. , Massuti B. , López-Vivanco G. , Provencio M. , Montes A. , Isla D. , Amador M. L. , Rosell R.
Published: March 2020

7020

Background: The EGFR TK inhibitor erlotinib is a standard treatment in previously treated NSCLC p. Recently, EGFR gene mutations have been reported to be a predictor of efficacy of this and related compounds. This phase II trial evaluated the efficacy and safety of erlotinib in untreated p with advanced NSCLC and mutated EGFR. Methods: Eligibility criteria included stage IIIB-IV chemotherapy-naive p with confirmed NSCLC and mutated EGFR, PS 0–2, age ≥ 18 years, adequate organ functions, measurable disease and written informed consent. DNA was extracted by laser capture microdissection. Exon 19 deletions were examined by Genscan and the L858R and T790M mutations with a TaqMan assay. Mutations were confirmed by sequencing. Erlotinib was given orally at 150 mg per day. Results: From March to December 2005, 37 (12.5%) of 297 tumors screened were found to have mutations in the TK domain of the EGFR gene (25 deletions; 11 L858R; no T790M). Median age: 68 years; 12 males, 25 females; histology: 28 adenocarcinoma, 4 BAC, 4 large cell carcinoma; 9 smokers. Response has been evaluated in 21 p so far: complete response, 6 p; partial response, 13 p; progressive disease, 2 p; overall response rate, 90% (95% CI:70%-90%). Responses occurred in 100% of tumors with exon 19 deletions and in 75% of those with L858R. All responses are ongoing (up to ≥8 months) and all but one p are still alive. Toxicity profile was predictable (mild to moderate rash, diarrhea, asthenia and emesis). No drug related severe adverse events occurred. Conclusions: Single-agent erlotinib produces a high response rate in previously untreated p with advanced NSCLC and mutated EGFR. In-frame deletions in exon 19 seem particularly predictive for response in this setting.

[Table: see text]
A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC)
Authors: Harpole D. H. , Petersen R. , Mukherjee S. , Bild A. , Dressman H. , Kratzke R. , Kelley M. J. , Garst J. , Crawford J. , Nevins J. R. , Potti A.
Published: March 2020

7026

Background. Although stage-specific classification identifies appropriate populations for adjuvant chemotherapy, this is likely an imprecise predictor for the individual patient with early stage NSCLC. Methods. Using previously-described methodologies that employ DNA microarray data, multiple gene expression profiles (‘metagenes’) that predict risk of recurrence in patients with stage I disease were identified. This analysis used an initial ‘test’ cohort of patients with NSCLC (n = 89) that represented an equal mix of squamous cell and adenocarcinoma. Also, each histologic subset had equal number of patients who survived more than 5 years and those who died within 2.5 years of initial diagnosis. The performance of the metagene-based model generated on the training cohort was then evaluated in independent ‘validation’ sets, including two multi-center cooperative group studies (ACOSOG Z0030 and CALGB 9761). Importantly, the CALGB validation was performed in a blinded fashion. Results. Classification tree analyses that sample multiple gene expression profiles were used to develop a model of recurrence, termed the Lung Metagene Model, that accurately assesses prognosis (risk of recurrence and survival), performing significantly (p<0.001, odds ratio: 16.1, multivariate analysis) better than pathologic stage, T-size, nodal status, age, gender, histologic subtype and smoking history. The accuracy of prognosis using the Lung Metagene Model exceeded 90% (leave-one-out cross validation) in the initial training set (n = 89), 72% in the ACOSOG (n = 25), and 81% in the CALGB (n = 84) datasets. The prognostic accuracy was consistent across histologic subtypes and stages of NSCLC. Importantly, this provides an opportunity to re-classify stage IA patients to identify a subset of ‘high risk’ patients that may benefit from adjuvant chemotherapy. Further, stage IB and II patients identified as ‘low risk’ for recurrence, and who present co-morbidities, could potentially be candidates for observation, and those patients predicted to be at ‘high risk’ may benefit from novel therapeutic trials. Conclusions. The Lung Metagene Model provides a mechanism to refine the estimation of an individual patient’s risk for disease recurrence and thus guide the use of adjuvant chemotherapy in NSCLC.

No significant financial relationships to disclose.
Proteomic analysis of lung cancer tumors
Authors: Kikuchi T. , Massion P. P. , Shyr Y. , Altorki N. K. , Dannenberg A. J. , Li M. , Gonzalez A. , Chaurand P. , Caprioli R. , Carbone D. P.
Published: March 2020

7028

Background: In this study we assess the utility of direct tumor tissue MALDI-MS in a large prospective collection of surgically resected lung cancers to distinguish cancer from non-cancer, histology, occult lymph node involvement, and survival. Methods: 175 non-small cell lung cancer specimens and 62 histologically normal lung tissues obtained at the time of surgery were used in this analysis. Twelve micron thick frozen sections were placed on conductive glass slides. Sections were stained with Cresyl Violet and matrix applied to areas identified by a pathologist under microscopic guidance as containing greater than 80% tumor before three separate areas involved with tumor was analyzed by MALDI MS. Relative intensities of selected peaks were used for class comparison. A class prediction model was built based on the weighted flexible compound covariate method of analysis (WFCCM). Results: We created a prediction model from a training cohort consisting 81 tumors and 19 histologically normal tissue samples. A total of 221 peaks were used for statistical analysis. In tumor/normal discrimination, 46 peaks were used for the prediction model (p<0.0001), while, 22 were used (p<0.005) to predict histology, 11 (p<0.05) to predict nodal involvement, and 14 (p<0.005) in survival prediction. Using these prediction models, classification accuracy was 90% in normal/tumor discrimination, 81.8% in histology and 61.7% in nodal involvement prediction. In the survival prediction model, patients with longer than median survival could be distinguished from those with shorter than median survival (p<0.0001, Log-rank test). We then validated the same features in a blind test set from the remaining 93 tumors and 43 normals. For tumor/normal discrimination, prediction accuracy in test cohort was 94.3%. Histology prediction accuracy was 93.9% in predicting squamous cell carcinoma. Nodal involvement prediction accuracy was 49.3%. Longer or shorter median survival was also predicted in this set with statistical significance p<0.08. (Log rank test). Conclusion: We report the analysis of a large set of tumor and normal samples by MALDI MS and confirm similar accuracy in tumor/normal, histology and survival discrimination to previous our report. This project was supported by the Lung SPORE P50 CA90949 (DPC) and NCI 5R33CA86243 (RMC).

No significant financial relationships to disclose.
CALGB 9761: A prospective analysis of IHC and PCR based detection of occult metastatic disease in stage I NSCLC
Authors: Maddaus M. A. , Wang X. , Vollmer R. T. , Abraham N. Z. , D’Cunha J. , Herzan D. L. , Patterson A. , Kohman L. J. , Green M. R. , Kratzke R. A.
Published: March 2020

7030

Background: CALGB 9761 was a prospective trial of tumor and lymph node collection during planned surgical resection in patients with clinical stage I NSCLC. The primary objective was to determine if occult micrometastases (OM) detected by immunohistochemistry (IHC) or real time PCR of CEA in histologically negative lymph nodes is associated with poorer survival. Methods: 502 patients with clinical stage I NSCLC were accrued. 302 (60%) were eligible for analysis. 200 were ineligible due to postoperative stage change or change in diagnosis. At surgical resection samples of primary tumor and N2 and N1 lymph nodes were harvested. Lymph nodes were split in half, one half was sent for standard surgical pathologic analysis and the other half snap frozen and sent for IHC analysis using a polyclonal anticytokeratin antibody cocktail. Results: Of 302 eligible patients, 173 were T1N0 and 129 T2N0 by routine postoperative pathology. The median follow-up time for eligible patients is 5.25 years. Overall survival at 5 years is 63.22%. Median survival is not yet estimable. 14% of patients had IHC positive tissue in lymph nodes, a rate lower than expected compared to published single institution studies. Overall survival for this group at 5 years is 55.96% compared to 65.65% for the IHC negative group (p=0.38). The failure free survival at 5 years is 41.74% for the IHC positive group and 60.25% for the IHC negative group (p=0.16). RT-PCR data is currently being analyzed. Data on the first 50 patients analyzed demonstrated presence of CEA in nodal tissues and potential upstaging in approximately 50% of the patients. Conclusions: In a multi-institutional setting, IHC detection of OM by use of a polyclonal cytokeratin cocktail in stage I NSCLC has limited capacity to detect OM and poorly predicts recurrence and survival.

No significant financial relationships to disclose.
Effect of gender on outcome in two randomized phase III trials of paclitaxel poliglumex (PPX) in chemonaïve pts with advanced NSCLC and poor performance status (PS2)
Authors: Ross H. , Bonomi P. , Langer C. , O’Brien M. , O’Byrne K. , Paz-Ares L. , Sandler A. , Socinski M. , Oldham F. , Singer J.
Published: March 2020

7039

Background: Women with NSCLC are younger and are more likely to be non-smokers than the overall NSCLC population. Estrogen seems to contribute to these differences in lung cancer biology, but its effect on treatment efficacy has not been well described. Methods: Two phase III trials in chemo-naïve PS2 patients with advanced NSCLC compared PPX to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to paclitaxel/carboplatin (STELLAR 3). Eligibility criteria were identical and pts were stratified for gender and age. Analysis of overall survival (OS), the primary study endpoint, showed similar survival between treatment arms. A trend to improvement with PPX for females but not males in both studies prompted an exploratory combined analysis of the 198 women in STELLAR 3 (93/400 pts) and STELLAR 4 (105/381 pts) using univariate and multivariate Cox regression analysis of OS. Results: Combined log-rank analysis of STELLAR 3 and 4 shows improved OS for females receiving PPX vs control (9.5 mo vs 7.8 mo; HR=0.70; p=0.03) and no difference in males (7.3 mo vs 6.9 mo; HR=1.06; p=0.53). Cox multivariate analysis identified treatment with PPX (HR=0.64; p=0.019), smoking (HR=1.50; p=0.037), and presence of extra-thoracic metastases (HR=1.76; p=0.003) as independent prognostic factors in these women. In the combined analysis, median survival advantage for PPX-treated pts was greater in women <55 years old (10.0 vs 5.2 mo, p=0.038) compared to women 55 or older (8.9 vs 8.6 mo, p=0.134). Pretreatment estrogen levels were available for 86 pts in STELLAR 3; pts with estrogen >30 pg/dl had a significant survival benefit when receiving PPX compared to paclitaxel (10.2 vs 5.5 mo; p=0.039). Conclusions: While the efficacy of PPX is comparable to other treatment options in NSCLC, PPX may be more effective female pts, particularly premenopausal women, compared to females in the control arms. Preclinical data suggest that estrogen enhances PPX distribution to lung tissue and upregulates the rate-limiting metabolic enzyme cathepsin B in NSCLC. To prospectively test the effect of estrogen on OS, a phase III trial (PIONEER) has been initiated to compare PPX to paclitaxel in chemo-naïve PS2 females with NSCLC.

[Table: see text]
Bone sialoprotein is predictive of bone metastases in resectable non-small cell lung cancer: A case-control study and prevalence data
Authors: Scagliotti G. , Kalebic T. , Volante M. , Cappia S. , Novello S. , Bacillo E. , Borasio P. , Chiusa L. , Papotti M.
Published: March 2020

7049

Background: Bone metastases (BM) in non small cell lung cancer (NSCLC) may be present at diagnosis or develop in the follow up, are associated with a worse prognosis, and currently there are no chemical or biological markers predicting their clinical onset. Methods: Thirty cases of resected NSCLC which subsequently develop BM (group A - mean follow up time 27.2 months) were matched for several clinico-pathological parameters (including age, sex, stage of the disease, histology, differentiation grade, adjuvant therapy) to 30 cases of resected NSCLC without any metastases (group B - mean follow up time 75.1 months) and 26 resected NSCLC with non-bone metastatic (group C - mean follow up 21.1 months). Primary tumor samples were investigated by immunohistochemistry for 10 markers previously recognized to be involved in bone resorption or metastatization process (cathepsin K, bone sialoprotein [BSP], VEGF, MMP-2, p53, RECK, TIMP-1, CD-117, Ki-67 and TRAcP). For statistical analysis the intensity of the staining was assessed by a semi-quantitative score (0, <10%, 10–50%, >50% +ve tumor cells). Differences among groups were estimated by X-square test, whereas the prognostic impact of clinico-pathological parameters and markers expression was evaluated by univariate and multivariate analyses. Results: Among the different markers investigated, BSP was strongly associated to bone dissemination (p < 0.001) and, independently, to poor outcome (p = 0.02 by Mantel-Cox test). None of the other markers was differentially expressed within the groups or demonstrated a prognostic impact, both in terms of overall survival and of time interval to metastases. Based on these findings, the prevalence of BSP in NSCLC was further estimated in a large series of 120 resected lung carcinomas (M:F ratio 3:1; mean age 67 years; adenocarcinomas 55%, squamous cell carcinoma 39%, others 6%; stages: I 54%, II 17%, III 29%). BSP prevalence reached 40%, without any statistically significant difference according to histotype or other clinico-pathological parameters. Conclusions: BSP protein expression in resected NSCLC strongly predicts bone dissemination, and may therefore be useful in selecting patients for treatments targeted to inhibit bone metastatic spread.

[Table: see text]