bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance characteristics of common immunologic biomarkers used in clinical trials
Authors: Goodell V. , Macleod B. , Slota M. , Disis M. L.
Published: March 2020

620

Background: Standardization of cell-based immunologic monitoring is becoming increasingly important as methods for measuring cellular immunity become more complex. We assessed the ability of 2 cell-based assays widely used in immune monitoring, the ELISPOT assay and a modified limiting dilution assay based on titrated thymidine incorporation, to predict T cell responses to a HER-2/neu protein vaccine in breast cancer patients. We also assessed the ability of these assays to predict T cell response to tetanus toxoid and CMV, and analyzed the correlation between results from the ELISPOT and modified limiting dilution assays. Methods: 27 Stage II, II, and IV HER-2/neu positive breast cancer patients were vaccinated against the HER-2/neu protein and tt. PBMC were collected before and after vaccination. Samples were analyzed by mLDA and ELISPOT for T cell response to HER-2/neu (a low level response), response to tt (moderate level) and T cell response to CMV (high level). Results: Correlation analysis indicates that there is a strong, significant association between results from the ELISPOT assay and the mLDA for HER-2/neu specific T cell response (Rs=0.547, p=0.02). ROC curves plotted to assess the diagnostic performance of the mLDA and ELISPOT assay indicate that T cell proliferation measurements are a significant indicator of T cell response to the HER-2/neu vaccine (p=0.05), as well as responses to tt (p=0.01) and CMV (p=0.016), respectively. Precursor frequency, as measured by ELISPOT, is a significant indicator of high level T cell response to CMV (p=0.03), but not of a moderate tt response (p=0.09), or HER-2/neu (p=0.09) T cell responses. Conclusion: The mLDA achieves greater assay accuracy in measuring low level T cell responses to HER-2/neu and moderate responses to tt than the ELISPOT assay.

No significant financial relationships to disclose.
c-kit: Identification of co-regulated genes by gene expression profiling and clinical relevance of two breast cancer subtypes with stem cell like features
Authors: Rody A. , Holtrich U. , Müller V. , Gaetje R. , Diallo R. , Gehrmann M. , Von Minckwitz G. , Engels K. , Karn T. , Kaufmann M.
Published: March 2020

622

Background: Expression of the proto-oncogene c-kit has been found in malignant tissue including a subset of breast cancers. c-Kit is also expressed in normal breast tissue and several authors found a loss of c-kit expression in breast carcinoma suggesting it might be involved in the growth control of mammary epithelium. Until now, only a few markers were described to be co-regulated with c-kit. To elucidate the possible role of c-kit in malignant transformation, we analyzed gene expression data of breast cancer patients. Methods: Tumor tissue of n=171 breast cancer patients were analyzed by gene expression profiling using Affymetrix Hg U133 Arrays (22,500 genes) and bioinformatic analyses. Tumor samples with high stromal and low epithelial cell content by gene expression profiling were excluded for further analysis. Validation was performed with n=100 independent samples. Results: A total of 10.5% of the tumors showed strong c-kit expression (2.5 fold above median). A careful dissection of global expression data revealed strong correlations of c-kit with the expression of a large cluster of genes containing several for whom c-kit coexpression was already described (HER1, CK-5/-17, PDGFR) as well as several members of the wnt signalling pathway, providing a possible novel link to mammary epithelial differentiation. Analysis of n=171 breast cancer samples according to this gene set allows the identification of putative “stem cell like” tumors (SCL) characterized by expression of several known stem cell markers. Surprisingly, a tight link of ER status and proliferation is restricted only to these SCL tumors but lost among non-SCL tumors. The clinical implications of our findings will be presented. Conclusions: For the first time these data bring together the description of two breast cancer subtypes identified by gene expression profiling with the actual stem cell model of the development of breast cancer.

No significant financial relationships to disclose.
Postoperative adjuvant therapy with tamoxifen, tegafur-uracil (UFT), or both in women with node-negative breast cancer: A pooled analysis of six randomized controlled trials (relapse-free survival data)
Authors: Nakamura S. , Abe O.
Published: March 2020

633

Background: In Japan, 6 randomized controlled trials of the oral 5-fluorouracil derivative tegafur-uracil (UFT) and tamoxifen (TAM), given alone or in combination, have been simultaneously performed in women with node-negative breast cancer. We performed a pooled analysis, based on the intention to treat, of individual patient data from these 6 trials (involving 2934 patients). Data on overall survival, the primary endpoint, have been reported previously (Noguchi et al., Journal of Clinical Oncology, 2005). We now report data on relapse-free survival (median follow-up, 6.2 years). Methods: Three 3-arm randomized controlled trials (surgery alone vs. surgery plus TAM vs. surgery plus UFT) and three 4-arm randomized controlled trials (surgery alone vs. surgery plus TAM vs. surgery plus UFT vs. surgery plus TAM and UFT) were performed in women with node-negative breast cancer. The results underwent a pooled analysis. Results: The 5-year relapse-free survival rate was 87.9% with surgery alone (n = 860; risk ratio [RR], 1), 90.5% with surgery plus TAM (n = 865; RR, 0.81; confidential interval [CI], 0.60–1.11; P = 0.21), 89.9% with surgery plus UFT (n = 860; RR, 0.83; CI, 0.66–1.21; P = 0.46), and 92.7% with surgery plus UFT and TAM (n = 349; RR, 0.63; CI, 0.39–0.99; P = 0.046). Subset analysis showed that combination therapy with UFT and TAM was not effective for women with estrogen-receptor-negative breast cancer (RR, 0.90; CI, 0.46–1.75; P = 0.75), but was very effective for women with estrogen-receptor-positive breast cancer (RR, 0.39; CI, 0.19–0.79; P = 0.009). Conclusions: Our results suggest that the effectiveness of oral fluoropyrimidine derivatives is enhanced by concurrent treatment with TAM in women with node-negative breast cancer. This contrasts with the results of previous studies showing that the response to anthracycline-based chemotherapy is attenuated in patients concurrently receiving TAM.

No significant financial relationships to disclose.
Premenopausal breast cancer and the association between estrogen receptor status, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin
Authors: Eng-Wong J. , Chang S. , Hursting S. , Perkins S. N. , Núñez N. , Hill H. L. , Bondy M. , Li D. , Singletary S. E.
Published: March 2020

640

Background: The IGF pathway and leptin are associated with breast cancer risk in premenopausal women. These proteins are implicated in breast carcinogenesis through their interactions with the estrogen pathway, potentially resulting in specific breast cancer histopathologic subtypes. Methods: Pretreatment serum IGF-I, IGFBP-3 and leptin levels were examined in newly diagnosed premenopausal breast cancer cases to determine whether an association with tumor estrogen receptor status exists. Odds ratios were determined by logistic regression analysis. Likelihood ratio tests for interaction with BMI were conducted. Results: One hundred and eight women were evaluated (mean age 42); 82 were ER positive and 26 were ER negative. 62 were normal weight (BMI<25) and 46 were overweight and obese (BMI≥25). Mean IGF-I, IGFBP-3 and leptin levels did not differ between the ER positive and ER negative tumors. No associations were found between IGF-I, IGFBP-3 or leptin and ER status of tumors overall or by subset analysis in normal weight versus overweight and obese individuals. A suggestion that elevated IGFBP-3 was associated with ER-negative disease did not reach statistical significance. Additionally, normal-weight women with ER-negative disease had higher leptin levels than their normal-weight ER-positive counterparts, although we lacked statistical power to detect an effect of BMI on the association between leptin levels and tumor hormone receptor status. Conclusions: This is the first report examining the IGF pathway and leptin in relation to ER status in premenopausal women with newly diagnosed breast cancer. Our small number of cases suggests a number of intriguing findings that should be evaluated in larger studies. Determining links between ER status and IGFBP-3 and leptin may help better define risk factors and potentially appropriate interventions for ER-negative versus ER-positive breast cancer.

No significant financial relationships to disclose.
Prognostic significance of HER-2/neu over-expression on the incidence of brain metastasis in newly diagnosed breast cancer
Authors: Abdulkarim B. S. , Gabos Z. , Sinha R. , Hanson J. , Chauhan N. , Hugh J. , Mackey J.
Published: March 2020

649

Background: As systemic therapy improves, brain metastases (BM) from breast cancer are becoming increasingly evident. An increased risk of BM in HER-2/neu over-expressing metastatic breast cancer patients has been suggested. However, the relationship between HER-2/neu over-expression and the risk of BM in newly diagnosed breast cancer patients is unknown. Methods: To determine incidence of BM in HER-2/neu over-expressing breast cancer patients, a cohort of patients between 01/1998 and 12/2003 with uniform HER-2/neu testing were identified from a cancer registry. A total of 460 patients with HER-2/neu over-expression and 500 patients with HER-2/neu negative disease were reviewed. Patients were excluded if there was breast cancer diagnosed before 01/1998 or others cancer. A total of 301 HER-2/neu over-expressing and 363 HER-2/neu negative patients were included for this analysis. The association between histological features and the occurrence of BM were evaluated with univariate and multivariate analyses. Results: BM were identified in 8% (24 patients) of HER-2/neu over-expressing breast cancer patients compared to only 1.7% (6 patients) in the HER-2/neu negative patients (hazard ratio 5.15 [2.079–12.78], p=0.0001). In patients with recurrent disease, the proportion of BM for HER-2/neu over-expressing patients was 24% compared to 10% in HER-2/neu negative patients. HER-2/neu over-expression, tumor size >2cm, ≥ 4 nodes positive and grade 2/3 were predictors of BM in univariate analysis. In multivariate analysis, HER-2/neu over-expression and tumor size>2cm were an independent prognostic factors for the development of BM, while hormone receptors expressions was protective (p=0.02). Conclusions: Our population based study show that newly diagnosed HER-2/neu over-expressing breast cancer patients are at significantly increased risk for BM. As most BM occur in HER-2/neu over-expressing patients with systemic metastatic disease, these findings could prompt consideration of brain prophylaxis strategies and/or serial radiologic screening to detect asymptomatic BM.

No significant financial relationships to disclose.
Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study
Authors: Druker B. J. , Guilhot F. , O’Brien S. , Larson R. A.
Published: March 2020

6506

Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed patients (pts) with CML-CP (O’ Brien et al, NEJM 2003). 1,106 pts were randomized between June 2000 and Jan 2001 to either IM 400 mg or IFN+Ara-C with 553 pts to each treatment. This abstract is based on data collected up to 54 months after last patient had been recruited on IM. 60-months (5-year) data will be available for presentation. Methods: Evaluations included complete hematologic response (CHR), complete/partial cytogenetic response (CCyR/PCyR - defined as 0% / 1–35% Ph+ metaphases respectively), major cytogenetic response (MCyR=CCyR+ PCyR), major molecular response (MMR) - defined as ≥ 3 log reduction of BCR-ABL transcript levels from the standardized baseline, time to progression - defined as loss of CHR/MCyR, evolution to accelerated phase/blast crisis (AP/BC), or death due to any cause during treatment, and overall survival. Results: With a median follow-up of 54-months, 72% of the 553 randomized pts remain on initial IM treatment (5% of pts discontinued due to adverse events, 9.5% due to unsatisfactory therapeutic effect and 11% due to other reasons another 2.5% crossed over to IFN+Ara-C). Overall, the cumulative best response rates of CHR, MCyR and CCyR are 97%, 88% and 82%, respectively. The overall estimated survival was 90% (93% when censored at bone marrow transplant). An estimated 84% of pts have not progressed on treatment and 93% of pts were free from progression to AP/BC. The annual rate of progression to AP/BC of < 1% in the fourth year was lower than each of the first three years (1.5, 2.8, and 1.6%, respectively). Of the pts with MCyR at 12 months (n=436), an estimated 96% were free of progression to AP/BC at 54 months whereas it was only 81% for the 73 pts who did not achieve a MCyR at 12 months (p< 0.001). No patient with a MMR within 12 months progressed to AP/BC within 54 months. Conclusions: This analysis confirms the high rates and durability of responses to IM. Encouragingly, the rate of progression in the fourth year was lower than in each of the preceding three years. Results further demonstrate the beneficial effect of cytogenetic and molecular responses on long-term outcomes.

[Table: see text]
Phase II clinical trial of ixabepilone in metastatic breast cancer (MBC) patients previously untreated with taxanes
Authors: Denduluri N. , Lee J. J. , Walshe J. M. , Yang S. X. , Vatas U. , Chow C. K. , Steinberg S. M. , Cox M. C. , Low J. A. , Swain S. M.
Published: March 2020

651

Background: Ixabepilone, an epothilone B analog, stabilizes microtubules by binding to tubulin. The response rate (RR) in taxane-pretreated patients at our institution was 22%. Methods: Patients (pts) were eligible if they had MBC previously untreated with taxanes and measurable disease by RECIST criteria. Ixabepilone was given at 6mg/m2/d intravenously days 1–5 every 3 weeks until unacceptable toxicity or disease progression. Primary objectives included RR and toxicity. Pts underwent pre and/or post treatment tumor biopsies for correlative studies. Acetylated α-tubulin, Tau-1, and p53 were stained with anti-acetylated α-tubulin, anti-Tau-1, and anti-p53 antibodies in samples from 13 pts. Staining was scored quantitatively using the Automated Cellular Imaging System. Results: Twenty-three pts received 197 cycles (C). Median of 7C (range 2–22) per pt were administered. Median age was 55 (range 22–79). Seven pts received 1 prior metastatic chemotherapy regimen. Ten of 23 or 43% (exact 95% confidence interval: 23.2% to 65.5%) pts had partial responses (PR), 9 (39%) stable disease (SD) (2 unconfirmed PRs), and 4 (17%) progressive disease (PD). Median time to progression was 5.3 months; median duration of response was 5.4 months from date of best response. Four pts required dose reductions for neutropenia, neuropathy or fatigue. Grade 3/4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), infection without neutropenia (9%), motor neuropathy (4%), and muscle weakness (4%). No grade 3/4 sensory neuropathy was seen, but 35% and 13% of pts had grades 1 and 2 neuropathy respectively. Median acetylated α-tubulin at baseline was 0.2 in responders and 17.6 in non-responders (p=0.069). There were no differences in response according to Tau-1 or p53 expression at baseline. Conclusion: Ixabepilone is an effective treatment for MBC with a 43% RR in 23 pts previously untreated with taxanes. There was minimal hematologic toxicity and no grade 3 sensory neuropathy. The use of baseline level of acetylated α-tubulin to predict response may warrant further study.

No significant financial relationships to disclose.
A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with chronic myelogenous leukemia (CML) in accelerated phase (AP)
Authors: Le Coutre P. D. , Ottmann O. , Gatterman N. , Larson R. , Rafferty T. , Alland L. , Tavorath R. , Giles F. , O’Brien S. G. , Kantarjian H.
Published: March 2020

6531

Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and is 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 AP pts. Results: Preliminary data are presented for 22 pts (77% resistant and 23% intolerant to imatinib. Treatment is ongoing for 16 (73%) pts. Median age was 62 (43–76) yrs. Median duration of AMN107 exposure was 124 (3–207) days. Median time from AP diagnosis was 6 (0.2–56) mos. Three of 5 patients with data available had a Bcr-Abl mutation at baseline. HR occurred in 14 (64%) pts of which 10 (45%) were complete, 3 (14%) were marrow responses/no evidence of leukemia, and 1 return to chronic phase. CyR occurred in 6 pts (1 each complete, partial minor, and 3 minimal). All AE’s occurring in ≥10% pts were thrombocytopenia (8 [36%] pts; Gr 3/4, 6 [27%] pts), fatigue (7 [32%]), anemia, (6 [27%]; Gr 3/4, 4 [18%] pts) pruritus, muscle spasms (6 [27%] pts each), bone pain, cough, (5 pts [23%] each) rash (5 [23%] pts; Gr 3/4, 1 [5%] pt), neutropenia (4 [18%] pts, all Gr 3/4), diarrhea, headache, myalgia, pyrexia (4 [18%] pts each), abdominal pain, chills, constipation, dyspnea, nausea, extremity pain, and peripheral edema (3 [14%] pts each). Two 2 deaths occurred, 1 pt with thrombocytopenia had a CNS bleed and 1 pt had disease progression. Conclusions: These data suggest AMN107 is clinically active and has an acceptable safety profile when administered to pts with CML-AP.

[Table: see text]
A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with Ph+ chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)
Authors: Giles F. J. , Larson R. , Le Coutre P. , Baccarani M. , Tavorath R. , Alland L. , Kantarjian H. M. , Hughes T. , Ottmann O.
Published: March 2020

6536

Background: AMN107 is a highly selective, aminopyrimidine which is 30-fold more potent in vitro than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: This open-label study evaluated safety and efficacy of AMN107 (400 mg bid) by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant/ intolerant BC or relapsed/refractory ALL pts. Results: Preliminary data from this ongoing study are presented for 18 BC and 6 ALL (5 relapsed/refractory, 1 minimal residual disease) pts. Baseline mutation data are available for 6 BC and 2 ALL pts: 2 and 1, respectively, had Bcr-Abl mutations. The overall median age was 54 yrs and the overall median exposure was 84 days. Seven patients remain on treatment (5 BC, 2 ALL) and 17 discontinued (3 adverse events, 9 progressive disease (PD), 3 deaths, 2 other). Two BC pts died of PD. 1 ALL pt had sudden cardiac death. HR was reported in 7 (38%) BC pts; 5 complete HR and 2 marrow responses/no evidence of leukemia. 3 BC pts had CyR (2 complete, 1 minor). Complete remission was reported in 2 (33%) ALL (1 relapsed/refractory and 1 MRD) pts. Adverse events in ≥ 10% were rash in 9 (37%) pts, thrombocytopenia in 8 (33%) pts (Gr 3/4 in 7 (29%), nausea in 7 (29%) pts, pyrexia in 7 (29%) pts (Gr 3/4 in 2 (8%)); vomiting in 7 (29%) pts (Gr 3/4 in 1 (4%), diarrhea, fatigue in 6 (25%) pts each, headache in 6 (25%) pts (Gr 3/4 in 1 (4%)), neutropenia in 6 (25%) pts (all Gr 3/4), anemia in 5 (21%) pts (Gr 3/4 in 4 (17%)), pain in extremity in 5 (21%) pts (Gr 3/4 in 1 (4%)), pain, peripheral edema in 4 (17%) pts each, pruritus in 4 (17%) pts (Gr 3/4 in 1 (4%)), leukocytosis in 3 (13%) pts (Gr 3/4 in 1 (4%)), arthralgia, pharyngolaryngeal pain, and upper abdominal pain 3 (13%) each. Conclusions: AMN107 has clinical activity and an acceptable safety and tolerability profile in pts with imatinib-resistant or intolerant BC and relapsed/refractory Ph+ ALL pts

[Table: see text]
Final analysis of the phase II, randomized, double-blind, placebo-controlled trial of single dose velafermin (CG53135–05) for the prevention of oral mucositis
Authors: Schuster M. W. , Anaissie E. , Hurd D. , Bensinger W. , Mason J. , McCarty J. , Rifkin R. , Maziarz R. , Halvorsen Y. , Annino V. , Hahne W.
Published: March 2020

6537

Background: Oral mucositis (OM) is a commonly occurring side effect of high-dose chemotherapy (HDCT) in patients (pts) undergoing autologous hematopoietic stem cell transplant (AHSCT). Velafermin, recombinant human fibroblast growth factor 20, is being investigated for prevention of OM. Velafermin promotes epithelial and mesenchymal cell proliferation in vitro and in vivo. Methods: A phase II trial was conducted to evaluate safety, efficacy, and pharmacokinetics (PK) of velafermin. Inclusion criteria: pts undergoing HDCT and AHSCT with or without total body irradiation (TBI) were enrolled. Velafermin at 0.03, 0.1, or 0.2 mg/kg or placebo was administered as single dose IV at 24h after stem cell infusion. Safety and PK were assessed. Pts were scored daily for presence of OM using the WHO grading scale. The primary endpoint was the incidence of Grade 3/4 OM. Results: A total of 212 pts were randomized to either placebo (n=51) or velafermin at 0.03 (n=50), 0.1 (n=56), or 0.2 (n=55) mg/kg (intent-to-treat or ITT sample). 206 pts (97%) received study drug or placebo. Pt diagnoses included multiple myeloma (57%), non-Hodgkin’s (25%), or Hodgkin’s (11%) lymphoma and 13 pts (6%) received TBI as part of the conditioning regimen. The Grade 3/4 OM incidence rates (%) in the placebo or velafermin arms (0.03, 0.1, and 0.2 mg/kg) were 37, 18, 38, and 36, respectively. The primary analysis of dose dependent reduction of severe OM was not statistically significant (p = 0.549). However, velafermin at 0.03 mg/kg did reduce the incidence of Grade 3/4 OM when compared to placebo alone (p = 0.031). Duration of Grade 3/4 OM was reduced significantly in the 0.03 mg/kg when every pt was evaluated or in the 0.1 mg/kg dose when only pts with Grade 3/4 OM were included in the analysis (p = 0.037 and 0.014, respectively). A total of 5 related SAEs (3 in 0.1 mg/kg, 1 in 0.03 mg/kg, and 1 in placebo cohort) occurred within 4hr of study drug infusion. All symptoms were transient. Conclusion: Single dose velafermin at 0.03mg/kg is may be active in reducing CT induced severe OM in AHSCT pts. Safety profile supports continuing study to define the optimal dose for prevention of severe OM. A new Phase II study will be conducted to confirm velafermin activity at 0.03mg/kg dose.

[Table: see text]
Human leukocyte antigen (HLA) DR4 is associated with inferior progression free survival (PFS) following allogeneic hematopoietic stem cell transplantation (allo HSCT) for lymphoid malignancies
Authors: Aggarwal C. , Gupta S. , Hahn T. , Padmanabhan S. , McCarthy P. L. , Battiwalla M.
Published: March 2020

6543

Background: HLA DR4 is associated with autoimmune disorders and response to cyclosporine immunosuppression in T-cell Large Granular Lymphoproliferative Disorder (BJH 2003;123(3)). We investigated the HLA DR4 role on graft-versus-host disease (GVHD) and graft-versus-leukemia effect in HLA-matched HSCT performed for lymphoid malignancies. Methods: We retrospectively reviewed 77 related and 22 unrelated consecutive allo HSCT patients (pts) treated between 1992 and 2003 at RPCI to investigate the influence of HLA DR4 on overall survival (OS), PFS and grade 2–4 acute and chronic GVHD (cGVHD) incidence. HLA DR B1 typing was determined by molecular (n=69) or serologic (n=30) methods. The pt proportion with one or two HLA DR4 antigens was 18% (18/99), similar to the general Caucasian population. Pt characteristics included: ALL (n=41), CLL (n=4), HD (n=7) and NHL (n=47); median age 36 y (range 6–64); Male (n=65), Female (n=34); Caucasian (>95%); Total Body Irradiation (TBI) conditioning regimens (n=79); Busulfan/Cyclophosphamide (BuCy) (n=6), Thiotepa/TBI (n=23), Cy/TBI (n=9), Etoposide/Cy/TBI (n=9), Fludarabine/Melphalan (n=8), Thiotepa/Carboplatin (n=8) or other combinations (n=6). Results: There was no difference in OS between the HLA DR4 positive vs negative pts in any disease or donor subgroups (p=0.25). Nine of 18 DR4 positive pts (50%) and 20 of the 81 DR4 negative pts (25%) had disease progression (p=0.033). PFS at 33 months was 70% in the DR4 negative group and 30% in the DR4 positive group (p=0.004). In a univariate analysis, DR4 positivity, conditioning regimen and disease stage at HSCT were significant factors for PFS. However in the multivariate analysis, DR4 positivity was the only significant factor for PFS (RR=3.2, p=0.007). By preliminary analysis, 0/18 of the HLA DR4 positive pts and 13/81 HLA DR4 negative pts developed cGVHD (p=0.06). Conclusions: These results suggest that HLA DR4 positive pts have reduced cGVHD leading to increased relapse and decreased PFS with no effect on OS. Increased sensitivity of HLA DR4 lymphocytes to GVHD prophylaxis agents or reduced binding affinity for the CD4 coreceptor are possible reasons for these observations.

No significant financial relationships to disclose.
Reduced-intensity allogeneic stem cell transplantation for diffuse large B-cell lymphoma: Clinical evidence of a graft-versus-lymphoma effect
Authors: Bishop M. R. , Dean R. M. , Steinberg S. , Odom J. , Pavletic S. Z. , Kasten-Sportes C. , Hardy N. , Pittaluga S. , Gress R. , Fowler D. H.
Published: March 2020

6546

Background: Despite being the most common non-Hodgkin’s lymphoma, there have been no specific reports on the use of reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT) to treat patients (pts) with diffuse large B-cell lymphomas (DBCL). This may be due to a lack of definitive evidence for a therapeutic graft-versus-lymphoma (GVL) effect against DLBC. We undertook a retrospective analysis to assess clinical outcomes and evidence of a GVL effect in DLBC pts undergoing RI alloSCT. Methods: The analysis was limited to 18 pts with primary refractory (n = 6) or relapsed (n = 12) DLBC. The median age was 43 years (range: 31–61); median number of previous treatments was 3 (range: 2–9). Nine (50%) pts had undergone autologous transplantation. Three (16%) pts were determined to have chemo-sensitive disease to last treatment prior to RI alloSCT. All pts received a RI conditioning regimen consisting of fludarabine (30 mg/m2/d × 4d) and cyclophosphamide (1200 mg/m2/d × 4d) followed by a T-cell replete allograft from HLA-matched siblings. Results: Median potential follow-up from transplant is 43 months. Seven (39%) pts developed grade II-IV acute GVHD. Response at day +100 post-transplant was as follows: complete response (CR/CRu) = 5; partial response = 5; progressive disease = 8. Nine of 17 (53%) evaluable pts developed chronic GVHD. Median progression-free survival (PFS) was 4.8 months; however, PFS after 9 months post-transplant was 31% with 5 pts in continuous CR/CRu > 12 months post-transplant. Among 14 pts who were not in CR/CRu (n = 12) or progressed after achieving a CR/CRu (n = 2) at day +100 post-transplant, 8 (57%) subsequently achieved a CR/CRu after removal of immune suppression and/or donor lymphocyte infusion (DLI) ± chemotherapy. Seven of these 8 pts remain in continuous (median = 34 months; range: 6–55+) CR/CRu without further treatment. Median survival for all 18 pts was 19 months with survival probability of 40% plateauing at 25 months post-transplant. Conclusions: The clinical observations of sustained CR/CRu after withdrawal of immune suppression and DLI suggest that a GVL effect exists against DLBC. RI alloSCT should be considered as a treatment option for pts with primary refractory and relapsed DLBC.

No significant financial relationships to disclose.
Low dose Vidaza and thalidomide is an effective combination for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)
Authors: Westervelt P. , Amirifeli S. , Mehdi M. , Mumtaz M. , Alhomsi S. , Wang S. , Miron P. , Lata C. , Galili N. , Raza A.
Published: March 2020

6570

Vidaza and thalidomide were administered to 29 patients with MDS or AML. Vidaza was given at a dose of 75mg/kg subq × 5 days q28 days and Thalidomide starting at 50mg/day and increasing to 100mg. Therapy was well tolerated. Median age was 70 years, and there were 16 males. Two patients had RA, 2 RARS, 9 RAEB, 4 CMMoL, 10 AML and 2 Unknowns. According to IPSS, 1 had low, 7 had Int-1, 5 had Int-2 and 4 had high risk disease, and 2 unclassified (10 had AML). Eleven patients had normal, 14 abnormal and 4 unknown for cytogenetics. Seven patients went off the study due to disease progression (5) or refused therapy (1), died within a week of treatment initiation (1) while 2 are on the first cycle and too early for evaluation. Twenty-five patients are evaluable for outcome. Ten patients received 5 or more cycles of Vidaza. HI was seen in 14/25 (56%), and stable disease in 6/25 (24%) while 5/25 (20%) had disease progression. Six patients experienced complete remission (CR) and are still receiving therapy (24%), 1 experienced HI-E, 2 HI-ANC, 3 HI-P, and 2 had a bilineage improvement (HI-P and ANC and HI-E and ANC). Of 10 AML patients, three went off study due to disease progression, 1 had stable disease, 6 responded with 4 complete remissions (CR), 1 HI-ANC and 1 HI-P. Interestingly, 6/10 AMLs had a history of prior MDS, 3/6 achieved CR, 2/6 had HI (ANC and platelets) and 1 has stable disease (continuing treatment). Among the 4 de novo AMLs, 1 had CR and 3 showed disease progression. We conclude that a combination of low dose Vidaza and thalidomide is well tolerated, and highly effective therapy for the treatment of patients with MDS as well as AML arising from a prior MDS. The ability to treat secondary MDS as out-patient and achieve such a high response rate represents a paradigm shift in AML therapy.

No significant financial relationships to disclose.
Clinical and cytogenetic responses to amonafide in secondary acute myeloid leukemia (AML)
Authors: Allen S. L. , Kolitz J. E. , Lundberg A. S. , Capizzi R. L. , Budman D. R.
Published: March 2020

6584

Background: Patients (pts) with secondary AML (AML following an antecedent hematologic disorder or following known exposure to leukemogenic agents) are often elderly, with comorbid illness, and have a dismal prognosis. Secondary AML responds poorly to standard chemotherapy, with low response rates and short durations of remission. Amonafide (Am) is an ATP independent topoisomerase 2 inhibitor that in prior clinical studies had myelosuppression as the dose-limiting toxicity. Two phase 1 trials evaluated Am as either a single agent or in combination with ara-C in pts with relapsed/refractory or secondary AML. This retrospective review was performed to assess the activity of Am specifically in pts with secondary AML. Methods: In study AM-03, 5 pts with secondary AML were treated with a fixed dose (1000, 1100, or 1400 mg/m2/day) of Am IV over 2 hrs daily × 5. In study AM-04, 15 pts with secondary AML were treated with ara-C 200 mg/m2/day CIV days 1–7 and a fixed dose (600, 700 or 800 mg/m2/d) of Am IV over 2 hrs daily on days 1–5. All clinical trial data were reviewed for assessment of hematological and cytogenetic response. Results: Across the two studies, 10 of 20 (50%) pts responded to Am (9 CR, 1 CRi). In study AM-03 (Am monotherapy), 3 of 5 (60%) pts responded, with median duration of response 7.5 months (range 2.5 - 8). None of these 3 pts received additional post-remission therapy. In study AM-04 (Am + ara-C), 7 of 15 pts (47%) responded, with median duration of response 8 months (range 1 ¾ to >60 months). 4 of these 7 pts received additional post-remission therapy. Cytogenetic analysis prior to and following Am therapy was available for 9 of the 10 pts with secondary AML who responded to Am in the 2 studies. Cytogenetics were abnormal prior to Am therapy in 5 of these 9 pts, 3 (60%) of whom achieved cytogenetic CR. Conclusions: Am shows significant activity in secondary AML, both as monotherapy and in combination with ara-C. A phase 2 trial of Am + ara-C in pts with secondary AML is currently enrolling patients.

[Table: see text]
Polymorphisms of DNA-repair genes associated with clinical outcome in metastatic breast cancer (MBC) patients treated with gemcitabine/cisplatin (GC) (California Cancer Consortium)
Authors: Gordon M. A. , Zhang W. , Yang D. , Spicer D. , Doroshow J. , Margolin K. , Synold T. , Albain K. , Chew H. , Gandara D. , Lenz H. J.
Published: March 2020

675

Background: DNA repair enzymes may play an important role in determining efficacy of chemotherapy in MBC. In particular, GC combination therapy may be dependent on activity of DNA repair enzymes in host cells, since cisplatin acts by inducing DNA damage. Cancer cells with increased DNA repair capacity may be resistant to GC, and specific genes may be responsible for this increased repair capacity. We examined whether polymorphisms in genes related to DNA repair were associated with clinical outcome in MBC patients treated with GC, enrolled in a parent phase II clinical trial (Ph II-14 A & B). Methods: Fifty-five patients with MBC were evaluated. Patients received the following regimen: 25 mg/m2 cisplatin on days 1–4; 1000 mg/m2 gemcitabine on days 2 and 8 of 21-day cycle. Thirteen polymorphisms in 10 cancer-related genes were tested for association with overall survival, time to tumor progression, and tumor response using a PCR RFLP based assay. Results: Of 55 patients evaluated, there were 17 responders (31%) and 33 non-responders (60%). Five patients (9%) inevaluable for response. Of 33 non-responders, 15 had stable disease, 18 had progressive disease. Median survival: 11.7 months with median follow-up 32.4 months for 4 patients alive at time of analysis. Median progression-free survival: 4.2 months. XPD Lys751Gln polymorphism was associated with overall survival and time to tumor progression (p=0.0003, p=0.006, respectively, log-rank test). Thirty-five patients carried Lys/Lys genotype, of which 29% resopnded. Fourteen patients carried Lys/Gln genotype, of which 54% resopnded. Five patients carried Gln/Gln genotype, with no responders. XRCC3 Thr241Met polymorphism was associated with time to tumor progression and tumor response (p=0.03, p=0.002, respectively). Eighteen patients had Met/Met genotype, of which 47% responded. Twenty-six patients had heterozygous genotype, of which 17% responded. Five patients had homozygous Thr/Thr, of which 100% responded. Conclusions: Our results suggest that polymorphisms in DNA repair genes XPD and XRCC3 may be important markers in predicting clinical outcome in MBC patients treated with GC. Supported by the following NCI grant: N01 CM1701.

[Table: see text]
Bone turnover markers in postmenopausal breast cancer patients treated with fulvestrant
Authors: Agrawal A. , Hannon R. A. , Cheung K. L. , Eastell R. , Robertson J. F.
Published: March 2020

680

Background: Aromatase inhibitor (AI) therapy in patients with breast cancer accelerates bone turnover with increased secretion and excretion of bone turnover markers. Here, we report the effect of fulvestrant, an estrogen receptor (ER) antagonist with no agonist activity, on bone metabolism. Methods: 23 patients with either locally advanced primary [LAPC] or metastatic [MBC] disease who had clinical benefit (objective response/stable disease ≥6 months) during fulvestrant therapy were included in the study. Sequential tumor biopsies and blood samples were taken at baseline and after 3, 6, 9, 12 and 18 months of fulvestrant treatment (disease being stable throughout the study period). Serum was analyzed for bone formation markers (N-terminal propeptide of procollagen Type 1 [PINP] and bone-specific alkaline phosphatase [bone ALP]) and for the resorption marker C-terminal telopeptide (CTX). Data are presented as median percentage change (from baseline) in marker level with 95% confidence intervals (CI). Data were analyzed separately for patients with LAPC and MBC. Results: Changes in bone ALP (reference range: 3.9–46.8 ng/mL), PINP (20.6–82.1 ng/mL) and CTX (0.14–1.35 ng/mL) in patients with LAPC, are shown in the table . In a further 5 patients with LAPC who were already established on fulvestrant, there were no significant changes in markers over a 15-month period. No changes in markers were noted in the 4 patients with MBC. Conclusions: In this study, there was long-term stability of bone turnover markers in postmenopausal women with LAPC treated with fulvestrant over a period of 18 months. This property may be exploited in future with the use of fulvestrant earlier in the sequence of endocrine therapies particularly in the adjuvant setting and/or in patients with pre-existing decreased bone mass.

[Table: see text]

[Table: see text]
ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial
Authors: Natale R. B. , Bodkin D. , Govindan R. , Sleckman B. , Rizvi N. , Capo A. , Germonpré P. , Stockman P. , Kennedy S. , Ranson M.
Published: March 2020

7000

Background: ZD6474 is a once-daily oral agent that targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinase activity. The efficacy and safety of ZD6474 was compared with that of gefitinib, an EGFR tyrosine kinase inhibitor. Methods: Patients with locally advanced or metastatic (stage IIIB/IV) non-small-cell lung cancer (NSCLC), after failure of 1st-line ± 2nd-line platinum-based chemotherapy because of toxicity or tumor progression, received daily oral doses of ZD6474 (300 mg) or gefitinib (250 mg) until disease progression or evidence of toxicity (Part A). After a washout period of 4 weeks, eligible patients had the option to switch to the alternative treatment, which continued until a withdrawal criterion was met (Part B). The dual primary objectives in Part A were assessments of progression-free survival (PFS) and safety/tolerability. All adverse events were assessed using Common Toxicity Criteria (CTC) version 2.0. Results: A total of 168 patients received initial treatment with ZD6474 (n=83) or gefitinib (n=85). In Part A, median PFS was 11.0 weeks for ZD6474 and 8.1 weeks for gefitinib (hazard ratio [95% CI] = 0.69 [0.50–0.96], P=0.025); disease control >8 weeks was achieved in 37/83 (45%) patients receiving ZD6474 and in 29/85 (34%) receiving gefitinib. The adverse event profile of ZD6474 in Part A was similar to that seen in previous trials, and included diarrhea (CTC grade 3/4, 8.4%), rash (CTC grade 3/4, 4.8%) and asymptomatic QTc prolongation (all CTC grade 1, 20.5%). There were no unexpected safety findings with gefitinib-treated patients. In Part B, disease control >8 weeks was achieved in 16/37 patients who switched to ZD6474 (from gefitinib) and in 7/29 who switched to gefitinib (from ZD6474). Overall survival was not significantly different between patients initially randomized to either ZD6474 or gefitinib (median 6.1 and 7.4 months, respectively). Conclusions: This study achieved its primary efficacy objective, with ZD6474 demonstrating a significant prolongation of PFS versus gefitinib. These data support further confirmatory trials of ZD6474 in patients with advanced NSCLC.

[Table: see text]
Randomized phase II trial of single agent erlotinib vs. standard chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2
Authors: Lilenbaum R. , Axerold R. , Thomas S. , Dowlati A. , Seigel L. , Albert D. , Van Duym C. , Bodkin D.
Published: March 2020

7022

Background: A previous CALGB trial suggested a benefit for carboplatin-paclitaxel (CP) over P alone in pts with PS 2. Erlotinib (E) has activity in previously treated pts with low PS but has not been formally tested in 1st line. Methods: In a multi-center randomized phase II trial, untreated pts with advanced NSCLC and PS 2 were randomized to E 150 mg daily or CP (AUC 6 and 200 mg/m2) for 4 cycles. Pts in CP who progressed, did not tolerate, or refused further therapy were allowed to cross over to E. The primary endpoint was progression-free survival (PFS). QoL analysis was performed in all pts and tumor samples were obtained whenever possible. Results: As of 12/05, 98 of 102 projected pts have been accrued. Results are reported for 88 (46 E; 42 CP). Demographics were balanced except for more females in E (59%) than CP (45%). Most pts had stage IV adenoca histology. Never-smokers comprised 13% and 7% of pts respectively. Response for E: 2% PR and 30% SD; for CP, 10% PR and 45% SD. Gr 2–4 toxicities for E: rash (34%) and diarrhea (11%); for CP: nausea (12%), neuropathy (14%) and fatigue (29%). Median PFS was 2.5 mo for E (95%CI 1.28 - 2.79) and 4.0 mo for CP (95%CI 2.66 - 4.86). Of 42 pts in CP, 21 have crossed over to E. Conclusions: This is the first randomized phase II trial of E in PS 2 patients. Based on preliminary results, PS 2 patients seemed to fare better with standard CP than single agent E as initial therapy. Mature survival and QoL data will be available in June.

[Table: see text]
Phase III study of cisplatin (P) plus etoposide (E) with concurrent chest radiation (XRT) followed by docetaxel (D) vs. observation in patients (pts) with stage III non-small cell lung cancer (NSCLC): An interim toxicity analysis of consolidation therapy
Authors: Bedano P. M. , Neubauer M. , Ansari R. , Govindan R. , Einhorn L. H. , Bruetman D. , White A. , Breen T. , Juliar B. , Hanna N.
Published: March 2020

7043

Background: Concurrent chemo radiotherapy is the standard treatment for pts with unresectable stage III NSCLC. A previously reported phase II study (Gandara et al J Clin Oncol 2003) suggests that consolidation D after concurrent PE/XRT may further improve survival. HOG LUN01–24, is an ongoing phase III clinical trial comparing chemo radiation. A preliminary analysis of the differences in toxicities between PE/XRT with or without consolidation D was performed. Methods: Eligible pts had previously untreated, unresectable stage III NSCLC, ECOG PS 0–1 at time of study entry (and PS 0–2 at the time of randomization), ≤ 5% weight loss in preceding 3 months, FEV-1 > 1 L. Treatment consisted of P 50 mg/m2 days 1, 8, 29, 36 with E 50 mg/m2 days 1–5 and 29–33, given concurrently with chest XRT to 5,940 cGy (180 cGy/day) beginning on day 1. Non-progressive pts were randomized (4–8 weeks after completing PE/XRT) to receive D 75 mg/m2 iv every 21 days for 3 cycles vs. observation. We report an interim toxicity analysis associated to consolidation D. Results: From 3/02 to 12/05 220 have been registered and 149 pts have been randomized to consolidation D (n=73) or observation (n=76). Median age was 63.6 years (range 33–86); male/female 34.1%/65.9%; PS 0/1 at study entry 59.1%/40.9%; stage III A/B 40.6%/59.4%; 50.2% had FEV-1 > 2 (range 1–4.2); 44.3% were current smokers. Randomized pts have PS 0/1/2 44.3%/53%/2.7. Selected grade 3/4 toxicities associated to D include: neutropenia 23.3%, febrile neutropenia 8.2%, and pulmonary toxicity 9.6%. In addition, 26.7% of pts had dose modifications or delays on D arm, 45.2% had at least one grade 3/4 toxicity and 20.5% were hospitalized due to D-related toxicity, including 4 pts (5.5%) whose death was considered therapy related. Conclusions: Concurrent PE/XRT followed by consolidation D is associated with a high rate of grade 3/4 toxicities and hospitalizations, including treatment-related deaths. Updated toxicity data will be presented at the ASCO meeting. Whether consolidation D confers a survival advantage is not yet known.

[Table: see text]
Three-dimensional conformal involved-field radiotherapy for stage III non-small cell lung cancer
Authors: Yuan S. , Yu J. , Sun X. , Li M.
Published: March 2020

7044

Background: Radiation dose escalation is limited by the high incidence of pulmonary and esophageal toxicity, leading to calls for the omission of elective nodal irradiation (ENI) and the willingness to use involved-field radiotherapy (IFRT) in patients with stage III non-small cell lung cancer (NSCLC). Methods and Materials: Patients with inoperable stage III NSCLC were enrolled and patients with previous treatment were ineligible, as were those with supraclavicular nodal metastases, pleural effusion, the Karnofsky performance status of <80 or a weight loss exceeding 10% of baseline in the preceding 3 months. Two-hundred patients were treated with concurrent chemo-radiotherapy and randomized into IFRT group or ENI group. Two cycles of cisplatin-based chemotherapy (CHT) were delivered before radiotherapy, and another 2–3 cycles were followed after radiotherapy by the same or changed regime according to different response to the first 2 cycles of CHT. Radiotherapy was delivered using 3D treatment planning in once-daily fractions of 2 Gy to 68–74 Gy for IFRT or 60–64 Gy for ENI. The involved field consisted of the pre-CHT (or greatest) tumor volume, and any mediastinal nodes confirmed by biopsy or with a short-axis diameter of ≥1 cm on CT. Results: 193 patients had complete follow-up data. Radiation pneumonitis rate of patients with ENI was higher than patients with IFRT (29% vs. 17%, P = 0.044 ).The main cause of failure was local failure in 49% patients with ENI group and 41% with IFRT within 2 years. Only 7% of patients with IFRT developed a failure in an elective nodal region. Patients in IFRT group achieved a better overall response than ENI group (90% vs. 79%, P = 0.032). The overall survival at 1, 2, and 3 years was 59.7%, 25.6%, and 19.2% for ENI group vs. 67.2%, 38.7, and 27.3%for IFRT (P = 0.048). Conclusions: Local and distant failures remain the overwhelming modes of failure for stage III NSCLC patients. The omission of ENI did not result in any increase in isolated nodal failures, and it allowed a dose of 68–74 Gy to be safely administered to a substantial proportion of patients with inoperable Stage III NSCLC. Dose-escalation by conformal IFRT combined with CHT may improve the outcome for stage III NSCLC.

No significant financial relationships to disclose.