bluuebunny/crossref_metadata_2025_split huggingface dataset:
K562/GM-CSF vaccination reduces tumor burden, including achieving molecular remissions, in chronic myeloid leukemia (CML) patients (PTS) with residual disease on imatinib mesylate (IM)
Authors: Smith B. , Kasamon Y. L. , Miller C. B. , Chia C. , Gocke C. , Kowalski J. , Tartakovsky I. , Biedrzycki B. , Jones R. J. , Hege K. , Levitsky H. I. 
Published: March 2020

6509 Background: Despite high rates of clinical responses to IM, molecular complete responses are rare. The curative potential of allo transplantation and donor lymphocyte infusions underscores CML’s responsiveness to T cell mediated immunity. K562/GM-CSF is a tumor vaccine derived from a CML cell line that expresses several defined CML associated antigens and has been genetically engineered to produce GM-CSF. A pilot vaccination strategy was developed to determine if K562/GM-CSF immunotherapy in combination with IM could enhance T cell reactivity and clinical responses in pts having persistent, measurable disease despite 1 or more years on IM. Methods: Eligibility required pts to have achieved a major cytogenetic response (<35% Ph+ cells) while on a stable dose of IM. Disease burden was measured serially over 12 wks prior to vaccines. 4 vaccines were administered in 3 wk intervals, each consisting of 1 × 108 irradiated K562/GM-CSF cells distributed over 10 sites, with or without topical 5% Aldara (a Toll-like receptor 7 agonist) used as a vaccine adjuvant. Disease burden was measured at 6 wk intervals for 9 mos from the first vaccine and specimens were banked for measurement of immune responses. Results: The trial enrolled 19 pts, all have completed the planned 4 vaccinations and 14 pts have completed all planned disease burden measurements. The median age is 52 (range 28–76) yrs with a median time from dx to enrollment of 57 (range 16–111) mos. Pts were on IM for a median of 37 (13–53) mos prior. 4 of 19 pts had FISH pos as their best previous response (BPR) with 2 becoming FISH neg post-vaccine (1 became PCR neg and 1 achieved a >1 log reduction in disease burden by PCR). Of the 15 pts whose BPR was FISH neg/PCR pos, 4 are now PCR neg post vaccine, 4 experienced a >1 log and 1 had 0.5–0.99 log reduction by PCR. Mean PCR levels for the 19 pts declined btwn pre- and post-vaccine measures (p=0.01). 3 of 5 pts achieving PCR neg remain so beyond 6 months. Only 1 pt progressed having entered the study with a heavy disease burden (30% FISH pos). Conclusions: K562/GM-CSF vaccine appears to improve responses in pts on IM, including achieving complete molecular remissions, despite long durations of previous IM therapy. [Table: see text]
Nonmyeloablative hematopoietic cell transplantation (HCT) for treatment of patients (pts) with fludarabine-refractory chronic lymphocytic leukemia (CLL) results in prolonged median survival
Authors: Sorror M. , Sandmaier B. , Maris M. , Storer B. , Radich J. , Agura E. , Niederwieser D. , Blume K. , Storb R. , Maloney D. 
Published: March 2020

6520 Background: Pts with fludarabine-refractory CLL have a poor prognosis with median survival of 12 months. A phase II trial of Campath resulted in median survival of 16 months. Curative alternatives are required. Methods: We previously reported 2-year overall survival (OS) of 60% for 64 pts treated with nonmyeloablative HCT from related (n=44) or unrelated (n=20) donors (Sorror. JCO, 2005). Those pts were refractory to fludarabine (88%) ± additional agents. Eligibility criteria, conditioning and immunosuppression regimens, and primary endpoint were previously described. Here, we extended the follow up to 38 (range: 10–74) months after HCT ( Table ). Results: Chronic extensive graft-versus-host disease (GVHD) at 3 years was 53% and non-relapse mortality (NRM) was 27%. Among 30 pts who achieved initial responses {25 complete (CR) and 5 partial (PR)}, one patient died while in CR from NRM, one patient with PR progressed, while remaining 28 pts continued alive and in remission. CR and relapse rate at 3 years were 54% and 32%, respectively. Unrelated recipients had a significantly higher CR rate than related recipients. Ten responding pts were tested for molecular eradication of their disease and all were negative at a median of 52 months. There were 6 deaths in this extended follow up, 5 from relapse/progression and one from pneumonia. Overall, 33 pts are alive; 24 in CR, 4 in PR, 2 with stable disease, and 3 with relapse/progression. Estimated 3-year rates of OS, disease-free survival (DFS), and NRM were 54%, 42%, and 27% respectively. In multivariate analysis, high pretransplant comorbidity scores predicted higher NRM and worse OS while bulky lymphadenopathy predicted increased risk of progression. Conclusion: Nonmyeloablative HCT resulted in an extended median survival of greater than 3 years for pts with fludarabine-refractory CLL. The use of unrelated grafts was associated with a trend toward better DFS. [Table: see text] No significant financial relationships to disclose.
Treatment of patients (pts) with chronic myeloid leukemia (CML) and imatinib failure after developing BCR-ABL kinase mutations with allogeneic stem cell transplantation (ASCT)
Authors: Champlin R. E. , Jabbour E. , Cortes J. , Kantarjian H. , Andersson B. S. , Giralt S. , De Lima M. 
Published: March 2020

6545 Background: ASCT is curative for many pts with CML, and may be effective after imatinib failure. Resistance to imatinib is most often associated with point mutations in the Bcr-Abl kinase domain. The outcome of pts with Bcr-Abl kinase mutations after ASCT is not known. Methods: We assessed the outcome of ASCT in 10 pts with CML (chronic phase [CP]=3, accelerated phase [AP]=4, blast phase [BP]=3) harboring 9 different protein kinase mutations. P-loop mutations were detected in 5 (50%) pts; the most common type of mutation was T315I detected in 2 pts (one AP and one CP). At the time of ASCT, one pt was in major molecular remission (MMR) (BP, Q252H), one was in major cytogenetic response (CP, T315I), and 2 were in complete hematologic response (2 BP, Y253H and E255K). Preparative regimen was busulfan based regimen in 7 and fludarabine + melphalan in 3 pts. Eight male and 2 female pts, median age of 44 years (range, 26–63 years), received their ASCT between July 2002 and October 2005. Donor was fully matched related in 5 (50%) and unrelated in 5 (50%) pts. Source of stem cells was peripheral blood and bone marrow in 3 and 7 pts, respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini methotrexate. Results: All patients engrafted; there was no treatment-related mortality. Chimerism studies at day 30 and 100 post ASCT were available in 9 pts and were 100% of donor type in all but one. Nine pts responded: 7 achieved a complete molecular remission (CMR) and 2 achieved a MMR. Two (22%) pts (Q252H [BP] and T315I [AP]) relapsed and died of disease progression after a median of 9 months. All the remaining 7 pts were in CMR for a median of 17 months (range, 3–22+ months). Conclusions: ASCT is an important salvage option for pts who develop resistance to imatinib through Bcr-Abl mutations. Early introduction of such strategy may result in better outcome. No significant financial relationships to disclose.
Autologous or allogeneic stem cell transplantation versus chemotherapy in acute myeloid leukemia and subgroups: A multicenter trial by the German AML Cooperative Group
Authors: Buchner T. , Berdel W. E. , Kienast J. , Kolb H. , Staib P. , Reichle A. , Schoch C. , Haferlach T. , Sauerland M. C. , Hiddemann W. 
Published: March 2020

6556 Background: From the data available the role of autologous and allogeneic stem cell transplantation (auto/allo SCT) versus post-remission chemotherapy appears uncertain and is readdressed in the present trial. Methods: Pts were stratified for cytogenetic groups, de-novo/secondary AML, LDH, WBC, and were up-front randomized in one step to induction by HAM-HAM vs TAD-HAM, and to G-CSF priming vs. no G-CSF. These two randomizations did not result in different outcome. Pts were also upfront randomized to auto SCT vs monthly maintenance chemotherapy. Within the two randomized arms pts with histocompatible family donors underwent priority allo SCT. Results: Since 1999 840 pts 16–60 y of age entered the trial. 14%, 62%, 21%, and 3% of pts had favorable, intermediate, unfavorable and unknown karyotype, and 19% had secondary AML. 70% of pts went into complete remission (CR). The probability of overall survival (OS) at 3 years in the auto SCT and the maintenance arm is 43% vs 41% (p=0.52), the relapse-free survival (RFS) is 40% vs 40% (p=0.78), and the ongoing remission duration (RD) is 48% vs 46% (p=0.65). Among pts alive and in CR 73% did receive auto SCT or maintenance or allo SCT, similar to previous trials (NEJM 332:217,1995, Blood 90:2978,1997, Lancet 351:700,1998, NEJM 339:1649,1998). The outcome according to therapy given in the auto SCT arm and the maintenance arm shows ongoing RD of 44% vs 50% (p=0.31), RFS of 44% vs 48% (p=0.35), and OS of 53% vs 69% (p=0.005). 128 pts underwent allo SCT. In a matched pair analysis with concordance of pairs in karyotype, de-novo/secondary AML, induction chemotherapy, and RFS at the time of SCT, RD shows a superiority of allo SCT (p<0.001), while OS is similar between the two arms (p=0.65). No prognostic subgroup with a special benefit from auto or allo SCT can be identified so far. Conclusions: Among current alternative strategies only novel approaches in allo SCT reducing the high transplant related death rate may further improve the cure of pts with AML and subgroups. No significant financial relationships to disclose.
Combination therapy with arsenic trioxide (ATO), all-trans retinoic acid (ATRA), and gemtuzumab ozogamycin (GO) in relapsed acute promyelocytic leukemia (APL)
Authors: Aribi A. M. , Kantarjian H. , Estey E. , Freireich E. , Koller C. , Thomas D. , Kornblau S. , Faderl S. , Laddie N. , Garcia-Manero G. , Cortes J. 
Published: March 2020

6558 Background: Relapse occurs in 20 to 30% of patients with APL treated with ATRA. ATO is an effective agent for salvage of APL relapse, and GO has shown activity in APL due to the high expression of CD33. Methods: We investigated the efficacy of a combination regimen of ATO, ATRA and mylotarg in 8 patients with APL in 1st relapse. All patients had been previously treated with regimens that included ATRA and chemotherapy. Patients received ATO 0.15 mg/kg intravenously until marrow complete remission (CR). Once in marrow CR patient was observed until CR. Once CR was achieved or 60 days from the start of induction therapy, consolidation therapy was initiated with 1) ATO 0.15 mg/kg intravenously for 5 days per week for 4 weeks, repeated every 8 weeks for total of 5 courses, 2) ATRA 45mg/m2 orally twice daily 10 days per month for 10 months, and 3) GO 9 mg/m2 intravenously monthly for 10 months. Patients then received maintenance with 1) idarubicin 8mg/m2daily on day 1 and 2 every month for 3 months, 2) ATRA 45mg/m2orally daily 10 days per month for 14 months, 3) 6-MP 50 mg orally 3 times per day for 11 months and methotrexate 15mg/m2 orally once a week for 11 months. Results: The median age is 51years (range, 18–68 years), median WBC count 1.9 ×109/L (range 0.9–7.7 ×109/L), platelets 71 ×109/L (range, 6–164 ×109/L). The median duration of 1st CR was 7 months (range, 3 to 17 months). Seven patients achieved CR with median time to remission of 8 weeks (range 3–15 weeks). One patient achieved marrow CR after 3 weeks of therapy but is too early to evaluate for CR. All 7 are still in CR after a median follow up of 36+ months (range, 1+ to 51+ months). All seven patients achieved molecular remission. All patients had myelosuppression but there was no grade 3–4 extramedullary toxicity. Two patients died, one died secondary to complication related to metastatic lung adenocarcinoma, and the other patient died of sepsis. Conclusions: We concluded that the combination of ATO, ATRA and mylotarg is effective and may achieve durable remissions in many patients with APL in first relapse. It should be considered as an effective alternative to allogeneic or autologous transplant. No significant financial relationships to disclose.
The financial impact of trastuzumab in metastatic breast cancer: The experience of the Institut Curie
Authors: Doz M. A. , Le Tourneau C. D. , Guilhaume M. S. , Dieras V. , Vincent-Salomon A. , Courbard M. , Le Vu B. , Buron C. C. , Livartowski A. 
Published: March 2020

663 Purpose: To estimate, in term of public health on the scale of a region, the cost of trastuzumab and to point out the financial impact of this new targeted therapy in the adjuvant setting. Methods: To understand the consequences of the spending on of trastuzumab at a macroeconomic level in the French hospital financing system, we decided to focus on an establishment in particular, and to analyze the increasing spending of trastuzumab at a micro-economic level, to provide a cost analysis of patients treated with trastuzumab for HER2-overexpressing metastatic breast cancer. We retrospectively reviewed 137 medical reports of patients who received trastuzumab either in combination with chemotherapy or as a single agent and in maintenance therapy. Median age of the patients was 52 years (range 32- to 79+). Eighty five percent had 3+ HER2 overexpression and fifteen percent had 2+ HER2 (FISH amplified). Results: Median survival from first treatment with trastuzumab was 38.5 months (range 0,04–53,06+). The cost of the first year treatment is in average €43,435.58 per patient, for the second year €36,419.01 and for the third year €37,198.94. Drugs cost represents 78% of the hospital stays cost for a patient and 2.9% of the budget of Institut Curie. Conclusions: This retrospective analysis showed the very high level of expenses of trastuzumab to treat metastatic breast cancers. With the adjuvant use of trastuzumab, it is expected that these expenses are going to increase exponentially. No significant financial relationships to disclose.
Biomarkers detected by proteomic analysis predicts breast cancer response to neoadjuvant chemotherapy
Authors: Shen D. , He J. , Gornbein J. , Chen Z. , Faull K. F. , Whitelegge J. P. , Chang H. R. 
Published: March 2020

669 Background: Neoadjuvant chemotherapy provides an excellent opportunity for objective assessment of treatment-induced tumor response and for studying biomarkers characteristic of therapy-induced tumor responses. Methods: Proteomic analysis of T3/T4 breast cancer was performed in patients with locally advanced breast cancer in a phase II clinical trial. The breast cancer specimen was obtained before and after four cycles of Taxotere/Carboplatin/±Herceptin treatment. Two proteomic approaches, SELDI mass spectrometry and Clontech Ab Microarray 500, were used to screen for protein biomarkers that predict response of breast cancer to chemotherapy. Results: Five tumors with pathologically complete response (pCR) and 29 tumors with various amounts of residual tumors (Non-pCR) were analyzed by SELDI-TOF using the NP 20 chip. The normalized mass signals were compared between pCR vs Non-pCR at each aligned location by Wilcoxon rank sum test. Statistically significant differences were found at 22 m/z locations using a liberal p <0.20 criterion. The best univariate predictor occurred at m/z 14960 (p=0.004), which correctly classified 5/5 pCR spectra (100%) and 24/29 Non-pCR spectra (83%). A multivariate classification tree developed using m/z 14960 and m/z 12138 intensities correctly classified all 34 spectra. Ab microarray analysis was performed on five pCR tumors and in five tumors with the largest residual cancer. The Internal Normalization Ratio (INR) was calculated and used to compare the difference of protein expression between the two groups. Eight differentially expressed protein biomarkers were selected with the criteria of a statistically significant (Student t, p<0.05) expression change of <0.77 or >1.3 fold. Three proteins (Tat-SF1, PYK2 and PTP1B) were higher, and five (E2F2, IL1b, FEN1, CDC37 and ACM1) were lower in tumors with pCR. The unsupervised hierarchical clustering of the 10 samples by these eight proteins completely separated the pCR tumors from the poor responders. Conclusions: Our study suggests that bothSELDImass spectrometry and antibody microarray may be used to predict the tumor response to neoadjuvant chemotherapy. Proteomic analysis may be useful in developing tailored chemotherapy for breast cancer. [Table: see text]
Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial
Authors: Mehta M. P. , Gervais R. , Chabot P. , Shapiro W. R. , Patchell R. A. , Glantz M. J. , Recht L. , Phan S. , Smith J. A. , Renschler M. F. 
Published: March 2020

7014 Background: In a previous randomized study, RT plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM) (p=0.048). Methods: This Phase 3 trial randomized pts with BM from NSCLC and KPS ≥70 to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10. A sample size of 550 was based on α=0.001, β=0.8, hazard ratio (HR)=0.65, with a primary endpoint of TNP determined by a blinded events review committee. Results: 554 pts received RT (N=275) or RT+MGd (N=279), 348 in North America (NA), 206 in Europe and Australia (EA). Treatment arms were balanced for factors of known prognostic importance. Most pts had multiple BM (81%), extracranial metastases (51%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with >92% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4%), ALT increase (3%), and fatigue (3%). TNP improved from 10 months (mo) for RT to 15.4 mo for RT+MGd, p=0.12, HR=0.78. Time to neurocognitive progression was also improved, p=0.089, HR=0.79. More RT pts required salvage brain surgery or radiosurgery than RT+MGd pts (41 RT, 19 RT+MGd). In NA pts, statistically significant prolongation of both TNP, from 8.8 mo for RT to 24.2 mo for RT+MGd, p=0.004, HR=0.53, and time to neurocognitive progression, p=0.04, HR=0.69, were observed. In NA, RT was started sooner after the diagnosis of BM than in EA (median/mean 1.6/2.2 weeks NA vs. 3.0/6.5 weeks EA). There was a significant interaction between earlier RT and MGd benefit, p=0.017. When RT was initiated within 3 weeks of BM diagnosis, regardless of region, TNP was significantly prolonged by addition of MGd (N=378, p=0.006, HR=0.59). When initiation of RT was delayed beyond 3 weeks after BM diagnosis (N=176, 21% of NA pts, 50% of EA pts), MGd benefit was lost. A major reason for RT delay was use of chemotherapy as initial treatment for BM in 41 pts, 17% NA, 83% EA. Conclusions: MGd significantly prolonged TNP in NSCLC patients with BM receiving prompt RT in this randomized Phase 3 trial. The majority of patients in NA received prompt RT (79%), leading to a statistically and clinically significant benefit when combined with MGd. [Table: see text]
Excision cross-complementing group 1 (ERCC1) single nucleotide polymorphisms (SNPs) and survival in cisplatin (cis)/docetaxel (doc)-treated stage IV non-small cell lung cancer (NSCLC) patients (p): A Spanish Lung Cancer Group study
Authors: Taron M. , Alberola V. , Lopez Vivanco G. , Camps C. , De Las Peñas R. , Alonso G. , Provencio M. , Salvatierra A. , Sanchez J. , Rosell R. 
Published: March 2020

7053 Background: SNPs are the result of historical errors in DNA replication or repair that have been inherited through generations and are now shared among individuals. ERCC1 belongs to the nucleotide excision repair pathway. We examined whether ERCC1 SNPs 118 C/T and C8092A affect the repair of cis DNA lesions and thereby influence survival in cis-treated NSCLC p. Methods: SNP genotyping of ERCC1 118C/T and C8092A was performed by the TaqMan assay, and results were correlated with median survival (MS) in 706 cis/doc-treated stage IV NSCLC p. Results: Characteristics: 590 male, 116 female; performance status (PS) 0: 216 p (30.6%), PS 1: 480 p (68%), PS 2: 10 p (1.4%); adenocarcinoma, 371 p (53%). Overall response rate: 30%. After a median follow-up of 7.8 months (m) (range, 1–47 m), overall MS was 8.9 m. SNP frequencies: 118 T/T, 40.2%; C/T, 45.4%; C/C, 14.4%; C8092A C/C, 57.6%; C/A, 36%; A/A, 6.4%. MS according to 118 C/T SNP: T/T, 8.9 m; C/T, 9.5 m; C/C, 10 m (P = 0.51). MS according to C8092A SNP: C/C, 9.3 m; C/A, 10.2 m; A/A, 7.2 m (P = 0.05). When stratified by PS, the association between C8092A and MS is stronger for p with PS 0: C/C, 15.9 m; C/A, 13.8 m; A/A, 8.7 m (P = 0.04). Conclusions: This is the largest study to date reporting the effect of ERCC1 C8092A SNP on MS in stage IV NSCLC p treated with a single regimen. The uncommon A/A genotype predicts poor survival in p treated with dis/doc. No significant financial relationships to disclose.
Cisplatin(P)-including triplets versus P-free doublets in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC): SICOG 0101 randomized trial
Authors: Comella P. , Palmeri S. , De Cataldis G. , Filippelli G. , Cioffi R. , Farris A. , Maiorino L. , Massidda B. , Roselli M. , Gambardella A. 
Published: March 2020

7103 Background: We previously reported that triplets with P-gemcitabine (G) plus vinorelbine (V) (PGV) or paclitaxel (T) (PGT) prolonged the survival (S) of advanced NSCLC patients (pts) in comparison with P-based doublets (PG or PV). Aims of the present study were: (1) to compare (log-rank test) the S of P-based triplets vs P-free doublets, and (2) to compare (Fisher test) safety and response rate (RR) of T- and V-regimens. Methods: A 2x2 factorial design was adopted. Pts aged ≤ 70 years, with PS (ECOG) < 2, inoperable stage IIIA, IIIB, or IV NSCLC were randomly treated with: GV = G 1,000 mg/m2 + V 25 mg/m2 on day (D) 1 and 8; GT = G 1,000 mg/m2 + T 125 mg/m2 on D 1 and 8; PGV = P 50 mg/m2 on D 1 and 8 + GV; PGT = P 50 mg/m2 on D 1 and 8 + GT. In all arms, cycles were repeated Q 3 weeks. Only responder pts after 3 cycles received further chemotherapy (CT). Thoracic RT was delivered after CT to pts with intra-thoracic disease. 330 events were required to have a 90% power to demonstrate (two-sided P < 0.05) a 30% reduction of hazard of death. Results: From April 2001 to December 2005, 431 pts were recruited in the 4 arms. Characteristics in % were well balanced in P-based triplets and P-free doublets: males, 84/91; PS 0, 25/23; squamous cell carcinoma, 38/42; weight loss, 22/29; stage IV, 66/65; CNS metastases, 5/8; ≥ 2 metastatic sites, 29/30. So far, 411 pts were assessed for response: RR of triplets vs doublets was 88/204 (43%) vs 68/207 (33%) (P = 0.020), and of T-based vs V-based regimens was 40% vs 36% (P = 0.218). To date, 313 deaths were registered: median and 1-year S were 10.6 mo. and 41% for pts treated with triplets, and 10.4 mo. and 39% for pts treated with doublets (P = 0.786). Over initial 3 courses, occurrence of grade ≥ 3 toxicity (T vs V, % pts) was: neutropenia, 18% vs 30% (P < 0.004); febrile neutropenia, 4% vs 7%; platelets, 7% vs 12% (P = 0.056); anemia, 5% vs 7%; vomiting, 1% vs 2%; diarrhea, 6% vs 3%; stomatitis, 3% vs 0.5%. Grade ≥ 2 neurotoxicity occurred in 1% of both groups. Conclusions: Activity was significantly higher with P-based triplets, but they did not affect the OS. T-based regimens were equally active and less toxic than V-based regimens. Therefore, the GT regimen may represent a new standard of care for advanced NSCLC pts. No significant financial relationships to disclose.