bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved outcome for acute lymphoblastic leukemia (ALL) in children and adolescents: Results of the MCP841—A two decades report from a developing country (India)
Authors: Sagar T. G. , Chandra A. , Devarajan S. 
Published: March 2020

6586 Background: In the 1970s, survival rates after treatment for ALL in children and young adults (< 25 years) in India were poor. The introduction of a standard protocol (MCP841) and improvements in supportive care led to an increase in the event-free survival (EFS) from <20% to 45–50% at 4 yrs. Results of treatment with protocol MCP841 between 1983–2002 have been briefly reviewed here. The MCP841 reports the first prospective, nonrandomized trial for ALL, in collaboration with NCI-US. The aim of this study was to classify immunophenotypes, to analyze clinical features and laboratory features, and to assess whether this protocol would improve the survival rate. Methods: From Jan. 1983 to Dec. 2002, 566 patients (0–25 years) were diagnosed with ALL were treated on MCP841 protocol with intensive induction, central nervous system (CNS) directed therapy and maintenance therapy. Results: From 1983–1989, 171 patients were enrolled and achieved a complete remission (CR) of 74.8% with 25.1% induction deaths and 47.6% relapsed after remission. During 1989–2002 with improvement in supportive care 395 patients enrolled. 328 (83%) of the patients achieved CR, 45 failed to respond and 59 (11.9%) had drug or disease related death before completing induction therapy. The overall 5-year EFS rate was 38.3%. The 5-year RFS rate was 44.5%. Relapse was noted in 147 of the 328 patients (44.8%). The cumulative incidence of CNS relapse was low. Age and white blood cell count is strongly associated with outcome in Western series, but was not a risk factor for EFS. At univariate and multivariate analysis the most significant determinant of a positive outcome was the achievement of CR. Comparison of patient characteristics with published series from Western nations indicated that patients had more extensive disease at presentation, as measured by WBC, lymphadenopathy and organomegaly. The proportions of ALLs with precursor T-cell immunophenotypes, were also increased. Conclusions: Our strategy to adapt to our population of patients and was effective in improving the EFS. It cannot be assumed that risk factors defined in Western populations are equally appropriate for patient assignment to risk-adapted therapy groups in less affluent countries. No significant financial relationships to disclose.
The frequency of the JAK2 V617F mutation in patients with polycythemia vera and its correlation with severity of disease
Authors: Silver R. T. , Lee S. , Jones A. V. , Rivera M. , Feldman E. J. , Roboz G. , Ritchie E. , Allen-Bard S. , Cross N. 
Published: March 2020

6587 Background: The frequency of the JAK2 V617F mutation in patients with polycythemia vera (PV) has ranged from approximately 65–97% in published reports from different institutions. Moreover, its expression has been variably correlated with certain aspects of the disease. Therefore, we quantified its frequency in patients from our institution, and also determined if its presence correlated with severity or duration of disease. Methods: We used stringent criteria to diagnose the disease PV. This included an initial CR51 red blood cell mass (RBCM) and I131 plasma volume. All causes of secondary PV were excluded. In an earlier cohort of 61 patients, we found that an increased RBCM, exclusion of secondary PV, and the presence of 3 of the following reliably diagnosed the phenotype of PV: serum erythropoietin level ≤ 5 mU/ml, platelet count ≥ 400 × 109/L, splenomegaly, clonal cytogenetic abnormalities, and an abnormal bone marrow histology. Results: JAK2 determinations were sequentially performed on 71 treated and untreated patients. Of these, 68 (97%) were V617F positive by allele-specific PCR analysis determined by pyrosequencing peripheral blood leukocyte DNA. We then ranked 48 patients who had not been treated with either imatinib or interferon (which affects JAK2 expression) by percent mutant allele arranged in quintiles. The highest percent mutation (80–100%) was noted in 11 patients with a phenotype of advanced disease which included massive splenomegaly (7/11 patients) and marrow fibrosis (6/11 patients). In contrast, of the group expressing 0–20% JAK2, 0/5 patients had palpable splenomegaly and 0/5 had fibrosis. The patients in the 2nd, 3rd and 4th quintiles had varying degrees of splenomegaly and fibrosis. Duration of disease could not be correlated with JAK2 V617F expression in our patients. Conclusions: We conclude that the JAK2 V617F mutation is an effective marker for diagnosing patients with PV and correlates with severity, but not duration, of disease. No significant financial relationships to disclose.
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against unmutated or mutant Bcr-Abl-expressing human leukemia cells
Authors: Fiskus W. , Pranpat M. , Balasis M. , Atadja P. , Manley P. , Giles F. , Bhalla K. 
Published: March 2020

6592 Background: AMN107 has potent in vitro and in vivo activity against the un-mutated and most mutant forms of Bcr-Abl tyrosine kinase (TK). We have previously demonstrated that in CML cells the pan-histone deacetylase inhibitor LBH589 depletes both unmutated and mutated Bcr-Abl, as well as attenuates p-AKT and Raf-1 levels. In the present studies we determined the effects of AMN107 and/or LBH589 in unmutated or mutated Bcr-Abl-expressing mouse BaF3 cells, or human CML K562 and LAMA-84 cells, as well as in primary CML cells procured from patients with imatinib mesylate (IM)-refractory CML. Methods: Cultured and primary CML cells were exposed to 20 to 100 nM AMN107 and/or LBH589 for 24 to 48 hours. Following this, the % of apoptotic cells was determined, as well as immunoblot analyses were performed to determine Bcr-Abl, p-STAT5, p-AKT, p-CrkL, Bim, Bcl-xL and p27 levels. Synergy between the apoptotic effects was determined by the median dose-effect isobologram analysis. Results: AMN107 was 20-fold more potent than IM, and was more potent in inhibiting Bcr-Abl TK activity and attenuating p-STAT5, p-AKT, Bcl-xL, and c-Myc levels in K562 and LAMA-84 cells. Co-treatment with LBH589 and AMN107 exerted synergistic apoptotic effects against human CML (but not the normal bone marrow progenitor cells), with more attenuation of p-STAT5, p-ERK1/2, c-Myc and Bcl-xL and increased p27 and Bim levels. LBH589 attenuated Bcr-Abl levels and induced apoptosis of mouse pro-B BaF3 cells containing ectopic expression of unmutated Bcr-Abl or the IM-resistant Bcr-AblT315I and Bcr-AblE255K. Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis in IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I. As compared to either agent alone, co-treatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Conclusions: These findings support in vivo testing of the combination of LBH589 and AMN107 against IM naïve or resistant CML, with the goal to eradicate IM sensitive or resistant CML. [Table: see text]
Cytogenetic correlation with efficacy on alemtuzumab (CAM) vs chlorambucil (CHLO) as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia (BCLL)
Authors: Dmoszynska A. , Fetni R. , Wang Y. , Belkaci M. , Sirard C. , Goldberg M. , Mayer J. , Robak T. , Skotnicki A. , Hillmen P. 
Published: March 2020

6601 Background: CAM307, a phase III, open-label, randomized comparative trial, enrolled 297 Rai stage I-IV BCLL patients with previously untreated, progressive disease requiring treatment. Patients were randomized to treatment with CAM (n=149) vs. CHLO (n=148) using standard dosing regimens. Methods: Cytogenetic assessment was conducted prior to the start of protocol-specified therapy. Chromosomal aberrations were detected by fluorescence in situ hybridization (FISH) using specific probes. Molecular cytogenetic analyses by FISH included deletions (del) 6q21, 6q telomere, 11q22–23, 13q14–14.3 and 17p13; trisomy bands of 8q24 and 12p11.1-q11.1. Results: A total of 271 patients have been evaluated. Chromosomal aberrations were detected in 207 patients (76%) while 64 patients (24%) exhibited normal karyotype. Cytogenetic abnormalities were evaluated by response [overall response rate (ORR) and complete response (CR)] to each therapy based upon an independent response review. The comparisons of ORR and CR between treatment arms for each mutation type were calculated using the Exact method. Conclusions: Preliminarydata demonstrate a statistically significant superior response to CAM in patients with del 13q (ORR and CR) and del 11q (ORR) as well as a statistically significant superior CR to CAM in patients with normal cytogenetics. In addition, although the sample size is small, there is a trend towards a better ORR in patients with del 17p. Further exploration of CAM response rates relative to cytogenetic abnormality is warranted. [Table: see text] [Table: see text]
Quality of life, depression and anxiety in chronic lymphocytic leukemia during phases of “watchful waiting” and active treatment
Authors: Levin T. 
Published: March 2020

6603 Background: Although chronic lymphocytic leukemia (CLL) accounts for 25–30% of leukemia cases in the USA, little is known about its quality of life (QOL) and psychosocial burden. The purpose of this study was to compare QOL, anxiety and depression in watch and wait versus actively treated CLL. Methods: Using a cross-sectional design, 105 patients were recruited from a CLL research database. 57 were classified as watch and wait and 48 as receiving or having received chemotherapy for CLL. The patients completed a battery of QOL measures including the SF-36, FACT-Lym, Beck Depression Inventory (BDI-II), Beck Anxiety Inventory (BAI) and the Patient Health Questionnaire. Results: No differences were found between the treatment groups on the main QOL outcome measures - Mental Component Score, Physical Component Score, FACT-G, FACT-lymphoma (15 item), BDI-II and BAI. There was a clear age effect: younger patients (<60 years old) have worse Mental Component (p=0.0001), FACT-G (p=0.060), depression (p=0.014), Role Emotional (p=0.042), Mental Health (p=0.001), FACT-Emotional (p=0.0001) and FACT-Social (p=0.002) scores. Younger watch and wait patients seem to be particularly vulnerable to anxiety (p=0.052). Social and emotional QOL are statistically similar in both newly diagnosed and patients diagnosed six or more years ago, although patients do carry a greater physical QOL burden with time (p=0.05). Conclusions: Overall QOL, depression and anxiety are remarkably similar in watch and wait versus actively treated CLL, despite the latter group having, by definition, later stage disease. Younger patients (<60 years old) seem particularly vulnerable to having a reduced emotional and social QOL and having more depression. Younger watch and wait patients stood out as suffering from more anxiety. Patients diagnosed for more than 6 years carry a greater physical QOL burden, but social and emotional QOL are similar to newly diagnosed patients. Implications of these findings are considered. [Table: see text] No significant financial relationships to disclose.
A multi-center, open-label study to evaluate the safety and efficacy of pentostatin, cytoxan, and rituxan (PCR) in the treatment of previously untreated or treated stage III or IV, low-grade CLL
Authors: Nyman D. W. , Mena R. , Robles R. , Auerbach M. , Pandit L. 
Published: March 2020

6606 Background: The decision to treat indolent CLL is often based on progressive bulky disease, worsening symptoms, and increasing hematological derangement. When treatment is indicated, these lymphoproliferative disorders are sensitive to combination immunochemotherapies utilizing pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), a potent anti-CD20 monoclonal antibody. P+C+R represents a promising new approach in the treatment of patients with low grade CLL. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with low-grade stage III/IV CLL (modified Rai classification). Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of 8 cycles. Clinical evaluation (including CT scan) was performed after cycles 2, 4, 6, and 8. Patients were stratified by disease and by prior treatment status. Results: The intent-to-treat (ITT) population consisted of 41 CLL patients (median age 64, range 36–85) who received a total of 207 cycles (median 4 per patient). ECOG status at enrollment was 0 (66%), 1 (27%) and 2 (7%). The overall response rate was 61% (CR 13%, PR 48%). One grade 4 neutropenia was documented. Four deaths have been recorded. An 81 YO patient was hospitalized 8 days after cycle 1; death, due to sepsis, occurred 22 days later. The death of an 83 YO was reported 10 days after cycle 2 as a result of an acute MI. An 83 YO patient, who developed gastroenteritis, was hospitalized 10 days after cycle 2. This progressed to dehydration and atrial flutter. Death came as a result of pulmonary edema and ASHD. An 82 YO man was hospitalized 4 days after completing cycle 2. He presented with extreme dyspnea but cause of death was CLL. Conclusions: This immunochemotherapeutic regimen is active in Grade III/IV CLL and the incidence of significant toxicities was low with deaths occurring only in elderly (>80 YO) patients. Updated results of this trial will be presented at the ASCO meeting. No significant financial relationships to disclose.
Bone and cardiac status in 10-year survivors of breast cancer
Authors: Trudeau M. E. , Lickley H. L. , Zhang L. , Hawker G. , Narod S. , Sawka C. 
Published: March 2020

681 Background: A prospective case-control study was carried out on 425 women treated for breast cancer who survived for 10 years without evidence of recurrence (cases) matched for age, race and length of follow-up from diagnosis to 425 women with benign breast disease followed for 10 or more years (controls). For cases, only 23% received chemotherapy and 33% hormone therapy. Methods: We examined multiple indicators of physical and emotional well-being and report here the results pertaining to cardiac and bone health. Bone mineral density (BMD) was assessed using DXA at the lumbar spine and hip, expressed as gm/cm2, and classified as normal/low bone mass/osteoporosis. Cardiac health was assessed using 10 year cardiovascular risk, calculated as low, moderate or high based on age, cholesterol and triglyceride levels, smoking history and blood pressure (according to the calculation published by Genest J et al. CMAJ 2003). Treatment received for both bone and cardiac disease was evaluated. The comparison of cases and controls was assessed using the Wilcoxon non-parametric or Chi-squared tests. Results: Body mass index (BMI) was significantly greater for cases versus controls (27.5 ± 2.4 vs 26.7 ± 4.9; p = 0.034). The mean BMD (corrected for weight) was 1.08 ± 0.05 g/cm2 at the spine for cases, compared with 1.11 ± 0.06 g/cm2 for controls (p <0.0001). Among those with osteoporosis at follow-up, 30% of cases compared with 35% of controls had been treated with bisphosphonates; 10% cases and 55% of controls with osteoporosis had received HRT. There were no significant differences in 10-year cardiovascular risk between the cases and controls. Overall, 78% were low, 18% moderate, and 4% high risk. Cholesterol-lowering medications were prescribed to only ≤23% of the moderate and high risk groups in both cases and controls. Conclusions: Despite greater BMI, cases had lower BMD and were less likely to have received treatment for osteoporosis than were controls. 10 year cardiovascular risk was not significantly different in the cases versus controls despite the greater use of HRT in the controls. Both groups appear to be undertreated with cholesterol-lowering medications by today’s standards of care. These findings can help to inform the content of survivorship programs. No significant financial relationships to disclose.
Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II trial
Authors: Socinski M. A. , Novello S. , Sanchez J. M. , Brahmer J. A. , Govindan R. , Belani C. P. , Atkins J. N. , Gillenwater H. H. , Palleres C. , Chao R. C. 
Published: March 2020

7001 Background: Sunitinib malate (SU11248) is an oral, multitargeted tyrosine kinase inhibitor targeting VEGFR, PDGFR, KIT, FLT3 and RET on tumor cells, tumor neovasculature and pericytes. This is the initial report of an open-label, two-stage, multicenter phase II trial evaluating the single-agent activity of sunitinib in refractory NSCLC. Methods: Eligibility criteria included confirmed diagnosis of NSCLC, ECOG PS 0–1, no recent gross hemoptysis, no brain metastases, patients (pts) previously treated with 1–2 chemotherapy regimens, and adequate end-organ function. Pts received sunitinib at 50 mg/day po for 4 weeks (wks) followed by 2 wks off treatment (6 wks considered a cycle). Results: A total of 64 pts were enrolled and 63 pts treated, median age 61 yrs (range 33–87); adenocarcinoma (64%), squamous cell carcinoma (22%), other (14%); 66% male; PS 0:1, 45%:55%; median number of prior regimens: 2 (range 1–4); median time since the prior regimen: 2 months (range 1–21). To date, 63 pts have started cycle 1, 46 cycle 2, 22 cycle 3, 6 cycle 4 and 1 cycle 5. Grade 3–4 toxicities included fatigue/asthenia (21%), nausea (7%), vomiting (7%), abdominal pain (7%), and hypertension (5%). Most toxicities were grade 1–2 and included asthenia/fatigue (68%), anorexia (40%), dyspnea (37%), cough (35%), nausea (33%), mucositis (32%), dysgeusia (25%), diarrhea (21%), vomiting (19%), and constipation (19%). Grade 5 toxicities include pulmonary hemorrhage (n=2) and cerebral hemorrhage (n=1). Thus far, 6 confirmed partial responses have been observed among 63 treated pts (9.5%, 95% CI: 3.6–19.6%). Stable disease has been observed in an additional 12 pts (19.0%). Survival data are pending and will be presented. Conclusions: Sunitinib has provocative single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents. Sunitinib is well tolerated in this population. The trial is being extended to explore a continuous dosing strategy of sunitinib at 37.5 mg/day po. Based on these results, further trials are warranted and are ongoing with sunitinib in combination with standard agents/regimens. [Table: see text]
Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633
Authors: Strauss G. M. , Herndon J. E. , Maddaus M. A. , Johnstone D. W. , Johnson E. A. , Watson D. M. , Sugarbaker D. J. , Schilsky R. A. , Vokes E. E. , Green M. R. 
Published: March 2020

7007 Background: In 2004, preliminary results of CALGB 9633 demonstrated statistically significant evidence that adjuvant chemotherapy with paclitaxel and carboplatin (PC) improved disease-free (DFS) and overall survival (OS) in resected stage IB NSCLC. Indeed, the study was closed early by the DSMB after a planned interim analysis demonstrated a p value for OS less than a prespecified stopping boundary. However, two larger trials, NCIC-JBR10 and ANITA, have shown significant OS advantages with adjuvant chemo, but failed to demonstrate improved survival in the stage IB subset. This report provides more mature data from CALGB 9633. Methods: InCALGB 9633, stage IB patients (pts) were randomized following resection to paclitaxel 200 mg/m2 and carboplatin AUC 6 q3wks ×4 cycles or to observation. While initially planned to accrue 500 pts, the accrual rate was <50% of expected. Because slow accrual allowed longer observation times for each pt, the accrual target was reduced to 384 pts. OS is the primary endpoint. The redesigned study had 80% power to detect a hazard ratio (HR) of 0.67 after 150 observed deaths using a 1-tailed logrank test conducted at the 0.05 level of significance. Results: Between 9/15/96 and 11/26/03, 344 pts were randomized. Median follow-up is 54 mo. Demographics and toxicity has been previously reported (JCO Sup, 22:621a, 2004). The current intent-to-treat analysis shows a significant improvement in DFS favoring adjuvant chemo (HR=0.74; 90% 2-sided CI: 0.57–0.96; p=0.027). There is a trend toward improvement in OS that is not significant (HR=0.80; 90% CI: 0.60–1.07; p=0.10). There is, however, a significant advantage in 3-yr survival (79% vs. 70%; p=0.045). Five-yr survival is not different (60% vs. 57%; p=0.32), although median follow-up is <5 yrs and CIs are wide. Continued follow-up is planned since only 131 of 150 deaths required for final analysis have been observed. Conclusions: This updated but “preliminary” analysis no longer shows a significant OS advantage for adjuvant chemotherapy in stage IB NSCLC. However, the re-designed study does not have adequate power to detect small differences in OS that may be clinically significant. Advantages in DFS and 3-yr survival support continued consideration of adjuvant PC in stage IB NSCLC. [Table: see text]
A randomized comparison of carboplatin/vinorelbine versus carboplatin/gemcitabine in advanced non-small cell lung cancer (NSCLC)
Authors: Helbekkmo N. , Sundtroem S. H. , Aaseboe U. , Brunsvig P. F. , Von Plessen C. L. , Bremnes R. M. 
Published: March 2020

7033 Background: Carboplatin/vinorelbine (CV) and carboplatin/gemcitabine (CG) are novel 2-drug combinations in the treatment of NSCLC. In a randomized national multicenter phase III study in stage IIIB and IV patients (pts), we compared these regimens with respect to efficacy, toxicity and quality of life (QoL). Methods: Chemonaive pts with histologically or cytologically proven NSCLC, stage IIIB or IV and ECOG performance status (PS) 0–2 were eligible. There was no upper age limit. Pts received vinorelbine 25 mg/m2 or gemcitabine 1000 mg/m2, both administered on day 1 and 8, in combination with carboplatin (Chatelut AUC 4) at day 1. Three courses were administered in 3-week cycles. QoL questionnaires were completed at baseline, before each cycle and then every 8 weeks up to one year. Primary endpoints were survival and QoL and secondary endpoints toxicity and time to progression (TTP). Stratification was done for age, stage and PS, and the planned sample size per arm was minimum 200. The analyses were performed on an intention-to-treat basis Results: From Oct 2003 through Dec 2004, 433 pts from 33 institutions were randomized to CV (n=218) or CG (n=215). Follow-up was minimum one year. There was no difference in overall survival between the two arms (p=0.89). Median survival was 7.3 vs. 6.5 months and 1-year survival 28% and 31% in the CV and CG arm respectively. TTP was significantly longer in the CG arm (p=0.006) with median TTP 4.2 vs. 3.9 months. There was significantly more grade 3–4 anemia and thrombocytopenia in the CG arm (p<0.001) and more grade 3–4 leucopenia in the CV arm (p= 0.001). More pts in the CG arm needed transfusions of blood (p=0.003) or platelets (p=0.001). There was no difference between the arms with respect to neutropenic infections (p=0.87). QoL data are still being analyzed and will be presented at ASCO. Conclusions: Overall survival was similar in the two treatment arms. In the CG arm, the median TTP was longer, but grade 3–4 toxicity requiring interventions, was more frequent when compared to the VC arm. No significant financial relationships to disclose.