bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating a new income source for medical oncologists: Market research
Authors: Hoffman K. R. 
Published: March 2020

6629 Background: Recently market research has become a ‘booming business‘ serving pharmaceutical and biotechnology firms and financial institutions. From internet studies and focus groups to consultations with Wall Street analysts, medical oncologists are getting increasing involved in providing their expertise in non-patient matters. Payment is usually of a greater amount that what one would earn from direct patient care. Potentially, this may be the source of significant income. Methods: 47 private practice-based medical oncologists agreed to anonymously complete questionaires on this subject. 32 were returned (68% response rate). 17 academic hematologists and oncologists were approached. 7 returned completed questionaires (41% response rate). While group comparisons could not be made, some interesting points were found. Results: Each week an average of 6 Internet and 1 phone-based invitations week were received by the private practitioners. Most physicians received 2–3’ ‘focus group’ or ‘in-person’ invitations/month and attended the majority of them. Like in- person interviews, Internet-based marketing participation was based on the amount of money being offered and not on ‘interesting topic.‘ The majority of studies with an honorarium averaging $150/hour were completed. Academicians were much less likely to participate in Internet research. 4 of the 7 responded that they did not even open them. All participated in interviews, particularly if invited as a ‘key opinion leader‘ (KOL). With respect to interviews, the 3 major differences between the private practitioners and academicians were: in the number of requests received (1 vs 3/week); type and timing of interview requests (KOL received the majority of their interview requests from financial analyists and were inundated at or just around major oncology meetings); and the amount of reimbursement for an hour of interview time (Individual interviews for privates were in the $200–300 range. KOL interviews were reimbursed in the $500 to $5,000 range with $1,000–1,500 being the norm.) Conclusion: Clearly, market research is playing an increasing important role in the financial health of many physicians. Much more planned research needs to be done to see how this interaction affects individual physicians, patient care and society. No significant financial relationships to disclose.
Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One-year results of CA180034
Authors: Shah N. P. , Kim D. W. , Kantarjian H. M. , Rousselot P. , Dorlhiac-Llacer P. E. , Milone J. H. , Bleickardt E. , Francis S. , Hochhaus A. 
Published: March 2020

7004 Background: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented. [Table: see text] [Table: see text]
Seventy percent of complete responders remain in continuous remission: Five-year follow-up of 300 patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy of CLL
Authors: Tam C. S. , O'Brien S. , Wierda W. , Lerner S. , Kantarjian H. , Keating M. J. 
Published: March 2020

7008 Background: The early results of 224 CLL patients receiving the FCR regimen were previously reported (JCO 23:4079). Mature follow-up data (median 62 months for survivors) is now available for the complete cohort of 300 patients. Methods: Eligible patients were =16 years old with previously untreated CLL requiring therapy. Median age was 57 years (31%=60 years, 14% =70 years), and 61% & 36% were in modified Rai intermediate & high risk categories respectively. Prognostic factors: B2m >2x normal 42% (n=295), CD38 positive 28% (n=253), abnormal metaphase cytogenetics 29% (n=221), IgVH unmutated 66% (n=94), ZAP-70 positive 49% (n=88). The planned six cycles of therapy were completed in 74% patients. Results: Responses were: 72% CR, 11% nodular PR (PRn) & 12% PR. On multivariate analysis, CR rates were inferior in patients with B2m >2N (p=0.001) and white cell count >150 × 109/L (p=0.01). Rai stage, CD38 positivity, IGVH mutational status and ZAP-70 positivity were not associated with inferior CR. Median Times to Progression (TTP) were 80 months for CR (n=216), 80 months for PRn (n=32) & 27 months for PR (n=36), with 77%, 65% and 28% projected to be progression-free at five years; projected 5 yr survival were 90%, 81% and 37% respectively. Restricting the analysis to 190 patients with at least five years followup, actual 5 yr TTP and 5yr survival were 70% & 88% respectively in complete responders. Five cases of Richter transformation and eight cases of MDS/AML occurred during remission, with projected 5 yr risk of 2% & 3% respectively. When compared with a historical cohort of patients receiving fludarabine (n=190) or fludarabine and cyclophosphamide/mitoxantrone (n=140) in multivariate analysis, FCR was independently associated with superior TTP (p<0.001) and survival (p<0.001). Conclusion: FCR is the most effective CLL frontline regimen reported to date. 70% of complete responders remain progression-free at five years. No significant financial relationships to disclose.
Identification of a new subgroup of adult acute T-lymphoblastic leukemia (T-ALL) with a very favorable outcome using low ERG and BAALC expression
Authors: Baldus C. D. , Martus P. , Burmeister T. , Schwartz S. , Goekbuget N. , Bloomfield C. D. , Hoelzer D. , Hofmann W. K. , Thiel E. 
Published: March 2020

7014 Background: High expression of the oncogenic ETS transcription factor ERG is an independent adverse prognostic factor in T-ALL and acute myeloid leukemia (AML). The gene BAALC similarly shows high expression in hematopoietic progenitors, downregulation with onset of differentiation, and prognostic significance in AML. Therefore, we assessed whether combined expression of ERG and BAALC would better predict outcome in T-ALL. Methods: ERG and BAALC mRNA expression was determined by realtime RT-PCR in pretherapy bone marrow of 152 adults with newly diagnosed T-ALL treated on German ALL protocols (05/93, 06/99). Patients (pts) were designated low (n=76) or high (n=76) ERG expressers based on median ERG expression and as low (n=111) or high (n=37) BAALC grouping the lower quartiles 1–3 vs. quartile 4. HOX11 and HOX11L2 expression was determined and immunophenotyping differentiated 3 T-ALL groups (early, thymic, mature). Results: High BAALC expression correlated with immature T-ALL with a higher frequency of early T-ALL (P<0.0001), CD34 positivity (P<0.0001), co-expression of myeloid markers (CD13 and/or CD33; P=0.03), and high ERG expression (P=0.02). Pts with high BAALC had fewer complete remissions (73% vs. 89%, P=0.03) and a higher relapse rate (67% vs. 32%, P=0.01) than low BAALC pts. Excluding 33 pts that had received stem cell transplantation (SCT), high expression of ERG (P=0.002) and of BAALC (P=0.0004) was associated with inferior relapse-free survival (RFS) and overall survival (OS, ERG: P=0.004; BAALC: P=0.0001) compared to low expression of ERG and BAALC, respectively. In contrast, pts with low expression of both ERG and BAALC had the most favorable outcome (5y-RFS: low ERG/low BAALC 81% vs. high ERG and/or high BAALC 33%, P<0.0001; 5y-OS: low ERG/low BAALC 69% vs. high ERG and/or high BAALC 26%, P=0.0001). On multivariable analysis low ERG/low BAALC expression was of independent favorable prognostic significance (RFS, HR: 0.18, P=0.0003; OS, HR: 0.3, P=0.001); the only other prognostic factor was the immunophenotype. Conclusions: Low expression of both ERG and BAALC identifies T-ALL pts with a distinctly favorable long term outcome, thus detecting pts that may not benefit from further treatment intensification including SCT. No significant financial relationships to disclose.
A unique microRNA signature associated with nucleophosmin mutations in normal karyotype acute myeloid leukemia
Authors: Garzon R. , Volinia S. , Falini B. , Croce C. M. 
Published: March 2020

7015 Background: Nucleophosmin (NPM) mutations are present in about 30 to 50 % of the patients with normal karyotype acute myeloid leukemia (NK-AML). The mutant NPM protein shows aberrant cytoplasmic location and is frequently associated with FLT3 mutations. Little is know, however how NPM mutants promote leukemia. To obtain insights about the biology of NPM+ AML we investigated the expression of microRNAs in NK-AML patients characterized for NPM mutations. Methods: We studied 85 adult NK-AML patients characterized for NPM, FLT3 ITD and FLT3 D835 mutations using a miRNA microarray platform containing 345 mature and precursors miRNAs. Mutation analysis for NPM, FLT3 ITD and FLT3 D835 were carried out in most of the patients as previously described (Falini, Blood 2006). The distribution of the mutations were as follows: NPMc+ (54 patients), NPMc- (31), FLT3 ITD+ (27), FLT3 ITD-(51) and FLT3 D835+ (21) and FLT3 D835-(26). Data were analyzed after background subtraction and normalization with a set of housekeeping genes using Significance Analysis of Microarrays and Predictive Analysis of microarrays. The results were validated using miRNA q-RT-PCR. Results: We identified a strong miRNA signature that distinguishes NPMc+ cases with high accuracy and includes the up-regulation of miR-10a, miR-10b and several let-7 family members. Many of the down-regulated miRNAs including miR-134, miR-194, miR-204, miR-526 and miR-28 are predicted to target many HOX genes suggesting that NPM mutants may induce HOX genes through the down-modulation of miRNA regulators of these genes. The signatures associated with FLT3 mutations were not accurate to predict this abnormality. However, when we analyzed the subgroup of NPMc+ FLT3 ITD + cases a distinctive signature was found with respect to other NPMc+ FLT3 negative cases. Conclusions: A unique miRNA signature is associated with NPMc+ mutations in AML. FLT3 ITD and FLT3 D835 are not clearly associated to any characteristic miRNA signature when analyzed individually. However the subgroup of NPMc+ FLT3 ITD has a distinctive miRNA signature. This data provide with new insights about the pathogenesis of NPMc+ AML that could be exploited to generate novel therapeutic strategies for one of the most common mutations in AML. No significant financial relationships to disclose.
Decitabine in older patients with acute myelogenous leukemia (AML)
Authors: Issa J. , Saba H. I. , Garcia-Manero G. , Shan J. , Kantarjian H. M. 
Published: March 2020

7021 Background: Advanced myelodysplasia and AML are age-related diseases with known poor prognosis in patients over age 60. AML is defined by World Health Organization (WHO) criteria as patients with =20% blasts in the bone marrow. SEER database analysis has indicated that 64% of AML patients over age 65 go untreated, other than with supportive care. Their median survival is 1.7 months. The main reason for this reluctance to treat is perceived toxicity of chemotherapy in this age group. Decitabine is a hypomethylating agent that provides a low-intensity alternative for patients with myeloid malignancies. Methods: We reviewed patients with =20% blasts in the bone marrow treated on a randomized study of decitabine vs. supportive care in myelodysplastic syndromes, and similar patients enrolled on two consecutive studies of decitabine alone or in combination with valproic acid, conducted at MD Anderson Cancer Center. Response to decitabine was analyzed by International Working Group criteria. Results: Overall, there were 33 patients with the WHO criteria of AML that were treated with decitabine alone (23 patients) or in combination with valproic acid (10 patients) as first-line therapy. There were 20 men (61%) and their median age was 72, range 39 to 85. Median bone marrow blasts at study entry was 26%, and 14 (42%) had >30% blasts. There were three different schedules of decitabine IV, which gave a total of 100–150 mg/m2/course over 3–10 days. Of the 33 patients treated, there were 8 CRs (24%) and 9 marrow CR/PR/Hematologic improvement (27%) for a total response rate of 17 (52%). Overall mortality at 4 weeks and 8 weeks was 3% and 15%, respectively. At a median follow-up of 20 months, median survival of the entire group was 12.6 months (95% CI: 6.5–23.0), and 2-year survival was 25% (95% CI: 13–48), which compares favorably to reported AML survival in this age group in the United States. Conclusions: We conclude that decitabine is an effective and less toxic treatment in this AML age group and may prolong survival compared with supportive care. No significant financial relationships to disclose.
A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP)
Authors: le Coutre P. , Gattermann N. , Hochhaus A. , Larson R. , Weitzman A. , Haque A. , Giles F. , O′Brien S. G. , Kantarjian H. M. 
Published: March 2020

7026 Background: CML-AP is often associated with imatinib-resistance and the occurrence of BCR-ABL mutations. This phase II open-label study was designed to evaluate the safety and efficacy of Nilotinib, a potent novel tyrosine kinase inhibitor, in imatinib-resistant or - intolerant CML-AP pts. Methods: Imatinib-resistance and -intolerance were defined using standard criteria, and all resistant pts failed imatinib >/= 600mg/day. Primary endpoint was a confirmed hematologic response (HR) determined by conventional ITT analysis. Nilotinib was started at 400mg BID and escalated to 600mg BID for inadequate responses. Results: Safety and efficacy are reported for first 64 consecutively enrolled pts completing >/= 8 mos treatment. 52 (81%) were imatinib-resistant; 12 (19%) -intolerant. Median duration of CML was 74 mos; median duration of prior imatinib use was 28 mos. Median duration of nilotinib exposure was 208 days; median average dose intensity (mg/days) was 787. Median cumulative duration of dose interruption was 23 days. Treatment is ongoing for 27 (42%) pts; 37 (58%) have discontinued (9 for AEs; 17 for disease progression). HR occurred in 38 (59%) pts, of which 15 (23%) were complete, 8 (13%) were marrow responses, and 15 (23%) returned to chronic phase. MCyR occurred in 23 (36%) pts; 14 (22%) were complete and 9 (14%) were partial. 6 (9%) pts did not respond; 5 (8%) pts had disease progression. Median time to HR was 1.0 (1–3) mos and to MCyR was 2.0 (1–8) mos. Estimated 1-yr survival rate was 69% and median duration of HR has not been reached. The most common Grade 3/4 AEs included neutropenia (45%), thrombocytopenia (40%), asymptomatic lipase elevations (17%), and anemia (16%) pts. No pts experienced Grade 3/4 peripheral edema, or pleural/pericardial effusions; 2 pts had pulmonary edema. Conclusion: In pts with CML-AP, nilotinib is an effective therapeutic option in CML-AP pts with imatinib-resistance or -intolerance and is generally well tolerated with acceptable rates of myelosuppression and minimal non- hematologic toxicities. No significant financial relationships to disclose.
TG101348, a potent, highly selective JAK2 inhibitor, inhibits colony formation in stem cells from polycythemia vera patients and prevents JAK2V617F-mediated splenomegaly and death in a mouse model
Authors: Hood J. , Doukas J. , Martin M. , Noronha G. , Jamieson C. , Soll R. 
Published: March 2020

7031 Background: The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia has been strongly linked to an activating mutation of JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino acid residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Methods: In order to address this unmet clinical need we designed, synthesized and performed preclinical evaluations on a series of structurally novel compounds optimized for JAK2 inhibition. Results: TG101348, a compound which potently inhibits JAK2V617F enzymatically and in human cells, was selected as a clinical development candidate from this medicinal chemistry campaign. TG101348 displays remarkable kinase specificity as shown by 83X selectivity versus JAK3 and potent inhibition of <2% of the kinases evaluated in a commercial, phylogenetically diverse panel of 212 kinases. TG101348 potently inhibits erythroid colony formation in patient-derived cells from polycythemia patients at doses 2–3X lower than in normal control patients. Consistent with this observation TG101348 inhibits JAK2-driven STAT5 phosphorylation, cell proliferation and cell survival in JAK2V617F-expressing cell lines. In vivo, TG101348 exhibits promising pharmacokinetic profiles in species ranging from mouse to monkey including oral availabilities >20%, and half-lives consistent with once or twice daily dosing. TG101348 reduces the number of circulating mutant JAK2 cells, inhibited splenomegaly and improved survival without significantly impacting normal hematocrit in an aggressive JAK2-driven circulating cell model of disease in rodents. Conclusion: TG101348 has considerable potential for the treatment of JAK2- driven myeloproliferative disorders based on its promising preclinical potency, selectivity and pharmaceutical properties. [Table: see text]
Binding mode of the tyrosine kinase inhibitor bosutinib (SKI-606) to Abl kinase
Authors: Soverini S. , Tasco G. , Grafone T. , Colarossi S. , Gnani A. , Baccarani M. , Casadio R. , Martinelli G. 
Published: March 2020

7049 Background: Bosutinib (SKI-606) is a 4-anilino-3-quinolinecarbonitrile Src/Abl kinase inhibitor. The crystal structure of Abl kinase domain in complex with bosutinib has not yet been determined and the mode of binding of this inhibitor is therefore unknown. Methods: In the present study, we used a molecular docking approach to investigate the following: a) Which Abl conformation(s) bosutinib is more likely to bind? b) Which Abl residues are likely to be involved in bosutinib binding? c) Which imatinib-resistant Abl mutants bosutinib is likely to be active against? A three-dimensional model of bosutinib was generated by Chemsketch ( http://www.acdlabs.com ). Modelling of the human Abl kinase in its inactive (closed) conformation was performed with the software Modeller, v7.7 ( http://salilab.org/modeller ) adopting the highly related Mus musculus Abl homologue as a template structure (PDB entry: 1OPJ , 0.175nm resolution). Active (open) Abl conformation is available as PDB entry 1OPL . Flexible docking of bosutinib to Abl was performed with Autodock v3.0 ( http://www.scripps.edu/mb/olson ). Results: Our binding hypothesis predicts that a) similarly to IM, the interaction between bosutinib and Abl seems to be more stable when the latter is in its inactive (closed) conformation; b) 21 Abl residues (including Y253, T315, F317 and F359 among others) surround bosutinib and engage H-bonds or Van der Waals interactions; c) bosutinib is likely to retain the ability to bind and inhibit the IM-resistant Y253H, M351T, F359V, F317L and E255V Abl mutants. In contrast, bosutinib binding to E255K and T315I mutants is predicted to be less efficient. Detailed models will be presented. Conclusions: Bosutinib is a promising second-line treatment for Ph+ leukemia patients harbouring several IM-resistant Abl mutations. The T315I remains the biggest hurdle for pharmacological therapy of Ph+ leukemias. Supported by European LeukemiaNet, AIRC, AIL, COFIN and FIRB projects, and by Fondazione del Monte di Bologna e Ravenna. No significant financial relationships to disclose.
Acute myeloid leukemia (AML) after a prior diagnosis of other hematological malignancies (HM), breast cancer (BC), and other cancers (OC) in the Australian female population between 1982 and 2002
Authors: Beadle G. , Baade P. , Fritschi L. 
Published: March 2020

7052 Background: AML is a widely reported complication of chemotherapy for HM and BC but few population based studies have investigated the nature and magnitude of AML risk after a diagnosis of cancer. Methods: This retrospective study examined 3 cohorts of female patients 30 years and over reported to state and territory cancer registries in Australia between 1982 and 2002. The cohorts comprised 40,030 women with HM, 162,142 with BC and 379,347 with OC. Results: The AML incidence rate/100,000 (IR) was 4.1 for all Australian females. The rate was much higher in the cohort with HM (IR 36.2; CI 25.3 –51.7), and slightly higher among those with BC (IR 11.7; CI 9.4 –14.9) and OC (IR 7.7; CI 6.4 –9.2). Standardized incidence ratio (SIR) estimates confirmed that women in the 3 cohorts had higher risks of subsequent AML than the general female population. These ranged from 5.5 times higher for those with HM (p <0.001), 2.7 for BC (p <0.001) and 1.7 for OC (p <0.001). Although the IR for AML rose sharply with age, the SIR estimates for HM and BC, but not OC, were highest in the young age group and decreased with increasing age (30–49 years HM 21.6, BC 5.1; 50–69 years HM 10.4, BC 2.9; 70 years and older HM 1.8, BC 1.9; all p values < 0.001). There was no evidence that time to diagnosis curves for AML were different for the 3 cohorts (53% within 5 years for HM, 60% for BC and 59% for OC). Conclusion: AML risk was higher for female cancer survivors than for the non-cancer population and was a continuing risk for long term survivors. Although the absolute risk increased with age, the relative risk was highest in young survivors of HM and BC, and decreased with age. There was no evidence of a disproportionate increase of AML risk for cancer survivors during this era of expansion of the evidence base for more extensive chemotherapy, although there was a significant increase in the risk of AML for the Australian female population. No significant financial relationships to disclose.