bluuebunny/crossref_metadata_2025 huggingface dataset:
Revolutionizing oncology patient enrollment in clinical trials: Just-in-time approach
Authors: Wiener M. B. , Newman H. M. , Spradley E. A.
Published: March 2020

6577

Background: In the US, adult oncology patient enrollment in clinical trials is estimated at 4% (Cancer 2006; 106(2):426–33). This is a major bottleneck in the development of new cancer treatments, especially for rare indications, like stage IV pancreatic cancer in treatment-naive patients. To overcome the challenge of low enrollment in clinical trials, Pharmatech developed the Just-In-Time (JIT) approach. JIT expands the potential patient population and allows research sites to pre-identify patients using standard of care information prior to site activation. This differs from a traditional approach where sites are activated prior to screening for patients. We postulated the JIT approach would impact patient accrual. Methods: With the JIT approach, a central IRB-approved protocol was presented to 38 research-ready sites but only 8 sites with a potential patient obtained IRB-site approval over a 6 month period. Within 5–10 business days after identifying a potential patient, sites obtained IRB approval, investigators at the site were trained, received study materials, and dosed the first patient. We compared traditional site activation conducted by the sponsor to JIT approach in this study. Results: Traditional approach vs JIT approach: No.of patients enrolled: 42 vs 18; No.of months open: 19 vs 6; No. of sites open: 13 vs 8; No. of non-enrolling sites: 2 vs 0; Patient accrual rate (pts/mo/site): 0.17 vs 0.38. Sites participating in the JIT approach accrued subjects at >2x the rate of traditionally activated sites. The JIT approach eliminated non-enrolling sites, increasing sites’ and sponsor's satisfaction with enrollment. JIT also enhanced patient options by providing access to a novel treatment alternative for this rare indication even at smaller research sites. Conclusions: With JIT, patient accrual rate, enrollment success and trial-related cost in a pancreatic cancer study were markedly better than with the traditional approach. Expanding JIT to other rare indications and to trials requiring specific genetic tumor-profiles will show whether these results are reproducible and whether JIT is a viable approach for trials with challenging eligibility criteria.

No significant financial relationships to disclose.
Cost-effectiveness of rituximab plus CVP for first-line treatment of advanced indolent lymphoma
Authors: Hornberger J. , Reyes C. , Verhulst E. , Lubeck D. , Valente N.
Published: March 2020

6583

Background: The addition of rituximab (RTX) to CVP (cyclophosphamide, vincristine, prednisone) in the treatment of advanced follicular lymphoma increases median time to progression by 17 months (15 month v 32 months; p < 0.0001) (Marcus et al, Blood 2005). A societal cost-effectiveness analysis was performed to estimate projected lifetime clinical and economic implications of this treatment. Methods: The cost-effectiveness (CE) of RTX + CVP versus CVP was estimated for a 50 yr old patient. Kaplan-Meier estimates of progression-free and overall survival, up to 4 years, were obtained from the M39021 trial. After 4 years, transition rates from initiation of treatment to progression or death were assumed to be the same in both arms. The clinical and economic implications of relapse and its treatment were included in the model. Incremental costs associated with addition of RTX were estimated using Medicare reimbursement rates and published retail price data. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature and a 3% discount rate was employed. Results: Projected mean overall survival is 1.5 yrs longer for patients assigned to RTX+ CVP versus only CVP (13.7 v 12.2 yrs). The addition of RTX to CVP is estimated to cost an additional $26,439 on average, with an expected gain of 0.85 year of quality-adjusted survival. Over a lifetime, the cost per QALY gained is $31,329. Sensitivity analyses revealed that the variables that most influenced cost-effectiveness were the time horizon (range: $18,800- $31,240) and the unit drug cost of RTX (range: $24,000-$38,000). Conclusion: The model estimates a cost-to-QALY gained ratio that is below that of many treatments used for oncology patients. The use of RTX + CVP for first-line treatment of advanced follicular lymphoma is projected to be cost-effective compared to CVP alone under a range of sensitivity analyses.

No significant financial relationships to disclose.
Evaluation of quality indicators (QIs) for colorectal cancer care in a community setting
Authors: Frisby K. , Meyer L. , Lee J. , Mathiason M. , Dietrich L.
Published: March 2020

6585

Background: We compared two existing sets of QIs for colorectal cancer care to evaluate our performance as compared to published data. We also explored reasons for non-adherence to these QIs to determine how we could increase our compliance. Methods: Chart review of all patients who were newly diagnosed with colorectal cancer at our institution in 2004 and 2005 for compliance with QIs for colorectal cancer care as presented by National Initiative for Cancer Care Quality (NICCQ) and Moffitt Network Initiative on Practice Quality (MNIPQ). When 85% compliance was not observed, charts were reviewed as to why care differed from QI. Results: Adherence rate was less than 85% in 5 of 25 NICCQ colon cancer measures and patients overall received 83% of recommended care. Reasons for <85% adherence on NICCQ were most often due to patient decision (patient decision after informed discussion, refusal of treatment, patient initiated delay) or co-morbidity (poor wound healing, infection, medical co-morbidity). In one item regarding counseling of family members about colorectal screening we were truly noncompliant without documentation of reason. Review of MNIPQ items observed less than 85% adherence rate in 2 of 9. Reason for non-adherence in MNIPQ review was due most often to co- morbidity, and true noncompliance (no reason documented for lack of pretreatment CEA). Conclusions: Our adherence rates for NICCQ and MNIPQ measures compare favorably with published values. Lower compliance rates on NICCQ and MNIPQ measures were most often due to patient choice or co-morbidities. In setting benchmarks for these individual QIs it should be noted that for some indicators (such as those regarding adjuvant therapy) higher percent adherence does not always reflect better care. Higher compliance may actually mean that thoughtful consideration of patient co-morbidity and complications, or including patients in decision making is not occurring or that the population being served is younger or has fewer co-morbidities. Other indicators such as those regarding staging documentation, documentation of chemotherapy, and patient education factors the higher the compliance the better. We conclude that some sampling of reason for non- adherence is necessary when assessing quality of care.

No significant financial relationships to disclose.
Adjuvant chemotherapy in non-small cell lung cancer (NSCLC): Referral and utilization patterns
Authors: Al-Fayea T. , Saint-Jacques N. , Virik K. , Morzycki W. , Younis T.
Published: March 2020

6590

Background: Adjuvant chemotherapy in Non Small Cell Lung Cancer (NSCLC) has become a new standard of care. However, referral and utilization patterns for adjuvant chemotherapy outside of clinical trials remain unknown. Methods: All patients with NSCLC who underwent curative-intent surgery in Nova Scotia, Canada, in year 2005 were identified. Data were abstracted from the provincial cancer registry, and the patients’ charts at the two provincial cancer centers. A retrospective exploratory analysis was conducted utilizing logistic regression models to determine the statistically significant variables associated with referral to medical oncology and/or utilization of adjuvant chemotherapy. Results: 108 patients who underwent curative-intent surgery (67% lobectomy, 15% pneumonectomy, and 19% wedge resection) for NSCLC (38% IA, 23% IB, 4% IIA, 21% IIB, 12% IIIA, and 2% IIIB) were identified. The median age was 66 years, and 56% were males. Common histologies included adenocarcinoma (43%), squamous cell carcinoma (32%), large cell carcinoma (7%), and broncheoalveolar carcinoma (7%). A referral to medical oncology for consideration of adjuvant chemotherapy was observed in 41% (44/108) of all patients including 62% (41/66) of those with stage > IA. Lower referral rate was associated with older age, stage I, and wedge resection while higher referral rate was associated with younger age, more advanced stage, large cell carcinoma subtype, and pneumonectomy. Adjuvant chemotherapy was prescribed in 27% (29/108) of all patients, including 41% (27/66) of those with stage > IA, and in 66% (29/44) of the patients referred to medical oncology. Of those referred to medical oncology, older patients and those who underwent wedge resection were less likely to receive chemotherapy. Of all patients, higher chemotherapy utilization was associated with younger age and more advanced stages. Conclusions: Adjuvant chemotherapy utilization in patients with resected NSCLC is low overall, especially among older patients and those with early-stage disease. However, a high proportion of the patients referred to medical oncology receive chemotherapy. Improved referral rates to medical oncology may increase the overall utilization rates of adjuvant chemotherapy in NSCLC.

No significant financial relationships to disclose.
Barriers to participation in breast cancer trials
Authors: Herasme O. , Goldberg J. , Sandoval R. , Harris C. , Ortiz-Pride Y. , Jacobson J. , Schmitt K. , Kumah C. , Hershman D. , Grann V.
Published: March 2020

6593

Background: Clinical cancer trials allow investigators to test the effectiveness and safety of new cancer drugs and treatments. Historically, fewer that 5% of cancer patients have participated in clinical trials. The purpose of this study was to assess attitudes, beliefs, and practical barriers to clinical trial recruitment. Methods: Women were recruited in the Herbert Irving Comprehensive Cancer Center while waiting for routine breast screening or for oncology care in connection with a diagnosis of breast cancer. The 29-item survey questionnaire covered demographic factors, prior cancer diagnosis or risk factors, past experience with clinical trials if any, willingness to participate in different types of trials, and attitudinal and practical barriers to participation. Results: Of 329 respondents, 48.9% were non- Hispanic white, 10.9% non-Hispanic black, 34.9% Hispanic, and 5.30% other/unknown. The mean age of participants was 52.5 (SD=12.1). Of 131 (39.8%) participants reporting that they had been asked to participate in clinical trial, 82 were white, 17 black and 32 Hispanic. Of those who enrolled, 64 were white, 14 were black, and 19 Hispanic. Of those asked to participate 56/63 breast cancer patients (88.9%) and 44/68 others (64.7%) enrolled (P=0.002). Of 48 who reported that they had child care responsibilities, 33 enrolled (68.8) compared to 67/83 (80.7%) of those without such responsibilities (P=0.07). Of the total sample, 88/220 (40.0%) of those without childcare responsibilities but only 32/109 (29.4) said they would be willing to participate in a placebo-controlled trial. Respondents were twice as likely to say they would participate in a trial comparing two active agents as a placebo-controlled trial. Conclusion: Our findings suggest that being asked to participate in a clinical trial may be associated with demographic factors, and that specific circumstances, such as child care responsibilities, may also affect trial participation. Awareness of these barriers may help investigators to develop effective strategies for overcoming them and for improving trial participation overall.

No significant financial relationships to disclose.
A clinical pathways project to promote evidence-based medicine in a large community oncology practice
Authors: Neubauer M. A.
Published: March 2020

6597

Background: Medical oncology therapy tends to vary widely due to a large number of drug choices and a wide array of reference sources for decision-making. It is assumed that this high variability reduces quality and efficient delivery of cancer care. We developed clinical pathways for common cancers in which we, after extensive review of seminal literature, distilled a succinct list of evidence- based regimens. We then instructed all physicians at KCCC (26 medical oncologists) to adhere to these pathways or write an exception to the pathway. Exceptions were reviewed by a practice peer-review committee before treatment was initiated. Methods: Included in this analysis is KCCC practice data on treatment choices for ALL patients who were started on treatment or had a change in treatment for breast cancer, non-small cell lung cancer, or colon cancer. All treatments required entry of patient information and staging information on a web-based pathway tool followed by selection of a pathway choice. If a physician preferred “off-pathway” treatment for his/her patient, then an exception sheet with an explanation for off-pathway therapy was submitted and reviewed before treatment. Data was collected from January 1, 2006 through October 31, 2006. The study endpoints were pathway adherence, pathway exception rate, and frequency of accrual to clinical trials. Results: Over a 10 month time period, there were 764, 624, and 326 patients treated for breast, non-small cell lung, and colon cancer, respectively. On-pathway treatment rates were 92.5%, 93.4% and 88.3%. Conversely, exceptions were utilized 7.5%, 6.6% and 11.7% of the time. Rate of accrual to clinical trials was 6.8%, 13.0% and 7.7% for breast, non-small cell lung and colon cancer. Conclusions: Strategies to support and enforce evidence-based medicine in a community based oncology practice can be successful in standardizing care, improving efficiencies, promoting clinical trial enrollment, and developing a practice profile. This pathway project is now being implemented throughout most of the US Oncology network.

No significant financial relationships to disclose.
Characteristics of a phase II study that predict for a positive phase III trial—A study of 383 clinical trials
Authors: Ueda S. M. , Sugiyama V. E. , Stave C. , Shin J. Y. , Monk B. J. , Kapp D. S. , Sikic B. I. , Osann K. , Chan J. K.
Published: March 2020

6604

Background: To identify the characteristics of a phase II study that predict for a subsequent positive phase III trial. Methods: All phase II studies and subsequent phase III clinical trials on biologics in advanced cancers published from 1985 to 2005 were extracted. Chi-square test and logistic regression models were used for analyses. Results: 383 phase III clinical trials and their preceding phase II studies were identified. 183 (47.8%) phase III trials were “positive” and 200 (52.2%) were negative. 220 trials (57.4%) used biologics alone and 162 (42.3%) used a combination of biologics and chemotherapy. Over the study periods 1985–1990, 1991–1995, 1996–2000, 2001–2005, the percentage of phase II studies that led to positive phase III trials increased from 37.7% to 33.3% to 56.0% to 76.8% (p<0.001). The interval between the publication of phase II and III studies, 0.5–5, 6–10, 11–15, and 16–20 years were also associated with the success of phase III trial, 55.6%, 42.2%, 32.6%, and 10.0%, respectively (p<0.001). Phase II studies from multiple rather than single institutions were more likely to have a successful trial (60.4% vs. 39.4%; p<0.001). The percent of successful trials from pharmaceutical companies was significantly higher compared to academic, cooperative groups, and research institutes (89.5% vs. 44.2%, 45.2%, 46.3%; p=0.002). The publication of the phase II studies in journals with an impact factor of 8 or greater compared to those less than 8 was also predictive (44.1% vs. 58.0%; p=0.024). Phase II studies with a lower attrition rate were also associated with a positive phase III trial (61.1% vs. 41.8%; p=0.025). On multivariable analysis, all factors, except for journal impact factor, were independent predictive factors for a positive phase III trial. Conclusions: In phase II biologic studies, characteristics such as larger number of patients, more recent year of study, multiple vs. single institution participation, shorter time period between publication of phase II to phase III trial, and lower rate of attrition were predictive factors of success in a phase III trial. Investigators need to be cognizant of these phase II study characteristics before designing phase III trials.

No significant financial relationships to disclose.
Economic evaluations of sunitinib versus interferon-alfa (IFN-α) in first-line metastatic renal cell carcinoma (mRCC)
Authors: Remák E. , Mullins C. D. , Akobundu E. , Charbonneau C. , Woodruff K.
Published: March 2020

6607

Background: A randomized phase III trial of sunitinib vs. IFN-a as first-line therapy for patients with mRCC is ongoing. An interim analysis of this study demonstrated superiority for the primary endpoint, progression-free survival (PFS), in the sunitinib arm vs. the IFN-a arm (median PFS = 11 months [95% CI: 10–12] vs. 4 months [95% CI: 4–6]; P<0.000001). Because of the clinical significance of these results, the objective of this study was to demonstrate the economic value of sunitinib vs. IFN-a in this setting from a US third-party payer perspective. Methods: Two Markov models with a 5- and 10-year time horizon were developed to evaluate the cost- effectiveness of sunitinib vs. IFN-a. The models projected survival and costs in 6-week cycles based on extrapolation of the trial survival data. Model 1 looked at first-line treatment followed by palliative care only, while Model 2 incorporated second-line treatment. Effectiveness was measured in terms of progression-free months (PFM) in Model 1, and life-years (LY) gained and quality adjusted life-years (QALY) gained in Model 2. Resource utilization included drugs, tests, scans, monitoring, physician visits, hospitalizations and treatment of adverse events. Costs and survival benefits were discounted annually at 3% and 5% in Model 1 and 2, respectively. All costs were adjusted to 2006 US dollars. Scenario and probabilistic sensitivity analyses were conducted. Results: Projected PFS and overall survival were longer for sunitinib than for IFN-a. The incremental cost-effectiveness ratios of sunitinib vs. IFN-a over 5- and 10-years were $7,769 and $7,782/PFM, respectively, in Model 1. Model 2 results at 10 years were $67,215/LY and $52,593/QALY gained. The key drivers of the model results were survival and sunitinib drug costs. Both models were robust in the tested scenarios. Conclusions: Both analyses found that sunitinib is a cost-effective alternative to IFN-a as first-line treatment in mRCC, with cost-effectiveness ratios within the established threshold that society is willing to pay for health benefits (i.e. $50,000–100,000/LY or QALY).

No significant financial relationships to disclose.
Quality of reports related to survival events in randomized clinical trials: A review of recent cancer trials published in eight major journals
Authors: Mathoulin-Pelissier S. , Gourgou-Bourgade S. , Bonnetain F. , Kramar A.
Published: March 2020

6611

Background: About ten years ago, Altman pointed the low quality of survival analyses published in cancer journals. Despite the development of Consort statement, the lack of quality standards remained in the reports of randomized clinical trials (RCT).The aim of this study was to evaluate quality of definitions and reports of survival endpoints in recent cancer RCTs. Methods: A computerized search in Medline databases identified 274 cancer RCTs published from January 2004 to December 2004 in 4 general medical journals (BMJ, JAMA, Lancet, NEJM) and 4 clinical oncology journals (BJC, Cancer, JCO, JNCI). Eligible papers were these that reported primary analyses of RCT with survival endpoints. Three methodologists have reviewed and scored 1/3 of papers according to 7 key points: prevalence of adequate definition of survival end-points (time to origin, survival events, censures) and relevant information about their analyses (Kaplan-meier method, confidence interval, number of events, patients at risk). Reliability of scoring was checked among a random subsample of 30 papers with an independent biostatistician (kappa coefficient). Results: Following eligibility screening, 149 papers were not included. Among the 125 selected papers, 104 trials were of phase III (83%) and 98 publications (78%) were obtained from the 4 oncology journals. Among these RCTs, a total of 268 survivals endpoints were recorded and overall survival (OS) was the most frequent outcome (118 terms, 44%). Survival terms were adequately defined in 116 endpoints (43%) and OS was most frequent adequately defined (49%). Accurate information about analysis was found in 51 endpoints (19%). The less adequate information was patient's number at risk (55%). Finally, according to the 7 key methodological points, optimal quality of report was found in 19 of the endpoints (7 %) i.e.6 articles (kappa value: 0.65). Conclusions: Majority of published papers failed to provide an adequate definition and analysis reports of survival endpoints. Finally survival definitions add another source of variability actually not controlled. Readers should critically pay attention to the reported definitions since the lack of these elements may lead to misinterpretation of the RCT results.

No significant financial relationships to disclose.
Prospective assessment of chemotherapy-induced neurotoxicity in breast cancer (HOR 02) and questionnaire survey of physicians’ perspectives
Authors: Kuroi K. , Shimozuma K. , Ohashi Y. , Takeuchi A. , Aranishi T. , Morita S. , Ohsumi S. , Makino H. , Watanabe T. , Hausheer F. H.
Published: March 2020

6619

Background: Physician-based instruments (e.g., NCI-CTC) are widely used to assess chemotherapy-induced peripheral neuropathy (CIPN). However, current evidence suggests that physician-based assessments under-report the incidence and severity of CIPN. To overcome this limitation, a patient-based questionnaire, patient neurotoxicity questionnaire (PNQ) was developed, and a phase III randomized adjuvant trial of breast cancer (N-SAS BC 02; AC followed by PAC/DOC vs. PAC/DOC alone) has demonstrated that PNQ is reliable and sensitive and responsive instrument to assess CIPN (Shimozuma et al., SABCS 2004; #6037). We prospectively evaluated the reliability and sensitivity of PNQ in advanced or metastatic breast cancer treated by weekly administration of paclitaxel. Moreover, a questionnaire survey was conducted on physician perspectives regarding the assessment of CPIN in Japan. Methods: CIPN and QOL were prospectively assessed in thirty-five patients with advanced or metastatic breast cancer who received weekly paclitaxel (80–100 mg/m2/w). PNQ and FACT-Ntx subscale were compared to NCI-CTC. Assessments were conducted at baseline, 8 wk, 16 wk after starting treatments. A questionnaire was sent to physician who participated in N-SAS BC 02 to clarify their perspectives regarding the CPIN. Results: Average response rate of the instruments was 89%. Sensory PNQ scores correlated with sensory FACT-Ntx scores (r=0.51), and NCI-CTC scores (r=0.58). NCI-CTC scores mainly distributed between 0 and 1, while PNQ scores widely distributed. Follow-up study revealed that sensory CIPN assessed by PNQ appeared to be sensitive as compared to NCI-CTC. In clinician survey, 47 out of 61 physicians (77%) responded, and majority of them considered neurosensory symptoms as diagnostic hallmark for CIPN. However, for the justification for treatment delay, dose modification, or treatment cessation, most laid weight on functional impairment in patients with CIPN. Most (80%) rated PNQ is helpful in management of patients at risk for CIPN. Conclusions: This study confirmed that physicians tended to underestimate CIPN, and PNQ was a more reliable and valid instrument to assess CIPN with high acceptability in physicians.

[Table: see text]
Conflicts of interest among articles published in the Journal of Clinical Oncology
Authors: George B. , Simhan S. , Lee J. A. , Mathiason M. A. , Go R. S.
Published: March 2020

6633

Background: The integrity of scientific and clinical research is dependent on the avoidance of conflicts of interest (COI). Hence, the American Society of Clinical Oncology (ASCO) has implemented a COI policy pertaining to articles published in the Journal of Clinical Oncology (JCO). In this study, we examined the prevalence and nature of COI among scientific articles published in JCO. Methods: We reviewed original articles, review articles and ASCO special articles published in JCO from August 2005 to January 2006. COI was categorized into employment/leadership position, consultancy, stock ownership, honoraria, research funding, expert testimonials and other remuneration. Results: Out of a total of 514 articles reviewed, original articles, review articles and ASCO special articles comprised 88.3%, 11.1% and 0.06% respectively. Overall 34.8% of the articles reported at least 1 COI. Among articles with COI, 21.8%, 27.4% and 50.8% reported 1, 2 and 3 or more COI, respectively. Consultancy (64.8%) was the most common COI, followed by honoraria (64.2%), research funds (58.7%), employment/leadership (40.2%), stock ownership (39.7%), testimonials (11.2%) and other remuneration (10.1%). COI was reported in 58.3% of clinical trials compared to 24.6% in other articles (P = 0.001). Out of the total of 4,944 authors, 14.0% reported a COI. Among authors with COI, 47.9%, 38.2% and 13.9% reported 1, 2 and 3 or more COI, respectively. The prevalence of COI among articles originating from North America, Europe and Asia/Australia were 38.2%, 31.8% and 13.8%, respectively (P = 0.020). Conclusions: COI were widely prevalent in articles published in JCO. Clinical trials had a higher prevalence of COI compared to other scientific articles. The prevalence of COI was equally high in articles originating from North America and Europe, but much lower in articles from Asia/Australia. The majority of reported COI were unrelated to research funds.

No significant financial relationships to disclose.
Hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL): 25-year experience at the University of Minnesota
Authors: Tomblyn M. B. , DeFor T. E. , MacMillan M. , Higgins P. D. , Dusenbery K. E. , Weisdorf D. J.
Published: March 2020

7001

Background: HCT is frequently used for management of ALL. Methods: We reviewed the records of 623 consecutive patients (63% male, median age 13 years) treated with myeloablative TBI-containing conditioning and either autologous or allogeneic transplantation between 1980 and 2005 at the University of Minnesota. Donor types were autologous (34%), related (45%), unrelated (16%) or cord (11%). Disease status at transplant was CR1 (24%), CR2 (50%), CR3 (18%) and relapse (8%). Univariate and multivariate analyses were performed for clinical endpoints including overall survival (OS), progression free survival (PFS), relapse, treatment-related mortality (TRM), and Grades II-IV acute and chronic graft versus host disease (GVHD). Results: Median follow-up among survivors was 8.3 years (1.0–22.9). The estimated incidence of acute GVHD was 42% and chronic GVHD was 16%. At 5 years, OS, PFS, and relapse were estimated at 29%, 26%, and 43% respectively. 5-year OS for each group: autologous (17%, 12–22%), related (35%, 29–41%), matched unrelated (42%, 29–55%), mismatched unrelated (21%, 11–33%), and cord blood (46%, 33–59%). TRM at 2 years was 28%. Multivariate analysis for OS, PFS, relapse and TRM for donor type is shown ( Table ). Acute GVHD was more frequent with unrelated donors (p<0.01) but similar for related donors and cords. Presence of acute GVHD led to improved PFS (RR 0.6, 0.4–0.7, p<0.01) and decreased relapse (RR 0.5, 0.3–0.8, p<0.01) at 1 year. 5-year OS improved significantly from 1980–1984 (28%, 20–37%) to 2000–2005 (45%, 33–56%), p < 0.01. Conclusions: Allogeneic HCT results in a durable PFS, although TRM is increased with unrelated mismatched donors. As expected, autologous HCT results in increased relapse rates. Despite significant mismatch, umbilical cord HCT led to similar OS, PFS, relapse, TRM and chronic GVHD compared to related donor HCT. Development of acute GVHD decreases relapse, resulting in improved PFS.

No significant financial relationships to disclose.

[Table: see text]
Long-term survival of patients with AML in remission after reduced intensity allogeneic hematopoietic stem cell transplantation (RISCT)
Authors: Popat U. R. , de Lima M. , Anderlini P. , Andersson B. , Couriel D. , Hosing C. , Kebriaei P. , Qazilbash M. , Alousi A. , Champlin R. , Giralt S.
Published: March 2020

7002

Background: RISCT was developed to harness graft versus leukemia effect to treat older patients (pts) and pts with comorbidities. Limited data are available on long term outcome of pts with high risk AML treated in complete remission (CR), a group most likely to benefit from this approach. Methods: Thirty six consecutive pts with AML in CR, treated between 1999 and 2006 with Fludarabine 120–125 mg/m2 and Melphalan 100–140 mg/m2 are included. Pts were not eligible for myeloablative transplantation because of age or comorbidity. Tacrolimus and Methotrexate were used as GVHD prophylaxis. Additionally pts receiving stem cells from an unrelated donor received rabbit antithymocyte globulin. Results: There were 24 males and 12 females with a median age of 57 (range 21–71). Eighteen(50%) pts had secondary AML. Thirty(83%) pts were in first CR and 6(17%) in second CR. Cytogenetic risk groups were as follows: 2 good risk (in CR2), 22 intermediate risk(61%), and 10(28%) poor risk. Source of stem cells was peripheral blood in 18 pts (50%) and bone marrow in 18 pts (50%). Donors were siblings in 21(58%) pts and unrelated in 15 (42%)pts. Hematopoietic cell transplant specific comorbidity score of 3 or higher was present in 26 pts (72%). All pts engrafted achieving full donor chimerism by day 30 with median time to neutrophil engraftment of 12.5 days (8–19 days). Cumulative incidence of grade 2–4 acute graft versus host disease (GVHD), grade 3–4 GVHD and chronic GVHD was 25% (95% CI; 14%–44%), 11% (95% CI; 4%–28%), and 63% (95% CI; 47%–84%) respectively. Cumulative incidence of nonrelapse mortality was 19% (95% CI; 8%–41%). With a median follow up of 852 days, 3 year overall and disease free survival is 75% (SE 9%) and 63% (SE 10%) respectively. Comorbidity scores didnot impact outcome. Conclusions: Reduced intensity allogeneic transplantation with Fludarabine and Melphalan conditioning produces durable long term remission in pts with high risk AML in complete remission. These results in older pts and/or pts with comorbidities are comparable to published results in younger pts receiving myeloablative transplantation. Comorbidity scores by themselves should not be used to exclude patients from receiving transplant.

No significant financial relationships to disclose.
MicroRNA (miR) expression signatures in molecular subsets of cytogenetically normal (CN) acute myeloid leukemia (AML): A Cancer and Leukemia Group B (CALGB) study
Authors: Radmacher M. D. , Marcucci G. , Paschka P. , Vukosavljevic T. , Whitman S. P. , Ruppert A. S. , Mrózek K. , Kolitz J. E. , Larson R. A. , Bloomfield C. D.
Published: March 2020

7010

Background: Aberrantly expressed miRs contribute to malignant transformation by hybridizing to specific mRNA targets and suppressing their translation into proteins. In CN AML, the largest cytogenetic AML subset, several molecular markers are associated with favorable [e.g., NPM1 mutation (mutNPM1)] or unfavorable [e.g., FLT3 internal tandem duplication (ITD) or high ERG expression (↑ERG)] outcome. We explored if differentially expressed miRs are associated with the aforementioned markers. If so, this might indicate a role for miRs in leukemogenesis and prognosis in CN AML. Methods: Diagnostic samples from 100 adults <60 years, treated on CALGB 19808 (Blood 2005; 106:122a), were analyzed on miR microarrays. Among 305 miR probes, we identified differentially expressed miRs (P<0.005) when comparing patients (pts) with or without mutNPM1, FLT3 ITD or ↑ERG. Results: Nine miRs were differentially expressed in FLT3 ITD compared with FLT3 wild-type pts. miR 155, previously reported in aggressive cancers, was upregulated in FLT3 ITD pts. Strong signatures were associated with mutNPM1 (42 miR probes) and ↑ERG groups (54 miR probes). Consistent with their better prognosis, pts with mutNPM1 had upregulated miRs 10 and 196 targeting HOX genes, miRs 15 and 16 targeting BCL2 and let-7 targeting RAS. Consistent with a more aggressive phenotype, ↑ERG pts had downregulation of let-7 and miR 15 and 16 but also miRs 30, 103, and 24 which target, respectively, CDK6, FBXW11 and MAPK14, all involved in cell cycle regulation and proliferation. Four miRs were associated with event free survival (EFS); all were also associated with ↑ERG. High expression of miRs 124, 129, and 194 was significantly associated with worse EFS and ↑ERG. Low expression of miR 181 was associated with worse EFS and ↑ERG. Notably, downregulation of mir 181 has also been reported in pts with aggressive B-cell chronic lymphocytic leukemia. Conclusions: We report the first miR expression signatures within molecular subsets of CN AML. Further study is warranted to elucidate mechanisms by which miRs contribute to leukemogenesis and impact prognosis, and to determine whether miRs can be therapeutically targeted.

No significant financial relationships to disclose.
Outcome prediction in adult core binding factor (CBF) acute myeloid leukemia (AML) with gene expression profiling: A Cancer and Leukemia Group B (CALGB) study
Authors: Paschka P. , Radmacher M. D. , Marcucci G. , Ruppert A. S. , Vukosavljevic T. , Whitman S. P. , Mrózek K. , Liu C. , Larson R. A. , Bloomfield C. D.
Published: March 2020

7011

Background: In CBF AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [abbreviated inv(16)], KIT mutations (mutKIT) and, in inv(16), trisomy 22 predict outcome and may guide the development of novel risk-adapted therapies. However, prognosis of patients (pts) lacking the aforementioned markers is less clear. Therefore, we profiled gene expression in t(8;21) (n=22) or sole inv(16) (n=25) pts who lacked mutKIT to identify signatures predictive of outcome. All pts were treated on CALGB trials incorporating consolidation therapy with multiple courses of higher dose cytarabine. Methods: Gene expression profiling was performed using Affymetrix U133 plus 2.0 arrays on diagnostic samples. As differences in gene expression distinguished all t(8;21) pts from all inv(16) pts, indicating two different biological entities, we pursued outcome prediction separately for each cytogenetic group. Gene expression-based outcome predictors for event-free survival (EFS) were constructed using a cross-validated prediction algorithm. Results: Among t(8;21) pts, EFS for predicted good (n=13) and poor (n=9) outcome groups differed strikingly (P=0.005; estimated 3-year EFS rates: 69% v 11%). Prediction was correct for 77% of pts. Among sole inv(16) pts, EFS for predicted good (n=18) and poor (n=7) outcome groups also differed (P=0.08; 3-year EFS rates: 78% v 29%). Prediction was correct for 76% of pts. FLT3 mutations appeared not to account for differences in EFS between the predicted groups; only the predicted outcome groups were associated with EFS (all baseline clinical characteristics at P>0.10). Pts with predicted poor outcome had higher expression of genes with leukemogenic potential such as WT1 [t(8;21) and inv(16)], CCNA1 [t(8;21)] and the oncogene MYCN [inv(16)]. Conclusions: Gene expression profiling improves outcome prediction in CBF AML pts lacking the known prognostic markers. Future studies should explore the clinical usefulness of targeting products of over- expressed genes, such as WT1 encoding a potential target for immunotherapy in AML.

No significant financial relationships to disclose.
High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): A Cancer and Leukemia Group B (CALGB) study
Authors: Langer C. , Ruppert A. S. , Radmacher M. D. , Whitman S. P. , Paschka P. , Baldus C. D. , Mrózek K. , Kolitz J. E. , Marcucci G. , Bloomfield C. D.
Published: March 2020

7013

Background: High BAALC expression predicts poor outcome in CN AML patients (pts). Yet, little is known about BAALC's function or its relation to other prognostic markers. We evaluated BAALC expression in the context of molecular markers and clinical outcome in 172 de novo CN AML adults, aged <60 years (y) treated on similar CALGB protocols (9621 and 19808). Methods: BAALC expression was measured by quantitative real-time RT-PCR in pretreatment blood samples. Pts were grouped as high (n=86) or low BAALC (n=86) expressers using the median expression value, by protocol, as a cutoff. Gene expression profiling (Affymetrix U133 plus 2.0 GeneChip) was performed on high (n=26) and low (n=24) pts. Results: BAALC expression was associated with several molecular markers ( Table ). Complete remission (CR) rate was lower in high BAALC pts (79% v 90%), for whom achieving CR was almost 4 times less likely than for low BAALC pts (P=.02; odds ratio=0.27), after adjusting for age (P=.004), ERG expression (P=.05) and white blood cell count (WBC; P=.04). With a median follow-up of 4.3 y, high BAALC pts had shorter overall survival (OS) (P=.002; 3-y OS: 42% v 59%). In a multivariable model, high BAALC provided further adverse prognostic information (P=.06; hazard ratio=1.66) independent of FLT3 ITD (P<.001), WBC (P=.007) and NPM1 (P=.02). A gene expression signature was identified consisting of 312 probe sets differentially expressed (P<.001) between BAALC groups. High BAALC was associated with overexpression of, among other genes, PROM1, CD34 and KIT indicating a less differentiated phenotype in these pts. Conclusions: Although associated with other prognostic markers, high BAALC expression independently predicts outcome and is associated with a distinct gene expression profile, potentially identifying new therapeutic targets in this pt subset.

No significant financial relationships to disclose.

[Table: see text]
Effect of delaying therapy in newly diagnosed AML
Authors: estey e. , Thall P. , Wang X. , Borthakur G. , Ravandi-Kashani F.
Published: March 2020

7020

Background: Given CR rates < 50% in pts with chromosome 5 and/or 7 abnnormalities given standard therapies, such pts might be offered investigational treatments at diagnosis. However the delay entailed in waiting for cytogenetic results might be problematic. Here we examine the effect on survival time and CR rate of the interval (TDT) from M.D. Anderson (MDA) diagnosis to start of treatment. Methods: At physicians’ discretion, therapy was delayed (TDT > 0) in 97% of the 1,378 pts with WBC < 50,000 treated at MDA 1996-2005. We used regression models to evaluate TDT's effect on survival and CR, after accounting for other covariates measured on day 1 of treatment. Covariates strongly associated with TDT were represented as binary variables (Z) and evaluated using interactive terms of the type Z*TDT. Results: TDT was = 2 days in 24% of pts, = 1 week in 68%, and = 10 days in 80%. TDT was longer in older pts, those with performance status (PS) 0–2, no fever or infection, a higher albumin, and lower WBC count and % marrow blasts (p < .02 for each). Considered alone, TDT had no effect on survival time (p= .33). However, longer TDT was independently associated with shorter survival in pts age > 62, with fever or infection, PS 3–4, (p < .001 for each), WBC > 5.0 and marrow blasts > 43% (p NS for each). A longer TDT was independently beneficial only for patients with an albumin > 3.4 (p= 0.007) with the values for the numerical covariates being the medians for the 1,368 patients. The albumin at MDA diagnosis remained unchanged relative to the median at time of treatment in 60% of the 103 pts in whom TDT = 7 days; corresponding value for WBC was 88%, with the presence (absence) of fever or infection unchanged in 85%. Adding the effect of the above noted covariates, delaying treatment within the range of TDTs seen here did not decrease survival in 86% of our 703 pts < age 63; exceptions were pts with PS > 2 or with fever/ infection. However longer TDT shortened survival in 57% of the 675 pts age > 62; exceptions were pts with PS < 3, albumin > 3.4, and no fever/infection. The effect of TDT on CR rate mirrored its effect on survival. Conclusions: Recalling the passage of time between outside diagnosis and referral to MDA, our results suggest that delaying start of treatment to ascertain cytogenetic (and in the future molecular) results is feasible in most younger, but probably not in most older, pts.

No significant financial relationships to disclose.
Drug treatment or stem cell transplantation as primary treatment for patients with CML
Authors: Hehlmann R. , Lahaye T. , Pfirrmann M. , Hochhaus A. , Müller M. C. , Hasford J. , Kolb H. J. , Heimpel H. , Hossfeld D. K. , Gratwohl A.
Published: March 2020

7028

Background: Early allogeneic stem cell transplantation (SCT) has been proposed as primary treatment modality for patients (pts) with chronic myeloid leukemia (CML). This concept has been challenged by persisting transplantation mortality and improved drug therapy. Methods: A randomized controlled trial was designed to compare primary SCT and best available drug treatment in 621 newly diagnosed CML pts in chronic phase (CP). Assignment to treatment strategy was by eligibility for SCT and genetic randomization according to availability of a matched related donor (MRD). 354 pts (62% male; median age 40 (11–59) years) were eligible and randomized. 135 pts (38%) had a MRD of which 123 (91%) received a transplant within a median of 10 (2–106) months from diagnosis. 4 pts died before scheduled SCT, 8 pts withdrew consent. 219 pts (62%) had no MRD and received drug therapy. Of these, 97 pts (44%) received a matched unrelated donor (MUD) transplant in 1st CP and were censored at the time of SCT. As 1st line drug treatment pts received interferon alpha based therapy. During the study 197 pts were switched to imatinib. Results: With an observation time up to 11.2 (median 8.9) years median survival of all 621 pts was 8.1 years. During the first 8 years after diagnosis survival curves of drug treated patients were superior to those of transplanted patients reflecting transplant-related mortality. Beyond 8 years survival curves were no longer distinct. 5 (10) year survival was 62% (53%) for transplanted and 73% (52%) for drug treated pts. Survival was superior for drug treated pts up to the cutpoint of survival curves at year 8 (p<0.041) and during the study period up to 11 years from diagnosis (p<0.049). Significantly higher proportions of complete cytogenetic remissions (91% vs 48%, p=0.002) and of major molecular responses (ratio BCR-ABL/ABL <0.1%; 81% vs 45%, p=0.001) were found in the transplant group. These results will be compared to those of a more recent randomized trial of the group (CML-study IIIA). Conclusions: The general recommendation of SCT as 1st line treatment option in CP CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first. Exceptions may be patients’ preference, very low transplantation risk and economic reasons.

No significant financial relationships to disclose.
Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study
Authors: Kantarjian H. M. , Giles F. J. , Fenaux P. , Becker P. S. , Boruchov A. M. , Bowen D. T. , Hellström-Lindberg E. , Larson R. A. , Lyons R. M. , Muus P.
Published: March 2020

7032

Background: The prevalence of thrombocytopenia in MDS ranges from 40% to 65%, hemorrhagic complications range from 3% to 53%, and hemorrhagic deaths range from 14% to 24% (Kantarjian 2006). Platelet transfusion can lead to reactions, infection, and alloimmunization. AMG 531 is a thrombopoiesis-stimulating peptibody that increases platelet production. This phase 1/2 study evaluated the safety and efficacy of AMG 531 in thrombocytopenic MDS patients. Methods: A minimum of 5 subjects with low risk MDS (IPSS low or intermediate-1) and a platelet count of = 50×109/L were enrolled to receive 3 QW SC injections of AMG 531 in each of 4 sequential dose cohorts. After evaluation at week 4, subjects could continue AMG 531 in an optional treatment extension at their assigned dose or escalated to a responding dose. Erythroid growth factors were allowed, but no other active treatment. Results: 28 subjects (9 transfusion-dependent) have been enrolled to date. All subjects were evaluable for response and entered the extension; 17 continue treatment. Dose-limiting toxicity (DLT) was defined as a drug-related grade 3 or 4 adverse event (AE) or a platelet count ≥ 600×109/L. Two DLTs occurred, both due to elevated platelet counts. No treatment-related severe AEs occurred. There was 1 treatment-unrelated death. Overall, 17 subjects (61%) achieved a platelet response. Median baseline platelet count for responders was 25×109/L with a median peak platelet count of 130×109/L during the 4 week treatment period. Of the 18 subjects to date completing at least 12 weeks of treatment, 11 (48%) achieved a durable response of at least 8 consecutive weeks (revised IWG criteria, Cheson 2006). A total of 90 clinically significant thrombocytopenic events (39 bleeding, 51 transfusions) were observed over both treatment phases. There were 16 such events (12 bleeding, 4 transfusions) in 6 subjects with a durable response, 6 events (6 minor bleeds, 0 transfusions) during the durable response period. There were 74 events (27 bleeding, 47 transfusions) in 11 subjects without a durable response. Conclusions: These preliminary data suggest that bleeding and transfusion events can be reduced in thrombocytopenic low risk MDS patients who respond to AMG 531.

[Table: see text]
A phase II study of nilotinib administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who also failed dasatinib
Authors: Giles F. J. , le Coutre P. , Bhalla K. , Rosti G. , Ossenkoppele G. , Alimena G. , Weitzman A. , Zheng M. , Kantarjian H.
Published: March 2020

7038

Background: Nilotinib and dasatinib are two new second generation tyrosine kinase inhibitors used in the treatment of imatinib-resistant/intolerant CML. There is limited data regarding the efficacy and safety of these therapies when given sequentially. Methods: This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib at a dose of 400mg BID in CML-CP, -AP, and -BC pts who previously received and either failed or were intolerant to imatinib and dasatinib. Results: A total of 42 pts are reported - CP (16), AP (9), and BC (17 total; 13 myeloid, 4 lymphoid). Overall 10 (24%) pts had extramedullary disease at baseline. For all pts, median time from first diagnosis was 16.8 (0.6–265) months. The median duration of nilotinib exposure was 81 days with median dose intensity of 800mg/day. A total of 13 (31%) pts with dasatinib failure remain on treatment, 29 (69%) discontinued (6 for AEs, 16 for disease progression). CP: Of the 16 pts, 5 (31%) had a MCyR (3 complete, 2 partial). Complete hematologic response (CHR) was reported in 5/13 (39%) pts without CHR at baseline. Disease progression only occurred in 2 pts. AP: 2/9 (22%) pts had a return to chronic phase (RTC), 6 pts were not evaluable and there was 1 death. Disease progression occurred in 5 pts. BC: 3/17 (18%) achieved CHR, 1 (6%) had RTC, and 4 (24%) pts had disease progression. For all pts, the most common Grade 3/4 AEs reported were thrombocytopenia (26%), neutropenia (24%), and anemia (7%) pts. Conclusions: Nilotinib has significant clinical activity in CML-CP, AP, and BC patients who have failed imatinib and dasatinib. Nilotinib is safe and well tolerated, consistent with its kinase selectivity profile.

No significant financial relationships to disclose.