bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac monitoring during adjuvant trastuzumab-based chemotherapy among older breast cancer patients.
Authors: Chavez-Mac Gregor Mariana , Zhang Ning , Niu Jiangong , Zhang Yufeng , Elting Linda S. , Buchholz Thomas A. , Valero Vicente , Giordano Sharon Hermes
Published: March 2020

6630

Background: Adjuvant trastuzumab improves outcomes but is associated with cardiotoxicity. Cardiac monitoring at baseline and at regular intervals during treatment is advised. No data exist on the adequacy of cardiac monitoring in the general population. Of particular interest is the pattern of monitoring in the elderly as they are at increased risk for cardiotoxicity. In a large cohort of trastuzumab-treated patients, we describe the patterns of cardiac monitoring, and evaluate factors associated with suboptimal monitoring. Methods: Breast cancer patients ≥66 years with full Medicare coverage, stage I-III breast cancer diagnosed between 2005-2007, and treated with adjuvant trastuzumab-based chemotherapy were identified in the SEER-Medicare and in the Texas Cancer Registry-Medicare databases. The frequency of echocardiograms/MUGAs was determined. Baseline monitoring (test in the 4 months prior to initiation of trastuzumab), adequate follow-up monitoring (a test every 4 months during trastuzumab treatment) and optimal monitoring (baseline test and adequate follow-up monitoring) were evaluated. Chemotherapy, trastuzumab use, echo/MUGA, and comorbidities were identified using ICD-9 and HCPCS codes. Prescribing physician characteristics were also evaluated. Descriptive statistics and logistic regression were used. Results: 1221 patients were identified; median age was 71 yrs. Baseline test was not performed in 22% of patients. Suboptimal follow-up monitoring during treatment was observed in 59.5% of the patients. Hispanics were less likely to have baseline test or adequate follow-up monitoring (OR 0.63; 0.4-0.99 and OR 0.60; 0.39-0.93 respectively). Factors associated with optimal cardiac monitoring included anthracycline use (OR 1.8; 1.39-2.36), recent year of diagnosis (OR 1.5; 1.09-2.08); female prescribing physician (OR 1.79; 1.31-2.44) or physician graduated after 1990 (OR 1.45; 1.02-2.06). Conclusions: A large proportion of elderly patients had suboptimal cardiac monitoring. Trastuzumab-related cardiotoxicitiy is reversible and early diagnosis is crucial. Cardiac monitoring should be encouraged, particularly in vulnerable populations.
Resource use and costs in the last year of life among Medicare beneficiaries who died from prostate cancer versus with the disease between 2000 and 2007.
Authors: Reed Shelby D. , Dinan Michaela A , Li Yanhong , Zhang Yinghong , Curtis Lesley H , George Daniel J. , Stewart Suzanne B
Published: March 2020

6631

Background: Prostate cancer is one of the leading sources of overall cancer care costs among men in the United States. Medical resource use and costs associated with prostate cancer care at the end of life, remain poorly understood. Methods: Retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) -Medicare data was used to characterize changes in resource utilization and health care costs to the Centers for Medicare and Medicaid (CMS) in patients diagnosed with prostate cancer who died of prostate cancer vs. non-prostate causes between 2000 and 2007. Results: A total of 34,727 patients with prostate cancer met study criteria. Patients who died of prostate cancer were significantly more likely to have been diagnosed with incident distant metastatic disease (27% vs. 4%) and had fewer comorbid conditions than patients who died of other causes. In the year prior to death, men who died of prostate cancer had lower mean inpatient costs ($20,769 vs. $29,851), resulting from fewer hospitalizations (1.8 vs. 2.1) and fewer days spent in the hospital (12.2 vs. 15.7) and the ICU (1.4 vs. 3.4) as compared to men who were diagnosed with prostate cancer but died of some other cause (all P< 0.001). Men who died of prostate cancer also had lower rates of SNF utilization (32.8% vs 36.2%) and spent fewer days in SNF institutions (11.7 vs 14.7) (both P< 0.001). Conversely, men who died of prostate cancer were more likely to have enrolled in hospice (62% vs. 28%) with higher mean hospice costs ($5,117 vs. $1,981) (both P< 0.001). The substitution of more hospice care relative to inpatient care for men who died of prostate cancer resulted in lower total health care costs ($42,572 vs. $45,830; P< 0.001) relative to men who died from non-prostate cancer causes. Conclusions: Among men with a diagnosis of prostate cancer who died between 2000 and 2007, those with prostate cancer-specific mortality had lower overall health care costs than those who died from other causes. Less aggressive inpatient care near the end of life may explain the differences in cost. Ongoing investigation of care at the end of life is warranted given recent changes in the treatment landscape of metastatic prostate cancer.
Creating a risk of readmission (ROR) score for gynecologic oncology (GO) patient.
Authors: Ward Kristy K. , Shah Nina R. , Davis Mitzie-Ann , Saenz Cheryl C. , McHale Michael T. , Plaxe Steven C.
Published: March 2020

6636

Background: The annual cost of 30 day hospital readmissions in the US is $16 billion. The objectives of this study are to determine factors associated with readmission among GO patients, and to create a risk score to identify populations at the highest risk of readmission. Methods: The University HealthSystem Consortium database was queried to identify readmissions among GO patients from 1/1/08 through 9/30/12. Risk factors for 30 day readmission were determined by univariate and multivariate analysis. For each risk factor found to be independently associated with readmission, the low risk group was scored 0 and the high risk group scored 1. The ROR score is the sum of the individual scores. Probability of readmission was calculated for each ROR score. Results: Overall, the readmission rate for GO patients was 4.5%. Vulvar cancer, medical MSDRG, urgent or emergent admission, length of stay > 4 days, and coverage by a public payer (during 1st admission) each was independently associated with readmission. Probability of readmission increases significantly with increasing risk score. Patients with a ROR score of 0 or 1 have a readmission rate of 3.9% (95% CI 3.7% to 4.1%); patients with a ROR score of >1 have a readmission rate of 10.7% (95% CI 10.1% to 11.2%). Conclusions: Specific risk factors and composite risk score are associated with 30 day readmission rate among GO patients. The patient specific ROR score may be used to target transitions of care interventions aimed at reducing readmissions. [Table: see text] [Table: see text]
Differences in 30-day preventable readmission rates after index cancer surgery in New York State hospitals.
Authors: Sarpel Umut , Egorova Natalia , Sosunov Eugene , Franco Rebeca , Taveras Yohana , Bickell Nina A.
Published: March 2020

6640

Background: 30-day readmission rates are currently being used as a measure of performance quality. Among surgical patients, readmissions may be reducible for certain complications such as deep venous thrombosis or wound infection. We report 30-day readmission rates for potentially preventable readmissions following surgical treatment of the most common malignancies in the US. Methods: The most common cancer hospitalizations were identified from the Healthcare Cost and Utilization Project. Previously reported ICD-9 codes of preventable readmissions from cancer surgery were used to assess 30-day readmissions in New York State in 2009. We measured comorbidity using CMS hierarchical condition categories. Hospital teaching status was based on the American Hospital Association designation. Random effect hierarchical logistic regression models were run to account for clustering within hospitals. Results: 21,945 index admissions for cancer surgery occurred in 2009 at 169 teaching and 73 non-teaching hospitals. The most common operations were for prostate, breast, colon, lung, and renal cancer. 51% of patients were male and 12% were black. The overall readmission rate was 9.3% with readmissions being higher in non-teaching hospitals (11.2%) vs. teaching hospitals (8.6%) (p<0.0001). There was a significant interaction between hospital teaching status and patient race. In teaching hospitals, there was no racial difference in readmission. However, in non-teaching hospitals, black patients were more likely to be readmitted (15.1% vs 10.9%; p=0.02). Multivariate models found that being male (OR=1.17; 95% CI: 1.04; 1.31; p=0.007), undergoing surgery at a non-teaching hospital (OR=1.16; 95% CI: 1.00; 1.35; p=0.048), black race (OR=1.47; 95% CI: 1.04; 2.08; p=0.029), and certain comorbidities increased a patient’s risk of 30-day readmission for a preventable cause. Conclusions: The 30-day preventable readmission rate after index hospitalizations for cancer surgery is higher in non-teaching hospitals, and this difference is more pronounced for black patients. Clinical protocols in teaching hospitals may play a role in this phenomenon. Efforts to address remediable causes of this disparity are warranted.
Improvement of cancer care by linking community cancer center oncologists to disease site-specific experts.
Authors: Hardenbergh Patricia H. , May Calloway B , Lyons-Mitchell Kimberly Anne
Published: March 2020

6641

Background: To improve the quality of cancer care across US by connecting community cancer center oncologists with highly specialized, disease site-specific oncologists through the use of online technology. Methods: Chartrounds.com was developed which allows community oncologists to interact online with disease site-specific oncologists and their peers on a scheduled basis in order to present and review treatment management and specific cases. Disease sites include breast, head and neck, gastrointestinal, gynecologic, prostate, central nervous systems, pediatric, lymphoma, lung cancer and palliative care. At the conclusion of each session, participants are asked to complete a questionnaire which requests feedback on the quality and relevance of the session and the manner in which it might result in practice changes. Results: To date, 825 community radiation oncology physician members from 50 states and 19 countries have enrolled online. In the initial 25-month period (12/2010-1/2013), 35 disease site-specific specialists have lead 256 chart rounds one-hour sessions with an average attendance ratio of 15 community physician members to 1 disease site-specific specialist. On a 5 point scale with 5 representing the greatest impact possible, of 1,756 responses the mean score to feedback questions is as follows: session quality: 4.6, time used effectively: 4.6, discussions relevant to daily practice: 4.6, session is likely to result in a change in practice: 4.0.Members reported that they would make the following changes in their practice: change in clinical management of the radiation patient: 40%, change in the selection of patients for radiation: 10%, change in radiation fields: 15%, change in radiation prescription dose: 10%. Conclusions: The Chartrounds.com program appears to be making an impact on the quality of radiation oncology practices resulting in changes in management and treatment of patients in community cancer centers. Future directions of this project are aimed at continuing to develop the site for medical oncologists and multidisciplinary tumor conferences. This work is funded by the Improving Cancer Care Grant of the ASCO Conquer Cancer Foundation supported by Susan G. Komen for the Cure.
Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with chronic myeloid leukemia.
Authors: Deininger Michael W. N. , Cortes Jorge E. , Kim Dong-Wook , Nicolini Franck E. , Talpaz Moshe , Baccarani Michele , Müller Martin C. , Lustgarten Stephanie , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G. , Guilhot Francois , Hochhaus Andreas , Goldman John M. , Shah Neil P. , Kantarjian Hagop M. , Hughes Timothy P.
Published: March 2020

7001

Background: BCR-ABL kinase domain mutations frequently cause tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia (CML). Ponatinib, a potent oral pan-BCR-ABL TKI, has shown preclinical activity against all single mutants tested, including T315I. The impact of baseline (BL) mutations on response to ponatinib (45 mg once daily) and end of treatment (EOT) mutations in pts discontinuing treatment were evaluated in the phase II PACE trial. Methods: Heavily pretreated chronic phase (CP) CML pts (93% received ≥2 prior TKIs, 60% ≥3) resistant or intolerant to dasatinib or nilotinib (N=203) or with T315I confirmed at BL (N=64) were enrolled. The primary endpt was major cytogenetic response (MCyR). Min follow up at analysis (9 Nov 2012) was 12 mos (median 15 [0.1-25]). Sanger sequencing was done at one central laboratory. Results: At BL, no mutations were detected in 51% of pts, 1 mutation in 39%, and ≥2 mutations in 10%; 26 unique mutations were observed. Responses were observed regardless of BL mutation status. MCyR rates were: 56% overall, 49% in pts with no mutations, 64% 1 mutation, 62% ≥2 mutations; 57% in pts with mutation(s) other than T315I, 74% T315I only, 57% T315I + other mutation(s). Responses were seen against each of the 15 mutations present in >1 pt at BL, including T315I, E255V, F359V, Y253H. 99 pts discontinued, 56 had EOT mutations assessed. 5 pts lost a mutation, 46 had no change, 5 gained mutations (Table). 11 pts lost MCyR (none with T315I); of the 6 discontinuing, 4 had EOT mutations assessed and no changes from BL were seen. Conclusions: Responses to ponatinib were observed regardless of BL mutation status. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. Data with a minimum follow up of 18 mos, including pts with advanced disease, will be presented. Clinical trial information: NCT01207440. [Table: see text]
Aberrant NFAT2 signaling in chronic lymphocytic leukemia.
Authors: Heitmann Jonas S. , Maerklin Melanie , Poljak Alexandra , Hackl Bettina , Stickel Juliane , Kanz Lothar , Kopp Hans-Georg , Wirths Stefan , Mueller Martin Rudolf
Published: March 2020

7019

Background: CLL is a malignancy of mature B cells and constiututes the most common leukemia in adults. It is characterized by a progressive accumulation of clonal B cells, which coexpress CD19, CD23 and CD5. NFAT is a family of highly phosphorylated transcription factors residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the significance of NFAT signaling in B-CLL. Methods: NFAT2 expression and aberrant nuclear translocation in CLL cells (n=30) was assessed by Western Blotting and immunofluorescence. In addition, NFAT2 mRNA levels were measured by qRT-PCR and its DNA binding capacity was assessed using an electrophoretic mobility shift assay. Transcriptional activity of NFAT2 proteins in CLL cells was further analyzed by determining the expression of several well characterized NFAT target genes. Results: We detected a profound overexpression of NFAT2 mRNA and protein in all CLL samples. Using qRT-PCR we found that CD19+CD5+ CLL cells exhibited a significant overexpression of NFAT2 as compared to CD19+ B cells isolated from healthy donors (8-200fold). This overexpression of NFAT2 in CLL cells could also be confirmed on the protein level. We could further demonstrate that even under resting conditions significant amounts of NFAT2 protein had translocated to the nucleus in CLL cells, whereas virtually all NFAT2 was in the cytoplasm in non-malignant B cells. Nuclear NFAT2 in CLL cells was able to bind DNA but its transcriptional activity with respect to several apoptosis-regulating genes (i.e. Spp1, Pdcd1) was severely compromised. Conclusions: These results provide strong evidence that the Ca2+/NFAT signalling axis is constitutively activated in CD5+CD19+ CLL cells. Reduced expression of several apoptosis regulators which are known target genes of NFAT2 links deregulation of this signaling cascade to CLL progression. Further investigation is warranted to investigate the therapeutic potential of modulating Ca2+/Calcineurin/ NFAT signaling in CLL.
Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).
Authors: Schub Andrea , Nägele Virginie , Zugmaier Gerhard , Brandl Christian , Hijazi Youssef , Topp Max S. , Kufer Peter , Wolf Andreas , Klinger Matthias
Published: March 2020

7020

Background: Blinatumomab is an anti-CD19/anti-CD3 bispecific T cell engager (BiTE) that induces target cell-dependent, polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+ target cells. Methods: In a phase 2 study, adult patients (N=36) with relapsed/refractory B-precursor ALL received continuous blinatumomab IV infusion for 28 days in ≤5 treatment/consolidation cycles. Whole blood and serum samples were collected throughout treatment and analyzed for lymphocyte subpopulations, cytokines, granzyme B, and blinatumomab serum concentrations. Results: Lymphocytes in all patients responded in a similar fashion. After infusion start, peripheral B cell counts dropped to ≤1 B cell/μL in <1 week and remained undetectable throughout treatment. Peripheral T cells showed a redistribution characterized by swift disappearance within the first 2-6 hrs and subsequent recovery to baseline within several days. Otherwise, T cell counts remained at least stable in most patients. In some patients even an expansion of the T cell compartments was observed, most likely due to specific proliferation of activated T cells but could not be defined as prerequisite for treatment efficacy. During the first infusion days, a significant proportion of T cells newly expressed the activation marker CD69, and the T cell effector molecule granzyme B was detectable in serum. Additionally, a transient cytokine release dominated by IL-10, IL-6 and IFN-γ was observed in most patients shortly after first infusion start, which was alleviated or absent in subsequent cycles. Blinatumomab serum steady state concentrations (mean±SD) were 198±61 pg/mL and 694±236 pg/mL at doses of 5 and 15 μg/m²/d, respectively, which is comparable to those from previous studies. Conclusions: Immunopharmacodynamic response to blinatumomab was characterized by B cell depletion, T cell activation and redistribution, and release of granzyme B and cytokines, suggesting T cell engagement according to the expected BiTE mode of action. The tested pharmacodynamic markers did not allow for predictive differentiation between patients achieving a hematologic response and those who did not. Clinical trial information: NCT01209286.
Efficacy and safety of quizartinib (AC220) in patients age ≥ 70 years with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia (AML).
Authors: Perl Alexander E. , Dohner Hartmut , Rousselot Philippe H. , Marie Jean-Pierre , Martinelli Giovanni , Shah Neil P. , Levis Mark J. , Gammon Guy , Trone Denise , Cortes Jorge E.
Published: March 2020

7023

Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in AML are each associated with early relapse after standard chemotherapy and poor survival. Quizartinib, an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: We provide detailed analysis from a Ph 2 study (N = 333) of quizartinib monotherapy, focusing on patients (pts) aged ≥ 70 y with AML that relapsed and/or was refractory to prior therapy. Results: A total of 83 pts age ≥70 y included 60 (72%) FLT3-ITD(+) and 23 (28%) FLT3-ITD(-). Median duration of treatment was 14.6 wks for FLT3-ITD(+) pts and 5.9 wks for FLT3-ITD(-) pts. Composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Of 60 FLT3-ITD(+) pts, 32 (53%) had a CRc (1 CR, 3 CRp, 28 CRi). Of 23 FLT3-ITD(-) pts, 10 (43%) had a CRc (2 CR, 1 CRp, 7 CRi). 12/27 FLT3-ITD(+) pts (44%) and 5/10 FLT3-ITD(-) pts (50%) refractory to prior therapy responded to quizartinib, and 12/83 (14%) survived >1 y. The most common (≥10%) Grade 3 or 4 treatment-related adverse events (TRAEs) were febrile neutropenia (22%), anemia (20%), transient QT interval prolongation (17%; no Grade 4), and thrombocytopenia (12%). 15 pts (18%) had TRAEs resulting in discontinuation. Conclusions: Because AML in the elderly, particularly in those aged ≥70 y, is genetically heterogeneous and often follows a myelodysplastic syndrome, there is a wide assumption that it may be less amenable to FLT3-targeted therapy than AML in younger pts. Our data argue against these conclusions and show that pts aged ≥70 y with chemotherapy-resistant AML have preserved high response rates, and promising survival to quizartinib. Clinical trial information: NCT00989261. [Table: see text]
Variations in FLT3 ligand levels during the course of AML treatment.
Authors: Grunwald Michael Richard , Levis Mark J.
Published: March 2020

7026

Background: FLT3 ligand (FL) is a hematopoietic growth factor expressed in many tissues. AML patients who are administered myeloablative therapy exhibit a marked and transient rise in plasma FL concentrations. Furthermore, the presence of high concentrations (1000 pg/mL) of FL impedes the efficacy of FLT3 tyrosine kinase inhibitors in vitro. However, the behavior of FL concentrations throughout the course of AML treatment remains unknown. This pilot study was undertaken to track the relationship between AML therapy and FL levels over time. Methods: Ten AML patients were enrolled in an IRB-approved procurement protocol. Blood samples were collected at weekly intervals for one year, and plasma was isolated by centrifugation. Plasma FL and stem cell factor (SCF) concentrations were measured by ELISA. Results: We observed four distinct patterns in FL fluctuations. First, in all cases where induction or consolidation chemotherapy resulted in an aplastic bone marrow (nine patients), FL concentrations rose markedly and consistently to levels >1000 pg/mL following the administration of chemotherapy. Second, in three of four patients whose leukemia was refractory to induction chemotherapy, FL concentrations remained below 500 pg/mL during induction. Third, in two patients receiving the FLT3 TKI sorafenib, FL concentrations did not rise above 500 pg/mL while on this medication. Fourth, in one patient receiving the hypomethylating agent 5-azacitidine, FL concentrations remained below 100 pg/mL throughout the course of therapy. SCF concentrations did not vary throughout the course of chemotherapy. Conclusions: An “FL surge” was seen when cytotoxic chemotherapy resulted in aplasia. This FL surge was not seen with sorafenib or 5-azacitidine. In addition, the FL surge was attenuated in three patients whose leukemia was refractory to chemotherapy. These observations give rise to two new hypotheses regarding FL: 1) It is possible to maintain lower FL levels with targeted agents than with chemotherapy; and 2) Residual leukemia appears to inhibit the FL surge, providing indirect evidence of cross-talk between leukemia and the stromal microenvironment. This inhibition may be the explanation for why AML patients develop pancytopenia early in relapse.
Outcomes of hematopoietic stem cell transplant recipients admitted to the medical intensive care unit.
Authors: Tran Duc Quang , Langston Amelia A. , Waller Edmund K. , Simon Melanie , Gleason Charise , Casbourne Daniela , Fisher Micah , Kaufman Jonathan L. , Flowers Christopher , Lonial Sagar , Nooka Ajay K.
Published: March 2020

7035

Background: Outcome results for hematopoietic stem cell transplant (HSCT) patients admitted to intensive care unit (ICU) and prognosis is infrequently reported during recent years, especially in view of increasing use of unrelated donors, increasing use of transplant maneuver in older patients using reduced intensity conditioning regimens and improvement in supportive care. We assessed our institutional survival outcomes and evaluated predictors of mortality in HSCT recipients admitted to ICU. Methods: Among the 390 HSCTs performed from March 2011 until July 2012, we retrospectively evaluated 34 HSCT patients admitted to ICU. 22 patients received mechanical ventilation (MV) or vasopressor support and were analyzed separately. All previously defined predictors of mortality were evaluated. SPSS version 20 was used for statistical analysis. Results: 9% of all HSCT patients were admitted to ICU. 65% of patients received allogeneic transplants. Major underlying hematological malignancies were AML/MDS (29%) and myeloma (24%). 41% were admitted for respiratory failure and 23.5% for sepsis. Median age was 55.5 (range: 27-76). Median length of ICU stay was 7 days (0-42) and median APACHE II score was 20 (9-39). 30 day and 60 day mortality rates are 47% and 62% among all patients; 54% and 68% among MV patients or receiving vasopressors. Predictors for day 30 mortality on univariate analysis among all patients were APACHE II score ≥26 (p=0.05). Predictors for day 60 mortality were APACHE II score ≥31 (p=0.001) and multiorgan failure (p=0.009). Among patients receiving MV or vasopressors, APACHE II score ≥31 is the only significant predictor of mortality (p=0.011). On multivariate analysis, APACHE II score ≥31 at day 30 hazards ratio (HR) 3.777 (95%CI 1.041-13.69; p=0.043) and at day 60 HR 3.789 (95%CI 1.07-13.45; p=0.039) are significant predictors of mortality. Conclusions: Significant predictors identified on multivariate analyses were APACHE II score ≥31 at day 30 and day 60. Interestingly, type of transplant is not a significant predictor of mortality. Future studies with larger patient samples and longer follow up are required for further understanding of prognosis in these patients.
Day 100 peripheral blood absolute monocyte/lymphocyte count prognostic score and survival in diffuse large B-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.
Authors: Velazquez Ana I. , Markovic Svetomir , Inwards David James , Micallef Ivana N. M. , Johnston Patrick B. , Hogan William J. , Ansell Stephen Maxted , Porrata Luis F.
Published: March 2020

7041

Background: Prognostic factors for diffuse large B-cell lymphoma (DLBCL) at day 100 post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) have not been evaluated. We previously reported that absolute monocyte (AMC)/lymphocyte count (ALC) prognostic score (AMLCPS) at diagnosis of DLBCL patients is a prognostic factor of survival, stratifying patients into three risk groups: low- (AMC<630/μL and ALC>1000/μL), intermediate- (AMC ≥ 630/μL or ALC ≤ 1000/μL) and high-risk (AMC ≥ 630/μL and ALC ≤ 1000/μL) (Leukemia 25: 1502-9, 2011). Therefore, we evaluated day 100 AMLCPS as a prognostic factor of survival by landmark analysis from day 100 post-APBHSCT in DLBCL patients. Methods: DLBCL patients that achieved complete response by day 100 post-APBHSCT qualified for the study. From 2000 to 2007, 134 consecutive DLBCL patients were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier analysis. Results: The median follow up from day 100 for the cohort was 5.5 years (range: 0.17-12.17 years) and for living patients (N=93) was 6.9 years (range: 2.5-12.17 years). Day 100 AMLCPS was able to stratify patients into three risk groups low-, intermediate-, and high-risk for OS [low: median OS = not reached, 5-year survival rate = 94% (95%CI 83.3%-98.1%); intermediate: median OS = not reached, 5-year survival rate = 70% (95%CI 58.0%-79.8%); high: median OS = 2.2 years, 5-year survival rate = 13% (95%CI 3.4%-40.5%); p<0.0001] and PFS [low: median PFS = not reached, 5-year progression free rate = 87% (95%CI 74.5%-94.3%); intermediate: median PFS = 10.9 years, 5-year progression free rate = 67% (95%CI 55.4%-77.5%); high: median PFS = 1 year, 5-year progression free rate = 13% (95%CI 3.4%-40.5%); p<0.0001]. The day 100 AMLCPS was balanced in relation to the International Prognostic Index (IPI; p=0.22), infused CD34+ stem cells (p=0.92), and disease status pre-APBHSCT (complete remission versus partial response; p=0.11). Conclusions: The day 100 AMLCPS is a simple biomarker that can help identify DLBCL patients post-APBHSCT with poor clinical outcomes.
Incidence of engraftment fever post autologous transplant for lymphomas and analysis of risk factors.
Authors: Pandey Avinash , Mittal Sushant S. , Thippeswamy Ravi , Rajamanickam K. Deepan , Gokarn Anant , Bhosale Bharatsinha Baburao , Mathew Libin , Kannan Sadhna , Bagal Bhausaheb Pandurang , Gawande Jayant Shankar , Khattry Navin
Published: March 2020

7043

Background: Engraftment fever (EF) is a phenomenon observed in some patients undergoing autologous transplant (ASCT). We analyzed our data to evaluate the incidence and risk factors associated with EF. Methods: Seventy-nine patients underwent ASCT (53-Hodgkin’s and 26- Non Hodgkin’s) from August 2007 – January 2013. All except 5 received LACE (Lomustine, Ara-C, Cyclophosphamide and Etoposide) conditioning regimen. EF was defined as onset of fever with rising white cell count for which no infectious cause was ascertained. Patients of EF and non-EF groups were compared for the following variables to determine risk factors. These included histology, number of lines of chemotherapy regimens pre-transplant, complete remission (CR) at transplant, peripheral blood CD 34 count on day 1 of collection (PBCD34-D1), CD 34 cell dose collected and infused and number of days of stem cell collection. Results: The median age at transplant was 23.5 years with 57 males and 22 females. Time to neutrophil and platelet engraftment was 10 and 13 days respectively. EF was seen in 35 patients (44 %) at a median of 9 days. Short course of methylprednisolone (n=28) or hydrocortisone (n=3) was given to which all responded. On univariate analysis, PBCD34-D1 > 50/uL (P = 0.037), CD 34 cell dose infused >5.9x106/kg (P=0.012),CD34 cell dose collected > 7.2 x 10 6 /kg (P=0.032) , those receiving ≤ 2 lines of chemotherapy regimens before transplant (P=0.04), those who had ≤ 2 days of stem cell collection (P=0.002) and patients in CR at transplant (P = 0.015) were associated with risk of developing EF. On multivariate analysis, patients in CR at transplant and those who had ≤ 2 days of collection had higher risk of EF. Conclusions: The incidence of EF is high. Patients with lesser days of stem collection and those in CR at transplant have significant risk of developing EF.
Rapid identification of drug-resistant BCR-ABL(+) leukemia.
Authors: Rieder Ronald J. , Zhao Zhihui , Chalmers Alex , Stone Richard M. , Galinski Ilene
Published: March 2020

7050

Background: Approximately 20% of patients with chronic myeloid leukemia and most patients with BCR-ABL-positive acute leukemia demonstrate resistance to imatinib mesylate resulting in treatment failure or suboptimal patient outcomes. We hypothesize that monitoring the development of cellular stress in BCR-ABL cells incubated with tyrosine kinase inhibitors (TKI) can be used as an early marker for determining the effects of the drugs on the cancer cells enabling rapid identification of drug-resistance and facilitating change to more effective therapies. Methods: The dielectric permittivities of non-leukemic peripheral blood mononuclear cells (PBMCs) and BCR-ABL cell lines known to be resistant (K562R and BaF3/T315I) or sensitive (K562 and HL60/BCR-ABL) to different TKIs were measured in the presence of imatinib (IMT), dasatinib (DAS), nilotinib (NIL), or ponatinib (PON) using the Z-Sense differential impedance sensing platform to record any changes in cellular stress. We also performed similar measurements on PBMCs from newly diagnosed CML patients exposed in vitro to the same TKIs. Results: Non-leukemic PBMCs showed no significant background levels when incubated with the following TKI concentrations: IMT (5 mg/mL), DAS (5 mg/mL), NIL (2.5 mg/mL), and PON (5 ng/mL). Normalized dielectric responses for all drug-resistant cell lines showed no change in value similar to control runs where no drugs were added. In contrast, all responses obtained for cell lines sensitive to these same TKIs were immediate and continuously decreased in value over time compared with resistant cell lines (p<0.01). All sensitivities were confirmed by MTT assay. Notably, the response of BaF3/T315I cells to PON was easily distinguished from the responses to IMT, DAS, and NIL. Of significance, all responses of BCR-ABL(+) patient blood to the four TKIs measured prior to commencing therapy were qualitatively similar to sensitive cell line measurements and subsequently confirmed to respond to IMT therapy. Conclusions: Drug-sensitive BCR-ABL(+) cells can be readily distinguished from drug-resistant cells without cell culturing in less than 60 minutes by monitoring the development of cellular stress in response to TKI drugs using differential impedance sensing.
Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update.
Authors: Larson Richard A. , Hochhaus Andreas , Saglio Giuseppe , Kim Dong-Wook , Jootar Saengsuree , Le Coutre Philipp D. , Reiffers Josy , Pasquini Ricardo , Goldberg Stuart L. , Clark Richard E. , Kemp Charisse N. , Fan Xiaolin , Menssen Hans D. , Hughes Timothy P. , Kantarjian Hagop M.
Published: March 2020

7052^

Background: In the 3-y follow-up (f/u) of ENESTnd, NIL demonstrated superior rates of molecular response and reduced progression to accelerated phase/blast crisis (AP/BC) vs IM. Here, we report results with a minimum f/u of 4 y. Methods: 846 adults with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Results: NIL continued to demonstrate higher rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS), MR4 (≤ 0.01%IS), and MR4.5 (≤ 0.0032%IS) vs IM (Table). No new progressions have occurred on treatment on any arm since the 2-y analysis. NIL had significantly lower rates of progression to AP/BC on treatment (n = 2, 3, and 12 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and when including f/u after discontinuation (n = 9, 6, and 19 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and higher overall survival (OS) vs IM. By 4 y, half as many pts acquired new BCR-ABL mutations on study with NIL vs IM (n = 12, 11, and 22 on NIL 300 mg BID, 400 mg BID, and IM, respectively). Since the 3-y analysis, 2 new mutations (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM) were reported. Safety profiles of both drugs were consistent with previous ENESTnd analyses. By 4 y, peripheral arterial occlusive disease (PAOD) events were reported in 4 and 5 pts in the NIL 300 mg BID, and 400 mg BID arms, respectively. No pt in the IM arm had a PAOD event. Conclusions: ENESTnd 4-y data continue to demonstrate the superiority of NIL over IM for achieving deeper responses with lower risk of progression, supporting the use of NIL as frontline therapy in CML-CP. Clinical trial information: NCT00471497. [Table: see text]
Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.
Authors: Spector Nelson , Leber Brian , Lipton Jeffrey Howard , De Souza Carmino , Moiraghi Beatriz , Steegmann Juan Luis , Schwarer Anthony P. , Cervantes Francisco , Hughes Timothy P. , Purkayastha Das , Collins LaTonya R , Szczudlo Tomasz K. , Rea Delphine
Published: March 2020

7053^

Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]
Phase I study of midostaurin and azacitidine in relapsed and elderly AML.
Authors: Cooper Brenda W. , Kindwall-Keller Tamila L. , Lazarus Hillard M. , Hamadani Mehdi , Tse William W. , Basu Soumit K. , Craig Michael
Published: March 2020

7058

Background: The Fms-like tyrosine kinase 3 (FLT3) receptor is expressed in 80% of AML and activating mutations are associated with an adverse prognosis. Midostaurin (mdn), an orally available agent, has been shown to inhibit FLT3 receptor signaling and induces cell cycle arrest and apoptosis of leukemic cells expressing both mutant and wild type FLT3 receptors. Preliminary data has shown modest single agent activity as well as safety and tolerablility of mdn in combination with standard induction chemotherapy. Methods: We conducted a phase I study of azacitidine (75 mg/m2 iv X 7days) with escalating doses of oral mdn (25 mg bid, 50 mg bid, and 75 mg bid) days 8-21 of a 28 day cycle in untreated elderly and relapsed AML. The protocol was IRB approved at participating institutions and all patients gave written informed consent. Dose limiting toxicities (DLTs) were defined as > grade 3 non-heme toxicity during cycle 1 excluding grade 3 hepatotoxicity < 7 days, grade 3/4 stomatitis or diarrhea that resolved by day 28, infections, and electrolyte abnormalities of any grade. Pharmacokinetics (pK) were obtained on day 8,15, and 21 before mdn dosing. Results: 17 pts (11 females and 6 males) ages 57-83 ( median 73) were enrolled of whom 5 patients had prior intensive treatment for AML. All pts were FLT3 negative; 5 had normal cytogenetics and 12 had high risk cytogenetics. ECOG PS: 0 (4pts), 1 (11pts), 2 (2pts). No DLT were observed during escalation or in the expansion cohort of 75 mg bid. Responses were evaluable in 14/17 pts and included 2 CR, 1 PR, and 2 HI (clearing of peripheral blasts, platelet tx independence). Median survival from enrollment was 3.5 months (range 1-12 months). 4 pts remain on treatment (2- 9+ cycles). 3 pts died within 60 days (2 PD, 1 treatment-related). Non-infectious, non hematologic SAE’s are listed on the table below. Plasma concentrations of mdn accumulated in the first week of treatment and declined thereafter despite continued dosing. Conclusions: The combination of azacitidine and midostaurin in safe and tolerable in elderly AML and should be further studied in FLT3 positive leukemia. Clinical trial information: NCT01093573. [Table: see text]
Safety and durability of ponatinib in patients with Philadelphia chromosome-positive (Ph+) leukemia: Long-term follow-up of an ongoing phase I study.
Authors: Mauro Michael J. , Cortes Jorge E. , Kantarjian Hagop M. , Shah Neil P. , Bixby Dale , Flinn Ian , O'Hare Thomas , Hu Simin , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G. , Druker Brian J. , Deininger Michael W. N. , Talpaz Moshe
Published: March 2020

7063

Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline BCR-ABL mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common treatment-related AEs were rash (42%), thrombocytopenia (34%), arthralgia (20%), and increased lipase (20%). Significant anti-leukemic activity was observed (Table). Responses (major cytogenetic response [MCyR] for CP-CML or major hematologic response [MaHR] for accelerated phase [AP] CML, blast phase [BP] CML, or Ph+ ALL) were observed against the following mutations detected in >1 pt at baseline: 14/19 T315I, 4/7 F317L, 2/4 G250E, 2/2 M244V, 2/2 M35IT, and 1/2 F359V. Among CP-CML pts, 73% with complete cytogenetic response (CCyR) and 63% with major molecular response (MMR) are estimated to maintain response at 2 yrs (Kaplan-Meier). Of 28 CP-CML pts with CCyR, 25 remained on study (19 with continuous CCyR); of 22 pts with MMR, 21 remained on study (15 with continuous MMR). Updated data will be presented. Conclusions: Significant and durable responses were observed in heavily pretreated CP-CML pts, regardless of mutation status, and ponatinib was generally well tolerated. Clinical trial information: NCT00660920. [Table: see text]
Results of omacetaxine plus low-dose cytarabine (LD-araC) in older patients with acute myeloid leukemia (AML).
Authors: Kadia Tapan M. , Daver Naval Guastad , Ravandi Farhad , Jabbour Elias , Pemmaraju Naveen , Pierce Sherry , Cortes Jorge E. , Kantarjian Hagop M.
Published: March 2020

7068

Background: Older patients with AML have poor tolerance to intensive chemotherapy and poor prognosis. Omacetaxine is active in AML and is part of standard combination chemotherapy in China under the name of homoharringtonine. Methods: The aim of the study was to evaluate the efficacy of low intensity therapy with omacetaxine and LD-ara C in newly diagnosed older patients (>/= 60 years) with AML or myelodysplastic syndrome (MDS). Older patients with AML not fit or who refuse intensive chemotherapy were eligible. Normal organ functions and performance status </= 2 were required. Other eligibility criteria were standard. Induction therapy consisted of omacetaxine 1.25 mg/m2 subcutaneously twice daily for 3 days and ara-C 20 mg subcutaneously twice daily for 7 days. Maintenance therapy was with the same induction schedule, repeated every 4-6 weeks for up to 2 years. Dose adjustments for prolonged myelosupression or severe non-hematologic toxicities were made by reducing the number of days of omacetaxine (-1 day by level) and cytarabine (-1 to 2 days by level). Results: 30 patients have been treated, with a median age of 71 years (range 64-81); 60% were age 70 years or older. AML post MDS in 20%; chromosome 5 and 7 abnormalities were present in 23%. Overall, 9 patients achieved CR (30%), 5 had CRp (17%) and 1 had PR (3%), for an overall response rate of 50%. Induction mortality was noted in 4 (Day 5, 27, 27, and 70 from start of therapy; 13%); resistant disease in 8 (27%); too early in 4 (13%). With the median follow-up time of 10 months the median survival is 9.3 months and the estimated 1-year survival rate 42%. No serious drug related adverse effects were observed with the combination. Conclusions: Low-intensity therapy with omacetaxine + LD-ara C shows promising activity and is safe in older patients with AML not fit for intensive chemotherapy. Clinical trial information: NCT01272245.
Comparison of two major intergroup induction intensive regimens in Hispanic adolescent and young adults (AYA) with acute lymphocytic leukemia (ALL): The importance of a complete molecular response.
Authors: Vigil Carlos Enrique , Escalante Lorena , Lopez Lourdes , Villena Marco , Quintana Shirley , Samanez Cesar Augusto , Casanova Luis Augusto
Published: March 2020

7072

Background: Novel intensive chemotherapy regimens impacted in the prognosis of adolescent and young adult pts with ALL. The application of pediatric inspired therapies demonstrated complete response reported to be > 80%, and long-term survival rates range from 30% to 45%. In the past, ALL treatments had been designed on the presence of risk factors as elevated WBC, time to complete remission or immunophenotype. Recently, MRD monitoring had risen as a risk predictor. Hypothesis: Complete response(CR) associated with a CMR has impact in disease-free survival. Methods: Between March> 2010 and November 2012, 101 adolescent and young adult pts were diagnosed and treated for (Ph)–negative ALL with the C10403 intergroup protocol (N=47) and the 2008 Spanish PETHEMA regimen (N=54). The residual disease status was assessed after induction by multiparametric flow cytometry (MRD <0.1%). Results: The median age of the pts was 17.56 years (range, 14-24); with 69 pts (68%) ≤ 18 year-old. 27 (26.7%) pts were WBC ≥ 50x109/L, 63 pts (62%) B immunophenotype, cytogenetics was unknown in 69 pts. After the induction, the CR was achieved in 81% vs 79.6% pts ( Int C10403 vs Pethema, respectively ). The induction mortality rate was 0% vs 7%. Slow responders to induction chemotherapy were 23.81% and 28.8% respectively (p=0.591). A CMR (CR+MRD ≤0.1%) was seen on 70.21% vs 63.27%. The kaplan-meier 2-year disease free-survival rate calculated for CMR patients on C10403 was 35% vs 17% for the Pethema, which was statistically significant (p< 0.04). A multivariate analysis of pts characteristics in CMR could not identified risk factors for disease prognosis. Conclusions: Two different regimens C10403 vs Pethema, could not demonstrate a statistic difference in morphological CR. Lately,the addition of minimal residual disease ≤0.1% (MRD) in the analysis, demonstrated a plausible monitoring variable of response. We suggest that a CMR (CR +MRD at induction) could be a new standard variable to assess responses regardless of previous risk categories. Further validation may be mandatory.