bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do ACE-I protect against the development of doxorubicin cardiac toxicity?
Authors: Blaes A. , Peterson B. A. , Yee D. , Virnig B. 
Published: August 2020

6623 Background: Doxorubicin (DOX), an anthracycline, has been associated with irreversible cardiotoxicity. Recently, newer agents such as angiotensin converting enzyme (ACE-I) inhibitors have been used in small trials to prevent cardiac toxicity in patients receiving DOX. This retrospective study analyzes whether ACE-I and other medications are protective in the development of DOX cardiomyopathy. Methods: Patients receiving DOX chemotherapy at the University of Minnesota Cancer Center who had two or more multigated blood pool imaging (MUGA) scan or echocardiograms performed were identified and reviewed. Patients who had at least a 10% drop in their ejection fraction (EF) to below the lower limits of normal (50%) or had an absolute decrease in EF of 15% or greater were identified and compared with those that did not have a decline in EF. Patient variables and the use of concurrent medications were compared between these two groups using logistic regression. Results: 350 patients received DOX chemotherapy between November 2004 and 2007. Of 142 patients who had two or more MUGA scans performed during the course of their therapy, 22 (15%) had a significant drop in EF. Median age was 52 years old (range 7–88). 85 (60%) were female. Cancer diagnosis was breast (n = 26), lymphoma (n = 92), and other (n = 25). The median baseline EF of all patients was similar (62% versus 63%). A stepwise variable selection retained two predictors significant at alpha = 0.1 in a logistic regression model: Age and ACE-I (p = 0.0252 and p = 0.0940, respectively). Adjusting for Age, the odds ratio for ACE-I is 0.267, suggesting that ACE-I has a protective effect, as it reduces the probability of a drop in EF. Cumulative DOX dose, obesity, hypertension, and history of tobacco use did not appear to be associated with a decline in ejection fraction. The use of beta-blockers, aspirin or statins did not appear to be associated with a decline in ejection fraction. Conclusions: DOX chemotherapy has been associated with the development of cardiomyopathies. While this is an observational study that is limited by its retrospective nature, the study supports our hypothesis that the use of ACE-I is possibly protective when given with DOX chemotherapy and warrants further investigation. No significant financial relationships to disclose.
Evaluating risk of hospitalization with G-CSF use in real-world oncology practice
Authors: Tan H. , Tomic K. , Daniel G. , Hurley D. , Barron R. 
Published: August 2020

6626 Background: Limited published data exist on how granulocyte colony-stimulating factor (G-CSF) treatment patterns affect risk of neutropenia-related hospitalizations. This study examines prophylactic vs. delayed use of G-CSF and compares the effectiveness of prophylaxis with filgrastim (FIL) vs. pegfilgrastim (PEG). Methods: A retrospective analysis of administrative claims from U.S. commercial health plans identified adult patients with non-Hodgkin's lymphoma, breast, or lung cancer, treated with chemotherapy between July 2004 and January 2008. For these patients, the first course of chemotherapy and each unique cycle with use of G-CSF (FIL or PEG) was identified and designated ‘prophylaxis’ if used within the first 5 days of each cycle, or ‘delayed', if after day 5. The risk of neutropenia-related hospitalization was then evaluated on a cycle basis. A generalized estimating equation (GEE) was used to adjust for baseline demographics and clinical characteristics. Results: Among 5,571 patient-cycles identified: 87.4% were prophylactic and 12.6% were delayed G-CSF. PEG use was primarily prophylactic (93.6%) in contrast to use of FIL which was delayed in 62.5% of patient-cycles. The rate of neutropenic hospitalization was 1.2% for prophylaxis (n=59) and 3.7% for delayed G-CSF (n=26) (P < 0.001). Among prophylactic patient-cycles, the neutropenic hospitalization rate was lower with PEG than FIL (1.1% (n=51) vs. 3.5% (n=8), p = 0.001). Multivariate analyses using GEE model showed consistent trends (Table). Conclusions: Prophylactic G-CSF use was associated with lower neutropenic hospitalization risk than delayed use. Among prophylactic use in real-world oncology practice, PEG was associated with about a two-thirds lower risk of neutropenic hospitalization compared with FIL. [Table: see text] [Table: see text]
MicroRNA 181a (miR-181a) expression as a prognosticator in cytogenetically normal acute myeloid leukemia (CN AML)
Authors: Schwind S. , Marcucci G. , Maharry K. , Radmacher M. D. , Whitman S. P. , Paschka P. , Mrózek K. , Kolitz J. E. , Larson R. A. , Bloomfield C. D. 
Published: August 2020

7001 Background: We showed recently that CEBPA mutations (mut) in CN AML are associated with better outcome and a unique microRNA expression profile, including miR-181a upregulation. Here we tested if miR-181a expression can predict outcome independently. Methods: We analyzed 187 de novo CN AML adult patients (pts) aged <60 years (y; median 45) similarly treated on CALGB 9621 and 19808. Of these, 122 had molecular high risk [FLT3-ITD or NPM1 wild type (wt)] and 65 low risk (no FLT3-ITD, NPM1 mut) CN AML. FLT3, NPM1, CEBPA, MLL, and WT1 mutations, and ERG and BAALC expression were analyzed centrally. miR-181a expression was measured in pretherapy marrow using OSUCCC v3.0 arrays. The mean of 2 miR-181a probe log intensities was used as a continuous variable for analyses. Results: Higher miR-181a levels (miR-181a↑) were associated with CEBPA mut, NPM1 wt, no FLT3-TKD, lower ERG expression, higher %FAB M1/M2, lower WBC and age, higher blood blasts, and lower % gum hypertrophy. miR-181a↑ tended to associate with more complete remissions (CRs; p = .07) and significantly associated with longer disease-free (DFS; p = .05) and overall (OS; p = .01) survival (median follow-up 6.5 y for pts alive). A stronger prognostic impact of miR-181a was observed in the molecular high risk group, where miR-181a↑ predicted more CRs (p = .03), and longer DFS (p = .0002) and OS (p = .0001). In multivariable analyses of the molecular high risk group, miR-181a↑independently predicted CR, and longer DFS and OS (Table). For descriptive purposes, we dichotomized pts at the median miR-181a expression value. For high v low miR-181a expressers, CR rates were 84% vs 72% and 5 y DFS and OS rates 43% vs 18% and 48% vs 19%, respectively. Conclusions: miR-181a expression is a prognostic marker in CN AML, mainly in the molecular high risk group, where it predicts outcome independently of other variables including CEBPA mutations. As miR-181a↑ confer better treatment response, novel approaches increasing miR-181a levels might benefit not only CN but also other AML pts. [Table: see text] No significant financial relationships to disclose.
Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): Three-year follow-up with dasatinib 100 mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS)
Authors: Stone R. M. , Kim D. W. , Kantarjian H. M. , Rousselot P. , Hochhaus A. , Dorlhiac-Llacer P. E. , Milone J. , Matloub Y. , Lambert A. , Shah N. P. 
Published: August 2020

7007 Background: The recommended dosing regimen of dasatinib for CML-CP is now 100 mg once daily (QD) (previously 70 mg twice daily [BID]), based upon a phase III dose-optimization study (CA180–034) that enrolled patients (pts) with CML-CP with resistance, intolerance, or suboptimal response to imatinib. While therapeutic milestones have been established for pts with CML-CP treated with imatinib, they have not been well established for pts treated with second-line TKIs. Methods: Pts were randomized using a 2 × 2 factorial design to one of four treatment arms: 100 mg QD (n = 167), 70 mg BID (n = 168), 140 mg QD (n = 167), or 50 mg BID (n = 168). Details of study design and endpoints have been described previously. Results: After a minimum of 24 months of follow-up, the 24-month PFS rate with 100 mg QD was 80% (vs. 75%-76% in other arms) and the overall survival rate was 91% (vs. 88%-94%). In all arms, high response rates were achieved in pts with or without a baseline BCR-ABL mutation. Dasatinib 100 mg QD was well tolerated and rates of key side effects showed only a minimal increment from 12 to 24 months. Among the four treatment arms, significant differences were observed in rates of drug-related pleural effusion (all grades: p = 0.049) and cytopenia (p = 0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. Dasatinib 100 mg QD treatment resulted in the lowest rates of treatment interruption, reduction, and discontinuation. In addition to providing 36-month follow-up, the likelihood of achieving long-term endpoints based on cytogenetic status at 6, 12, and/or 18 months will be presented. Conclusions: Dasatinib 100 mg once daily remains the optimal dosing schedule for pts with CML-CP. The landmark analyses to be presented should provide useful information to clinicians treating imatinib-resistant, -suboptimally responding, or -intolerant CML-CP pts with dasatinib 100 mg once daily based on cytogenetic response at key intervals. [Table: see text]
Efficacy of a novel schedule of decitabine in previously untreated AML, age 60 or older
Authors: Blum W. G. , Klisovic R. , Liu S. , Kefauver C. , Grever M. R. , Schaaf L. , Chan K. , Byrd J. C. , Villalona-Calero M. , Marcucci G. 
Published: August 2020

7010 Background: We established an optimal daily dose of decitabine in AML at 20mg/m2/day based on re-expression of epigenetically silenced genes, with promising clinical activity seen in poor risk older patients (pts) (Blum, J Clin Oncol. 2007). Methods: We designed a phase II study of decitabine for untreated AML pts of age≥60 who were not candidates for intensive chemotherapy (or who refused it). PS was ECOG <3. All pts received induction with decitabine at 20mg/m2 IV on days 1–10 of 4 week cycles. Pts with persistent AML at the end of a cycle received a repeat of the 10 day course, but responding pts received maintenance with abbreviated courses of 3–5 days depending on degree and duration of neutropenia. Results: 33 pts had median age of 74 years (range, 60–83). 15 pts had either secondary or t-AML. Median WBC count was 2400/μL (range, 400–58,800/μL) with marrow blasts of 44% (range, 21–92%). 13 pts had complex karyotype (≥3 abnormalities); 13 had normal karyotype; one pt had t(8;21). 31/33 pts had at least 2 poor-risk factors of age ≥70, antecedent hematologic disorder, unfavorable karyotype, or ECOG 2, and 28/33 had HCT-CI scores of ≥2. 42% of pts achieved CR (14/33). 58% achieved either CR or CRi (19/33). CR occurred in all subsets of disease and cytogenetic risk groups. CR durations to date are 2–14+ months. Median time from initial response to relapse for 6 pts who relapsed after CR was 6.5 months. Median OS has not been reached; median f/u of 19 surviving pts is 8 months. The median number of cycles received to date is 5 (range, 1–10). 9 of 14 pts who achieved CR required only a single 10 day course before initial response was achieved (CR, N = 2; CRi, N = 7). For pts who had CRi as initial response, the median number of additional cycles to achievement of full CR was 1 (range, 1–3). Death within 8 weeks of any cause occurred in 15% of pts (due to infection in each case). Though non-hematologic toxicities were infrequent, infection and/or febrile neutropenia were common (in 24/33 pts). Correlative studies are ongoing. Conclusions: Decitabine in this novel schedule of induction with outcome-adapted modification of maintenance therapy was highly active in this poor risk cohort. Survival results warrant comparison with intensive therapy for pts eligible to receive it. (supported by NO1-CM62207, K23 CA120708–01, RO1CA102031) [Table: see text]
Phase I/II study of idarubicin (Ida), high-dose ara-C, and sorafenib (S) in patients (pts) younger than 65 years with acute myeloid leukemia (AML)
Authors: Ravandi Kashani F. , Cortes J. , Faderl S. , Jones D. , Byrd A. , Brandt M. , Garcia-Manero G. , Levis M. , Andreeff M. , Kantarjian H. 
Published: August 2020

7018 Background: S is an oral multi-kinase inhibitor with activity against the Raf/ERK/MEK pathway and FLT3. It selectively induces apoptosis in FLT3-mutant human AML cell lines at nM concentrations. Methods: Objectives of this study are to determine the tolerability and efficacy of combination of S with chemotherapy. Ara-C 1.5 g/m2 over 24 hrs daily x 4 (x 3 for pts over 60) and Ida 12 mg/m2 daily x 3 are administered with S. In the phase I part, pts with relapsed AML were treated with escalating doses of S (400 mg qod, 400 mg daily, 400 mg bid) for 7 days during induction, and 400 mg bid was established as safe. Pts achieving CR receive up to 5 courses of consolidation with Ida 8 mg/m2 daily x 2 and Ara-C 0.75 g/m2 daily x 3 in addition to S 400 mg bid for up to 28 days per cycle repeated every 4 to 6 weeks. Maintenance is with S 400 mg bid for up to a year. Results: 10 pts (median age 34, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated in the phase I . 7 were FLT3-ITD positive. 4 achieved CR; 6 failed. In the phase II part, 45 pts (12 with FLT3-ITD and 2 with FLT3-TKD) were treated. Median age is 53 (range 18 - 65). Cytogenetics were diploid in 19, +8 in 5, -5/-7 in 5, 11q23 in 2, other in 14. Median presentation WBC was 4.9 x 109/L (range 0.6 - 122.7 x 109/L). 8 pts were FLT3-ITD+/NPM1-. 40 pts are evaluable for response and 85% achieved CR (n = 30) or CRp (n = 4) (13 of 14 FLT3 mutated pts); 5 pts are too early (1 FLT3 mutated). Most frequent grade 3 and higher related adverse events: hyperbilirubinemia (5), rash and hand-foot syndrome (3), raised transaminases (2), diarrhea (2), hypertension (2). With a median f/u of 5.4 mo (range, 0.5 - 11.3), the probability of survival at 6 mo is 81.6%. 5 pts have relapsed; median CR duration has not been reached, (range; 0.2+ - 10.6+ mo). Among pts with FLT3 mutation, 4 have relapsed and 9 remain in CR. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all with 5-fold more potent suppression against mutant versus wild-type FLT3. Conclusions: S can be safely combined with IA; it has a high CR rate in frontline therapy of younger pts with AML, in particular those with FLT3 mutations. Correlative studies confirm potent activity of S against FLT3 signaling. [Table: see text]
Sibling donor immunization with patient-derived Id-KLH vaccine prior to reduced-intensity allogeneic hematopoietic cell transplantation for multiple myeloma
Authors: Bishop M. R. , Kwak L. W. , Fowler D. H. , Giralt S. , Steinberg S. M. , Bryant K. , Neelapu S. S. 
Published: August 2020

7024 Background: Relapse is the most common cause of treatment failure after reduced-intensity allogeneic hematopoietic cell transplantation (RI-alloHCT) for multiple myeloma (MM). To enhance graft-versus-myeloma effects, we investigated the use of patient-specific idiotype (Id) vaccine in both donors and recipients. Methods: Id protein was obtained by plasmapheresis and conjugated to keyhole limpet hemocyanin (Id-KLH) to generate vaccine. Donors received 3 SQ injections of Id-KLH + GM-CSF at 10, 8, and 4 weeks before stem cell donation. MM pts received a reduced-intensity conditioning regimen (Flu/Cy) and GVHD prophylaxis consisted of cyclosporine plus methotrexate. MM pts were vaccinated with the Id-KLH+GM-CSF at 3, 4, and 6 months post-transplant. Humoral responses were determined by ELISA and Th1 (IL-2, IFN-γ, TNF-α, and GM-CSF) and Th2 (IL-4, IL-5, IL-10, and IL-13) cellular immune responses against Id and KLH were determined by multiplex cytokine assay. Results: Ten MM pts (median age: 54 years; IgG = 8, IgA = 2) and their respective donors were enrolled onto study. All 10 donors completed vaccinations without significant complications. Following vaccination, KLH-specific antibody and Th1/Th2 responses were noted in all 10 donors. Id-specific antibody responses were noted in 6 donors; Th1 and Th2 responses were noted in 5 and 6 donors, respectively. All 10 MM pts underwent RI-alloHCT; the median potential follow-up post-transplant is 43.8 months. Id-specific Th1 and Th2 responses were noted in 5 and 3 pts, respectively, prior to post-transplant immunization; antibody response was noted in 1 patient. Nine evaluable MM pts completed their post-transplant vaccinations. KLH-specific antibody and Th1/Th2 responses were detectable in all 9 pts post-transplant. Id and KLH immune responses were further enhanced by post-transplant vaccinations. Median progression-free survival is 27.3 months; median survival has not been reached. Conclusions: The data suggest Id-specific immunity can be safely induced in normal stem cell donors and passively transferred to recipients of RI-alloHCT. Donor vaccination with tumor-specific antigen represents a tactic to potentially reduce relapse after RI-alloHCT. No significant financial relationships to disclose.
BCR-ABL truncation due to premature translation termination as a mechanism of resistance to kinase inhibitors
Authors: Yeh C. , Ma W. , Kantarjian H. , Zhang Z. J. , Cortes J. , Albitar M. 
Published: August 2020

7028 Background: The major mechanism underlying imatinib resistance in patients with chronic myeloid leukemia (CML) is clonal expansion of leukemic cells with point mutations in the BCR-ABL tyrosine kinase. We describe three novel ABL premature termination mutations leading to BCR-ABL truncation in leukemia patients with multidrug (imatinib/nilotinib/dasatinib) resistance. Methods: Peripheral blood or bone marrow samples from drug-resistant CML patients were collected. Total nucleic acids were purified and subjected to two rounds of PCR analysis, with the first PCR designed to eliminate amplification of the wild-type, non-translocated ABL gene. Bi-directional sequencing was then performed. HL60 cells (a Ph-negative myeloid leukemia cell line) and peripheral blood of healthy subjects were used as negative controls; a human CML cell line (K562) was used as a positive control. Results: We identified an exon 7 deletion in three CML patients, a 4-nt insertion (908insCAGG) near the exon 5/6 junction in one CML case, and an exon 6 point mutation (997C>T) in one patient with acute lymphoblastic leukemia (ALL). These mutations all create premature stop codons and cause termination at residues 381, 315, and 333, respectively, leading to truncated proteins with only the first quarter of the kinase domain (P-loop) or lacking the C-terminus of ABL including the A-loop. Conclusions: These novel mutations, and the previously documented 35-nt insertion in exon 8, may constitute a new class of mutations that 1) cause truncation of the BCR-ABL kinase; (2) abolish the regulatory element in the ABL kinase domain and the downstream C-terminal region; and (3) confer significant drug resistance. [Table: see text]
Impact of azacytidine induction chemotherapies on post-transplant outcomes in patients with myelodysplastic syndromes
Authors: Cogle C. R. , Imanirad I. , Scornik J. , Wingard J. R. 
Published: August 2020

7032 Background: With the advent of azacytidines for treatment of MDS, disease remissions are achievable; however the disease nearly always relapses. In contrast, allogeneic hematopoietic cell transplantation (HCT) can be curative. Whereas cytotoxic induction chemotherapy in patients with MDS provides no clear benefit after HCT, the effects of azacytidine therapy prior to HCT are unknown. Methods: To address this question, we analyzed post-transplant outcomes in 43 MDS patients, 9 who received an azacytidine before transplant and 34 who did not. Although patients in both groups were equivalent in time to transplant, performance status, and transfusion dependence, patients who received an azacytidine were older (61 vs 48, p < 0.01), more immunosuppressed at HCT (absolute lymphocyte count 815 vs 1339, p = 0.04), and less likely to receive myeloablative conditioning (38% vs 78%, p = 0.03). Azacytidine patients were marginally more likely to have higher disease burden at HCT (WPSS 4 vs 3, p = 0.08) and more likely to have received a graft from an unrelated donor (66% vs 33%, p = 0.07). These patient characteristics reflect the current practice of using an azacytidine as a bridge to transplant for older patients who have no readily available, matched related donors. Results: With a median follow-up of 7 months, the group that received azacytidine pre-transplant demonstrated higher donor chimerism at days 30, 60 and 100 (p < 0.01). Rates of acute and chronic GVHD, and median overall survival (OS) did not differ significantly between groups. There was a trend toward higher relapse in the azacytidine group (44% vs 18%, p = 0.09). Conclusions: Our data indicate that induction with azacytidines results in higher short-term donor chimerism post-transplant. This effect is likely due to increased immunosuppression in an older population after azacytidine therapy. The increased rate of relapse in the azacytidine group likely reflects the progressive nature of chemotherapy-insensitive disease at HCT. Although only randomized controlled trials can establish a definite conclusion regarding use of azacytidines prior to HCT and duration of induction therapy before proceeding to HCT, the data presented support administration of azacytidines to MDS patients prior to HCT. [Table: see text]
A phase II study with CP-4055 in patients with second salvage AML
Authors: Giles F. J. , O'Brien S. , Rizzieri D. A. , Vey N. , Krug U. , Sekeres M. , Jacobsen T. F. , Nilsson B. I. , Staudacher K. 
Published: August 2020

7047 Background: CP-4055 (cytarabine 5'-elaidic acid ester) is a novel derivative of cytarabine, independent of nucleoside transporters to enter the cell. The aim of this study was to assess efficacy and safety of CP-4055 when given as second salvage therapy to patients (pts) with acute myeloid leukemia (AML). Methods: Adult pts who received two previous chemotherapy regimens and who had refractory/relapsed AML (CR after first salvage therapy lasting less than 6 months) were enrolled. CP-4055 2,000 mg/m2/d was administered over 24 h (CIV) in a day (d) 1–5 q3w schedule. After every 20-pts cohort, an Independent Data Monitoring Committee (IDMC) evaluated the results for futility and safety for recommendation of study continuation. Results: Forty pts (28 male and 12 female, median age 48 yrs [range 26–82]) were enrolled. 6 pts had previous transplant, the majority of the pts had previous ara-C based therapy, 12 pts had not obtained CR1 or CR2. Only 1 pt did not receive d1–5 dosing. The first 20-pt cohort (12 male, median age 53 yrs [range 26–82]) was evaluated by the IDMC. Most frequently reported related AE ≥ grade 3 (CTCAE v3.0) were myelosuppression, abdominal pain, colitis, diarrhoea, nausea, fatigue, liver function test (LFT) elevation. Clinical activity (IWG criteria for AML), 2 CR (1 with no CR1 or CR2), and 1 CRp (CR rate 15%), were reported. Toxicity was manageable, clinical activity reported and continuation recommended. Among all 40 patients 7 pts (18%) had LFT elevations of grade 3 or more and 4 pts (10%) had LFT elevations of grade 2. Clinical activity has been reported also among the last 20 pts. Therapy is ongoing. Conclusions: CP-4055 given as second salvage therapy to AML pts show manageable toxicity when administered at 2,000 mg/m2/d, 24 h CIV, in a d1–5 q3w schedule. Clinical activity (2 CR and 1 CRp) has been reported among the first 20 late stage AML pts. Data from 40 patients will be presented. [Table: see text]