bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of combination therapies with MOR00208, an Fc-enhanced humanized CD19 antibody, in models of lymphoma.
Authors: Winderlich Mark , Ness Daniel , Steidl Stefan , Endell Jan 
Published: March 2020

6574 Background: MOR00208 (formerly XmAb5574) is a Fc-engineered humanized anti-CD19 antibody with superior cytotoxicity in a number of in vitro and in vivo models of lymphoma and leukemia, currently being evaluated in patients with relapsed/refractory CLL. Bendamustine (BEN), an alkylating agent, fludarabine (FLU), a purine analogue, and the CD20 antibodies rituximab (RTX) and ofatumumab (OFA) were evaluated for their ability to enhance the cytotoxicity of MOR00208. Methods: Utilizing CD19/CD20+ MEC-1 CLL cells, cytotoxicity was assessed in vitro by flow cytometry. MOR00208 was tested alone and in combination with BEN, FLU, RTX and OFA using peripheral blood mononuclear cells as effector cells. Median survival (MS) was evaluated in a murine model of disseminated lymphoma, using i.v.-administered RAMOS cells (CD19+) and treatment with MOR00208 alone and in combination with FLU. Combinatorial effects were classified according to Chou-Talalay (Pharmacol Rev. 2006 Sep;58(3):621-81). Results: MOR00208-mediated in vitro cytotoxicity was synergistically enhanced by BEN, FLU and the CD20 antibodies irrespective of their different modes of action (Combination Index < 1). In vivo, FLU alone at doses up to the maximum tolerated dose (MTD) did not prolong MS, whereas MOR00208 at 3 mg/kg increased MS by 26% compared to the isotype control. Co-administration of MOR00208 with 125 mg/kg FLU significantly enhanced MS by 65%. Despite its lack of single agent activity, FLU thus significantly enhanced the cytotoxicity of MOR00208. Conclusions: The cytotoxic in vitro activity of MOR00208 on CD19+ B cells was synergistically enhanced by all studied drugs irrespective of their effector mechanisms. In vivo, the activity of MOR00208 in an aggressive lymphoma model was potentiated in combination with FLU. These results provide a mechanistic rationale for MOR00208 drug combinations which warrant further evaluation in clinical trials.
Quantitative detection of ZAP-70 expression in chronic lymphocytic leukemia.
Authors: Zhu Peixuan , Degheidy Heba A , Marti Gerald E , Li Shuhong , Abbasi Fatima , Wiestner Adrian , Amstutz Platte T , Tang Cha-Mei 
Published: March 2020

6581 Background: Intracellular ZAP-70 protein was recently recognized as prognostic marker in chronic lymphocytic leukemia (CLL). The specific objective of this study was to develop a simple and sensitive assay, for the quantitative detection of ZAP-70 protein in leukemic cells. Methods: Components of the assay system include sample preparation, immunomagnetic fluorescence assay, Signalyte-II spectrofluorometer. The leukemic cells were isolated from CLL patient blood samples and lysed to release the intracellular ZAP-70 protein. ZAP-70 protein was captured by magnetic beads coated with anti-ZAP70 capture antibody, and recognized by a fluorescent detector antibody, forming an immuno-sandwich complex. This complex was dissociated for measurement of the fluorescence signal, which was proportional to ZAP-70 concentration, using the spectrofluorometer. Results: The assay conditions were extensively optimized by selecting an optimal pair of capture/detector antibodies, conjugation of fluorescence dye, cell lysis condition and excitation/emission wavelengths. The protocol was further validated with two positive controls, Jurkat cell lysate and recombinant ZAP70 protein (rZAP70). The limit of detection was determined to be lower than 125 Jurkat cells and 39 pg of rZAP70 protein. The signal response was linear over a wide range of concentration, from 625 to 40,000 Jurkat cells per test (R2=0.9987) and from 0 to 40,000 pg rZAP70 protein per test (R2=0.9928). The results from 20 CLL patients correlated strongly with flow cytometry analysis. The concordance between the two methods for positive and negative results was 100% (7/7) and 92% (12/13), respectively, while the overall concordance between the two methods was 95%. Conclusions: The assay is a simple, reliable, and reproducible method for quantitative detection of ZAP-70 in patient leukemic cells, without the need for cell fixation or permeabilization. The entire assay could be completed in 5.5 hours. The ZAP-70 signal was linear over a wide dynamic range, which we believe enables quantitative assessment of small changes in ZAP-70 expression over the course of the disease and in response to therapeutic intervention.
Phase I study of TH-302, a hypoxia-activated cytotoxic prodrug, in subjects with advanced leukemias.
Authors: Konopleva Marina , Handisides Damian , Lorente Gustavo A. , Benito Juliana M. , Richie Mary Ann , Borthakur Gautam , Jabbour Elias , Faderl Stefan , Cortes Jorge E. , Kroll Stewart , Andreeff Michael , Kantarjian Hagop , Thomas Deborah A. 
Published: March 2020

6585 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with ALL have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PlosOne, in press). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and AML samples in vitro. Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. Methods: Eligibility: ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepatorenal function. A standard 3+3 dose escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 minutes daily on Days 1-5 of a 21-day cycle. The objectives were to determine the MTD and PK profile of TH-302 with this schedule and to assess preliminary clinical activity of TH-302. Results: 34 subjects with previously treated AML (n=26), ALL (n=6) or CML in blast phase (n=1) received TH-302 at doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=16) or 550 (n=4) mg/m². No skin or mucosal toxicity was noted in participants treated with TH-302 doses ≤240 mg/m2. At 330 mg/m2, grade 2 dermatological toxicities included skin ulcer (n=1) and hand/foot syndrome (n=1). Grade 2 mucositis (n=3) and grade 2 skin toxicity (e.g. skin rash, skin ulcers; n=3) were reported at 460 mg/m2; none were dose-limiting. Two of 3 evaluable subjects treated at the 550 mg/m2 cohort experienced DLTs of grade 3 esophagitis. Eight subjects had stable disease or better after 1 cycle. One ALL subject (at 120 mg/m2) cleared marrow blasts with persistent neutropenia. One AML subject (at 550 mg/m2) achieved CRp after 1 cycle with resolution of leukemia cutis. Conclusions: TH-302 administered daily for 5 consecutive days every 3 weeks is well-tolerated with increased incidence of skin and mucosal toxicity at higher dose levels. Clinical activity has been noted with a few objective responses, but majority of cytoreductions in the AML subset were transient. Clinical trials combining TH-302 with various chemotherapeutics with established efficacy in AML and ALL are planned.
Albumin as a prognostic factor for overall survival in newly diagnosed patients with acute myeloid leukemia (AML).
Authors: Khan Awais M. , Lancet Jeffrey E. , Kharfan-Dabaja Mohamed A. , Al Ali Najla , List Alan F. , Komrokji Rami S. 
Published: March 2020

6586 Background: Hypoalbuminemia (HA) is an adverse prognostic factor in multiple neoplastic diseases. Severe hypoalbuminemia (<3.0 g/dl) at day +90 post allogeneic hematopoietic cell transplant (AHCT) was reported as an independent predictive variable for non-relapse mortality and overall survival (Kharfan-Dabaja, et al Biol Blood Marrow Transplant 2009; 15). We examined the prognostic value of serum albumin level prior to induction chemotherapy in patients with newly diagnosed AML. Methods: Data were collected retrospectively in newly diagnosed AML patients receiving induction chemotherapy (3+ 7 regimen). Primary objective was to examine the relationship between serum albumin at baseline and probability of achieving complete remission (CR) or incomplete remission (CRi) and overall survival (OS). The Kaplan–Meier method used to estimate median overall survival; chi-square test used for comparison of categorical variables and t-test for continuous variables. Log rank test used to compare Kaplan–Meier survival estimates between two groups. Results: Between November 2004 to July 2007, 135 patients who received 3+7 induction chemotherapy were included. Patient baseline characteristics were similar between patients with serum albumin < 3.5 g/dl (HA) and those with serum albumin ≥ 3.5 g/dl (no HA) with respect to age, sex, FAB subtype, history of antecedent MDS, karyotype, and chemotherapy . In patients with HA, mean age was 60 years compared to 56.5 years in non HA group. The median OS for patients with HA was 221 days (95%CI 149.5-292.5) compared to 421 days (95%CI 236.7-605) with normal serum albumin (p<0.005). (Figure-1) The CR/CRi rate was 64%% for HA and 77.6% for those with normal albumin (p=0.09). In a multivariable Cox regression analysis including age ≥ 60 years, history of MDS, karyotype, and serum albumin level at baseline; only age, karyotype and serum albumin were independent predictors of OS [Hazard ratio 0.47 (95%CI 0.31-0.71) (p<0.005) for normal serum albumin group]. Conclusions: In newly diagnosed AML, we demonstrate that hypoalbuminemia < 3.5 g/dl is an independent covariate for overall survival with conventional chemotherapy management. The prognostic value of low serum albumin should be validated in a prospective study.
Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI) therapy in accelerated-phase CML (CML-AP).
Authors: Ohanian Maro , Kantarjian Hagop , Quintas-Cardama Alfonso , O'Brien Susan Mary , Verstovsek Srdan , Borthakur Gautam , Ravandi Farhad , Garcia-Manero Guillermo , Burton Elizabeth M , Trinh Long , Ferrajoli Alessandra , Jabbour Elias , Kadia Tapan M. , Cortes Jorge E. 
Published: March 2020

6587 Background: For patients (pts) presenting with CML-AP, TKIs are recommended. Although generally well tolerated, dose reductions and/or interruptions are often required. The impact of TKI dose intensity (DI) on CML-AP outcome has not been described. Aim: To determine impact of TKI dose interruptions and/or reductions on outcome in de novo CML-AP. Methods: Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or parallel clinical trials with TKIs as initial therapy: imatinib (n=36), dasatinib (n=5), or nilotinib (n=17). CML-AP features included: blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100x109/L (n=3), cytogenetic clonal evolution (n=22), or >1 feature (n=3). We examined the impact of dose reductions, treatment interruptions, and DI (ratio of the dose received vs. the intended dose for the entire treatment duration) on event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: Among 58 pts, 37 required treatment interruptions and/or dose reductions (29 required dose reductions). 12 pts required dose reductions and/or interruptions due to hematologic toxicity and 23 for non-hematologic toxicities. Pts were divided into 3 DI tiers: 100% (n= 21), 90-99%, (n=10), and <90% (n=27). Outcomes were analyzed based on DI tiers and presence or absence of dose reductions as shown in the table. Pts with dose reductions and/or interruptions for hematologic toxicities vs. non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100% (p=0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo or later were 100% and 91%, respectively (p =0.7). Conclusions: DI has no significant impact on de novo CML-AP outcome. However, dose interruptions and/or reductions for hematologic toxicities are associated with worse 24-mo EFS, suggesting myelosuppression may in some patients be more a feature of the disease than toxicity from therapy. [Table: see text]
Impact of ABL kinase domain mutations on the outcome of patients with chronic myeloid leukemia (CML).
Authors: Sweet Kendra Lynn , Komrokji Rami S. , Al Ali Najla , Crescentini Robert M. , Domingo Gelenis , Chavez Julio C. , Dalia Samir , Tinsley Sara , Lancet Jeffery , Zhang Ling , Pinilla-Ibarz Javier 
Published: March 2020

6588 Background: Patients with CML who develop resistance to imatinib commonly have mutations in the BCR-ABL kinase domain (KDM). Studies looking at outcomes in patients with P-loop versus non-P-loop mutations within the ABL-Kinase Domain have produced conflicting results. Methods: The Total Cancer Care (TCC) database was used to identify patients with CML treated at Moffitt Cancer Center (MCC). Descriptive data were reported, chi square test was used for categorical variables, and Kaplan Meier curves were used for OS and PFS. Log rank test was used to compare survival times between groups. Results: Between 1992 and 2011, 540 CML patients were treated at MCC. Of those, 51% were male and 71% were under the age of 60. Sixty percent (n=322) were diagnosed after 2001. Of the 540 patients, 6.5% (n=35) were found to have mutations of which 26 were detected in patients diagnosed after 2001. Of the 35 patients, 74% (n=26) had single mutations and 26% (n=9) had compound mutations. P-loop mutations were seen in 17% (n=6) and 43% (n=15) had T315I mutations. Patients with KDM progressed to accelerated or blast phase in 46% (n=16) of cases compared to 27% (n=136) without mutations (p=0.03). Median OS was 126 months, 109 months, and not reached in patients with P-loop, T315I, and non-P-loop mutations respectively (p=0.17). The corresponding median PFS was 85 months, 89 months, and not reached (p=0.20). In patients with one mutation median OS was not reached compared to 105 months in patients with compound mutations (p=0.27). After 2001, patients with KDM had a median PFS of 75 months and OS of 126 months while neither was reached in the non-mutation cohort (p=0.007, p=0.26 respectively). Median PFS in patients with single mutations was 85 months versus 10 months in those with compound mutations (p=0.037). Patients with KDM had additional Ph+ clones on cytogenetics in 49% of cases compared with 19% of cases in the non-mutation group (P < 0.005). Conclusions: T315I and P-loop KDM predict PFS and OS in CML patients, and convey a trend for worse prognosis. The presence of additional Ph+ clones in patients with BCR-ABL KDM indicates a higher level of genetic instability and clonal evolution, which may be the contributing factor to poor outcomes.
Monitoring and switching patterns in chronic myelogenous leukemia (CML) pts treated with imatinib (IM): A chart review analysis.
Authors: Chen Lei , Guerin Annie , Aberki Clemence , Wu Eric Q. , Ericson Solveig , Jabbour Elias 
Published: March 2020

6594 Background: The objective of this study is to evaluate compliance to National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) guidelines regarding monitoring frequency and switching practices in CML patients (pts) treated with IM in community practices. Methods: Physicians treating CML pts were selected from 28 community practices throughout the USA. Each physician reviewed and extracted up to 15 pt charts of CML pts in chronic phase not previously enrolled in clinical trials. Pts were required to have initiated 1st-line IM between 1/2006 - 10/2010. Data on 1st-line IM treatment response monitoring frequency and outcomes, and corresponding therapy switching patterns were extracted. Results: Information was collected on treatment monitoring and response from a total of 297 pt charts. Median IM duration was 320 days. Percentages of pts monitored according to both guidelines are reported. In addition, the proportion of pts who missed milestones and the proportion of pts who did not switch to a 2nd-line tyrosine kinase inhibitor (TKI) when they missed milestones are reported. Conclusions: There is considerable undermonitoring of CML pts receiving IM, which is likely to result in a significant portion of pts with suboptimal response left undetected. The switching rate to 2nd-line TKI among pts with suboptimal response to IM is much lower than recommended by either NCCN or ELN guidelines. [Table: see text]
A phase II study of clofarabine and daunorubicin in patients age 60 or older with newly diagnosed adult acute myeloid leukemia.
Authors: Vigil Carlos Enrique , Griffiths Elizabeth A. , Thompson James E , Tan Wei , Greene Jessica , Ford Laurie Ann , Wang Eunice S. , Wetzler Meir 
Published: March 2020

6602 Background: The outcome of acute myeloid leukemia (AML) patients (pts) ≥60 years (yrs) old remains poor, with a median overall survival of a few months. Neither the addition of other drugs during induction of the traditional 7+3 regimen nor an increase of cytarabine or daunorubicin doses has improved their overall survival. We have therefore designed a combination of clofarabine and daunorubicin. Aims: Determine the safety and efficacy of clofarabine and daunorubicin in pts ≥ 60 yrs of age. Methods: Induction-clofarabine 20 mg/m2 /d in a 1-hour IV for 5 days followed 3 hrs later by daunorubicin 50 mg/m2 IV over 5 minutes on days 1, 3, and 5. Pts who did not achieve complete remission (CR) or CR without platelet recovery (CRp) were eligible for a second round of induction as above. Consolidation - 2 cycles of clofarabine 20mg/m2 /d for 3 days and daunorubicin 50 mg/m2/day on days 1 and 3. Results: Twenty-one pts were enrolled. The median age was 69 (range 60-85) yrs. Seven pts (34%) had secondary AML and 52% had complex karyotype. Twenty-one pts completed one induction cycle, one pt received a second induction due to residual disease and 6 pts underwent consolidation therapy. The principal toxicity was grade ≥3 infections and prolonged thrombocytopenia and neutropenia, which occurred in 18% and 21% of pts, respectively. Three deaths were documented from treatment complications (sepsis and fungal infections). Eight (38.1%) pts achieved either a CR or CRp. Responses were observed in 5/11 (45.5%) pts with high risk features (complex karyotype and/or presence of FLT3). The median disease free-survival was 1.9 (range, 0.9-8) months and the median overall survival was 6.5 (range, 4.2-14.2) months. The 1-yr overall survival was 35%. Conclusions: These preliminary results suggest that clofarabine in combination with daunorubicin is safe, well-tolerated with minimal toxicity, and active for the upfront treatment of ≥60 yrs old AML pts, including those with adverse features. Future trials will explore additional modifications to this regimen in order to optimize therapy for this group of pts with high risk features and frequent treatment failure.
Pooled safety analysis of omacetaxine mepesuccinate in patients with chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors (TKIs).
Authors: Wetzler Meir , Kantarjian Hagop , Nicolini Franck E. , Lipton Jeffrey Howard , Akard Luke Paul , Baccarani Michele , Craig Adam , Brown Peter D. , Cortes Jorge E. 
Published: March 2020

6604 Background: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a reversible, transient inhibitor of protein elongation that does not depend on BCR-ABL signaling. It showed significant clinical activity in two phase 2, open-label, multicenter studies of patients with CML who were resistant/intolerant to prior TKI therapy. However, omacetaxine tolerability data across the 3 phases of CML are limited. Methods: Safety data were pooled from all patients in the 2 studies plus a small pilot study. Omacetaxine 1.25 mg/m2 was given subcutaneously twice daily: ≤14 successive days per 28-day cycle for induction, ≤7 days/cycle as maintenance. Days of dosing could be adjusted and recombinant growth factors given, as clinically indicated. Results: Of 207 pooled patients (median age, 57 years), 108 were in chronic (CP), 55 in accelerated (AP), and 44 in blast phase (BP). Median treatment was 4 cycles (range, 1–41). On study, 80% of patients had ≥1 hematologic adverse event (AE), 60% had a serious AE (SAE), 30% had a hematologic SAE, 34% had an SAE that resulted in hospitalization, and 15% discontinued treatment due to an SAE (most commonly disease progression). There were 49 (24%) deaths (15 CP, 11 AP, and 23 BP). Of the 8 that were treatment related (5 CP, 2 AP, 1 BP), the most common cause was sepsis (3 patients). The most common AEs were thrombocytopenia (60%), anemia (51%), diarrhea (40%), neutropenia (37%), and nausea (30%). Injection site reactions (eg, injection site pain, erythema) occurred in 32%, with the majority being low grade. Infections (eg, pneumonia, bronchitis) occurred in 51%. Treatment-related grade 3/4 hematologic AEs included thrombocytopenia (52%), neutropenia (31%), anemia (30%), leukopenia (12%), and febrile neutropenia (11%). The most common treatment-related grade 3/4 nonhematologic AE was fatigue (4.3%). Overall, there were 34 (16%) grade 3/4 infections (12 CP, 11 AP, 11 BP). Conclusions: In the largest safety analysis to date, subcutaneous omacetaxine 1.25 mg/m2 showed an acceptable safety profile in all phases of CML. AEs were primarily hematologic, and grade 3/4 nonhematologic AEs were not common. Support: Teva Pharmaceutical Industries Ltd.
Assessment of age as its own risk factor in AML.
Authors: Buchner Thomas , Berdel Wolfgang E. , Haferlach Claudia , Schnittger Susanne , Stelljes Matthias , Silling Gerda , Staib Peter , Grueneisen Andreas , Reichle Albrecht , Balleisen Leopold , Eimermacher Hartmut , Giagounidis Aristoteles , Rasche Herbert , Lengfelder Eva , Krug Utz , Sauerland Maria Cristina , Heinecke Achim , Wormann Bernhard J. , Hiddemann Wolfgang ,   German Acute Myeloid Leukemia Cooperative Group
Published: March 2020

6610 Background: Patients’ age is an important issue in treatment decisions for AML, while its role in this disease remains poorly explained. Methods: In the AMLCG 1999 trial 1223 patients (pts) were 16-59y and 1470 pts were 60-85y of age. Their treatment was randomized between TAD-HAM vs HAM-HAM induction (TAD, standard dose thioguanine, cytarabine, daunorubicin 60mg/m² x 3; HAM, high-dose cytarabine 3g/m² x 6, mitoxantrone 10mg/m² x 3), TAD consolidation and monthly maintenance vs autologous SCT, any chemotherapy + vs - G-CSF priming. All randomization was done upfront. Pts of <60y received routine double induction and full dose HAM while pts of 60+y preferentially received only one course induction and HAM at 1g instead of 3g cytarabine /m² x 6. Results: With little differences according randomizations, pts <60y and 60+y achieved a complete remission rate (CR) of 70.2% and 53.5% (p<.001), overall survival (OS) at 5y of 41.3% and 12.9% (p<.001) and a relapse rate (RR) of 49.0 and 72.0% (p<.001). We also focussed on pts around 60y of age and compared the 172 pts of 57-59y with the 261 pts of 60-62y excluding pts undergoing allogeneic stem cell transplantation. According to their similar age the two groups showed similar baseline characteristics. In contrast and due to the cut-off point for age adaption at 60y they differed considerably in treatment. Expressed by the cumulative dosage of cytarabine, the difference between the two groups was by factor 2.9. This difference, however, did not translate into a different outcome being 62% vs 60% CR, 28% vs 21% 5y OS (p=0.25), and 73% vs 73% RR at 5y. A multivariable analysis in all pts between 16 and 85y of age identified cytogenetik/ molecular risk and age as a continuous variable, to be risk factors predicting CR, OS, as well as RR. In pts of 16-60y those below and above the median age of 47y differed in their CR rate by 75% vs 66% (p<.001), their OS by 49% vs 35% (p<.001) and in their RR by 45% vs 53% (p=.007). In pts of 60-85y those below and above the median age of 67y differed in their CR rate by 57% vs 51% (p=.023), and their OS by 16% vs 11% (p<.001), while their RR was similarly 71%. Conclusions: The outcome in pts with AML is substantially determined by patients’ age as its own risk factor, and not by treatment intensity.