bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 Study of ABT-263, a Bcl-2 Family Inhibitor, in Relapsed or Refractory Lymphoid Malignancies.
Authors: Wilson Wyndham H , O’Connor O. , Czuczman Myron S. , LaCasce Ann , Gerecitano J. , Leonard John P. , Tulpule Anil , Xiong Hao , Chiu Yi-Lin , Busman Todd , Knight Raymond A. , Enschede Sari , Krivoshik Andrew , Humerickhouse Rod 
Published: April 2020

Abstract
ABT-263 is a novel, orally bioavailable BH3 mimetic that binds with high affinity (Ki ≤1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays potent mechanism-based activity (EC50 ≤ 1μM) against human lymphoid and small cell lung cancer cell-lines. Mechanistic toxicities observed preclinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, presumably mediated by inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-814, a phase 1 dose-escalation study is employing a modified Fibonaci 3 + 3 design to assess ABT-263 safety, pharmacokinetics and anti-tumor activity of two dosing schedules in patients with relapsed or refractory lymphoid malignancies. Enrollment continues with 42 patients (39 on a 14/21 day and 3 on a 21/21 day dosing schedule) enrolled. ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued escalation to 440 mg, with 315 mg defined as tolerable. The pharmacokinetic profile of ABT-263 on the 14/21 day schedule was linear from 10 – 440 mg with a t1/2 of 14 – 20 h. Consistent with preclinical models, a dose-dependent reduction in circulating platelets was observed. Typically, platelet nadirs were transient, occurring on days 3–5 with subsequent recovery during continued dosing, consistent with accelerated platelet apoptosis and compensatory increased bone marrow release and production. Thrombocytopenia was predictable and manageable. A one week lead-in dosing period at 150mg ABT-263 and a 21/21 day dosing schedule beginning at 200 mg, are being evaluated as measures to ameliorate the platelet nadir. Dose limiting toxicities on cycle 1 in the 14/21 day dosing schedule occurred at 160 mg (bronchitis), 315 mg (elevated ALT and gr 4 thrombocytopenia), and 440 mg (dyspnea). Responses were observed in 3 patients including a 75% and 99% reduction of bulky masses in 2 CLL/SLL and a 75% reduction in a NK/T cell lymphoma. Minor nodal responses occurred in 4 patients with follicular lymphoma and 3 patients with CLL/SLL. Additionally, 2 patients with CLL/SLL had ≥50% decreases in leukemic cells for at least 2 months. ABT-263 is a well tolerated oral small molecular inhibitor of Bcl-2 family proteins with a linear PK, toxicity profile indicative of on-target activity and anti-tumor activity in patients with relapsed or refractory lymphoid malignancies. Accrual continues.
Plasma Alemtuzumab Levels at End of Treatment Correlate with Response and Response Duration in Patients with CLL Receiving Treatment for Residual Disease.
Authors: Wierda William G , Kipps Thomas J , Keating Michael J , Brown Jennifer R , Gribben John G , Rassenti Laura Z , Greaves Andrew W , Neuberg Donna , O’Brien Susan M 
Published: April 2020

Abstract
We conducted a phase II trial with alemtuzumab self-administered, subcutaneously (SQ) to eliminate residual disease after chemotherapy or chemoimmunotherapy for patients (pts) who were in partial remission (PR) or pts in complete remission (CR) with 2-color flow cytometry evidence of disease. Pts received alemtuzumab SQ 3mg, 10mg, 30mg on days 1,2,3 then 30mg thrice weekly for a total of 12 doses, including rampup. After the 12th dose, pts with residual disease could receive a second course of 12 additional doses. Responding pts were pts in PR who converted to nodular PR (NPR) or CR by NCI-WG ‘96 criteria or pts in CR who remained in CR and had no evidence of disease by 2-color flow cytometry. There were 26 pts enrolled in PR, 5 pts in CR. 7 pts received a second course of alemtuzumab. End of treatment plasma alemtuzumab levels were measured by a flow cytometry-based assay (Rebello and Hale, J Immunol Methods, 2002). The response rate in the intent-to-treat population was 74%. We retrospectively evaluated patients’ bone marrow for minimal residual disease by 4-color flow cytometry. A disappointing 18% of pts evaluated was MRD-negative in bone marrow by this method. Responding pts had mean plasma alemtuzumab level of 8μg/ml verses 3μg/ml for non-responders (p=.003). The median plasma alemtuzumab level for responders was 6μg/ml. Responders with end of treatment plasma alemtuzumab level greater than 6μg/ml had a significantly longer median response duration of 21.2 months versus 8.9 months for pts with less than 6μg/ml (p=.048). End of treatment plasma alemtuzumab level correlated with response to treatment and response duration for patients treated with alemtuzumab SQ. Future studies to optimize dose and schedule for alemtuzumab SQ as treatment for CLL, including for residual disease, should include measurement of end of treatment plasma alemtuzumab levels and evaluation of bone marrow for minimal residual disease by 4-color flow cytometry. Furthermore, consideration of these results should be given to optimize the effective duration of treatment with alemtuzumab SQ.
Dasatinib Is Associated with Rapid and Durable Complete Hematologic Responses in Patients with Chronic-Phase Chronic Myeloid Leukemia (CPCML).
Authors: Liu Delong , Matloub Yousif , Mukhopadhyay Jaydip , Liu David , Goldberg Stuart L 
Published: April 2020

Abstract
Achieving a quick and durable complete hematologic response (CHR) is a near-term treatment goal in CP-CML. This is particularly relevant in patients with late CP-CML who are receiving second-line tyrosine kinase inhibitors (TKIs) after failing imatinib therapy. The rapidity of the CHR provides an early assessment of sensitivity or resistance to second-line TKIs and should be used to guide treatment decision in this patient population. In the CA180-013 trial (START-C), 387 subjects resistant to or intolerant of imatinib were treated with dasatinib. At 2 years of follow-up, CHR was achieved in 91% of all subjects (90% of 288 resistant subjects, and 94% of 99 intolerant subjects). Of the 233 patients with abnormal peripheral blood counts at baseline, 203 (87%) achieved CHR (86% imatinib-resistant and 92% imatinib-intolerant). The time to achieve CHR (defined as the duration between the first dose of dasatinib until the first day CHR criteria were met) was rapid, with a median time to CHR of 2.1 weeks (C.I: 2.1 to 2.4) across all cohorts. Furthermore, most subjects who achieved CHR did so within the first two months of treatment. In addition, CHRs achieved with dasatinib were durable; the 12- and 24-month CHR were 92% and 83%, respectively. Moreover, in an optimization trial (CA180-034) comparing efficacy between 100mg and 140mg total dasatinib administered in one or two doses, the rates of, time to, and duration of CHR were comparable to that observed in START-C (Table 1). No difference in time to or duration of CHR was observed between the two schedules. In summary, dasatinib is associated with a rapid and durable CHR in a majority of subjects with CP-CML resistant to or intolerant of imatinib therapy.
Table 1: Percentage of Dasatinib-Treated Patients with CHR who are Imatinib Resistant (CA180-034 trial)
Number (%) of Subjects by Treatment Group QD BID Best Hematologic Response 100 mg N = 124 140 mg N = 123 Total N = 247 50 mg N = 124 70 mg N = 126 Total N = 250 CHR 110 (89) 106 (86) 216 (87) 114 (92) 112 (89) 226 (90) no CHR 14 (11) 17 (14) 31 (13) 10 (8) 14 (11) 24 (10)
Long Term Follow-up and Matched Pair Analysis of Adjuvant Donor Lymphocyte Transfusions Following Allogeneic Stem Cell Transplantation after Reduced Intensity Conditioning for High-Risk AML.
Authors: Schleuning Michael , Schmid Christoph , Koenecke Christian , Hertenstein Bernd , Baurmann Herrad , Schwerdtfeger Rainer , Kolb Hans-Jochem 
Published: April 2020

Abstract
Adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation. We report our data on aDLT in high-risk AML. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and aDLT. For aDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression and free of GvHD. 30% of patients (n=46) alive at day +120 fulfilled the criteria for aDLT. They had been transplanted for refractory (n=11) or relapsed leukemia (n=24) or in CR1 because of unfavourable cytogenetics (n=7) or other unfavourable criteria (n=2) or in CR2 with unfavourable cytogenetics (n=2). 24 patients had an unfavourable karyotype, 10 with complex aberrations. Thirty-one patients with similar disease characteristics and fulfilling similar selection criteria (being alive in CR at d +120, no cGVHD and no history of aGVHD&gt; II°) transplanted during the same time period served as control. Of these, 10 pts. were transplanted at a different center not using aDLT and 21 at the center in Wiesbaden during 2000 and 2002 prior to the introduction of the protocol at this center. The median time from transplant to first aDLT was 160 days (range 71–303). Median follow up of the surviving transfused patients is 3.6 years (range 1.8–7.8). Seven patients received 1, 15 patients received 2, and 24 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at aDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or patient’s refusal. Induction of GvHD was the main complication; grade II/III acute GvHD developed in 4, and chronic GvHD in 8 patients. So far, 9 (19.6%) patients have relapsed despite aDLT, as compared to 52.9% in the control group (Fisher-exact: p=0.004). Of these, 8 pts. finally died despite adoptive immunotherapy and only one patient is now surviving more than 3 years after relapse was treated by a second transplantation. Non relapse mortality post DLT was low with patients dying from infection, severe cGvHD, and secondary solid tumour one each. At the time of analysis, 35/46 patients are alive and all are in CR at a median of 3.2 years post first DLT. The actuarial overall survival four years after transplant is 79% as compared to 34% in the control group and at six years 63% vs. 31%, respectively (p=0.000). In conclusion, aDLT is safe, when given in escalating doses and to a selected group of patients. Results are encouraging, and improved long term leukemia-free survival can be achieved.
No Impact of Postremission Consolidation Chemotherapy Before Allogeneic Transplant in Patients with First Remission Acute Myeloid Leukemia with Intermediate or High Risk Cytogenetics.
Authors: Sproat Lisa O. , Bolwell Brian , Rybicki Lisa , Kalaycio Matt , Dean Robert , Sobecks Ronald , Pohlman Brad , Andresen Steve , Sungren Shawnda , Chan Josephine , Sweetenham John , Copelan Ed 
Published: April 2020

Abstract
Despite a lack of evidence that postremission consolidation chemotherapy improves outcome of allogeneic transplantation in patients with acute myeloid leukemia (AML) in first remission, high dose cytarabine and other regimens are commonly administered to these patients. We studied a consecutive cohort of 73 adult patients with AML at high risk of relapse by published criteria who underwent allogeneic transplantation in first remision to determine whether specific patient and treatment characteristics identified subgroups of patients who might benefit from consolidation therapy prior to allogeneic transplantation. Pretransplant cytogenetics were available for 56 patients. Transplantation occurred between 1988 and 2008. The primary analysis grouped patients according to cytogenetic risk (poor versus intermediate) and consolidation chemotherapy (yes versus no).
Consolidation Chemotherapy No Consolidation Chemotherapy None of the measured outcomes (relapse mortality (RM), non-relapse mortality (NRM), overall survival (OS)) differed significantly between groups. Poor Risk Cytogenetics 9 13 Intermediate Risk 18 16 Cytogenetics P Values for Consolidation Versus No Consolidation by Cytogenetic Risk Poor Risk Cytogenetics Intermediate Risk Cytogenetics When cytogenetic risk was not stratified the results between consolidation and no consolidation were also not significant. RM 0.95 0.74 NRM 0.73 0.19 OS 0.77 0.21 P Values for Consolidation Versus No Consolidation RM 0.70 NRM 0.12 OS 0.14
Neither this study nor others provide evidence that consolidation chemotherapy is beneficial to all patients with AML in first remission who undergo allogeneic transplant or to cytogenetic subgroups. Delays in referral to a transplant center, in tissue typing or physician preference to administer consolidation chemotherapy are not justified and expose patients to the inconvenience, risk, and cost of unnecessary treatment. Clinicians should avoid consolidation chemotherapy and expedite allogeneic transplantion in patients with AML in first remission in whom transplantation is the preferred treatment.
Oral (po) and Intravenous (iv) Clofarabine for Patients (pts) with Myelodysplastic Syndrome (MDS)
Authors: Faderl Stefan , Garcia-Manero Guillermo , Ravandi Farhad , Borthakur Gautam , Estrov Zeev , Thomas Deborah A. , Gandhi Varsha , Plunkett William , Byrd Anna , Kwari Monica , Kantarjian Hagop M. 
Published: April 2020

Abstract
Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in pts with acute myeloid leukemia (AML). Early reports also suggested activity in MDS, but the role of CLO in MDS has not been defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies of IV CLO and PO CLO, respectively. Pts were eligible with MDS and ≥5% blasts or IPSS intermediate-2 and high-risk, CMML, and RAEB-t by FAB. Hematopoietic growth factor support prior to and during the study was permitted. In the IV study pts were adaptively randomized (based on response) to receive CLO 15 or 30 mg/m2 IV over 1 hr. daily × 5 every 4–6 weeks. For the PO study, the starting dose of CLO was 40 mg/m2 orally daily × 5 every 4–6 weeks (oral bioavailability assumed ~ 50%, based on preclinical data), which was decreased to 30 mg/m2 orally daily × 5 after 6 pts had been treated on the higher dose. Sixty-one pts (6 RA/RARS/RCMD, 17 RAEB-1, 16 RAEB-2, 11 CMML, 11 RAEB-t) were treated. Forty-two pts (69%) had high- or intermediate-2 risk disease by IPSS. Thirty-six pts received IV CLO and 25 PO CLO. Median age was 67 yrs (range 25–89) (IV) and 70 yrs (54–86) (PO). Overall, &gt; 80% of pts were older than 60 yrs. Approximately 1/3 of pts had secondary MDS: 13 (36%) (IV) and 8 (32%) (PO), respectively. Seventeen (47%) (IV) and 10 (40%) (PO) of pts had unfavorable cytogenetics (by IPSS definition). Thirty-nine (64%) pts failed prior hypomethylator therapy with either decitabine or azacitidine (22 [61%] pts on IV and 17 [68%] pts on PO CLO). Responses of 60 evaluable pts (one pt refused continuation of therapy on D4 of first course) are summarized in the Table:
Response (%) Route Dose (mg/m2) N CR CRp HI PO 40/30 24 7 (29) 2 (8) 3 (13) IV 15 20 7 (35) 3 (15) - 30 16 4 (25) 2 (13) - Total - 60 18 (30) 7 (12) 3 (5)
Six pts (10%) died on study (all IV CLO; most commonly related to infectious complications). All pts were evaluable for toxicities. Common AEs were nausea, vomiting, skin rash, hyperbilirubinemia and transaminase elevations. Toxicities ≥ grade 3 were rare. Acute renal failure occurred in 7 pts (2 IV [15 mg/m2], 3 IV [30 mg/m2], 2 PO). Myelosuppression and hospitalizations for neutropenic fever were common, but prolonged myelosuppression (&gt; 42 days) was rare. In conclusion, CLO has activity in pts with higher-risk MDS. Optimal dose and schedule for PO and IV CLO remain to be defined. Lower doses of CLO are also associated with responses. Additional dose finding trials are underway to define the MTD and DLT of IV and PO CLO in high-risk MDS.
GATA1s Mutant Protein Contributes to “Down” Syndrome Megakaryoblastic Leukemia by Derepression of E2F Targets.
Authors: Klusmann Jan-Henning , Godinho Frank , Pushpanathan Thanaseelan , Reinhardt Dirk , Orkin Stuart H , Li Zhe 
Published: April 2020

Abstract
Somatic mutations in the hematopoietic transcription factor GATA1, leading to the production of a GATA1 variant (GATA1s) lacking its N-terminal domain, are a critical event in the development of Down syndrome (DS) associated transient myeloproliferative disease (TMD) and myeloid leukemia (ML-DS). Mice carrying Gata1s germline mutation exhibit a transient population of abnormal yolk sac/fetal liver megakaryocytic progenitors, hyperproliferating both in vitro and in vivo. However, either Gata1s mice alone or in conjunction with two DS mouse models (Ts65dn, Ts1Cje) fail to recapitulate human TMD or leukemia. Using a retroviral insertional mutagenesis screening in Gata1s fetal progenitors, we generated murine acute megakaryoblastic leukemia (AMKL) closely resembling human ML-DS. We demonstrate that retroviral integrations at the Evi1 and Plag1 loci cooperated with Gata1s in leukemogenesis. Through an integrated genomic approach, we show that restoration of full length Gata1 expression in these murine Gata1s AMKL blasts leads to downregulation of gene sets containing E2F target genes. In addition, most of these same gene sets are also enriched in Gata1s primary fetal liver-derived megakaryocytes compared to wild type megakaryocytes, in flow sorted human ML-DS leukemic blasts compared to sorted non-DS M7 leukemic blasts, and in ML-DS CMK cell line compared to other leukemic cell lines. Using a genetic approach, we could demonstrate that the hyperproliferative phenotype of Gata1s FL megakaryocytic progenitor cells can be rescued by broadly repressing the function of E2F factors. Additionally, the CMK cell line ceased to proliferate upon E2F inactivation. Thus, we discovered a new mechanism of GATA1 mediated growth regulation by controlling E2F function. GATA1s mutant protein contributes to leukemogenesis through insufficient repression of E2F targets, perturbing the coordination of proliferation and terminal differentiation. Our study reveals a previously unknown function of the N-terminal domain of GATA1 and adds a significant step towards our understanding of the role of GATA1 mutants in leukemogenesis.
OTT-MKL1 and MKL1 Inhibit Wnt Signaling.
Authors: Halene Stephanie , Cheng Ee-chun , Schulz Vincent , Tuck David , Krause Diane 
Published: April 2020

Abstract
The OTT-MKL1 fusion gene product is generated as a result of t(1;22) in a subset of acute megakaryoblastic leukemia predominantly encountered in young children. Due to myelofibrosis and the age at presentation, patient samples are scarce. We generated Human Erythroid Leukemia (HEL) cell derived cell lines with tet-inducible OTT, MKL1 and OTT-MKL1 to further elucidate the function of the respective proteins. HEL cells can be induced to differentiate down the megakaryocyte lineage by TPA. Induction with doxycycline resulted in transcription and translation of the respective genes within hours. While overexpression of MKL1 led to enhancement of megakaryocytic differentiation, both OTT and OTT-MKL1 overexpression led to cell death over the course of several days by apoptosis as evident by staining for Annexin V and morphology. The apoptotic cell death was greatly enhanced by concomitant induction of differentiation by TPA. We performed microarray analysis comparing uninduced and 8-hour tet-induced samples in the presence or absence of TPA. While overexpression of OTT had only a minimal effect on the transcriptome of the HEL cells, both MKL1 and OTT-MKL1 significantly affected the gene expression of many genes. Using a false discovery rate cut-off of p &lt; 0.05, and assessing only those genes whose expression changed by greater than 2-fold, OTT-MKL1 and MKL1 induced the upregulation of 157 and 168 genes, respectively, and the downregulation of 56 and 62 genes, respectively. Only 20 genes were upregulated by both OTT-MKL1 and MKL1, and 12 genes were downregulated greater than 2-fold by both OTT-MKL1 and MKL1. GeneGo analysis comparing OTT-MKL1 over-expressing versus non-expressing cells revealed over-representation of the Wnt pathway. Among the differentially expressed genes implicated in the Wnt pathway were Frat1 and Frat2, which have been shown to inhibit GSK3β and lead to β-catenin nuclear accumulation, and thus stimulation of the Wnt pathway. At the same time, inhibitory NLK was upregulated and several down-stream targets of the Wnt pathway were downregulated. Spenito, the homolog of OTT in Drosophila, is known to have promoter-specific activating and inhibiting effects on Wnt target genes. We thus performed reporter assays to study the effects of OTT, MKL1 and OTT-MKL1 on the Wnt pathway. Using the TOP-/FOP-FLASH reporter system in 293T cells, there was a dose-dependent inhibition of β-catenin-mediated activation of the Tcf/Lef binding site promoter by MKL1 and OTT-MKL1. Full length OTT showed a minimal stimulatory effect only at low doses., while N-terminal OTT, lacking the SPOC domain and a dominant negative form of MKL1 lacking the transactivation domain each enhanced β-catenin induced Tcf/Lef mediated transcriptional activation. Studies to define the domains of OTT and MKL1 and the underlying mechanisms in hematopoietic cells are underway. These results suggest that MKL1 and OTT-MKL1 inhibit canonical Wnt signaling by inhibiting β-catenin induced transcription.
Activation of the Unfolded Protein Response (UPR) Induces CEBPA mRNA Decay in AML Cells.
Authors: Eyholzer Marianne , Schardt Julian , Shan Deborah , Mueller Beatrice U , Pabst Thomas 
Published: April 2020

Abstract
The myeloid key transcription factor CEBPA (CCAAT-enhancer binding protein alpha) is crucial for normal neutrophil differentiation, and cebpa-deficient mice lack mature granulocytes. In addition, deregulation of CEBPA function is a frequent event in AML patients. The endoplasmatic reticulum (ER) is involved in proper protein folding. Alterations in calcium levels or insufficient protein folding capacity leads to ER stress, thereby inducing rescue pathways that are commonly summarized as the unfolded protein response (UPR). The UPR aims either to re-establish ER homeostasis or to induce cell death. So far, induction of ER stress has been associated with a number of non-hematopoietic diseases. Here, we analyzed whether activated ER stress in leukemic cell lines and in AML patients affects the myeloid key regulator CEBPA. We induced ER stress in the leukemic HL60 cell line by treatment with 0.4mg/ml of Calcimycin (deregulation of calcium homeostasis) or with 3mg/ml of Tunicamycin (block of protein glycosylation). Consistently, we observed a rapid decrease of CEBPA mRNA to 10% after 6 hours of treatment. In accordance, CEBPA protein was no more detectable after 8 hours. Experiments in HL60 cells with Actinomycin D and Cycloheximide as well as competition experiments with various constructs of wild-type CEBPA sequences suggest a decay mechanism involving one or several elements in the 3’UTR of the CEBPA mRNA. We excluded microRNA-124a, a previously identified CEBPA regulator acting through the 3’UTR, to be involved. The precise elements mediating ER stress induced CEBPA mRNA decay remain to be elucidated. We also determined the expression of CEBPA mRNA and mediators of UPR - such as CHOP and GRP78 as well as alternative splicing of the XBP1 mRNA - in leukemic cells from 76 AML patients of all FAB subtypes. We found that AML patients with induced ER stress (13%) tended to have two-fold lower CEBPA mRNA expression, thus underlining the in vitro results reported above. In conclusion, our experiments indicate activated ER stress to be involved in a significant subgroup of AML patients. Moreover, it suggests that activation of the UPR in myeloid leukemic cells efficiently induces 3’UTR mediated decay of CEBPA mRNA expression, thereby contributing to the block in myeloid differentiation in these leukemias.