bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significant Disease Burden in Paroxysmal Nocturnal Hemoglobinuria Patients with Lower Levels of Hemolysis, Mild Anemia and Minimal Transfusion: Clinical Improvement with Eculizumab Therapy.
Authors: Bessler Monica , Schrezenmeier Hubert , Maciejewski Jaroslaw P. , Hill Anita , Rollins Scott A. , Young Neal S. , Luzzatto Lucio 
Published: October 2019

Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease. However, disease burden in patients with lower lactate dehydrogenase (LDH), higher hemoglobin and minimal transfusion support has not been determined. The terminal complement inhibitor, eculizumab (Soliris™), was shown to significantly reduce hemolysis, improve anemia and fatigue, and reduce thrombosis in a broad PNH population. We examined the long-term efficacy of eculizumab in multiple patient subgroups. Efficacy data included hemolysis (as assessed by LDH), transfusion requirements, fatigue (measured by Functional Assessment of Chronic Illness Therapy-Fatigue instrument, FACIT-Fatigue), and thrombosis. Data were analyzed by lower baseline hemolysis (LDH <1490 U/L, n=46), mild anemia (Hgb ≥10.5 g/L, n=54), and minimal transfusion (0 or 1 episodes in prior yr, n=21) among 187 PNH patients who had been enrolled in eculizumab trials (Phase 2 Pilot, Phase 3 TRIUMPH and SHEPHERD studies) and who continued to receive eculizumab in a long-term extension trial (median duration, 22 months). Eculizumab provided significant clinical benefit to patients regardless of baseline degree of hemolysis, anemia, or transfusion requirement (Table). Fatigue improved with eculizumab across all baseline LDH quartiles. Of interest, reduced hemolysis with eculizumab improved fatigue even in patients with only mild anemia and little or no transfusion requirement, suggesting that lowering hemolysis improves fatigue, independent of anemia. Fatigue scores increased during the first 6 mos of treatment and continued to improve throughout the last six months of treatment. Transfusion requirements also maintained during long-term treatment; patients requiring >1 transfusion in the year prior received a median of 8.5 units in the 6 months prior to eculizumab, 2.0 units in the first 6 months of treatment, and 0 units in the last 6 months of treatment. In patients with evidence of marrow failure (n=25; platelets <100,000/mm3 and no prior thrombosis) compared with pre-treatment, hemolysis (LDH) was reduced by 1217±211 U/L, median units transfused were reduced from 8 (mean 9.2±1.2) to 0 (4.4±1.4) and fatigue improved by 8.1±2.1 points (p≤0.001 for each) during the last six mos of eculizumab therapy. Thromboembolism (TE) was examined in all eculizumab trial patients (N=195). The TE rate was elevated in the pre-treatment period for patients with lower baseline hemolysis, mild anemia and minimal transfusion; eculizumab reduced TE in these patient subgroups by 58% (p=0.009, n=48), 84% (p<0.001, n=55) and 100% (p=0.063, n=22), respectively. In conclusion, patients who may be expected to have less severe disease suffer from significant disease burden, and long-term treatment with eculizumab provides substantial clinical improvement.
ENMD-1198 in Combination with Vincristine Shows Synergistic Activity in Leukemia Cells and Prolonged Mouse Survival in Human Leukemia Xenografts.
Authors: Liaw Tracy T.Y.E. , Burke Patricia P.A. , Chen X. , LaVallee Theresa T.M. , Lock Richard , Kavallaris Maria 
Published: October 2019

Abstract
ENMD-1198 (2-methoxyestra-1, 3, 5, (10), 16-tetraene-3-carboxamide), an analogue of 2 methoxyestradiol (2ME2 or Panzem®), is a microtubule destabilizing agent that binds to the colchicine-binding site of β-tubulin. ENMD-1198 has shown anti-angiogenic and anti-proliferative activities in several tumour models and is currently being evaluated in a Phase 1 clinical trial. To date however, the efficacy and mechanisms of action of ENMD-1198 in leukemia are not well-studied or fully understood. Hence, in order to assess the efficacy of ENMD-1198 in leukemia, a clinically relevant model of primary human ALL cells xenografted into immuno-deficient (NOD/SCID) mice was used (1). Three human ALL xenografts (ALL3, ALL7 and ALL19) that exhibit intrinsic differences in response to vincristine (VCR) (1) were treated with 100 mg/kg ENMD-1198 by gavage (daily for 28 days), commencing treatment when engraftment rates reached 1% human CD45+ in mouse peripheral blood. Treatment with ENMD-1198 significantly increased the mouse survival rates compared to vehicle control in all three xenografts (Leukemia Growth Delay (LGD) for ALL3 = 17.3 days, p < 0.005; ALL7 = 21.5 days, p < 0.005; ALL19 = 16.7 days, p < 0.005). Interestingly, ALL7, the least sensitive xenograft to vincristine, showed the best response to ENMD-1198 with a growth delay factor of 21 days. To determine whether the combination of ENMD-1198 and VCR has therapeutic advantages in leukemia, anti-proliferative studies of the drug combination in CCRF-CEM leukemia cells were carried out. A synergistic effect was observed when ENMD-1198 and VCR were combined. The effect of this drug combination was further examined in the ALL human xenograft mouse model. Mice inoculated with ALL7 xenograft were treated with 50 mg/kg ENMD-1198 (daily for 28 days) and 0.5 mg/kg VCR (weekly for 4 weeks) by intraperitoneal injection. The drug combination significantly prolonged mouse survival rates compared to single ENMD-1198 and VCR treatments (LGD 35.19days; p < 0.005). Functional analysis of the drug combination treatment in CCRF-CEM cells in vitro showed that the cells arrested at G2/M followed by sub-G1 (apoptosis) phase, with decreased HIF-1α and JAK-2 proteins. Apoptosis in vitro was associated with increased DR5, active caspase 3 and cleaved PARP proteins in CCRF-CEM cells treated with the combination. In summary, ENMD-1198 alone, and in combination with VCR, has shown promising results in the treatment of preclinical models of leukemia.
A Phase I Study of the Farnesyltransferase Inhibitor Tipifarnib in a Week-On Week-Off Dose Schedule in Acute Myelogenous Leukemia.
Authors: Kirschbaum Mark H. , Stein Anthony Selwyn , Tuscano Joseph , Zain Jasmine M. , Popplewell Leslie , O’Donnell Margaret R. , Karanes Chatchada , Wright John , Pulone Bernadette , Rincon Amalia , Frankel Paul , Forman Stephen J. , Newman Edward 
Published: October 2019

Abstract
Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M.
RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.
Phase I Study Demonstrates Activity and Tolerability of Diphtheria Toxin Interleukin-3 Fusion Protein in Patients with AML and MDS.
Authors: Frankel Arthur E. , Smith E.R. , George T.A. , Liu J.S. , Lee J. , Park S.K. , Rizzieri David A. , Hogge Donna E. 
Published: October 2019

Abstract
Interleukin-3 receptor (IL-3R) proteins are over-expressed on blasts and cancer stem cells of multiple hematologic malignancies. The recombinant diphtheria toxin fusion protein, DT388IL3, specifically targets IL-3R and is composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3). DT388IL3 demonstrated selective toxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo, and was prepared for a Phase I clinical study in AML and myelodysplasia (MDS) patients. FDA approval (BB IND#11314) and IRB approvals were obtained. 80 AML and MDS patients were screened and 38 AML and 3 MDS patients were treated. The median age of treated patients was 62 years (range, 25–81 years). There were 22 males and 19 females. AML disease was de novo in 5, 1st relapse in 12, 2nd relapse in 8, and refractory in 12. MDS disease was high-grade in one and intermediate-grade in 2. Five AML patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. AML cytogenetics was unfavorable in 15, intermediate in 21, and not done in 2. Seven patients were treated with 4 ug/kg, eight patients with 5.3 ug/kg, thirteen patients with 7.1 ug/kg, seven with 9.4 ug/kg, and six with 12.5 ug/kg DT388IL3 for up to six treatments (one cycle). Of note, patients have not yet received a second cycle. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, transaminasemia, hypoxemia, and hypoalbuminemia. Pretreatment anti-DT antibody levels ranged from 0 – 9.6ug/mL (mean = 2.3ug/mL); day 15 post-treatment antibody levels were 0 – 600ug/mL (mean = 92ug/mL); day 30 antibody levels were 1.1 – 306ug/mL (mean = 82ug/mL). Day 1 Cmax ranged from 0 – 350 ng/mL and correlated with dose; Day 12 Cmax ranged from 0 – 179 ng/mL and correlated with Day 12 anti-DT antibody levels. Development of anti-DT antibody levels at Day 15 and 30 did not interfere with response. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among 38 evaluable AML patients, we have observed one CR of 8 months duration, 2 partial remissions (PRs) lasting one and three months, and 3 minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90%, and 90% lasting one to two months. In one evaluable MDS patient, we achieved a PR lasting four months with improvement in hematologic parameters and conversion to transfusion independence. Patient accrual is proceeding with correlative IL3R content of blasts and cancer stem cells. These results of activity and tolerability are encouraging and suggest that DT388IL3 may achieve a role in the management of patients with myeloid malignancies.
Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) and Decitabine in Patients with Relapsed, Refractory or Poor Prognosis Leukemia.
Authors: Ravandi Farhad , Faderl Stefan , Thomas Deborah , Burger Jan , Koller Charles , Garcia-Manero Guillermo , Morris Gail , Torma Ritva , Kantarjian Hagop , Issa Jean-Pierre 
Published: October 2019

Abstract
Few effective treatment strategies are available for patients with relapsed and refractory leukemias and their prognosis remains poor. Epigenetic therapy by targeting epigenetic pathways is currently under investigation as a potential strategy to reverse transcriptional silencing of tumor suppressor genes leading to the reversal of the neoplastic phenotype. 5-Aza-2′-deoxycytidine (DAC, Decitabine) and suberoylanilide hydroxamic acid (SAHA, Vorinostat) can affect epigenetic change in leukemic cells through promoter CpG island hypomethylation and inhibition of histone deacetylation, respectively. We have conducted a phase I study of combination of DAC plus SAHA (using a sequential dosing schedule) in patients with relapsed, refractory, or high risk leukemias. Five cohorts (Dose levels 0 – 4) of 6 patients each received escalating doses of decitabine (10, 10, 15, 20 and 25 mg/m2 IV daily x 5) followed by SAHA (100 mg PO tid x 14 in the first cohort and 200 mg PO tid x 14 in all subsequent cohorts). From 7/06 to 8/07, 31 patients (21 M, 10 F) have been accrued with the last cohort receiving DAC 25 mg/m2 daily x 5 followed by SAHA 200 mg tid x 14. Median age was 62 years (range, 22 – 82). Twenty one patients (68%) had refractory AML (5 with prior MDS), 1 (3%) refractory acute biphenotypic leukemia, 3 (10%) relapsed MDS, 3 (10%) refractory ALL, 1 (3%) untreated high risk MDS, and 2 (6%) Philadelphia chromosome-negative myeloproliferative disease. Median number of prior regimens was 2 (range, 0 – 8). One patient did not receive therapy due to rapid disease progression and 30 were evaluable for assessment of toxicity. Median number of cycles of DAC + SAHA administered was 2 (range, 0 – 6). One patient had pulmonary embolism and one grade 3 diarrhea, both considered to be dose limiting. Other adverse events included syncope, neutropenic fever, diarrhea, fatigue, renal failure, rash, nausea, thrombosis, and angioedema. Of the 30 evaluable pts, 1 patient achieved complete remission lasting 5.5 weeks, 4 had significant reductions in the bone marrow blasts, 4 had stable disease, 7 are too early for response evaluation, and 14 had no response/disease progression. We conclude that the sequential combination of DAC and SAHA is safe and has activity in advanced leukemia. Correlative studies evaluating DNA promoter methylation and histone acetylation will be presented.
A Phase I Study with CP-4055 In Patients with Hematologic Malignancies.
Authors: Giles Francis , Kantarjian Hagop M. , Vey Norbert , Rizzieri David , Ravandi Farhad , Prebet Thomas , Jacobsen Tove Flem , Nilsson Bo I. , Staudacher Karin , O’Brien Susan 
Published: October 2019

Abstract
Background: CP-4055 (ELACYT™, cytarabine 5′-elaidic acid ester) is a novel cytotoxic nucleoside analogue. While CP-4055 has similar mechanisms of action to cytarabine, it is, unlike cytarabine independent of nucleoside transporters for cellular uptake. This is the first study in patients with haematologic malignancies. CP-4055 is currently in Phase II studies in patients with solid tumors. Aims: Determination of the maximum tolerated dose and the preferred infusion time in patients with haematologic malignancies.
Methods: The study was initiated in May 2006. Patients (pts) received IV CP-4055 over 2 hours (2 hr IV, Arm A) or 24 hours (CIV, Arm B) in a day 1–5 q3w schedule. The starting dose in Arm A was 300 mg/m²/day and in Arm B 200 mg/m²/day, with standard definitions of DLT for haematologic malignancies. Dosing increments were by 50% until non-haematologic toxicities, and thereafter increments were by 30%.
Results: In the ongoing study, 40 pts [25 male, median age 60.5 yrs (range 25–77); ECOG PS 0–1: 32 pts, ECOG PS 2: 8 pts; AML 35 pts, BAL 1 pt, MDS 1 pt, ALL 2 pts, CML-BP 1pt, average 2–3 lines prior chemotherapy (range 0–7)] have been treated at 2 US and 1 European centres. Five patients are ongoing. Two treatment-related serious adverse events (SAE) have been observed. One patient experienced fever and one patient had transaminase increase. Both patients recovered from their SAE while still on the study. No DLT has been observed and dose escalation is ongoing at 1950 mg/m²/day in Arm A and at 1500 mg/m²/day in Arm B. Nausea, anemia, diarrhea and thrombocytopenia were the most common possibly related AEs. One patient (875 mg/m²/day Arm B) with CRp received one course of consolidation therapy. Five patients with stable disease/mild myelosuppression received more than 2 cycles of CP-4055: one pt (AML) received 4 cycles and four patients (3 AML, 1 CML-BP) received three cycles. One of these patients was referred to stem cell transplantation. Fifteen patients received 2 cycles of therapy.
Summary/Conclusion: Patients with haematologic malignancies tolerated CP-4055 well up to a dose of 1500 mg/m²/day (2 hr IV) and 1150 mg/m2/day (CIV) in a d1–5 q3w schedule. Myelosuppression has been observed with minimal toxicity. Accrual is ongoing.
In Vivo Correlates of Response for Phase I Trial of Oral Tipifarnib (T) Combined with Oral Etoposide (E) for Adults Age ≥ 70 with Newly Diagnosed Acute Myelogenous Leukemia (AML) Who Are Not Candidates for Traditional Cytotoxic Chemotherapy (TCC).
Authors: Ricklis Rebecca M. , Karp Judith E. , Feldman Eric J. , Galkin Suzanne , Greer Jacqueline M. , Ironside Valerie , Mirjafary Kim , Talbot Timothy D. , Morris Lawrence E. , Wright John J. , Kaufmann Scott H. 
Published: October 2019

Abstract
T is a farnesyltransferase inhibitor with clinical activity in elderly adults with newly diagnosed AML who are not candidates for TCC. For adults age ≥ 65 with poor-risk AML, T 600 mg BID for 21 out of 28–63 days induced complete remissions (CR) in 14%, median duration 7.3 mos, median survival 18.3 mos (Lancet JE, et al, Blood109:1387–1394,2007). In vitro, T+E exhibits synergistic anti-AML activity. In an attempt to increase CR rates in elderly AML pts, we conducted a Phase I trial of oral T+E, with escalation of both drugs and 14 vs. 21 days of T every 28–63 days (median 31 days, range 29–50). T+E resulted in a 25% CR rate (21/84 pts), duration 2 – 26+ mos, with best rates achieved with T dose ≥ 400 mg BID for 14 days (Karp JE, et al, Blood108:130a,2006). In the context of this trial, we have conducted longitudinal laboratory studies of changes in DNA damage and apoptosis in AML marrow blasts obtained from 84 patients prior to T+E (Day 0) and on Day 8 of T+E. Blasts were enriched by Ficoll density gradient separation and fixed in 70% ethanol. Persistent, unrepaired DNA damage was quantified by flow cytometry of cells stained with antibody to phosphorylated histone H2AX (γH2AX). Apoptosis was measured by flow cytometry of propidium iodide-stained cells with sub2n DNA content as observed in cell cycle distribution. To date, we have analyzed changes in in vivo γH2AX from 10 pts (4 CR, 6 stable disease or no response, SD/NR). CR pts had a 2-fold increase (range 1.91–2.22) in DNA damage induced by Day 8 of T+E relative to Day 0 values, while patients with SD/NR had no such increase (0–1.06) in DNA damage. Similarly, the apoptotic fraction of the cell cycle distributions of CR patients increase by 2-fold (range 1.2–5.3) for Day 8 marrow blasts. In contrast, changes in apoptosis were widely divergent for SD/NR patients (range 0.2–7.0). Taken together, these preliminary studies on AML marrow blasts obtained prior to and during T+E therapy suggest a possible linkage among induction of DNA damage, apoptotic response, and clinical outcome. Full analysis of all acquired specimens is ongoing.
Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan Is Safe and Effective for Autotransplantation for Multiple Myeloma.
Authors: Qazilbash Muzaffar H. , Saliba Rima M. , Parikh Gaurav , Hosing Chitra , Mendoza Floralyn , Qureshi Suhail P. , Weber Donna M. , Wang Michael , Flosser Thuy , Couriel Daniel R. , Kebriaei Partow , Popat Uday , Alousi Amin , de Lima Marcos , Champlin Richard E. , Giralt Sergio 
Published: October 2019

Abstract
Background: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a randomized phase II trial to determine the safety and efficacy of a combination of ATO, melphalan, and ascorbic acid (AA) as a preparative regimen in patients undergoing autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact of ATO levels on melphalan pharmacokinetics, engraftment, and toxicity.
Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age, 54; range 35–70) were treated between 4/04 and 8/05. All patients received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms: no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2), and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had received a prior autograft, with a median 4.5 x 106/kg (range 2.3–10.9) CD34+ cells infused.
Results: Patients in all 3 arms were evenly matched. Twenty-nine patients (60%) were transplanted for consolidation of first remission and 19 patients (40%) for relapsed disease. With a median follow-up of 26 months (range 10–37) post-autograft, no dose-limiting toxicity, or nonrelapse mortality was reported. Toxicity was limited to grade 1 or 2 nausea, vomiting, and diarrhea and was comparable in all 3 arms. Melphalan pharmacokinetics was not altered by ATO pretreatment. Median time to neutrophil engraftment (absolute neutrophil count >500/dL) was 9 days, with no engraftment failures or delays in either the control or ATO arms. The complete response (CR) rate for all patients was 25% (12/48), and the partial response rate was 60% (29/48) for an overall response rate (ORR = CR + PR) of 85%. Progression-free survival (PFS) and overall survival (OS) after 24 months of follow-up were 59% and 91%, respectively. Median PFS was 29 months; median OS has not been reached. There was no significant difference in CR, ORR, PFS, or OS among the 3 arms (P =.9, .9, .5, and .6, respectively). PFS and OS were comparable among patients with chromosomal abnormalities or relapsed disease at transplant and patients undergoing a second autotransplant for salvage.
Conclusions: Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for autotransplants in patients with MM, including high-risk patients. There was no adverse impact of ATO on engraftment. Longer follow-up is necessary to assess the efficacy of this combination on PFS and OS.