bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tipifarnib in combination with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS)
Authors: Ravandi-Kashani F. , Kantarjian H. , Garcia-Manero G. , O’Brien S. , Verstovsek S. , Estrov Z. , Faderl S. , Giles F. , Wright J. , Cortes J. 
Published: March 2020

6557 Background: Tipifarnib (Zarnestra [Z]) is a non-peptidomimetic farnesyl transferase inhibitor (FTI) with clinical activity in AML and MDS. In vitro studies have demonstrated synergy when combining tipifarnib with chemotherapeutic agents. Methods: We have conducted a study where pts (aged 15 to 60 years) with previously untreated AML or high-risk MDS (blasts >10%) were treated with Idarubicin 12 mg/m2/d on days 1–3, cytarabine 1.5 g/m2 IV over 24 hours daily on days 1–4 and Z; the first cohort (7 pts) received Z 200mg orally twice daily (BID), and all others 300 mg BID for 21 days. Pts achieving CR received consolidation (5 courses) with Idarubicin 8 mg/m2/d on days 1–2, cytarabine 0.75 g/m2/d on days 1–3, and Z 300 mg BID for 14 days every 4–6 weeks. Maintenance was with Z 300 mg BID for 21 days every 4–6 wk for 6 months. Results: We have treated 33 pts; median age 51 yrs (17–59 yrs). Twenty two pts (67%) have achieved CR, 3 (9%) CRp, and 2 (6%) PR. There were no induction deaths. Response (CR/CRp) by cytogenetics was: 13/15 (86%) for diploid, 5/6 (83%) with −5/−7, 1/2 (50%) with t(8;21), and 6/10 (60%) with other abnormalities. Response by Flt3 was 19/22 (86%) for unmutated Flt3, 3/5 (60%) for mutated Flt3. CR by age (excluding t(8;21)) was 13/16 (81%) if ≤ 50yrs, 4/6 (67%) if >50yrs and diploid, and 5/8 (63%) if >50yrs and other cytogenetics. With a median follow-up of 45 weeks, 5 pts have relapsed after 13 to 39 weeks and 1 died (in CR) after 18 wks. The most common grade 3 adverse events include reversible diarrhea in 7 (21%) and hyperbilirubinemia in 6 (18%). Twenty (61%) and 8 (53%) pts have required dose reductions during induction and consolidation courses, respectively. Conclusions: Z combined with Idarubicin and cytarabine induces a high rate of CR in AML/high risk MDS, with increased incidence of diarrhea and hyperbilirubinemia. Role of Z in prolongation of CR duration requires further follow-up. [Table: see text]
A phase I study of GTI-2040 (G), an antisense to ribonucleotide reductase (RNR), in combination with high-dose AraC (HiDAC) in acute myeloid leukemia (AML)
Authors: Marcucci G. , Klisovic R. B. , Wei W. , Liu S. , Paschka P. , Huynh L. , Zwiebel J. A. , Byrd J. C. , Grever M. R. , Chan K. , Blum W. 
Published: March 2020

6561 Background: RNR converts ribonucleotides to deoxyribonucleotides for DNA synthesis. AraC is converted into AraC triphosphate (AraCTP) and competes with deoxycytidine for DNA incorporation. We hypothesized that RNR downregulation by G leads to lower deoxycytidine levels, preferential AraCTP incorporation into DNA and increased cytotoxicity. A CTEP-sponsored Phase I dose escalation study of G +HiDAC in relapsed/refractory AML tested this hypothesis. Methods: Cohort I (18–59 yrs) received G (dose level (DL) 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 + AraC IV q12 hrs on d 2, 4, 6 (DL1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received G CIVI on d 1–6 +AraC IV on d 2 −6 (DL1: 1500 mg/m2/d). An ELISA-based assay measured plasma and intracellular concentration (IC) of G. Results: To date, cohort I included 9 pts with relapsed and 9 with refractory AML; 9 had intermediate and 9 adverse risk cytogenetics (CyG); 8 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory AML; 8 pts had intermediate and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC alone. The younger pts had higher AUC and longer t1/2. Of 16 pts evaluable in cohort I (median time to 1st relapse 6 mos), 6 had complete remission (CR) and 1 incomplete CR (no disease and incomplete blood count recovery). In cohort II, no responses were observed. At 120 hrs of antisense infusion, median G IC in marrow cells was higher (i.e., 175 vs75 nM) in younger than in older pts. A median 50% decrease in RNR protein was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I, a median 50% decrease and 200% increase in RNR was noted in CR (n=4) and non-responder (NR; n=9) pts, respectively. In cohort II R2 downregulation did not predict response. In cohort I 62% of the ICs was in nucleus and 21.2% in cytoplasm in CR pts (n=3) vs. 20.3% and 53.5% in NR pts(n=5). Conclusions: G/HiDAC is feasible. Robust plasma and IC levels of G and target downregulation are achievable in vivo. Responses (41%) were observed only in the younger cohort, where CR pts had higher G nuclear IC and target downregulation than NR pts. Dose escalation continues in the younger cohort to establish a dose for Phase II trials. No significant financial relationships to disclose.
Tranfusion independence assessed using three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes
Authors: Anthony S. , Lyons R. , Cosgriff T. , Modi S. 
Published: March 2020

6574 Background: The dosing schedule of azacitidine (75 mg/m2/day subcutaneous [SC] × 7 days, every 28 days) decreased transfusion requirements in myelodysplastic syndrome (MDS) patients in a CALGB trial by Silverman et al (JCO 2002;20:2429). Our study assessed effects on transfusion requirements in MDS patients receiving 3 alternative azacitidine dosing regimens not requiring weekend injections. Methods: This phase II, multicenter study enrolled MDS patients with any FAB subtype, life expectancy ≥7 months, and ECOG performance grade of 0–3. RA/RARS patients had to have ≥1 of the following: hemoglobin <110 g/L with transfusion need, platelet counts <100 × 109/L, or ANC <1.5 × 109/L. Patients were randomized to 1 of 3 SC regimens: AZA 5–2-2 (75 mg/m2/day × 5 days, followed by 2 days no treatment, followed by 75 mg/m2/day × 2 days), AZA 5–2-5 (50 mg/m2/day × 5 days, followed by 2 days no treatment, followed by 50 mg/m2/day × 5 days), or a 3rd regimen added later by protocol amendment: AZA 5 (75 mg/m2/day × 5 days). After 6 cycles, patients meeting International Working Group MDS response/improvement criteria (Blood 2000;96: 3671) of ≥ stable disease could continue in study for 12 more cycles. Results: In all, 75 patients (median age, 74.5 years; 61% male) are currently enrolled with 49 evaluable (completed ≥ 2 treatment cycles). To date, 12, 9, and 1 patient(s) have received ≥6 cycles of AZA 5–2-2, AZA 5–2-5, or AZA 5, respectively. RA + RARS, defined by FAB (60%) or WHO (47%), are the most common MDS subtypes. Of 24 patients, RBC transfusion dependent at baseline, 13 (54%) became independent ( Table ). Only 2 patients were platelet transfusion dependent at baseline; both became independent. After a median followup of 24 weeks, median duration of transfusion independence has not been reached. Conclusions: Treatment with azacitidine yields transfusion independence rates of 40%-60%. These preliminary results are similar across the 3 alternative doses and consistent with previous azacitidine data. [Table: see text] No significant financial relationships to disclose.
Response to azacitidine (AZA) in patients with secondary myelodysplastic syndrome
Authors: Abdulhaq H. , Haq B. , Rossetti J. , Lister J. , Shadduck R. 
Published: March 2020

6578 Background: Myelodysplastic syndrome (MDS) is characterized by maturation defects in hematopoietic progenitor cells that result in ineffective hematopoiesis, various cytopenias and risk of progression to acute myeloid leukemia. MDS can arise de novo or secondary to exposure to myelotoxic drugs or ionizing radiation. Secondary MDS (t-MDS) tends to have more aggressive behavior than de novo MDS. Azacitidine (AZA), a DNA methyl transferase inhibitor has activity in MDS. To date there is little data in patients with t-MDS Methods: The records of 21 patients with t-MDS treated with AZA between 05/96 and 01/06 were reviewed to determine response, duration of response and tolerability in these high-risk patients. 15 of the 21 patients received AZA as part of a National Cancer Institute special exception program (75mg/m2 subcutaneously for seven days every four weeks). Patients who received at least 2 cycles were considered evaluable for response (N=16). All patients were evaluated for toxicity. The International working group standardized response criteria for MDS were used for evaluation. Results: Patients had a median age of 68 years; male: female ratio was 3:1. 11 patients had refractory anemia, 6 had refractory anemia with excess blasts, 3 had chronic myelomonocytic leukemia, 1 had refractory anemia with ringed sideroblasts. Response was seen in 8 (50%) of 16 patients, with 2 (12.5%) partial remissions, 6 (37.5%) showed major hematological response. The median duration of response was 12.3 months (range 4–38). Stable disease was seen in 5 patients (31%), with an average duration of 6.5 months (range 2–15). 3 patients failed therapy due to disease progression or death. Treatment was well tolerated in general, with the most side effects being nausea, vomiting, diarrhea and cytopenias. Febrile neutropenia was seen in 5 patients. Conclusions: Azacitidine appears to be effective and well tolerated in patients with t-MDS. [Table: see text]
A phase I study of busulfan consolidation/intensification therapy for patients with high risk acute myeloid leukemia (AML)
Authors: Gharibo M. M. , Schaar D. , Rubin A. , Grospe S. , Dudek L. , Strair R. 
Published: March 2020

6580 Background: Elderly AML patients have a poor prognosis. More effective well-tolerated treatments are needed to improve outcomes. Busulfan is an effective anti-leukemia drug commonly used in transplant regimens. We designed a phase I dose escalation study of single dose busulfan as consolidation/intensification therapy for elderly patients with AML. Methods: Patients in CR1 not candidates for transplantation or anticipated to benefit from high-dose cytarabine were enrolled. Cohorts were studied at 100mg/m2-120mg/m2, as a single oral dose of busulfan. The starting dose was based on a previous report (Ranson et al. Br J Haematol 79:162.1991). GM-CSF was started after busulfan until ANC> 2000/mm3. Dilantin was used for seizure prophylaxis. Results: 15 patients median age 71 (range 64–82) received treatment and are evaluable for toxicity, 14 are evaluable for response. No DLT was observed. Ongoing remission was seen in 3 patients (range 3 +- 7 + years). One patient (AML/MDS) was in remission for 52 months and died from small cell lung cancer and 1 patient was in remission for 15 months and died from cervical cancer. Two additional patients had prolonged remissions (32 and 55 months) prior to relapse. Seven patients relapsed between 4 weeks and 6 months. Treatment was well tolerated with no prolonged neutropenia. In patients who recovered without evidence of leukemia transient grade 3/4 thrombocytopenia occurred with average duration of 16 days (10–23 days) requiring 0–5 transfusions (average 2). Only 2 patients required RBC transfusion. No infectious complications or hospitalizations occurred in the absence of recurrent AML. Three patients experienced side effects from GM-CSF and received G-CSF in it’s place. Two patients experienced grade 2 fatigue and dyspnea. Conclusions: Single dose oral busulfan is an effective and well-tolerated outpatient consolidation/intensification therapy for patients with high-risk, AML. Prolonged remissions have been seen in 6 of 14 evaluable patients treated to date. Only transient bone marrow suppression requiring minimal transfusion support was seen. There were no hospitalizations or infections noted in patients without recurrent AML. The dose escalation will continue until MTD reached. No significant financial relationships to disclose.
A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias
Authors: Deangelo D. J. , Stone R. M. , Silverman L. B. , Stock W. , Attar E. C. , Fearen I. , Dallob A. , Matthews C. , Stone J. , Freedman S. J. , Aster J. 
Published: March 2020

6585 Background: Functional screening of T-ALL cell lines for sensitivity to NOTCH inhibitors has led to the discovery of frequent NOTCH1 gain-of-function mutations in the majority of human T-ALL. Gamma secretase catalyzes the cleavage of the Notch receptor within the transmembrane domain thereby releasing the Notch intracellular domain, which translocates to the nucleus to activate transcription of target genes. Gamma secretase inhibitors can induce G0/G1 arrest, decrease cell viability, and cause apoptosis of T-ALL cell lines carrying Notch activating mutations. MK-0752 is a potent gamma secretase inhibitor in clinical development (IC50 ∼50 nM). Methods: Patients with relapsed T-ALL and other leukemias were enrolled using an accelerated dose escalation scheme with 1 patient/dose level until ≥ grade 2 toxicity, followed by 3–6 patients/level. MK-0752 was administered by once-daily oral dosing in 28 day cycles. DLT was grade 3 or 4 non-hematologic toxicity during cycle 1. Plasma pharmacokinetic (PK) profiles and Abeta40 peptide levels were measured. Results: Six adult and two pediatric patients with leukemia (seven with T-ALL and one with AML) received MK-0752 dosed at 150, 225, and 300 mg/m2. Treatment duration ranged from 2 days to 56 days before patients discontinued for disease progression or drug-related toxicity. Dose-limiting toxicity (DLT) was Grade 3/4 diarrhea at 300 mg/m2. Four of the seven T-ALL patients had Notch activating mutations. One patient with T-ALL and a Notch activating mutation treated with 150 mg/m2 (300 mg) daily achieved a 45% reduction in a mediastinal mass at the end of 28 days as best response, but subsequently progressed by 56 days. Mean PK parameters at 150, 225, and 300 mg/m2 on Day 1 were AUC0–24hr = 723, 754, 1592 μM·hr, Cmax = 55, 40, 121 μM, C24hr = 18, 28, 59 μM, and tmax = 1, 8, 9 hr. Measurements of gamma secretase inhibition showed a 24–69% decrease in plasma Abeta40 peptide levels on Day 14 compared to predose. Conclusions: MK-0752 was well-tolerated in a limited number of patients below 300 mg/m2, and further enrollment is underway to establish the MTD. Plasma concentrations of MK-0752 at all doses were sufficient to inhibit gamma secretase. Leukemia samples will be assessed for Notch inhibition. [Table: see text]
A phase II study of AMN107, a novel tyrosine kinase inhibitor, administered to patients (pts) with systemic mastocytosis (SM)
Authors: Schatz M. , Verhoef G. , Gattermann N. , Ottmann O. G. , Schimansky T. , Alland L. , Rafferty T. , Gratwohl A. , Follows G. , Hochhaus A. 
Published: March 2020

6588 Background: SM is a clonal hematologic disorder associated with a constitutive activation of c-kit based on point mutations of this tyrosine kinase and is characterized by mast cell infiltration of extracutaneous organs. AMN107 is a novel aminopyrimidine which potently inhibits Bcr-Abl, as well as the PDGFR and c-kit kinases. Methods: This phase II, open-label study was designed to evaluate the safety and efficacy of AMN107 (400 mg bid). SM pts meeting specific disease criteria and with a clinical indication for treatment were enrolled. Preliminary data are presented for the first 23 pts accrued prior to September 1, 2005. Results: The median age was 49 (range 33–78) yrs and the median time from diagnosis of SM was 27 (range 1 to 292) months. For those with data available, 13/17 pts had a c-kit D816V mutation in bone marrow cells. The median exposure to AMN107 was 144 days. Treatment is ongoing for 18 (78%) pts; 5 (22%) discontinued, 3 (13%) for adverse events and 2 (9%) withdrew consent. Three (13%) responses were reported (2 incomplete remissions and 1 minor response), based on serum tryptase, bone marrow mast cell infiltration and improvement of clinical symptoms. Baseline mutation data are available for 2 of the 3 responding pts and revealed the c-kit D816V mutation. Anemia was reported in 2 (9%) pts. Non-hematologic toxicities in ≥10% of pts were headache in 12 (52%) pts (Gr 3/4 in 2; 9%), fatigue in 9 (39%) pts (Gr 3/4 in 1; 4%), nausea in 8 (35%) pts, vomiting in 7 (30%) pts, pruritus in 7 (30%) pts (Gr 3/4 in 2; 9%), muscle spasms in 6 (26%) pts (Gr 3/4 in 1; 4%), diarrhea in 5 (22%) pts (Gr 3/4 in 1; 4%), upper abdominal pain, rash in 5 (22%) pts each, dizziness, pain in extremities in 4 (17%) pts each (Gr 3/4 in 1; 4% each), dyspnea, myalgia, in 4 (17%) pts each, increased ALAT in 4 (17%) pts (Gr 3/4 in 2; 9%), bone pain, abdominal pain, cough, hard feces, pustular rash in 3 (13%) pts each, and hypotension in 3 (13%) pts (Gr 3/4 in 2; 9%). There were no deaths. Conclusions: These data suggest that AMN107 has clinical activity and an acceptable safety and tolerability profile in pts with SM. [Table: see text]
Prospective study of incidence and severity of epiphora and canalicular stenosis in patients with metastatic breast cancer receiving docetaxel
Authors: Amin S. R. , Valero V. , Rivera E. , Adinin R. , Banay R. , Arbuckle R. , Do K. , Esmaeli B. 
Published: March 2020

659 Background: To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving weekly or every-3-weekly docetaxel. Methods: In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and at every 4–6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with Tobradex drops. If epiphora worsened or findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered. Results: 28 patients received weekly and 28 patients received every-3-weeks docetaxel. 18(64%) patients who received weekly docetaxel developed epiphora. Epiphora was mild in 7 patients, moderate in 5, and severe in 6. Nine patients had resolution of epiphora with Tobradex. Nine patients had worsened canalicular stenosis; 6 underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. 11 (39%) patients who received every-3-weeks docetaxel developed epiphora. The median cumulative docetaxel dose at the time of onset of epiphora in this group was 420 mg. Epiphora was mild in 9 patients, moderate in 1, and severe in 1. Nine patients had resolution of epiphora in response to Tobradex. Two patients underwent surgery. Conclusions: Epiphora occurred in 64% of patients in the weekly group and 39% of patients in the every-three-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and none of the patients in the every-3-weeks group. [Table: see text]
The combination of rituximab and GM-CSF in elderly patients with chronic lymphocytic leukemia (CLL)
Authors: Ferrajoli A. , O’Brien S. , Faderl S. , Wierda W. G. , Schlette E. , Jorgensen J. L. , Reuben J. M. , Albitar M. , Keating M. J. 
Published: March 2020

6602 Background: CLL is a disease found more frequently in the elderly (50% of the patients are age ≥70 at diagnosis). Nevertheless treatment startegies for elderly patients have not been optimized. Elderly patients are often excluded from chemotherapy programs because of fear of severe toxicities resulting from myelosuppression. Therefore, we explored the activity of rituximab in combination with GM-CSF in elderly patients with CLL. The rationale for this combination stems from in vitro data showing increased activity of rituximab when administered togheter with GM-CSF (Venugopal P. Leuk. Res.2000). Methods: Patients age ≥70 years, untreated or previously treated, were eligible if they had indications for treatment (NCI-WG criteria). Treatment consisted of rituximab 375 mg/m2 administered weekly for 4 weeks and GM-CSF 250 mcg s.q. three times weekly for 8 weeks. In the first week GM-CSF was given on day 1 and 3 and rituximab was given on day 4. Genomic aberrations, IgVH mutation status, ZAP-70 and CD38 expression were evaluated prospectively. Correlative studies measured changes in cell surface and soluble CD20, apoptosis and quality of life (FACT-An V4). Results: 39 patients have been enrolled, 28 are evaluable for response and 31 for toxicity. According to NCI criteria the OR rate was 61%. 7% of the patients achieved CR, 11% nodular PR and 43% PR. Thirty patients are alive and the median time to treatment failure has not been reached with a median follow up of 5 months. Toxicity attributable to GM-CSF was G1 injection site reaction observed in 16% of the patients. OR rates were higher in naive than in previously treated patients (74% vs 46%), in patients with favorable genomic features (73% vs 40%) and mutated IgVH (89%vs 44%). No difference in OR was found in patients expressing high or low CD38 (60% vs 55%). Upregulation of surface CD20, measured 24h after the 2nd dose of GM-CSF, was observed in 3 out of 4 patients studied. Fatigue level was reduced by a mean of 7 points according to the FACT-An scale (6 patients). Conclusions: Treatment with rituximab and GM-CSF induced a high response rate with minimal toxicity in elderly patients with CLL. Priming with GM-CSF resulted in increased expression of surface CD20. This combination of rituximab and GM-CSF improved systemic symptoms such as fatigue. [Table: see text]
A single arm phase II trial of gemcitabine (G) and irinotecan (I) in metastatic breast cancer: Can localization of topoisomerase I (topo I) predict response to topo I inhibitors?
Authors: Moulder S. L. , Valkov N. , Minton S. , Munster P. , Gump J. , Lacevic M. , Rocha-Lima C. , Horton J. , Lush R. , Sullivan D. 
Published: March 2020

661 Background: The incorporation of G into DNA enhances cleavage complexes in vitro when combined with a topo I inhibitor. Topo I poisons require enzyme interaction with DNA to exert activity. Methods: Two stage accrual design, primary endpoint: response (RR) using RECIST criteria. Inclusion criteria: male and female patients (pts) with MBC, prior anthracycline therapy, measurable disease, ECOG PS of ≤ 2, adequate organ function, and ≤ 3 prior chemotherapy regimens for MBC. 51 eligible pts received therapy with G at 1000mg/m2 and I at 100mg/m2 on days 1 and 8 of a 21-day cycle. Optional tumor biopsies were obtained in 9 pts (18%) prior to therapy to determine localization of topo I using immunofluorescence. PK: Irinotecan: A validated limited sampling strategy was used. Gemcitabine: Serial blood samples were collected over 24 hrs following the first dose. Intracellular nucleotides were quantitated in PBMCs. Results: 45 pts have been evaluated with a RR of 27% (CR=0, PR=12; 95% CI 13–37%). 4 pts had SD for ≥6 months for a clinical benefit rate (PR+SD) of 36%. 3 pts received < 1 cycle of therapy before protocol withdrawal and were not evaluable for RR. RR for the final 3 patients will be available at the time of presentation. 7/9 tissue biopsies were assessable for topo I with results listed below. PK and toxicity data will be available at presentation.Conclusion: GI is active in MBC. Topo I localization can be measured in MBC. In this limited data set, the two lowest nuclear to cytoplasmic (N/C) ratios were associated with lack of response to irinotecan. Further validation is needed. [Table: see text] [Table: see text]