bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of voreloxin as single agent therapy for elderly patients (pts) with newly diagnosed acute myeloid leukemia (AML)
Authors: Maris M. B. , Ravandi F. , Stuart R. , Stone R. , Cripe L. , Cooper M. , Strickland S. , Turturro F. , Stock W. , Berman C. 
Published: August 2020

7048 Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Interim results of REVEAL-1, a phase II study of single agent voreloxin in newly diagnosed elderly AML pts, are reported. Methods: Phase II study of 3 voreloxin schedules (approximately 30 pts/schedule): A) 72 mg/m2qw x 3; B) 72 mg/m2qw X 2; or C) 72 mg/m2/dose on D1 and D4. Eligibility: newly diagnosed AML (de novo or secondary AML), pts age ≥ 60 and ≥ 1 additional adverse risk factor (age ≥ 70, secondary AML, intermediate or unfavorable cytogenetics, or PS 2). PK were evaluated in a pt subset in cycle 1. ex vivo sensitivity of pt BMA to voreloxin was evaluated by CellTiter-Glo proliferation assay. Results: Enrollment targets for schedules: A) (29) and B) (31) are met. Demographics (N = 54): 66% male, 35% female; median age 75 years; ECOG PS 0–1 90%, PS 2 10%. 20% AHD and cytogenetics were intermediate in 29%, unfavorable in 34%, and unknown in 36%. Final CR + CRp rate: A) 38%; B) too early to evaluate. Median duration of remission has not been reached. Thirty day all-cause mortality: A) 17%; B) 1 of 22, 4.5%. Infection was the most common cause of early mortality. Tolerability improved markedly in B): G3 or higher pneumonia (A 24%, B 11%) and mucositis (A 21%, B 11%) incidence were reduced. Voreloxin PK were similar to those in an earlier single agent phase I study in relapsed/refractory AML. C) enrollment is pending. Ex-vivo sensitivity did not predict clinical response. Conclusions: In REVEAL-1, voreloxin demonstrates clinical activity with 2 dosing schedules in previously untreated elderly (age ≥ 60) patients with AML who are unlikely to benefit from standard chemotherapy. CR + CRp rate was 38% (11 of 29 pts) for 3 weekly voreloxin doses (A). Early results from 2 weekly voreloxin doses (B) show 6 CR + CRp of 21 evaluable pts, with 2 pts in heme recovery, and improved tolerability. Enrollment to (C), voreloxin dosed D1 and D4, is pending. [Table: see text]
High-sensitivity detection of M351T, F317L, and F311C BCR-ABL kinase domain mutation in chronic myeloid leukemia patients treated with novel tyrosine kinase inhibitors (TKIs) imatinib and dasatinib
Authors: Mir A. R. , Sazawal Sazawal S. , Saxena A. , Saxena R. 
Published: August 2020

7061 Objectives: (1) To study the detection of M351T, F317L, and F311C ABL kinase domain mutation in CML patients treated with TKIs (imatinib and dasatinib). (2) To evaluate the effect of imatinib dose esculation in the CML patients carrying M351T mutations. Methods: One hundred CML patients were treated with imatinib at 400 mg/day from 2 to 4 years .They were diagnosed by RT-PCR for BCR-ABL transcripts. Early screening for the M351T, F317L, and F311C mutations was performed by allele specific-oligonucleotide-PCR (ASO-PCR). Results: We evaluated 100 CML patients for kinase domain mutation by ASO-PCR after three years of imatinib initiation. Patients were categorized into three groups. Group A All 100 CML patients were treated with imatinib at conventional dose of 400 mg/day and were screened for M351T mutation after three years of imatinib initiation. (40%) 40/100 were positive for M351T mutation consequently 20/40 were treated with high dose imatinib at 600 to 800 or 1,000 mg/day. After 11 months of dose escalation, 15/20 lost M351T mutation but remaining five who resist M351T mutation, developed a more fatal mutation called gate keeper mutation T315I. 2/5 died, three progressed to advanced disease. Group B All 100 CML patients were screened for F311C mutation after three years of imatinib initiation and (10%) 10/100 were positive. After 10 months, 4/10 developed a more fatal mutation in 315 and consequently 2/4 died and one progressed to advanced disease. Group C It included 12 imatinib-resistant CML patients treated with dasatinib at 70 to 100 mg/day. At the initiation of dasatinib, no one was positive for F317L and T315I mutation. After 10 months of dasatinib treatment, all were screened for F317L/ T315I mutation by ASO-PCR, 4/12 were positive for F317L mutation and no one was positive for T315I mutation. After 6 months of mutation detection 2/4 progressed to blast crisis, and 1/4 died. Conclusions: ASO-PCR proved to be a very economical, sensitive, and rapid technique for detection of KD mutations M351T, F317L, and F311C ABL mutation and is more sensitive than mutation detection by sequencing. The detection of M351T, F317L, and F311C -ABL mutation at any stage has prognostic significance. No significant financial relationships to disclose.
Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase—Care to cure
Authors: Biswajit D. , Rejiv R. , Manjunath N. , Prasad G. , Lakshmi S. , Devika P. , Geetha K. , Sagar T. G. 
Published: August 2020

7072 Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA), Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248 young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of study population was 27 years (4–35). The male to female ratio was 1.9: 1. Risk stratification was done using Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic (FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and 16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%), diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen > 8 cm (p = 0.02), high sokal index (p = 0.02), and loss of CHR (p < 0.001) were associated with poor outcome. Conclusions: Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to offer stem cell transplantation at the earliest. No significant financial relationships to disclose.
A phase II pilot study of valproic acid in relapsed/refractory chronic lymphocytic leukemia
Authors: Ganesan P. , Raina V. , Kumar R. 
Published: August 2020

7081 Background: Valproic acid (VA) has demonstrated cell-kill by triggering pro-apoptotic pathways in chronic lymphocytic leukemia (CLL) in preclinical studies. We studied the safety and efficacy of VA in patients with relapsed and refractory CLL. Methods: Adult patients with CLL diagnosed by the NCI-WG criteria who had received at least one previous fludarabine-based therapy and subsequently progressed or relapsed with ECOG performance status (PS) ≤3 and normal organ functions were included. Patients were started on VA 10 mg/kg which was gradually increased to 20 mg/kg. Efficacy (NCI-WG criteria) and safety (NCI common toxicity criteria) were assessed at 3 months. Responding patients were continued on the study medication. Results: Five patients have so far been included, age 48–70 years (mean 62 years); sex: 3 males/ 2 females; disease duration: 2–16 years (mean 5.4 years). Previous therapies included fludarabine/alkylators in all patients; in addition rituximab was given in one and lenalidomide in two. Three patients have completed three months of therapy and are evaluable. One patient had partial response and one had stable disease. In the third patient the total leucocyte count continued to rise but there was response in other parameters like decrease in lymphadenopathy by 50%, stabilization of hemoglobin, increase in absolute neutrophil (ANC) and platelet counts. Two of these patients who were requiring 2–3 blood transfusions per month and frequent admissions for infectious complications have not required further transfusions or hospital admissions since starting VA. Significant improvements were also seen in their ECOG PS from 3 to 0–1, 61% and 230 % rise in ANC and 50% and 83% rise in platelet counts. Grade 3 hypersensitivity skin rashes developed in one patient at one month and the therapy was discontinued. Most patients had mild drowsiness and two patients had significant weight gain of grade 2. Conclusions: VA produces very impressive palliation in advanced/ refractory CLL in terms of improvement of hemoglobin, ANC, platelets, PS, and a reduction in the number of infective episodes –apparently a sequel to significant rise in neutrophils. We are encouraged by these results and are continuing the study. No significant financial relationships to disclose.
The pharmacokinetics of azacitidine following subcutaneous treatment in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)
Authors: Laille E. , Ward R. , Nasser A. , Stoltz M. , Cogle C. , Gore S. , Skikne B. S. , Garcia-Manero G. 
Published: August 2020

7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (<2%). AZA was well tolerated and no unexpected toxicities were observed. Conclusions: The AZA AUCinf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA. [Table: see text]
Abrogation of tumor necrosis alpha (TNF-alpha) pathway by anti-TNF therapy in hematological malignancies
Authors: Ramanarayanan J. , Pahuja S. , Elefante A. N. , Hernandez-Ilizaliturri F. J. 
Published: August 2020

7093 Background: Tumor necrosis factor-alpha (TNF-alpha) enhances tumor growth and mediates cancer-related inflammatory symptoms by inducing secretion of cytokines. Anti-TNF approaches have been evaluated in pilot studies for cancer treatment and for alleviation of cancer related cachexia, fatigue, and other constitutional symptoms with conflicting results. While the incidence of malignancies with TNF alpha inhibitors (infliximab, adalimumab, etanercept) are not significantly higher than the untreated control population, their role in cancer treatment itself is unclear. We explored the activity and tolerance of TNF-alpha inhibitors in various hematological malignancies. Methods: We reviewed the English literature by conducting systematic MEDLINE using the terms TNF-, infliximab, adalimumab, etanercept, cancer therapy, hematologic malignancies, myelodysplastic syndrome (MDS), multiple myeloma (MM), myeloproliferative disease (MPD), chronic lymphocytic leukemia (CLL), and lymphoma from January 2001 to August 2008. We also performed a complete literature search of American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) published abstracts. Studies were analyzed for observed activity of TNF alpha inhibitors and also for reported safety. Results: Overall 11 phase I and II studies (n = 237; CLL n = 44, MM n = 10, MDS n = 109, MPD n = 51, HCL n = 3, TCL 13, FL 7) that involved anti-TNF- therapy in hematological malignancies were identified. As a single agent, etanercept did not yield significant responses. In conjunction with ATG or azacitidine in low-/intermediate-risk MDS, TNF inhibitors resulted in improvement in cytopenia. Improvement in constitutional symptoms were noted in at least 50% of patients with myelofibrosis(MF)/Ph- MPD. No significant clinical benefit was seen among lymphoproliferative disorders, but treatment was well tolerated. Conclusions: Existing data suggests that anti-TNF therapy by itself does not induce a therapeutic response in hematologic malignancies. Combination strategy with TNF inhibitors has to be evaluated further to determine any anti-tumor activity and their role to alleviate constitutional symptoms particularly in MF/MPD. No significant financial relationships to disclose.
Effect of mobilization chemotherapy with cyclophosphamide and etoposide on stem cell collection by lenalidomide
Authors: Talamo G. , Claxton D. F. , Ehmann W. C. , Mierski J. , Rybka W. , Ibrahin S. 
Published: August 2020

7096 Background: The combination of dexamethasone and lenalidomide is currently considered one of the standards of care for induction therapy of patients with multiple myeloma (MM) before autologous stem cell transplantation (ASCT). Increasing evidence suggests that lenalidomide impairs the ability to collect peripheral blood stem cells (PBSC). Methods: We retrospectively analyzed the outcomes of PBSC collections of MM patients who received induction therapy with dexamethasone and lenalidomide, and who were collected with either granulocyte-colony stimulating factor (G-CSF) alone, 10–16 mcg/Kg/day (group A, n= 12), or G-CSF 5 mcg/kg/day + mobilization chemotherapy, consisting of cyclophosphamide 5,000 mg/m2 and etoposide 1,000 mg/m2 (group B, n=27). In all patients, lenalidomide was stopped 2 weeks before the predicted day of PBSC collection. Results: The median number of PBSC collected was 3.2 million CD34+ cells/Kg in group A (range, 0.3–6.3) and 28.1 million CD34+ cells/Kg in group B (range, 4.8–134) (p<0.01). The median number of days to collect PBSC was 1 in group A (range, 1–4) and 2 in group B (range, 1–5) (p=0.015). Three patients in group A failed to collect an adequate number of PBSC, either for a single ASCT (n=1) or tandem ASCT (n=2). No PBSC collection failures were observed in group B. No difference in the rapidity of PBSC engraftment was seen between the two groups. Conclusions: Chemotherapy with cyclophophamide and etoposide can overcome the inhibitory effect of lenalidomide in the collection of PBSC for ASCT in MM patients. No significant financial relationships to disclose.
Expansion of umbilical cord blood mesenchymal stem cells
Authors: Peters R. E. , Heikenwälder M. , Knuth A. 
Published: August 2020

7103 Background: Umbilical cord blood (UCB) is known to harbor 2 major types of stem cells, the hematopoietic stem cells (HSC) & the non-hematopoietic or mesenchymal stem cells (MSC). Under appropriate conditions, MSCs can give rise to cells of bone, fat, hepatic lineages, etc. Based on this potential, MSC hold promise for clinical applications in regenerative medicine. Methods: Stroma-free liquid culture: UCB cryopreserved mononuclear cells (MNC) were cultured in the presence of early growth factors: Flt-3 & SCF (25ng/ml), MGDF (10ng/ml) & human serum (10%). MNC derived adherent MSC were passaged at day 14 during HSC expansion & after enriching in MesenCult medium. Results: We developed a technology to generate & expand HSC & stromal/ MSC from all UCB units (5/5) at the same time using one culture system (stroma-free liquid culture). Following repeated passages, MSC count increased 357- 600-folds & CFU-Fibroblasts colonies (CFU-F) increased too (61–513 & 648–697) after 10 and 20 passages respectively. We used the CFU-F assay to demonstrate MSC activity in stromal cell formation in vitro. Phenotypically, MSC were negative for hematopoietic antigens (CD45, CD34 & CD14) & MHC class-II but >95% + for CD73, CD105, CD29, CD44 & MHC class I. To demonstrate MSC differentiation capacity in vitro, cells were incubated in various induction media to differentiate into adipocytes (fat)), osteoblasts (bone) and hepatocytes (liver) at passage 5. Following induction, positive staining with oil red O for cells of adipocyte and with alkaline phosphatase for cells of osteoblsts lineages was observed. The identity of hepatocytes was verified by the characteristic hexagonal hepatocytic shape as well as albumin, cytokeratin (CK) 18 and CK14 expression, as assessed by flow cytometry. Our data were corroborated by RT-PCR analysis. Conclusions: MSC described herein exhibit in vitro properties of multipotent stem cells. The established, stroma-free culture system facilitates expansion of MSC from all tested UCB units. Our data underline that it will be possible in the future to substitutes properly differentiated hepatocytes which might lead to efficient applications in patients suffering from various end stage liver disease. No significant financial relationships to disclose.
The role of prophylactic antimicrobials during autologous stem cell transplantation: A single center experience
Authors: Yoon D. , Sohn B. , Kim J. , Yoo C. , Kim S. , Lee D. , Kim S. , Huh J. , Lee J. , Suh C. 
Published: August 2020

7105 Background: The aim of this retrospective study was to investigate the efficacy of antibiotic prophylaxis during autologous peripheral stem cell transplantation (ASCT) in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Methods: We searched Asan Medical Center Registry for NHL and MM: Total 114 cases received antimicrobial prophylaxis; while 118 cases did not receive antimicrobial prophylaxis during ASCT. Results: In prophylaxis group, 80 of 114 (70.2%) patients had experienced febrile episodes at median day +6 after transplantation with a statistically significant difference (P<0.001). In no-prophylaxis group, 111 of 118 (94.1%) patients had experienced at median day +5. Documented infection occurred in 14 of 114 (12.3%) patients in prophylaxis group, and 16 of 118 (13.6%) patients in no-prophylaxis group (P=0.846). In these patients, the positive blood culture was seen in 12 (10.5%) of 114 patients in prophylaxis group, and 12 (10.7%) of 118 patients in no-prophylaxis group (P=1.000). Documented viral infection or reactivation was not observed in prophylaxis group, but observed in 4 patients of no-prophylaxis group. Both groups showed no invasive fungal infection or serious adverse event during ASCT. The day of infection resolved was a median day +15 (range, 3–29) in prophylaxis group and day +14 (range, 2–70) in no-prophylaxis group (P=0.945). The duration of antimicrobial treatment was median 10 days both in prophylaxis group and in no-prophylaxis group (P=0.565). Conclusions: In our experience, the antimicrobial prophylaxis seems to decrease the incidence of febrile episodes during ASCT, but seems to have no beneficial effect on reducing infectious complications. The antimicrobial prophylaxis of our study did not show the difference in the detection of causative organism as an infective agent, duration of antimicrobial therapy and hospitalization between two groups. No significant financial relationships to disclose.
Results of autologous transplants for lymphomas from a tertiary cancer center in India
Authors: Jeevangi N. , Joshi A. , Shah M. , Kannan S. , Gupta S. , Nair R. , Khattry N. 
Published: August 2020

7106 Background: Autologous stem cell transplanation is the standard of care for patients of relapsed and refractory non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). We report the results of transplants in lymphomas from our center and role of possible prognostic factors. Methods: All 50 consecutive patients who underwent transplant for HL (70%) and NHL (30%) from August 1994- August 2008 were included in this retrospective study. Fifty eight percent of patients received BEAM (carmustine, etoposide, ara-c and melphalan), 30% LACE (lomustine, ara-c, cyclophosphamide and etoposide), 8% ICE (ifosfamide,carboplatin and etoposide) and 4% high dose melphalan (200mg/m2) conditioning regimens. Seventy eight percent of patients received peripheral blood stem cells (PBSC), 8% bone marrow (BM) and 14% both PBSC and BM. Prognostic factors evaluated for progression free survival (PFS) were serum albumin level and body mass index (BMI) at the time of transplant, stage at diagnosis and source of stem cells, while for over all survival (OS), status of disease at transplant was also included. Results: The median time to transplant was 2.25 years from the time of diagnosis. The median age at transplant was 25 years. Seventy four percent of patients were male. At the time of transplant, thirty two percent were in complete remission (CR), 50% in partial remission (PR) and 18% had refractory disease (RD). The median serum albumin and BMI at the time of transplant were 4 g/dl and 22.5 kg/m2 respectively. The best disease response rate was 86% (CR+PR) in patients evaluable for response. Thirteen patients relapsed at a median interval of 11 months post transplant. The cumulative probability of OS and progression free survival PFS at 5 years were 40% and 34% respectively for the whole group. Multivariate analysis using cox regression identified serum albumin greater than 4 g/dl and those receiving PBSC grafts as independently associated with improved OS and PFS. Conclusions: These data provide the first published report of outcomes of autologous transplants in lymphomas from India. Our data suggests that serum albumin level at the time of transplant and stem cell source are important prognostic factors for PFS and OS. No significant financial relationships to disclose.