bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does BCR-ABL transcript type predict cytogenetic response to imatinib mesylate in chronic phase, chronic myeloid leukemia patients?
Authors: Sharma P. , Kumar L. , Mohanty S. , Bose S. , Kochupillai V. 
Published: March 2020

7043 Background: We prospectively studied BCR-ABL transcript type (b2a2, b3a2, e1a2 and e19a2 in 100 CML-CP patients treated with Imatinib mesylate therapy and studied their correlation with the cytogenetics responses. Methods: Between Aug, 2004 and Sep, 2006, 100 CML –CP patients (median age was 32 years, range, 11 to 62 years, M: F: 2.5: 1) were treated prospectively with imatinib mesylate 400 mg daily on outpatients. 70 patients were pre-treated with interferon Alfa. The mean duration of Gleevec treatment was 24 months (range 3 to 38 months). Patients were monitored closely for clinical, hematological, cytogenetic & molecular response as per standard guidelines. Bone marrow was studied at 3, 6, 9 then 4–6 months interval for cytogenetic response (CGR) and also for the presence of BCR-ABL transcript types by multiplex and nested RT-PCR technique. Results: 96% of patients achieved complete hematological remission (CHR); median time being 21 days, ranging from 7 to 110 days. 60% of patients achieved Major CGR (complete 32, partial CGR-28); median time 8 months, ranging from 6 to 22 months. Previously untreated patients had higher major (70% vs 55.7%) and complete (46.6% vs 25.7%) CGR compared to patients previously treated with interferon alfa. Analysis for BCR-ABL transcript type revealed - b2a2 in 38%, b3a2 -54% and both in 8% of patients. 28 of 38(74%) patients with b2a2 type acieved Major CGR compared to 24 of 54 (44%) patients with b3a2 transcript, p<0.002. Of remaining 40 patients with minor or no CGR, 10(25%) had b2a2 compared to 30 (75 %) b3a2 type, p<.002. However, there was no significant correlation between transcript type and pre-treatment characteristics e.g. spleen size (in cm), Hb (G/dl), WBC & platelets counts. Conclusions: Present study suggests that site of breakpoint in major breakpoint cluster region might be predictive of cytogenetic responses to Imatinib Mesylate in CML patients. No significant financial relationships to disclose.
Discontinuation and dose modification of imatinib in clinical practice
Authors: Hamdan M. Y. , Sanders L. , Oliveria S. , Campbell U. , Willey V. , Hirji I. , Davis C. , Ulcickas Yood M. 
Published: March 2020

7045 Background: Imatinib mesylate induces response in most patients with chronic myelogenous leukemia (CML). Although recent evidence shows benefit from a starting dose of 800mg/day, the recommended starting dose is 400 mg/day for chronic phase patients and 600 mg/day for accelerated phase/blast crisis patients. This study describes trends in imatinib dosing and reasons for dose changes in CML patients. Methods: Using medical and pharmacy claims in the HealthCore Managed Care Database, we identified all patients with CML from 1/1/00–3/31/04. Chart review supplemented claims and confirmed CML diagnosis, obtained phase, treatment, and clinical outcomes through 3/31/05. Results: Among 216 patients receiving imatinib, 87% were diagnosed in chronic phase, 5% in accelerated phase, 1% in blast phase; 7% were unable to be determined. Among 156 patients (72%) with a starting imatinib dose of 400mg/day, 21% had a subsequent dose reduction of at least 100mg/day. The most common reasons for dose reduction were neutropenia, anemia, and nausea/vomiting. Among 29 patients (13%) with a starting dose of at least 600mg/day, 59% had a subsequent dose reduction; the most common reasons for dose reduction in these patients were thrombocytopenia and gastrointestinal bleeding. Among 9 patients (4%) with a starting imatinib dose of at least 800mg/day, 67% had a subsequent dose reduction; the most common reason for dose reduction was myelosuppression. Imatinib therapy was suspended in sixty-two patients (29%), most often because of anemia (11%) or thrombocytopenia (11%); 46 patients (74%) restarted imatinib therapy following a median time of 21 days and the remaining 16 (26%) patients were permanently discontinued. Of the 64 patients (30%) who experienced a dose escalation of at least 100mg/day over starting dose, 34% patients had a subsequent dose decrease; the most common reason for dose reduction among these patients was neutropenia (18%). Conclusions: Among CML patients treated with imatinib, discontinuation and dose changes occurred frequently; the most common reason was myelosuppression. More than 50% of patients starting at higher doses required dose reductions and 1/3 of those receiving dose escalations did not remain on higher doses. No significant financial relationships to disclose.
Imatinib (I) compared to I + cytarabine (Ara-C) for the frontline treatment of chronic phase (CP) chronic myeloid leukemia (CML)
Authors: Hurtado-Monroy R. , Vargas P. , Martinez A. , Cruz J. , Enriquez V. , Gutierrez O. , Candelaria M. , Aguayo A. , Cervera E. 
Published: March 2020

7048 Background: Imatinib is now worldwide accepted as the standard frontline therapy of CP CML. Regardless of their impressive clinical results and low toxicity profile, a small proportion of CP CML patients could develop primary or secondary resistance. Main objective of present trial was to increase the hematological (HR) and major cytogenetical responses (MCR) with the addition of Ara-C to standard doses of I as a frontline therapy of CP CML. Methods: on September, 2003 we began this multicentric, phase III randomized, clinical trial, comparing I (400 mg/day) vs I (400 mg/day) plus subcutaneous Ara-C (10 mg/m2/day, for 10 days/monthly cycles), doses could be adjusted due to tolerance and toxicity. Inclusion criteria: newly diagnosed CP CML, not elective to allogeneic transplant. Primary endpoint was the acquisition and time to acquisition of HR, MCR by conventional criteria. Secondary endpoints were main toxicities, dead to progression and overall survival. Results: 61 patients were randomized with median follow-up of 850 days (range 85–1151) for entire group. Table 1 shows results for both treatment arms. Table 1 Both treatment arms were well tolerated and the toxicity profile was low and manageable. Statistical analysis (chi- square, paired T-student, Log-rank survival analysis) did not show significant differences among treatment arms. Conclusions: The addition of cytarabine to conventional I doses on frontline therapy CP CML does not produce significant benefit on HR or MHR. Larger I doses or other therapeutic options should be explored. [Table: see text] [Table: see text]
Oral chemotherapeutic agents in elderly acute myeloid leukemia (AML) patients, a study from a developing country
Authors: Mukhopadhyay S. , Chitalkar P. , Gupta P. , Roy U. , Mukhopadhyay A. 
Published: March 2020

7057 Background: Almost 60% of the patients with Acute Myeloid Leukemia (AML) are over the age of 60 years. Age is one of the strongest adverse prognostic factor for AML, both for induction remission and for survival. Studies have shown that elderly patients have reduced tolerance to aggressive chemotherapy especially the myelosupressive effects. Elderly patients with Leukemia who receive intensive treatment often die as a result of chemotherapy. Aggressive chemotherapy is also costly which the relatives in developing country are reluctant to spend for the elderly patients. The aim of our study was to see the outcome, tolerability and cost effectiveness of oral chemotherapeutic agents. Methods: We selected consecutive 100 patients more than 50 years of age in haemato oncology department of NCRI (Netaji Subhas Chandra Bose Cancer Research Institute) during the period from Jan 2004 to Dec 2006. The mean age of the patients was 65 (range 50 –71) years. There was male preponderance. The inclusion criteria were performance status more than 60% (Kornofsky), Morphological, Cyto-Chemical and Immunophenotyping diagnosis of Acute Myeloid Leukemia (AML), normal liver (billirubine < 2) and kidney function ( Creatinine <2%). After the incent consent all patient were started oral chemotherapeutic agents 6 Mercptopurine (6MP) 75mg/m2. Etoposide 70mg/m2 and Prednisolone 40mg/m2. All agents are given 3 weeks followed by 7 days gap every month and continued for 6 months. Bone Marrow was repeated after 3rd & 6th course of chemotherapy. Results: Fifteen (15%) and thirtyeight patients (38%) had complete hematological response after 3rd & 6th course of chemotherapy. Seven patients (7%) died because of grade III/IV Neutropenia. Median duration of Myelosupression was 18 days (2 to 48 days).12% required hospitalisation. With median follow up of 19 months (range 2–36 months) the disease free survival (DFS) and over all survival (OS) was 18 % and 32 % respectively. Conclusions: The combination of oral chemotherapeutic agents consisting of 6MP, Etoposide & Prednisolone were well tolerated by elderly patients with good induction remission, low mortality and median survival. It was cheaper and well accepted by the patients. No significant financial relationships to disclose.
Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)
Authors: Garcia-Manero G. , Yang A. S. , Klimek V. , Luger S. , Newsome W. M. , Berman N. , Patterson T. , Maroun C. , Li Z. , Ward R. , Martell R. 
Published: March 2020

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.
Phase I study of sapacitabine, an oral nucleoside analogue, in patients with advanced leukemias or myelodysplastic syndromes
Authors: Plunkett W. , Garcia-Manero G. , Faderl S. , Cortes J. , Boone P. , Hilbe C. , Green S. , Chiao J. H. , Kantarjian H. 
Published: March 2020

7063 Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to induce G2 cell cycle arrest and cause irreparable single-strand DNA breaks, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg b.i.d.×7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTD of the above dosing schedule and the secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which =2/6 patients experienced a DLT during the first treatment cycle. Results: Twenty- nine patients received sapacitabine. Median age was 64 (range: 36 - 91). The majority of patients had AML (n=24) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 - 6). MTD was reached at the dose level of 375 mg b.i.d. with 2/7 patients experienced the DLT of small bowel obstruction (n=1) or neutropenic colitis (n=1). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included nausea, vomiting, diarrhea, anorexia, alopecia, and fatigue, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 7 patients (5 AML, 2 MDS) had a reduction in bone marrow blast counts to = 5% including 1 CR in refractory AML with incomplete platelet recovery and 1 CR in relapsed MDS. In addition, 2 AML patients with relapsed leukemia cutis had a significant reduction in leukemia infiltrates in skin. Conclusion: The RD of sapacitabine for the b.i.d.×7 days every 21 days schedule is 325 mg b.i.d. The DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS. No significant financial relationships to disclose.
First-line treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and chemotherapy
Authors: Ghavamzadeh A. , Alimoghaddam K. , Ghaffari S. , Rostami S. , Jahani M. , Khodabandeh A. , Mossavi S. , Iravani M. , Eini E. , Moghadam Z. , Afshar F. 
Published: March 2020

7073 Background: Standard treatment of APL is ATRA plus chemotherapy but Arsenic Trioxide (ATO) is most potent single agent against APL cells. Role of ATO in first line therapy of APL needs to clarify. Methods: Between may 2000 and September 2006,we treated 141 new cases of APL(Median age 28±12.8 y/o min=11,max=71) by 2 hours iv infusion of 0.15mg/kg ATO until complete remission. Trial approved by IRB and consent form obtained. Diagnosis was by clinical and morphologic characteristics and confirmed by cytogenetic and RT-PCR for detection of t(15,17) and presence of PML-RARa. After complete remission patients received consolidation by 28 days infusion of ATO for one or four courses.(one consolidation one month after CR and for some patients second, third and forth consolidations one month after first one and two another , one year and two year after CR) Results: : complete remission observed in 121 cases(85.8%) and early mortality rate was14.9%(most common cause of early mortality was APL syndrome,61.9%).Median follow up was 28 months. For patients who achieve to complete remission,one, two and three year disease free survival were 95.6%± 2%, 76.9±4% and 57± 6%,respectively. Many relapsed patients salvaged again with ATO alone so, two and three years overall survival for this cohort was 95.6%±2% and 83.7%±4%. Increasing number of consolidation from one to four couldn’t increase DFS or OS in one and two years after CR. Conclusions: ATO is effective in treatment of new cases of APL. Introduction of ATO in first line treatment of APL(with or without ATRA plus chemotherapy) needs a multi center randomized clinical trial. No significant financial relationships to disclose.
Baseline predictors of response to treatment with darbepoetin-alpha (DA) in anemic patients with low-risk myelodysplastic syndrome (MDS)
Authors: Gabrilove J. , Paquette R. , Lyons R. , Mushtaq C. , Sekeres M. , Tomita D. , Lillie T. 
Published: March 2020

7081 Background: Patients (pts) with MDS often develop anemia, resulting in fatigue and an increased requirement for transfusions. The erythropoiesis-stimulating agent (ESA) DA can raise hemoglobin (Hb) levels in low-risk MDS pts. Previous analyses suggest that baseline (BL) endogenous erythropoietin (eEPO) levels and French-American-British (FAB) disease category are predictors of response to ESAs. Methods: This was a phase 2, open-label, 52-week (wk) study of DA administered 500 mcg every 3 wks (Q3W) to anemic (Hb=11g/dL), low- or intermediate-risk MDS pts. Pts received 500 mcg DA Q2W if they did not respond by wk 7. The last DA dose was at wk 52; end of study was wk 53 or 55 for pts receiving DA Q2W or Q3W, respectively. The primary endpoint was % pts with an erythroid response (International Working Group criteria) by wk 13. Other endpoints included change from BL in Hb and FACT-F score. Exploratory analyses examined the incidence of erythroid responses adjusted by FAB category (refractory anemia [RA], RA with ringed sideroblasts [RARS], or RA with excess blasts [RAEB]). Results: Final 53/55 wk data will be presented. Results were stratified by whether pts received an ESA before enrollment (ESA-naive [ESA-N] vs ESA-treated [ESA-T]). ESA-T pts are a heterogeneous group and their data are difficult to interpret; thus, predictors of response will be presented for ESA-N pts only. Of 144 ESA-N pts, 56% had RA, 37% had RARS, and 7% had RAEB. Most ESA-N pts achieved the target Hb and had a major erythroid response ( Table ). Pts with RA were more likely to achieve a major erythroid response than pts with RARS or RAEB. For ESA-T pts, demographics and type/length of ESA treatment will be presented. Of all pts, serious adverse events (SAEs) were reported in 62 (30%) pts and treatment-related SAEs in 2 (1%) pts. Conclusions: FAB category may affect response to DA in MDS pts. Additional data will be presented on the effect of BL eEPO, transfusion needs, and previous ESA treatment on response and duration of response. [Table: see text]
A novel denaturing high-performance liquid chromatography (D-HPLC) based method for kit mutation screening of patients (pts) with systemic mastocytosis (SM)
Authors: Colarossi S. , Soverini S. , Gnani A. , Rondoni M. , Gatto S. , Merante S. , Zanotti R. , Martinelli G. , Baccarani M. , Tiribelli M. 
Published: March 2020

7085 Background: SM is characterized by activating mutations of Kit tyrosine kinase. While the enzimatic site (ES) type mutation D816V renders Kit resistant to imatinib, regulatory type mutations are sensitive to inhibition. Kit mutations screening with sensitive methods is important for an appropriate therapeutic management of SM. Methods: Our aims were: to set up and optimize a D-HPLC-based screening method for mutations in critical regions of Kit; to assess the sensitivity and reliability of our D-HPLC assay as compared to RFLP analysis; to characterize additional mutations. The analysis was performed on 51 SM pts. Results: For each sample, a RT-PCR product spanning the catalytic and activation loops (ES) was screened in parallel by D-HPLC, followed by sequencing of D-HPLC-positive cases, and by RFLP according to an reported method for the D816V detection. By RFLP analysis, 34/51 pts were positive for the D816V. By D- HPLC analysis, an abnormal eluition profile was seen in 36/51 pts - all the 34 RFLP-positive cases as well as two additional pts. Direct sequencing confirmed the presence of the D816V in all the 34 RFLP-positive cases and showed that in two of these cases a I798I polymorphism was also present. The two pts scored positive by D-HPLC but negative by RFLP were found to have the I798I polymorphism. The 15 pts who did not harbour ES type mutations were further investigated by D-HPLC analysis of a RT-PCR product spanning the transmembrane (TM) and juxtamembrane (JM) domains. D-HPLC showed an abnormal elution profile in 5 pts. By direct sequencing one patient showed the K546K mutation and 4 pts showed the M541L polymorphism. Conclusions: Our D-HPLC-based assay proved a straightforward, reliable and sensitive method for Kit mutation analysis and highlighted the importance of screening for mutations other than the D816V. No significant financial relationships to disclose.
Dasatinib therapy for patients with Philadelphia-negative (ph-) myeloproliferative disorders (MPDs), including systemic mastocytosis
Authors: Verstovsek S. , Atallah E. , Thomas D. , Cortes J. , Ravanid-Kashami F. , Nicaise C. , Sams I. , GIles F. , Kantarjian H. 
Published: March 2020

7086 There are no curative medical therapies for Ph- MPDs. Over last several years several of the MPDs have been associated with the abnormal expression of selected tyrosine kinases (e.g. c-kit in SM) and others are suspected to be involved too. Therefore, we engaged in conducting a Phase II study with dasatinib, an orally available multi targeted kinase inhibitor, for patient with Ph- MPDs. Dasatinib is administered at 70 mg PO BID continuously (one month equals one cycle). Response is assessed every 3 cycles, and the therapy is discontinued in those without response after 6 cycles of therapy. Patients are observed for any toxicity; in such cases the dose of dasatinib is adjusted to 50 mg PO BID, then to 40 mg PO BID, or discontinued. The study is ongoing and has enrolled 55 patients; 44 are evaluable for response and toxicity, including 24 with SM (6 with aggressive SM, 4 with SM and associated hematologic non-mast cell disease and 14 with indolent SM with uncontrolled symptoms despite optimal supportive care measures), 10 CIMF, 6 HES, 3 unclassifiable MPD and one PV. Median age is 65 years (range, 27–75); 25 males and 19 females. The overall response rate in SM was 42% (10 pts). Of those, two patients (8%) achieved complete remission, one with SM-CIMF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). Symptoms related to SM improved significantly in additional 8 patients, however, no significant response in percentage of bone marrow mast cells or blood tryptase levels have been observed so far. The 6 patients with HES had previously failed imatinib therapy and had no evidence of the FIP1L1-PDGFRA fusion transcript; one achieved complete remission (normalization of blood and bone marrow eosinophil percentage) while others did not respond. No responses have been recorded in patients with CIMF, PV and unclassifiable MPD. No grade 4 toxicity has been observed. Dasatinib is active in SM (overall response rate 42%) mainly by improving symptoms. Updated clinical results on all enrolled patients will be presented. No significant financial relationships to disclose.