bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of the combination of 5-azacytidine(5-AC), all-trans retinoic acid (ATRA) and valproic Acid (VPA) in patients with myelodysplastic syndrome (MDS) and leukemia
Authors: Soriano A. O. , Yang H. , Verstovsek S. , Wierda W. , Koller C. , Estrov Z. , Ouzounian S. , Kantarjian H. , Issa J. , Garcia-Manero G. 
Published: March 2020

6563 Background: The combination of a hypomethylating agent with a histone deacetylase inhibitor (HDACI) has synergistic activity. The combination of ATRA with either a hypomethylating agent or a HDACI restores ATRA sensitivity in resistant cells. The combination of VPA and ATRA has activity in patients with MDS. Based on this, we developed a phase I/II study of the combination of 5-AC, VPA and ATRA for patients with MDS or AML. Methods: The dose of 5-AC was fixed: 75 mg/m2 sq daily × 7. ATRA dose was: 45 mg/m2 orally daily × 5 starting on day 3. Three dose levels of VPA were studied: 50, 62.5 and 75 mg/kg orally daily × 7. The phase I portion of the study followed a 3+3 design. Patients with high risk MDS (≥10% blasts) or relapsed/refractory AML and patients older than 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible. Results: Nineteen patients were registered and 16 were evaluable. Median age was 68 years (5–78). All, but one patient with MDS had AML. Median number of prior therapies was 2 (0–5). Twelve patients (75%) had abnormal cytogenetics. At a VPA dose of 50 mg/kg, 1 of 6 patients developed grade 3 confusion; at 62.5 mg/kg, 0 of 6, and at 75 mg/kg, 2 of 6. One patient had a CR, 2 a complete marrow response (marrow blasts < 5%), and 1 a CRP (same criteria as of CR but without complete platelet recovery), overall response rate was 30% of 13 patients that have completed 1 course. All 4 responses occurred during the first cycle. The CR occurred at a VPA dose of 75mg/kg. The other 3 responses occurred at 62.5 and 75 mg/kg. One out of 2 previously untreated older patients achieved a CR. To assess the hypomethylating effect of 5-AC, we used the LINE assay. Median LINE methylation pretreatment was 62.5% (57–67%), declined to 58% by day 7 and returned to baseline by day 0 of next cycle (p<0.001). Analysis of histone acetylation and gene re-expression are ongoing. Conclusions: The combination of 5-AC with VPA and ATRA is well tolerated. The dose of 62.5 mg/kg daily × 7 is currently being expanded. Significant clinical activity was observed and the effects are potentially mediated by the synergistic action of the combination including induction of DNA hypomethylation and histone acetylation. [Table: see text]
Quality of life (QOL) of older adults with acute myeloid leukemia (AML): Effects of treatment and time
Authors: Leach M. , Kowgier M. , Kermalli H. , Schattner A. , Gupta V. , Minden M. , Tomlinson G. A. , Alibhai S. M. 
Published: March 2020

6566 Background: AML in older adults has a poor prognosis. Although intensive chemotherapy may be associated with a modest improvement in survival, this needs to be balanced against possible worsening of QOL. However, published research in this area is limited. Methods: English-speaking patients aged 60 or older presenting with newly diagnosed AML to our referral centre were enrolled. Patients were excluded if life expectancy was <1 month. QOL was measured at baseline and at 1, 4, and 6 months. Questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 (global health and 5 QOL domains) and the Functional Assessment of Cancer Therapy Fatigue subscale. Patients were stratified into intensive (IT) and non-intensive treatment (NIT) groups. Baseline scores between groups were compared using Student’s T-test. Repeated measures modeling was used to compare the groups over time. Results: From June 2003 to December 2005, 63 patients (mean age 72, 46 IT, 17 NIT) were enrolled. At baseline, physical function and social function were the most affected domains and most patients had moderate fatigue. IT patients had better physical function and slightly less fatigue at baseline than NIT patients but were similar in 4 QOL domains and global health scores. By 6 months, 44% of IT and 60% of NIT patients had died. Over time, global health, role function, and emotional function improved but physical function, social function, and cognitive function did not change. Improvements in QOL domains were similar for IT and NIT patients for all measures. Fatigue scores remained unchanged over time. Conclusion: Intensive chemotherapy is not associated with worse QOL than NIT in older patients with AML, although our small sample size and attrition bias may overestimate QOL among survivors. Concerns about worse QOL with IT appear to be unfounded and this should not deter clinicians from considering IT for older adults with AML. No significant financial relationships to disclose.
Quantitative analysis of PML-RARα in newly diagnosed acute promyelocytic leukemia patients treated with arsenic trioxide as a front-line therapy
Authors: Ghaffari S. H. , Rostami S. , Bashash D. , Alimoghaddam K. , Ghavamzadeh A. 
Published: March 2020

6571 Background: Recently, patients with acute promyelocytic leukemia (APL) have experienced significant clinical gains after treatment with arsenic trioxide (As2O3). However, the potential role for use of this agent as a front-line therapy for newly diagnosed patients is unclear. Methods: From 95 patients with APL, 85 patients who achieved complete remission (CR) were sequentially evaluated during 4–60 months period of follow-up by conventional RT-PCR. A total of 30 patients (6 relapsed and 24 in continued long remission) were selected and monitored by quantitative real-time PCR (RQ-PCR) assay. Using ‘Hybridization Probes‘ technology, the expression of PML-RARα/G6PDH transcript ratio was analyzed in serial PB samples taken at different courses of disease and the results were compared with the clinical outcome. Results: More than 90% of patients obtained molecular remission, as determined by conventional RT-PCR in 1–3 months after start of arsenic therapy. RQ-PCR analyses showed a rapid rate of clearance of PML-RARα/G6PDH transcript level during the courses of arsenic therapy. In majority of the patients in CR the level of PML-RARα/ G6PDH ratio was always below 5×102 in PB samples. In all the relapsed cases with follow-up intervals of 1–6 months (median 3) clinical relapse was predictable by increasing transcript level above this threshold. Conclusions: Using a sensitive and quantitative method provided valuable information about effectiveness of arsenic as a front-line therapy in the management of newly diagnosed APL. Our study highlights the usefulness of PB and the definition of threshold level for early prediction of relapse. The threshold level correlates well with relapse risk; therefore, transcript ratio below the level should be regarded as a goal in the clinical management of this disease. No significant financial relationships to disclose.
Darbepoetin alfa for treating anemia in patients with low-risk myelodysplastic syndromes: Exploratory analysis of baseline predictors of response
Authors: Gabrilove J. , Paquette R. , Lyons R. , Mushtaq C. , Sekeres M. , Lam H. , Dreiling L. 
Published: March 2020

6579 Background: Patients (pts) with myelodysplastic syndromes (MDS) often develop anemia, resulting in fatigue and increased transfusions. The erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in low-risk MDS pts. Baseline (BL) endogenous erythropoietin (eEPO) levels, transfusion history, and FAB sub-type can be predictive factors of response to ESAs (Hellström-Lindberg et al., 2003). Methods: This is an ongoing, fully enrolled (n = 209), phase 2, single-arm, 52-week (wk) study of DA 500 mcg every three weeks (Q3W) for treating anemia (Hb ≤ 11 g/dL) in low- or intermediate-risk MDS pts. A planned interim analysis was done after 13 wks (n = 189). The primary endpoint is the proportion of pts with an erythroid response by 13 wks. Other endpoints include change in Hb levels and in FACT-F score from BL. Results are stratified by whether pts received an ESA before enrollment: ESA-naïve (ESA-N) pts vs ESA-treated (ESA-T) pts. Exploratory analyses of the percentage of pts with an erythroid response adjusted by BL eEPO or FAB category were done. Results: Of 130 ESA-N pts, 52% were women, 86% were white, 58% had refractory anemia (RA), 34% had RA with ringed sideroblasts (RARS), 8% had RA with excess blasts (RAEB), and the mean (SD) age was 74.8 (10.1) years. The 59 ESA-T pts had similar demographics. A majority of ESA-N pts had an erythroid response, achieved a target Hb of 11 g/dL, and had a clinically significant rise in FACT-F score; ESA-N pts with lower BL eEPO levels were more likely to have a major erythroid response ( Table ). A major erythroid response was seen in 50% of pts with RA (n = 111), in 30% of pts with RARS (n = 64), and in 23% of pts with RAEB (n = 13). Of all 189 pts, 78% had an adverse event (AE), 1 had a serious treatment-related AE (hypertension), and none had thrombotic events. Conclusions: These interim results suggest that FAB sub-type and BL eEPO may affect response. Final 13-wk data from all enrolled pts (n = 209) will be shown. [Table: see text] [Table: see text]
Design and first interim analysis of a randomized phase III trial comparing imatinib versus imatinib (IM) based combination therapies in newly diagnosed chronic myelogenous leukemia patients in chronic phase
Authors: Maloisel F. , Dubruille V. , Varet B. , Escoffre-Barbe M. , Berthaud P. , Meresse V. , Mahon F. , Preudhomme C. , Guilhot J. , Guilhot F. 
Published: March 2020

6589 Background: Despite impressive results achieved with IM 400 mg/day alone, only a minority of pts reached a complete molecular remission at 12-month. Higher dose of IM or its combination with other therapies might improve molecular remission. Design of the trial: the 3 experimental arms are IM 400mg daily in combination with Peg-IFN-α2a (Peg-IFNα2a, 90 μg weekly) or with Ara-C (20 mg/m2/day, days 15–28 of 28-day cycles) or IM 600mg daily. The reference arm is IM 400mg daily. All pts (over 18 years of age with Bcr-Abl positive CML) receive IM 400 mg/day as monotherapy days 1–14 and then start the assigned regimen for at least 12 months. The endpoints are overall survival (primary), rate and duration of hematologic, cytogenetic and molecular responses and tolerability. An interim analysis of the first 636 pts at 1 year from randomization will allow evaluation of molecular response rates, one of the experimental arm being selected for further comparison with IM 400. An experimental arm would be selected if it increased the 4 log reduction response rate at 12-month by at least 20 percentage points, (15% to 35%), with an acceptable tolerability. Results: This evaluation is based on a cohort of 370 pts with a median time of observation of 16 months, recruited between 9/2003 and 9/2005. [median age 53 yrs (18–81); Sokal distribution: 38% of pts low, 38% intermediate, and 24% high]. At 1 month 80% of pts achieved complete hematologic response. At 12 months, 138 pts (72%) achieved a major cytogenetic response, being complete in 120 pts (63%). Grade 3/4 hematologic toxicity occurred in 8% of IM400 pts, 9% of IM600 pts, 41% of IM+IFN pts and 33% of IM+Ara-c pts respectively. Dose of Peg IFN was reduced in 16% of pts, 45 μg per week being well tolerated. Grade 3/4 non hematological toxicity occurred in 11% of IM400 pts, 16% of IM600 pts, 10% of IM+IFN pts (maily skin rash) and 11% of IM+Ara-c pts. Discontinuation of experimental treatment occurred in 17% of IM600 pts, 36% of IM+IFN pts and 16% of IM+Ara-c pts. Conclusion: This first analysis confirmed both feasibility of IM combinations and high response rates. However a substantial hematological toxicity requires a careful assessment of pts. [Table: see text]
Regulation of pathways downstream of mTOR by imatinib mesylate in CML cells
Authors: Aranha O. , Kaur S. , Smith J. , Sassano A. , Platanias L. C. 
Published: March 2020

6595 Background: The differential regulation of signaling pathways downstream of the BCR-ABL tyrosine kinase are being defined in an effort to improve therapeutic strategies for patients with CML. We have previously shown that imatinib mesylate suppressed p70 S6 kinase activity, consistent with inhibition of BCR-ABL-mediated activation of the mTOR/p70 S6 kinase pathway. In this study we examined the effects of imatinib mesylate on other target proteins downstream of mTOR. Methods: BCR-ABL expressing cell lines (K562, KT1 and BV173) were treated with 1μM of imatinib mesylate for 30, 60 and 90 minutes, and then lysed in phosphorylation lysis buffer. Immunoblotting was done using standard enhanced chemiluminescence (ECL) methods. In the experiments in which the pharmacologic inhibitor of mTOR, rapamycin was used, the cells were pretreated for 60 minutes with the inhibitor and subsequently treated with imatinib. Results: The translational repressor 4E-BP1 is constitutively phosphorylated in CML cells. In the presence of imatinib mesylate in concentrations as low as 1μM, the phosphorylation of 4E-BP1 on threonine sites 37 and 46 is decreased. The phosphorylation of eIF-4G on serine site 1108 is also inhibited by imatinib mesylate treatment as early as 60 minutes. The combination of the mTOR inhibitor rapamycin and imatinib mesylate was more potent in suppressing phosphorylation of 4E-BP1 than imatinib alone, suggesting a mechanism for the enhancing effects of rapamycin on imatinib mesylate-dependent inhibition of growth of BCR-ABL cells. Conclusions: Our results further suggest the potential development of future clinical-translational studies utilizing rapamycin in combination with imatinib for the treatment of patients with CML. No significant financial relationships to disclose.
Phase II trial of ixabepilone in patients with metastatic breast cancer (MBC) who are resistant to an anthracycline, a taxane and capecitabine
Authors: Thomas E. , Perez E. A. , Mukhopadhyay P. , Lerzo G. , Pivot X. , Bosserman L. D. , Mullaney B. , Vahdat L. , Hortobagyi G. N. 
Published: March 2020

660 Background: Patients (pts) with MBC previously treated with an anthracycline, a taxane and capecitabine have very limited treatment options. Ixabepilone is the first semi-synthetic analog in a new class of cytotoxic agents, the epothilones. It has shown activity in breast and other tumors. Methods: This single-arm Phase II trial was designed to assess the objective response rate (ORR) of ixabepilone in MBC pts resistant to an anthracycline, a taxane and capecitabine. Pts had to be resistant to each regimen as defined by progression within 8 wks in the metastatic setting or recurrence within 6 months (mo) of adjuvant anthracycline/taxane. Capecitabine must have been given in the metastatic setting. Response was assessed by an independent radiology review committee (IRRC; primary analysis) and by each investigator per RECIST. Ixabepilone was administered IV at 40 mg/m2 over 3 h every 3 wks. Results: A total of 126 pts were treated: median age 51 yrs (range 30–78), Karnofsky PS range 70–100% and 70% pts had baseline liver metastases. 88% pts had received ≥2 prior metastatic regimens. 113 pts were response evaluable (had target disease by IRRC and met eligibility criteria for prior therapy). Median duration of response was 5.3 mo. Stable disease (SD) was the best response in 50% pts and 14% pts had SD ≥6 mo duration. Median PFS was 3.1 mo. Pts received a median of 4 cycles (range 1–16). The most common Grade 3/4 treatment-related adverse events were sensory peripheral neuropathy (14%), fatigue (10%), myalgia (7%), and stomatitis (6%). The neuropathy was cumulative and reversible. Time to resolution (to Grade 1 or baseline) for Grade 3/4 neuropathy was 5.4 wks by Kaplan-Meier analysis. Grade 3/4 neutropenia and thrombocytopenia occurred in 54% and 7% of pts, respectively. Febrile neutropenia was reported in 3% pts. Conclusions: Ixabepilone demonstrates promising clinical activity and a manageable safety profile in patients highly resistant to standard chemotherapy. [Table: see text] [Table: see text]
Subcutaneous alemtuzumab in patients with refractory/relapsed B-CLL after a fludarabine-based regimen
Authors: Bezares R. , Stemmelin G. , Argentieri D. , Lanari E. , Guy-Garay E. , Campestri R. , Bartomioli M. , García J. , Giralt S. , Milone G. 
Published: March 2020

6600 Background: Alemtuzumab is the only immunotherapy that is effective as a single agent in patients with B-CLL who are refractory to, or who have relapsed after, fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. We report the first interim analysis of a new, less intensive schedule of alemtuzumab SC to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg bid during the second and third weeks, and 30 mg once weekly during weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg tid. Results: Patients (N = 36) with refractory (19%) or relapsed (81%) B-CLL had a median age of 67 years (range, 43–86 years), 28 were male, 61%/39% had Binet stage B/C disease, and 2 had B-cell prolymphocytic transformation. The median number of prior therapies was 1 (range, 1–4). The median duration of treatment was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 412 mg (range, 150–1,080 mg). Thirty-two patients were evaluable for response. The overall response rate of 93%: complete response (CR), 34%; unconfirmed CR, 6%; partial response (PR), 53%. Two patients (7%) did not respond to therapy. Of the 7 refractory patients, 5 had a PR, 1 did not respond, and 1 was not yet evaluable. Median overall survival was 10 months, which correlated with response and pretreatment status. Minimal residual disease (MRD) was measured by flow cytometry in 5 patients who achieved a CR: 3 patients had <0.5% of CD5/CD19/CD23+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, 5 patients experienced grade 3/4 infection; 2 patients had grade 3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusions: Results of this interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy. No significant financial relationships to disclose.
A phase II study of fludarabine (F), cyclophosphamide (C), and mitoxantrone (M) plus rituximab (R) (FCM-R) in previously untreated patients (pts) with CLL ≤ 70 years (yrs)
Authors: Faderl S. , Wierda W. , O’Brien S. , Ferrajoli A. , Detry M. , Ravandi F. , Kantarjian H. M. , O’Neal B. , Keating M. J. 
Published: March 2020

6607 Background: Rituximab plus chemotherapy has demonstrated higher and better quality responses (MRD-negative) than chemotherapy alone. FCR produced overall response rates of 95% and complete remissions in 73%. Responses were lower in pts ≥ 70 years and β2M levels > 2 × ULN, and myelosuppression-associated complications were more frequent. High response rates of 60% and 88% have been reported with FCM in pts with relapsed and untreated CLL. We here report results of FCM plus rituximab and pegfilgrastim in patients ≤ 70 yrs. with previously untreated CLL. Methods: Pts ≤ 70 yrs with untreated, symptomatic CLL (NCI-WG criteria) were eligible. Pts were excluded for β2M > 2 × ULN and ECOG PS > 2. For course 1, doses of fludarabine were 25 mg/m2 i.v. daily d2–4, cyclophosphamide 250 mg/m2 i.v. daily d2–4, mitoxantrone 6 mg/m2 i.v. d2, and rituximab 375 mg/m2 i.v. d1. Pegfilgrastim was 6 mg s.c. on d4. Courses were repeated q4–6 wks. For courses 2–6, FCM started day 1 with rituximab 500 mg/m2. Study endpoints included evaluation of efficacy (clinical and 2-color flow [CD5/CD19] response rate after 3 and 6 cycles) and toxicity. Results: Twenty-three pts have been treated, 19 are evaluable for response after 3 and 11 pts after 6 cycles. Median age: 57 yrs (38–69). Twelve pts (52%) were male. Rai stage ≥ 3 was present in 17%. Median β2M was 2.7 mg/dL (1.4–4) and median WBC 59.9 × 109/L (5.6–355). Unfavorable FISH abnormalities were present in 3/17 (18%), unmutated IgVH in 9/12 (75%), and ZAP-70 immunohistochemistry was positive in 10/14 (71%) pts. After 3 cycles, all 19 pts responded (4 [21%] CR, 5 [26%] nPR, 10 [53%] PR). Six pts (32%) had <1% CD5/CD19-positive cells in the marrow. Response rates after 6 cycles: 2 (18%) CR, 1 (9%) nPR), 8 (73%) PR (PR due only to failure to recover counts in 7 pts) for an OR rate of 100%. Six pts (55%) had < 1% CD5/CD19-positive marrow cells at 6 months. Only 2 pts stopped prematurely because of persistent neutropenia. Conclusions: FCM-R achieves high clinical response rates. The frequency of pts with flow cytometry response < 1% CD5/CD19-positive cells was similar to FCR. Myelosuppression-related complications were infrequent. Use of hematopoietic growth factors with chemoimmunotherapy regimens is recommended. [Table: see text]
Impact of prognostic markers on outcomes in patients with advanced chronic lymphocytic leukemia treated with the regimen of fludarabine/rituximab plus oblimersen (Bcl-2 Antisense)
Authors: Mavromatis B. , Rai K. , Wallace P. K. , Soho C. , Landrigan B. , Meyn P. , Wei T. , Chan K. K. , Chanan-Khan A. 
Published: March 2020

6609 Background: Bcl-2, an anti-apoptotic protein is associated with treatment resistance and poor prognosis in pts with chronic lymphocytic leukemia (CLL). Preclinical studies have shown that oblimersen (Obl) enhances apoptosis induced by fludarabine (Flu) and rituximab (Rit). Increased CR and nPR in a phase 3 study confirmed the clinical benefit of combining Obl with a standard Flu+cyclophosphamide regimen in relapsed or refractory CLL pts. Similarly, in a phase 2 study, we found encouraging clinical activity when Obl was added to Flu/Rit. Here we report on outcomes related to baseline prognostic markers. Methods: All patients received Flu+Rit+Obl. Pts received Obl 1.5mg/kg/d, d1–7 by continuous IV, Rit (125 mg/m2 on d4, 250 mg/m2 on d6), and Flu 25mg/m2/d, d6–8 in the 1st cycle, and Obl 3mg/kg/d and Rit 375mg/m2 on d5 only, plus Flu on d5–7 in later q28 d cycles. Baseline data were collected on baseline cytogenetics and expression of Zap-70 and CD38 expression. Results: In the initial cohort, 24 pts (19 PT, 5 UT) were treated. CD 38 over-expression, Zap-70 expression, and abnormal cytogenetics were common; normal karyotypes (NK) were observed in only 5 (3 UT, 2 PT) pts. Median number of Flu+Rit+Obl cycles was 6. Overall, 5/5 UT and 12/19 PT pts responded. Two molecular CRs were noted (by flow and IgVh gene analysis), including 1 UT (CD38+, NK) and 1 PT (13q deletion) that had been refractory to Flu+Rit+Obl. Three nPRs were noted (2 UT [both CD38 and Zap-70+; 1 trisomy 12; 1 NK], and 1 PT [13q deletion]). Two PRs were observed in pts refractory to Flu and Flu+Rit, respectively. Two PRs were observed in 2 pts with poor risk (11q-) cytogenetics. Overall, 8/10 CD38+ pts and 5/11 Zap-70+ pts responded. Conclusions: Flu+Rit+Obl is an active and tolerable regimen in CLL. Major responses were noted in Flu- and/or Rit-refractory pts. Activity is noted despite poor prognostic markers. Accrual is ongoing. Efficacy, safety, and Bcl-2 regulation data will be presented. [Table: see text] [Table: see text]