bluuebunny/crossref_metadata_2025 huggingface dataset:
Trastuzumab and vinorelbine or taxane chemotherapy for HER2+ metastatic breast cancer: The TRAVIOTA study
Authors: Burstein H. J. , Keshaviah A. , Baron A. , Hart R. , Lambert-Falls R. , Marcom P. K. , Gelman R. , Winer E. P.
Published: March 2020

650

Background: The optimal trastuzumab/chemotherapy regimen for advanced breast cancer is not known. We performed a multicenter, randomized clinical trial to compare TRastuzumab And VInorebline Or TAxane (TRAVIOTA) chemo- and bio-therapy combination treatment given on a weekly schedule for HER2+ metastatic breast cancer. Patients and Methods: Eligible patients had stage IV breast cancer, measurable disease (by RECIST criteria), HER2+ tumors (IHC 3+ or FISH+), no prior chemotherapy or trastuzumab for advanced breast cancer, and LVEF > 50%. Patients were randomized 1:1 to trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter) with either weekly vinorelbine (25 mg/m2) or weekly taxane (paclitaxel 80 mg/m2 or docetaxel 35 mg/m2, selected by the treating investigator). The primary endpoint was response rate. The study opened in August 2001 and planned to accrue 250 patients. It was closed in December 2003 having accrued only 85 patients. Results are presented for the 81 patients who received any protocol-based therapy. Results: Patients receiving trastuzumab and vinorelbine tended to have higher response rates and TTP than those assigned trastuzumab and taxane therapy but the results were not statistically significant (see Table ). Vinorelbine therapy was associated with more frequent grade 3 or 4 hematological toxicity and dose delay because of myelosuppression. Other toxicities generally reflected the known side effects of the chemotherapy agents. Conclusions: The TRAVIOTA study suggests at least comparable clinical activity of trastuzumab with vinorelbine as with weekly taxane chemotherapy in HER2+ metastatic breast cancer, with side effect profiles consistent with previous experience with these regimens.

[Table: see text]

[Table: see text]
Cytogenetic responses to the hypomethylating agent, decitabine (DAC), in a phase III trial of DAC vs supportive care (SC) in patients (pts) with myelodysplastic syndromes (MDS)
Authors: Issa J. , Kantarjian H. M. , Saba H. I.
Published: March 2020

6501

Background: Clonal cytogenetic abnormalities are detected in 40%-70% of cases of de novo MDS and 95% of cases of therapy-related MDS, and the incidence increases with poor risk. DAC is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. In this analysis, we asked whether the hypomethylating agent DAC leads to cytogenetic response in MDS. Methods: We report cytogenetic response data from a Phase III randomized, open-label trial of DAC vs SC in 170 MDS pts. Eligibility requirements included confirmed MDS (de novo or secondary) fitting any of the recognized French-American-British classifications and an International Prognostic Scoring System (IPSS) score of 0.5 or more as determined by complete blood count, cytogenetics, and bone marrow assessment. Cytogenetics was assessed as a secondary endpoint, whereas primary endpoints were response rate (CR+PR) and time to AML or death. For pts with clonal abnormalities at baseline, follow-up cytogenetic evaluations at study end were available for 26 pts in the DAC arm and 21 pts in the SC alone arm. Results: As previously reported, overall response rate according to International Working Group MDS criteria was 17% (15/89) for DAC vs 0% for SC (p<0.001). Responses occurred in all IPSS groups and were also seen in pts with 5q and 7 deletions. Response rate was 13% (2/16) in pts with 5q deletions and 21% (4/19) in pts with 7 deletions. In pts without 5q or 7 deletions, response rates were 16% (11/67) and 14% (9/64), respectively. Complete cytogenetic responses were observed in 35% (9/26) of DAC pts vs 10% (2/21) of SC pts (p=0.08, Fisher’s exact). Also, 1 pt receiving DAC had a minor cytogenetic response. 10/10 DAC pts with cytogenetic response had clinical benefit (6 CR, 2 PR, 1 hematologic improvement, and 1 with normalization of marrow blast count). The primary toxicity was myelosuppression. Conclusion: DAC induces a substantial rate of cytogenetic responses in pts with MDS, suggesting that the clinical improvements induced by this agent are related to elimination of the neoplastic clone rather than to pure differentiation effects.

[Table: see text]
Dasatinib (D) vs high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial
Authors: Shah N. P. , Rousselot P. , Pasquini R. , Hamerschlak N. , Holowiecki J. , Gerard B. , Dejardin D. , Kantarjian H.
Published: March 2020

6507

Background: High dose imatinib (800 mg/day) has been shown to have efficacy in a subset of CML patients with resistance to IM, although the durability of responses is not well-established. Dasatinib (BMS-354825) is a novel, highly potent, oral multi-targeted kinase inhibitor of BCR-ABL and SRC with activity against 18/19 imatinib resistant BCR-ABL mutants tested in vitro. Methods: START-R is a multicenter randomized (2:1 ratio) trial of D 70 mg twice daily (bid) and IM 800 mg/day in pts with CP-CML resistant to prior IM 400 to 600 mg/day. Cross-over was allowed for lack of response or intolerance (grade 3–4 non hematologic toxicity). D dose escalation to 90 mg bid was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40 mg bid for drug toxicity. IM dose reduction to 600 mg/day was allowed. Evaluations consisted of weekly blood counts for the first 12 wks, bone marrow cytology and cytogenetics every 12 wks. The primary endpoint was major cytogenetic response (MCyR) rate at wk 12. Results: From February 2005 to November 2005, 150 pts were randomized of whom the first 36 pts (D 22, IM 14) are reported. Median age was 57 yrs, with 12 males and 24 females. Treatment groups were balanced with respect to CML characteristics; median time from initial diagnosis was 61 months for D and IM; prior interferon 64% and 79%; no prior CyR on IM 36% and 57%. BCR-ABL mutations were documented in 10 D pts and 1 IM pt. Dose reductions were required in 8 D pts and 1 IM pt. Complete hematologic response was documented in 21 D and 13 IM pts. MCyR rate at 12 wks was 45% for D and 21% for IM (7 complete for D and 1 for IM). With a 95% CI on the difference between D and IM was - 9.9 to +51.2. Two (9%) D and 11 (79%) IM pts crossed over for intolerance (1 D and 6 IM) or no MCyR (1 D and 5 IM). Grade 3–4 neutropenia or thrombopenia occurred in 8 and 9 dasatinib pts and in 8 and 2 IM pts. Most common grade 1–2 non-hematologic toxicities in D and IM groups were diarrhea (7 and 1 pts), nausea (7 and 7 pts), and facial/peripheral edema (8 and 7 pts). Conclusions: Dasatinib was effective in pts with CP-CML resistant to IM 400 to 600 mg/day. Preliminary data suggest that D is more effective and better tolerated than high dose IM. An updated analysis of all randomized pts will be presented.

[Table: see text]
Clofarabine in previously untreated elderly (>65 yrs) AML patients with an unfavourable cytogenetic profile who are considered unfit for standard intensive chemotherapy
Authors: Burnett A. K. , Baccarani M. , Johnson P. , Yin J. , Russell N.
Published: March 2020

6513

Background: Elderly AML patients (>65 yrs) are a very poor prognostic population. Standard treatment achieves an 18% overall response (OR) rate (low dose Ara-C, U.K. AML 14 trial) with no little or no responses observed in high-risk cytogenetic patients. BIOV-121 is a Phase II non-randomized study of clofarabine, a novel, next generation purine nucleoside analogue, in older patients (>65 yrs) with previously untreated acute myeloid leukemia (AML) for whom standard intensive chemotherapy is not considered suitable. Methods: 66 patients aged > 65 yrs with untreated AML were enrolled in study BIOV-121. All patients were considered unfit for standard intensive chemotherapy based primarily on age (> 65 years) and/or performance status. All patients received clofarabine 30mg/m2 for 5 consecutive days repeated every 28 days (1 course) for a maximum of 6 courses. The primary study endpoint was overall response rate (ORR) defined as the number of patients achieving a CR, CRi, or PR according to the international working group guidelines. A preliminary analysis was conducted on both patients with an unfavourable cytogenetic profile (11/44 patients), for whom data was available, and on patients > 70 years of age (36/66 patients). Unfavourable cytogenetic prognostic risk was defined as the presence of a complex karyotype, monosomies of chromosome 5 (del [5q]/5q-), or 3q abnormalities as reported by Grimwade et al (U.K. MRC AML 10 trial). Results: Of 44 patients for whom cytogenetic data was available, 25% (11/44) had an unfavourable cytogenetic prognostic risk profile. The median number of clofarabine courses administered in this patient group was one. With a median age of 68 years the overall response rate (ORR) in this unfavourable cytogenetic patient group was 36% (4/11) with a 27% complete response (CR) rate. 55% (36/66) of patients were aged >70 years. The ORR and CR rate was 56% and 44% respectively in patients aged >70 years. The toxicity of clofarabine was acceptable and manageable in elderly AML patients. Conclusions: Clofarabine appears superior to current standard treatment (low-dose Ara-C) in both unfavourable cytogenetic AML (>65 years) and AML patients > 70 years (all cytogenetic risk groups).

[Table: see text]
Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) or refractory (ref) chronic lymphocytic leukemia (CLL)
Authors: Miller K. , Czuczman M. S. , Dimiceli L. , Padmanabhan S. , Lawrence D. , Bernstein Z. , Takeshita K. , Spaner D. , Byrne C. , Crystal C. , Chanan-Khan A. A.
Published: March 2020

6517

Background: Tumor microenvironment (ME) is critical in CLL pathogenesis. Targeting the ME is a novel approach in CLL therapeutics. Lenalidomide (Revlimid, L) is an immunomodulating agent (IMiD), approved for pts with transfusion-dependent low or intermediate-1 risk myelodysplastic syndrome with deletion 5q cytogenetic abnormality. Its antitumor activity is possibly mediated through (a) downregulation of cytokine(s) - TNF-α, VEGF, PDGF and IL-6 and/or (b) activation of immune effector cells (T & NK cells). We investigated its antitumor activity in rel/ref CLL pts. Here we present the final results of the first cohort of pts treated with 25mg daily dose of L. Methods: Oral L was given at 25mg/day for 21 out of a 28 day cycle. Anti-leukemic effects were recorded after each cycle using NCI-WG 1996 criteria. Treatment was continued until molecular complete response (mCR) or progressive disease (PD). Those with PD were then treated with L in combination with rituximab (reported separately). Polymerase chain reaction (PCR) for immunoglobulin heavy chain gene was used to determine molecular remission (mCR). Results: Twenty-nine pts (median age 64 years; range: 47–75) have been enrolled. Toxicity is reported on all, while response on 19 evaluable pts. Nine pts are inevaluable (2 withdrew consent and 5 received < 2 months of therapy due to toxicity). Major response was noted in 13 of 19 evaluable pts (68%) with 3 CR (2 mCR) and 10 PR. Toxicity: Most common grade 3/4 adverse effects (AE) were neutropenia (60%) and thrombocytopenia (55%). Another common AE was tumor flare (79%); characterized by tender swelling of lymph nodes and/or rash, noted in almost all pts. Conclusions: L at 25mg/day dose given on days 1–21 in a 28 day cycle yields high ORR including mCR in rel/ref CLL. Hematologic toxicity was the most common AE requiring dose reduction. Overall safety profile was predictable and manageable. A slow dose escalation schema, starting at 15mg is being investigated.

[Table: see text]
E7389, a novel anti-tubulin, in patients with refractory breast cancer
Authors: Forero J. BlumL. , Heiskala M. K. , Meneses N. , Chandrawansa K. , Fang F. , Shapiro G. , Fields S. Z. , Silberman S. , Vahdat L.
Published: March 2020

653

Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies.

[Table: see text]
Imatinib mesylate is effective in the treatment of polycythemia vera: A multi-institutional clinical trial
Authors: Feldman E. J. , Spivak J. L. , Lee S. , Rivera M. , Fruchtman S. M. , Salvado A. , Silver R. T.
Published: March 2020

6532

Background: We previously reported that the erythrocytosis of polycythemia vera (PV) was controlled with imatinib mesylate in a cohort of patients. This effect may involve inhibition of tyrosine phosphorylation of c-Kit, the stem cell factor receptor essential for erythroid progenitor cell proliferation. Methods: We report treating an expanded cohort of 37 PV patients with imatinib in a multi-institutional phase II trial. All patients had an increased 51Cr RBC mass determination at diagnosis and fulfilled the stipulated criteria for the diagnosis of PV. Men were initially phlebotomized to a hematocrit (HCT) ≤ 45%; women to HCT ≤ 42%. Imatinib was started at 400 mg qd escalating 100 mg every 2 weeks to a maximum of 800 mg for persistent phlebotomy (PHL) requirements or for platelet counts > 600 × 109/L. All patients received 81 mg of aspirin qd. Results: There were 21 men, 16 women, median age 51 years, range 29–83. Prior to imatinib, mean disease duration was 60.2 mos; average number of PHLs per year ranged from 0–23 (mean=9). After 1 year of imatinib, PHLs ranged from 0 to 9 (mean=2). There were 9 complete remissions (PHL-free, platelets ≤ 600 × 109/L, no splenomegaly) and 10 partial remissions (PHL and/or splenomegaly decreased by 50% of initial values with platelets ≤ 600 × 109/L, or platelets > 600 × 109/L but no PHL requirements or splenomegaly); 1 patient, protocol violation. Thus, of 36 evaluable patients, 19 (53%) responded. Of the remaining 17, 10 failed due to disease progression: myelofibrosis (n=2); platelets > 1,000 × 109/L with PHL and/or splenomegaly (n=2); repeated PHLs (n=1); cytogenetic abnormalities (n=1); increasing thrombocytosis (n=1); and a TIA (n=1). Seven of 17 with no remission developed toxicity: grade 3 dermatologic (n=2); grade 3 diarrhea (n=2); grade 3 bone pain (n=1), liver (n=1); heart failure (n=1). Median treatment duration: 17.2 months. Conclusions: We conclude that imatinib is useful for treating erythrocytosis and controlling splenomegaly in a significant proportion of PV patients, but is less effective for controlling thrombocytosis or splenomegaly in others. These data suggest heterogeneity of hematopoietic stem cell proliferation in PV or patient variability with respect to imatinib metabolism.

[Table: see text]
Changes in thymidine phosphorylase expression in response to neoadjuvant chemotherapy for primary breast cancer
Authors: Puglisi F. , Mansutti M. , Minisini A. , Russo S. , Cardellino G. , Andreetta C. , Rijavec E. , Pizzolitto S. , Pandolfi M. , Di Loreto C.
Published: March 2020

655

Background: Thymidine phosphorilase (TP) is a key enzyme involved in nucleoside metabolism. Recently, it has been hypothesized that TP modulation could enhance the therapeutic activity of TP-targeting chemotherapy such as capecitabine. In addition, some evidence exists that anticancer agents could upregulate TP. The present study analyzed TP immunohistochemical expression in response to neoadjuvant chemotherapy for primary breast cancer. Methods: Fifty-five women with operable breast cancer (T ≥ 2 cm, N0–1, M0) were treated with anthracycline-based (all cases) and anthracycline/taxane-based (n= 40 cases) neoadjuvant chemotherapy. Tumor samples from diagnostic large core biopsy (n=55) and from surgery (n=53) were available for histological evaluation and immunohistochemical analysis of TP. Immunohistochemistry was performed at a single central laboratory using a primary mouse anti-TP monoclonal antibody (Roche molecular biochemicals).TP expression was evaluated on tumor cells (nuclear and cytoplasmic staining) and on stromal cells. The intensity of cytoplasmic immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak, moderate and strong staining, respectively. Results: An increase in TP cytoplasmic expression was observed in 35.89% (95% CI: 0.21–0.52%) of tumor samples after neoadjuvant chemotherapy. In particular, increases in cytoplasmic TP score were more common after taxane-containing regimens (40.74%, 95% CI: 0.22–0.61%) than after regimens without taxanes (25%, 95% CI: 0.05–0.57%). No significant changes of TP expression were found in nuclei of tumor cells after neoadjuvant chemotherapy. Similarly, no significant changes of TP expression were observed in stromal cells. There was no significant association between clinical or pathological response rate and TP changes in both tumor and stromal cells. Conclusions: This study provides further evidence that, at least in breast cancer, TP is upregulated after anthracycline and/or taxane-containing chemotherapy. According to these results, a strong rationale exists in combining TP-inducing and TP-targeting anticancer agents.

No significant financial relationships to disclose.
Elevated serum ras level predicts decreased survival in patients with hematologic malignancies
Authors: Nelli E. M. , Leitzel K. , Ali S. M. , Al-Mondhiry H. A. , Demers L. , Harvey H. A. , Carney W. P. , Hamer P. J. , Lipton A.
Published: March 2020

6562

Background: Ras is a GDP/GTP binding G protein that acts as a molecular switch converting signals from the cell membrane to the nucleus to regulate cell proliferation, differentiation, and protein synthesis. Activation of ras oncogenes has been identified in a variety of cancers, including 30% of acute myelogenous leukemia patients. The purpose of our study was to evaluate serum ras levels and correlate with survival in hematologic cancer patients. Methods: A novel ras p21 ELISA (Oncogene Science/Bayer Diagnostics, Cambridge, MA) employing two monoclonal antibodies reactive with H, K, and N ras was utilized to quantify total ras levels in serum obtained from patients with various hematologic malignancies including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Results: The total leukemia patient group consisted of 52 patients. At the 75th percentile serum ras cutpoint (524 pg/ml) 11/52 patients were defined as elevated for serum ras. From this patient group, 38 patients had clinical followup available and were included in the Kaplan-Meier analysis of overall survival. Patients with elevated serum ras (>524 pg/ml) had significantly shorter overall survival compared to those without (median OS 205 vs. 677 days) (p= 0.04). In a multivariate analysis including serum ras level and type of leukemia, serum ras level remained a significant independent variable for shorter overall survival (p=0.004). Within leukemia subtypes 2/18 AML, 4/9 CML, 3/7 ALL, and 0/4 CLL patients had elevated serum ras levels. Conclusions: Leukemia patients with elevated serum ras levels had a significantly shorter overall survival. Serum ras should be evaluated as a potential biomarker in larger leukemia trials, especially for response to treatment with inhibitors of the ras signaling pathway.

[Table: see text]
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]
Increased antiresorptive activity of zoledronic acid (Z) administered in the night as compared to morning administration in breast cancer (BC) patients with bone metastases
Authors: Bottini A. , Generali D. , Berruti A. , Tampellini M. , Torta M. , Tedoldi S. , Bonardi S. , Tucci M. , Gorzegno G. , Dogliotti L.
Published: March 2020

677

Background:
Z is an effective bisphosphonate in preventing skeletal related events (SREs) in bone metastatic patients. Decrease in bone resorption markers during Z therapy is a potential surrogate of drug efficacy. Bone resorption markers maintain a circadian rhythmicity in metastatic BC patients (Generali et al ASCO 2005), suggesting that Z may be more active if administered in a chronomodulated way. Raised PTH after Z could impair the drug efficacy (Berruti et al ASCO 2006).
Methods:
Forty-four BC patients with bone metastases were randomised to receive Z, 4 mg i.v. at 11.00 p.m or 11 a.m every 28 days for 4 times. Serum cross laps (CTX), urinary n-telopeptide (NTX) and serum parathyroid hormone (PTH) levels were measured at baseline and after 4, 7, 14, 28, 56 and 84 days, respectively.
Results:
Z administration in the night resulted in a greater decrease of either serum CTX or urinary NTX and lower increase in serum PTH (
Table
) than morning administration.
Conclusions:
Z administration in the night might be more efficacious than morning administration.

Treat
baseline
Day 4
Day 7
Day 14
Day 28
Day 56
Day 84

p
*

CTX ng/ml

day
0.77 (0.09)
0.09 (0.02)
0.10 (0.01)
0.13 (0.02)
0.16 (0.03)
0.16 (0.02
0.17 (0.02)
<.05

night
0.72 (0.09)
0.09 (0.02)
0.07 (0.01)
0.10 (0.02)
0.12 (0.03)
0.10 (0.02)
0.08 (0.02)

NTX nmol/mmol creatinine

day
164.4 (28.1)
32.2 (6.6)
33.5 (6.1)
50.7 (8.7)
60.9 (9.4)
53.4 (8.9)
45.8 (8.0)
<.05

night
138.7 (26.6)
36.4 (6.3)
40.0 (5.8)
44.0 (8.2)
39.3 (8.9)
33.6 (8.5)
46.3 (7.6)

PTH ng/ml

day
40.3 (17.3)
106.3 (17.5)
120.8 (19.3)
102.7 (20.9)
88.4 (18.5)
148.6 (49.3)
95.8 (27.5)
<.0001

night
52.7 (16.0)
66.3 (16.2)
65.1 (17.9)
61.3 (19.4)
55.5 (17.2)
63.5 (45.6)
48.4 (25.4)

Data are mean (standard error)

*

Mixed random effect model of multivariate analysis of variance

No significant financial relationships to disclose.