bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with chronic myelogenous leukemia (CML) in accelerated phase (AP)
Authors: Le Coutre P. D. , Ottmann O. , Gatterman N. , Larson R. , Rafferty T. , Alland L. , Tavorath R. , Giles F. , O’Brien S. G. , Kantarjian H. 
Published: March 2020

6531 Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and is active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: This open-label study was designed to evaluate the safety and efficacy of AMN107 (400 mg bid) defined by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant or intolerant AP pts. Results: Preliminary data are presented for 22 pts (77% resistant and 23% intolerant to imatinib. Treatment is ongoing for 16 (73%) pts. Median age was 62 (43–76) yrs. Median duration of AMN107 exposure was 124 (3–207) days. Median time from AP diagnosis was 6 (0.2–56) mos. Three of 5 patients with data available had a Bcr-Abl mutation at baseline. HR occurred in 14 (64%) pts of which 10 (45%) were complete, 3 (14%) were marrow responses/no evidence of leukemia, and 1 return to chronic phase. CyR occurred in 6 pts (1 each complete, partial minor, and 3 minimal). All AE’s occurring in ≥10% pts were thrombocytopenia (8 [36%] pts; Gr 3/4, 6 [27%] pts), fatigue (7 [32%]), anemia, (6 [27%]; Gr 3/4, 4 [18%] pts) pruritus, muscle spasms (6 [27%] pts each), bone pain, cough, (5 pts [23%] each) rash (5 [23%] pts; Gr 3/4, 1 [5%] pt), neutropenia (4 [18%] pts, all Gr 3/4), diarrhea, headache, myalgia, pyrexia (4 [18%] pts each), abdominal pain, chills, constipation, dyspnea, nausea, extremity pain, and peripheral edema (3 [14%] pts each). Two 2 deaths occurred, 1 pt with thrombocytopenia had a CNS bleed and 1 pt had disease progression. Conclusions: These data suggest AMN107 is clinically active and has an acceptable safety profile when administered to pts with CML-AP. [Table: see text]
A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with Ph+ chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)
Authors: Giles F. J. , Larson R. , Le Coutre P. , Baccarani M. , Tavorath R. , Alland L. , Kantarjian H. M. , Hughes T. , Ottmann O. 
Published: March 2020

6536 Background: AMN107 is a highly selective, aminopyrimidine which is 30-fold more potent in vitro than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: This open-label study evaluated safety and efficacy of AMN107 (400 mg bid) by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant/ intolerant BC or relapsed/refractory ALL pts. Results: Preliminary data from this ongoing study are presented for 18 BC and 6 ALL (5 relapsed/refractory, 1 minimal residual disease) pts. Baseline mutation data are available for 6 BC and 2 ALL pts: 2 and 1, respectively, had Bcr-Abl mutations. The overall median age was 54 yrs and the overall median exposure was 84 days. Seven patients remain on treatment (5 BC, 2 ALL) and 17 discontinued (3 adverse events, 9 progressive disease (PD), 3 deaths, 2 other). Two BC pts died of PD. 1 ALL pt had sudden cardiac death. HR was reported in 7 (38%) BC pts; 5 complete HR and 2 marrow responses/no evidence of leukemia. 3 BC pts had CyR (2 complete, 1 minor). Complete remission was reported in 2 (33%) ALL (1 relapsed/refractory and 1 MRD) pts. Adverse events in ≥ 10% were rash in 9 (37%) pts, thrombocytopenia in 8 (33%) pts (Gr 3/4 in 7 (29%), nausea in 7 (29%) pts, pyrexia in 7 (29%) pts (Gr 3/4 in 2 (8%)); vomiting in 7 (29%) pts (Gr 3/4 in 1 (4%), diarrhea, fatigue in 6 (25%) pts each, headache in 6 (25%) pts (Gr 3/4 in 1 (4%)), neutropenia in 6 (25%) pts (all Gr 3/4), anemia in 5 (21%) pts (Gr 3/4 in 4 (17%)), pain in extremity in 5 (21%) pts (Gr 3/4 in 1 (4%)), pain, peripheral edema in 4 (17%) pts each, pruritus in 4 (17%) pts (Gr 3/4 in 1 (4%)), leukocytosis in 3 (13%) pts (Gr 3/4 in 1 (4%)), arthralgia, pharyngolaryngeal pain, and upper abdominal pain 3 (13%) each. Conclusions: AMN107 has clinical activity and an acceptable safety and tolerability profile in pts with imatinib-resistant or intolerant BC and relapsed/refractory Ph+ ALL pts [Table: see text]
Final analysis of the phase II, randomized, double-blind, placebo-controlled trial of single dose velafermin (CG53135–05) for the prevention of oral mucositis
Authors: Schuster M. W. , Anaissie E. , Hurd D. , Bensinger W. , Mason J. , McCarty J. , Rifkin R. , Maziarz R. , Halvorsen Y. , Annino V. , Hahne W. 
Published: March 2020

6537 Background: Oral mucositis (OM) is a commonly occurring side effect of high-dose chemotherapy (HDCT) in patients (pts) undergoing autologous hematopoietic stem cell transplant (AHSCT). Velafermin, recombinant human fibroblast growth factor 20, is being investigated for prevention of OM. Velafermin promotes epithelial and mesenchymal cell proliferation in vitro and in vivo. Methods: A phase II trial was conducted to evaluate safety, efficacy, and pharmacokinetics (PK) of velafermin. Inclusion criteria: pts undergoing HDCT and AHSCT with or without total body irradiation (TBI) were enrolled. Velafermin at 0.03, 0.1, or 0.2 mg/kg or placebo was administered as single dose IV at 24h after stem cell infusion. Safety and PK were assessed. Pts were scored daily for presence of OM using the WHO grading scale. The primary endpoint was the incidence of Grade 3/4 OM. Results: A total of 212 pts were randomized to either placebo (n=51) or velafermin at 0.03 (n=50), 0.1 (n=56), or 0.2 (n=55) mg/kg (intent-to-treat or ITT sample). 206 pts (97%) received study drug or placebo. Pt diagnoses included multiple myeloma (57%), non-Hodgkin’s (25%), or Hodgkin’s (11%) lymphoma and 13 pts (6%) received TBI as part of the conditioning regimen. The Grade 3/4 OM incidence rates (%) in the placebo or velafermin arms (0.03, 0.1, and 0.2 mg/kg) were 37, 18, 38, and 36, respectively. The primary analysis of dose dependent reduction of severe OM was not statistically significant (p = 0.549). However, velafermin at 0.03 mg/kg did reduce the incidence of Grade 3/4 OM when compared to placebo alone (p = 0.031). Duration of Grade 3/4 OM was reduced significantly in the 0.03 mg/kg when every pt was evaluated or in the 0.1 mg/kg dose when only pts with Grade 3/4 OM were included in the analysis (p = 0.037 and 0.014, respectively). A total of 5 related SAEs (3 in 0.1 mg/kg, 1 in 0.03 mg/kg, and 1 in placebo cohort) occurred within 4hr of study drug infusion. All symptoms were transient. Conclusion: Single dose velafermin at 0.03mg/kg is may be active in reducing CT induced severe OM in AHSCT pts. Safety profile supports continuing study to define the optimal dose for prevention of severe OM. A new Phase II study will be conducted to confirm velafermin activity at 0.03mg/kg dose. [Table: see text]
Human leukocyte antigen (HLA) DR4 is associated with inferior progression free survival (PFS) following allogeneic hematopoietic stem cell transplantation (allo HSCT) for lymphoid malignancies
Authors: Aggarwal C. , Gupta S. , Hahn T. , Padmanabhan S. , McCarthy P. L. , Battiwalla M. 
Published: March 2020

6543 Background: HLA DR4 is associated with autoimmune disorders and response to cyclosporine immunosuppression in T-cell Large Granular Lymphoproliferative Disorder (BJH 2003;123(3)). We investigated the HLA DR4 role on graft-versus-host disease (GVHD) and graft-versus-leukemia effect in HLA-matched HSCT performed for lymphoid malignancies. Methods: We retrospectively reviewed 77 related and 22 unrelated consecutive allo HSCT patients (pts) treated between 1992 and 2003 at RPCI to investigate the influence of HLA DR4 on overall survival (OS), PFS and grade 2–4 acute and chronic GVHD (cGVHD) incidence. HLA DR B1 typing was determined by molecular (n=69) or serologic (n=30) methods. The pt proportion with one or two HLA DR4 antigens was 18% (18/99), similar to the general Caucasian population. Pt characteristics included: ALL (n=41), CLL (n=4), HD (n=7) and NHL (n=47); median age 36 y (range 6–64); Male (n=65), Female (n=34); Caucasian (>95%); Total Body Irradiation (TBI) conditioning regimens (n=79); Busulfan/Cyclophosphamide (BuCy) (n=6), Thiotepa/TBI (n=23), Cy/TBI (n=9), Etoposide/Cy/TBI (n=9), Fludarabine/Melphalan (n=8), Thiotepa/Carboplatin (n=8) or other combinations (n=6). Results: There was no difference in OS between the HLA DR4 positive vs negative pts in any disease or donor subgroups (p=0.25). Nine of 18 DR4 positive pts (50%) and 20 of the 81 DR4 negative pts (25%) had disease progression (p=0.033). PFS at 33 months was 70% in the DR4 negative group and 30% in the DR4 positive group (p=0.004). In a univariate analysis, DR4 positivity, conditioning regimen and disease stage at HSCT were significant factors for PFS. However in the multivariate analysis, DR4 positivity was the only significant factor for PFS (RR=3.2, p=0.007). By preliminary analysis, 0/18 of the HLA DR4 positive pts and 13/81 HLA DR4 negative pts developed cGVHD (p=0.06). Conclusions: These results suggest that HLA DR4 positive pts have reduced cGVHD leading to increased relapse and decreased PFS with no effect on OS. Increased sensitivity of HLA DR4 lymphocytes to GVHD prophylaxis agents or reduced binding affinity for the CD4 coreceptor are possible reasons for these observations. No significant financial relationships to disclose.
Reduced-intensity allogeneic stem cell transplantation for diffuse large B-cell lymphoma: Clinical evidence of a graft-versus-lymphoma effect
Authors: Bishop M. R. , Dean R. M. , Steinberg S. , Odom J. , Pavletic S. Z. , Kasten-Sportes C. , Hardy N. , Pittaluga S. , Gress R. , Fowler D. H. 
Published: March 2020

6546 Background: Despite being the most common non-Hodgkin’s lymphoma, there have been no specific reports on the use of reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT) to treat patients (pts) with diffuse large B-cell lymphomas (DBCL). This may be due to a lack of definitive evidence for a therapeutic graft-versus-lymphoma (GVL) effect against DLBC. We undertook a retrospective analysis to assess clinical outcomes and evidence of a GVL effect in DLBC pts undergoing RI alloSCT. Methods: The analysis was limited to 18 pts with primary refractory (n = 6) or relapsed (n = 12) DLBC. The median age was 43 years (range: 31–61); median number of previous treatments was 3 (range: 2–9). Nine (50%) pts had undergone autologous transplantation. Three (16%) pts were determined to have chemo-sensitive disease to last treatment prior to RI alloSCT. All pts received a RI conditioning regimen consisting of fludarabine (30 mg/m2/d × 4d) and cyclophosphamide (1200 mg/m2/d × 4d) followed by a T-cell replete allograft from HLA-matched siblings. Results: Median potential follow-up from transplant is 43 months. Seven (39%) pts developed grade II-IV acute GVHD. Response at day +100 post-transplant was as follows: complete response (CR/CRu) = 5; partial response = 5; progressive disease = 8. Nine of 17 (53%) evaluable pts developed chronic GVHD. Median progression-free survival (PFS) was 4.8 months; however, PFS after 9 months post-transplant was 31% with 5 pts in continuous CR/CRu > 12 months post-transplant. Among 14 pts who were not in CR/CRu (n = 12) or progressed after achieving a CR/CRu (n = 2) at day +100 post-transplant, 8 (57%) subsequently achieved a CR/CRu after removal of immune suppression and/or donor lymphocyte infusion (DLI) ± chemotherapy. Seven of these 8 pts remain in continuous (median = 34 months; range: 6–55+) CR/CRu without further treatment. Median survival for all 18 pts was 19 months with survival probability of 40% plateauing at 25 months post-transplant. Conclusions: The clinical observations of sustained CR/CRu after withdrawal of immune suppression and DLI suggest that a GVL effect exists against DLBC. RI alloSCT should be considered as a treatment option for pts with primary refractory and relapsed DLBC. No significant financial relationships to disclose.
Low dose Vidaza and thalidomide is an effective combination for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)
Authors: Westervelt P. , Amirifeli S. , Mehdi M. , Mumtaz M. , Alhomsi S. , Wang S. , Miron P. , Lata C. , Galili N. , Raza A. 
Published: March 2020

6570 Vidaza and thalidomide were administered to 29 patients with MDS or AML. Vidaza was given at a dose of 75mg/kg subq × 5 days q28 days and Thalidomide starting at 50mg/day and increasing to 100mg. Therapy was well tolerated. Median age was 70 years, and there were 16 males. Two patients had RA, 2 RARS, 9 RAEB, 4 CMMoL, 10 AML and 2 Unknowns. According to IPSS, 1 had low, 7 had Int-1, 5 had Int-2 and 4 had high risk disease, and 2 unclassified (10 had AML). Eleven patients had normal, 14 abnormal and 4 unknown for cytogenetics. Seven patients went off the study due to disease progression (5) or refused therapy (1), died within a week of treatment initiation (1) while 2 are on the first cycle and too early for evaluation. Twenty-five patients are evaluable for outcome. Ten patients received 5 or more cycles of Vidaza. HI was seen in 14/25 (56%), and stable disease in 6/25 (24%) while 5/25 (20%) had disease progression. Six patients experienced complete remission (CR) and are still receiving therapy (24%), 1 experienced HI-E, 2 HI-ANC, 3 HI-P, and 2 had a bilineage improvement (HI-P and ANC and HI-E and ANC). Of 10 AML patients, three went off study due to disease progression, 1 had stable disease, 6 responded with 4 complete remissions (CR), 1 HI-ANC and 1 HI-P. Interestingly, 6/10 AMLs had a history of prior MDS, 3/6 achieved CR, 2/6 had HI (ANC and platelets) and 1 has stable disease (continuing treatment). Among the 4 de novo AMLs, 1 had CR and 3 showed disease progression. We conclude that a combination of low dose Vidaza and thalidomide is well tolerated, and highly effective therapy for the treatment of patients with MDS as well as AML arising from a prior MDS. The ability to treat secondary MDS as out-patient and achieve such a high response rate represents a paradigm shift in AML therapy. No significant financial relationships to disclose.
Clinical and cytogenetic responses to amonafide in secondary acute myeloid leukemia (AML)
Authors: Allen S. L. , Kolitz J. E. , Lundberg A. S. , Capizzi R. L. , Budman D. R. 
Published: March 2020

6584 Background: Patients (pts) with secondary AML (AML following an antecedent hematologic disorder or following known exposure to leukemogenic agents) are often elderly, with comorbid illness, and have a dismal prognosis. Secondary AML responds poorly to standard chemotherapy, with low response rates and short durations of remission. Amonafide (Am) is an ATP independent topoisomerase 2 inhibitor that in prior clinical studies had myelosuppression as the dose-limiting toxicity. Two phase 1 trials evaluated Am as either a single agent or in combination with ara-C in pts with relapsed/refractory or secondary AML. This retrospective review was performed to assess the activity of Am specifically in pts with secondary AML. Methods: In study AM-03, 5 pts with secondary AML were treated with a fixed dose (1000, 1100, or 1400 mg/m2/day) of Am IV over 2 hrs daily × 5. In study AM-04, 15 pts with secondary AML were treated with ara-C 200 mg/m2/day CIV days 1–7 and a fixed dose (600, 700 or 800 mg/m2/d) of Am IV over 2 hrs daily on days 1–5. All clinical trial data were reviewed for assessment of hematological and cytogenetic response. Results: Across the two studies, 10 of 20 (50%) pts responded to Am (9 CR, 1 CRi). In study AM-03 (Am monotherapy), 3 of 5 (60%) pts responded, with median duration of response 7.5 months (range 2.5 - 8). None of these 3 pts received additional post-remission therapy. In study AM-04 (Am + ara-C), 7 of 15 pts (47%) responded, with median duration of response 8 months (range 1 ¾ to >60 months). 4 of these 7 pts received additional post-remission therapy. Cytogenetic analysis prior to and following Am therapy was available for 9 of the 10 pts with secondary AML who responded to Am in the 2 studies. Cytogenetics were abnormal prior to Am therapy in 5 of these 9 pts, 3 (60%) of whom achieved cytogenetic CR. Conclusions: Am shows significant activity in secondary AML, both as monotherapy and in combination with ara-C. A phase 2 trial of Am + ara-C in pts with secondary AML is currently enrolling patients. [Table: see text]
Polymorphisms of DNA-repair genes associated with clinical outcome in metastatic breast cancer (MBC) patients treated with gemcitabine/cisplatin (GC) (California Cancer Consortium)
Authors: Gordon M. A. , Zhang W. , Yang D. , Spicer D. , Doroshow J. , Margolin K. , Synold T. , Albain K. , Chew H. , Gandara D. , Lenz H. J. 
Published: March 2020

675 Background: DNA repair enzymes may play an important role in determining efficacy of chemotherapy in MBC. In particular, GC combination therapy may be dependent on activity of DNA repair enzymes in host cells, since cisplatin acts by inducing DNA damage. Cancer cells with increased DNA repair capacity may be resistant to GC, and specific genes may be responsible for this increased repair capacity. We examined whether polymorphisms in genes related to DNA repair were associated with clinical outcome in MBC patients treated with GC, enrolled in a parent phase II clinical trial (Ph II-14 A & B). Methods: Fifty-five patients with MBC were evaluated. Patients received the following regimen: 25 mg/m2 cisplatin on days 1–4; 1000 mg/m2 gemcitabine on days 2 and 8 of 21-day cycle. Thirteen polymorphisms in 10 cancer-related genes were tested for association with overall survival, time to tumor progression, and tumor response using a PCR RFLP based assay. Results: Of 55 patients evaluated, there were 17 responders (31%) and 33 non-responders (60%). Five patients (9%) inevaluable for response. Of 33 non-responders, 15 had stable disease, 18 had progressive disease. Median survival: 11.7 months with median follow-up 32.4 months for 4 patients alive at time of analysis. Median progression-free survival: 4.2 months. XPD Lys751Gln polymorphism was associated with overall survival and time to tumor progression (p=0.0003, p=0.006, respectively, log-rank test). Thirty-five patients carried Lys/Lys genotype, of which 29% resopnded. Fourteen patients carried Lys/Gln genotype, of which 54% resopnded. Five patients carried Gln/Gln genotype, with no responders. XRCC3 Thr241Met polymorphism was associated with time to tumor progression and tumor response (p=0.03, p=0.002, respectively). Eighteen patients had Met/Met genotype, of which 47% responded. Twenty-six patients had heterozygous genotype, of which 17% responded. Five patients had homozygous Thr/Thr, of which 100% responded. Conclusions: Our results suggest that polymorphisms in DNA repair genes XPD and XRCC3 may be important markers in predicting clinical outcome in MBC patients treated with GC. Supported by the following NCI grant: N01 CM1701. [Table: see text]
Bone turnover markers in postmenopausal breast cancer patients treated with fulvestrant
Authors: Agrawal A. , Hannon R. A. , Cheung K. L. , Eastell R. , Robertson J. F. 
Published: March 2020

680 Background: Aromatase inhibitor (AI) therapy in patients with breast cancer accelerates bone turnover with increased secretion and excretion of bone turnover markers. Here, we report the effect of fulvestrant, an estrogen receptor (ER) antagonist with no agonist activity, on bone metabolism. Methods: 23 patients with either locally advanced primary [LAPC] or metastatic [MBC] disease who had clinical benefit (objective response/stable disease ≥6 months) during fulvestrant therapy were included in the study. Sequential tumor biopsies and blood samples were taken at baseline and after 3, 6, 9, 12 and 18 months of fulvestrant treatment (disease being stable throughout the study period). Serum was analyzed for bone formation markers (N-terminal propeptide of procollagen Type 1 [PINP] and bone-specific alkaline phosphatase [bone ALP]) and for the resorption marker C-terminal telopeptide (CTX). Data are presented as median percentage change (from baseline) in marker level with 95% confidence intervals (CI). Data were analyzed separately for patients with LAPC and MBC. Results: Changes in bone ALP (reference range: 3.9–46.8 ng/mL), PINP (20.6–82.1 ng/mL) and CTX (0.14–1.35 ng/mL) in patients with LAPC, are shown in the table . In a further 5 patients with LAPC who were already established on fulvestrant, there were no significant changes in markers over a 15-month period. No changes in markers were noted in the 4 patients with MBC. Conclusions: In this study, there was long-term stability of bone turnover markers in postmenopausal women with LAPC treated with fulvestrant over a period of 18 months. This property may be exploited in future with the use of fulvestrant earlier in the sequence of endocrine therapies particularly in the adjuvant setting and/or in patients with pre-existing decreased bone mass. [Table: see text] [Table: see text]
ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial
Authors: Natale R. B. , Bodkin D. , Govindan R. , Sleckman B. , Rizvi N. , Capo A. , Germonpré P. , Stockman P. , Kennedy S. , Ranson M. 
Published: March 2020

7000 Background: ZD6474 is a once-daily oral agent that targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinase activity. The efficacy and safety of ZD6474 was compared with that of gefitinib, an EGFR tyrosine kinase inhibitor. Methods: Patients with locally advanced or metastatic (stage IIIB/IV) non-small-cell lung cancer (NSCLC), after failure of 1st-line ± 2nd-line platinum-based chemotherapy because of toxicity or tumor progression, received daily oral doses of ZD6474 (300 mg) or gefitinib (250 mg) until disease progression or evidence of toxicity (Part A). After a washout period of 4 weeks, eligible patients had the option to switch to the alternative treatment, which continued until a withdrawal criterion was met (Part B). The dual primary objectives in Part A were assessments of progression-free survival (PFS) and safety/tolerability. All adverse events were assessed using Common Toxicity Criteria (CTC) version 2.0. Results: A total of 168 patients received initial treatment with ZD6474 (n=83) or gefitinib (n=85). In Part A, median PFS was 11.0 weeks for ZD6474 and 8.1 weeks for gefitinib (hazard ratio [95% CI] = 0.69 [0.50–0.96], P=0.025); disease control >8 weeks was achieved in 37/83 (45%) patients receiving ZD6474 and in 29/85 (34%) receiving gefitinib. The adverse event profile of ZD6474 in Part A was similar to that seen in previous trials, and included diarrhea (CTC grade 3/4, 8.4%), rash (CTC grade 3/4, 4.8%) and asymptomatic QTc prolongation (all CTC grade 1, 20.5%). There were no unexpected safety findings with gefitinib-treated patients. In Part B, disease control >8 weeks was achieved in 16/37 patients who switched to ZD6474 (from gefitinib) and in 7/29 who switched to gefitinib (from ZD6474). Overall survival was not significantly different between patients initially randomized to either ZD6474 or gefitinib (median 6.1 and 7.4 months, respectively). Conclusions: This study achieved its primary efficacy objective, with ZD6474 demonstrating a significant prolongation of PFS versus gefitinib. These data support further confirmatory trials of ZD6474 in patients with advanced NSCLC. [Table: see text]