bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study
Authors: Le Coutre P. D. , Giles F. , Hochhaus A. , Apperley J. F. , Ossenkoppele G. , Haque A. , Gallagher N. J. , Baccarani M. , Cortes J. , Kantarjian H. 
Published: August 2020

7057 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in chronic phase or AP who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-AP pts resistant or intolerant to IM. Methods: Primary endpoint was confirmed hematologic response (HR). Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival (OS), and safety. Results: 137 CML-AP pts (80% IM-resistant; 20% IM-intolerant with resistance) with minimum follow-up of 11 months (mos) (median age, 57 years; median duration of prior IM treatment, 28 mos) were included. IM-intolerant pts were also IM-resistant and without MCyR at study entry. 79% pts had prior IM ≥600 mg/day. Median dose intensity of nilotinib was 775 mg/day and median duration of exposure was 272 days. 56% had confirmed HR and 31% had complete hematologic response (CHR). 30% of IM-resistant and 37% of IM-intolerant pts achieved CHR. Responses were rapid, with a median time to first HR of 1 mo. HRs were durable at 24 mos with 54% of pts maintaining their response. MCyR was achieved in 32% of pts (30% in IM-resistant, 41% in IM-intolerant) and complete cytogenetic response in 20% of pts (18% in IM-resistant, 30% in IM-intolerant). Cytogenetic responses were also durable with 70% of pts maintaining MCyR at 24 mos; 83% of pts maintained CCyR at 12 mos. Estimated OS at 24 mos was 67%. Only 9% of pts discontinued therapy due to drug-related adverse events (AE). The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (41%), neutropenia (42%), anemia (25%), elevated serum lipase (18%), and hypophosphatemia (14%). The rates of grade 3/4 myelosuppression were low, predictable, and easily managed with median onset of 14 to 29 days and median duration of 8 to 26 days. Grade 3/4 non-hematologic AEs were rare (< 1%) and included nausea, fatigue, and diarrhea. Conclusions: These long-term follow-up results confirm that nilotinib induces rapid and durable responses in CML-AP pts who failed prior IM due to intolerance or resistance, with a favorable risk/benefit. [Table: see text]
Occurence of venothromboembolism (VTE) in patients (pts) with acute lymphocytic leukemia (ALL), Burkitt's leukemia/lymphoma (BL), or lymphoblastic leukemia (LL)
Authors: Luong N. V. , Kantarjian H. M. , Faderl S. H. , Thomas D. A. , Vu K. D. 
Published: August 2020

7059 Background: Venous thromboembolism (VTE) is a significant public health issue. Although neoplastic diseases are known risk factors for the development of VTE, little is known about the incidence and predisposing factors of VTE among leukemia patients (pts). Methods: We performed a retrospective study to determine the incidence and risk factors associated with development of VTE among pts with ALL, BL, LL at M. D. Anderson Cancer Center between 1999 and 2005. Medical records of 299 ALL pts were reviewed and analyzed. All computations were conducted using Stata 10. Results: Of the 299 pts with a male/female ratio of 182/117 and a median age of 43 yrs (range 15–83 yrs), 18% had VTE. Recurrent VTE occurred in 10 pts. VTE were identified in upper extremities (59%), lower extremities (30%), pulmonary vasculature (7%), and within venous catheters (4%). In a univariate model, pts with baseline platelet (plt) count 50–99 x 109/L were 2.2 times (95% CI: 1.05–4.55) more likely to develop VTE than pts who had plt >100 x 109/L. Pts aged 40–59 yrs were 2.3 times (95% CI: 1.15–4.59) more likely to develop VTE than pts aged 15–39 yrs. Women were 1.8 times (95%CI: 1.04–3.4) more likely than men to have a VTE. Pts with a history of VTE were 15.2 times (95% CI: 2.97–77.51) more likely to develop a VTE than pts who had no prior VTE history. Pts with > 3 comorbidities were 2.6 times (95% CI: 1.19–5.48) more likely to develop VTE than pts without comorbidities. Pts who used oral contraception or hormone replacement therapy (OCP/HRT) were 2 times (95% CI: 1.07–3.92) more likely to develop VTE than non-users. Pts with Philadelphia chromosome (Ph)-positive ALL were 3 times (95%CI: 1.41–6.17) more likely to develop VTE than pts with Ph-negative ALL. In a multivariate model, significant predictors of VTE were age 40–59 yrs, plt count 50–99 x 109/L, diagnosis of Ph-positive ALL, history of VTE, and OCP/HRT use. Conclusions: Pts with ALL have a high VTE rate. In addition to traditional risk factors, disease-specific features may also predispose pts to higher VTE risk. Further studies should be done in other leukemias to establish guidelines in the prevention and management of VTE in pts with leukemia. [Table: see text]
Effects of the Flt3 ITD on response to chemotherapy in a murine model of acute myeloid leukemia
Authors: Pardee T. S. , Zuber J. , Lowe S. W. 
Published: August 2020

7060 Background: Acute myeloid leukemia (AML) is an aggressive, genetically heterogeneous malignancy. This heterogeneity is thought to underlie the divergent responses to treatment observed and contribute to relapse. The Flt3 receptor tyrosine kinase containing an internal tandem duplication (Flt3 ITD) is a common mutation in AML and associated with a poor prognosis; however, its effect on chemotherapy response is currently unknown. Methods: Murine AML was generated by retroviral transduction of an MLL-ENL fusion protein into fetal liver cells and subsequent transplantation into syngeneic mice. Blasts were harvested from moribund animals and myeloid lineage confirmed by immunophenotyping. Flt3 ITD sequence was inserted into a GFP tagged vector. Blasts were infected with Flt3 ITD or control virus. For competition assays mixtures of infected and uninfected blasts were exposed to chemotherapy for 72 hours. Among the remaining viable cells, percentages of infected blasts were determined by flow cytometry. For in vivo competition assays animals were injected with mixtures of blasts, treated with chemotherapy and percentages of Flt3 ITD positive blasts as well as total leukemic burden in femoral bone marrow was assessed. Results: Presence of the Flt3 ITD confers an advantage to doxorubicin (dox) in vitro. After exposure to dox at 5ng/mL more infected blasts remained viable when compared to controls (p = 0.0001). Presence of the Flt3 ITD increased sensitivity to cytarabine (Ara-C). After exposure to 50 nM Ara-C fewer Flt3 ITD blasts remained viable (p = 0.0293). Flt3 ITD confers sensitivity to Ara-C in vivo. Bl6 mice were injected with 1x106 blasts, 10% containing Flt3 ITD. After 12 days mice were treated for 5 days with either Ara-C at 200mg/kg, dox at 3mg/kg or observation. Ara-C treated animals had fewer Flt3 ITD blasts than controls (p = 0.0030) or dox treated animals (p < 0.0001) and lower leukemic burden (p < 0.0001). In contrast there was no difference in leukemic burden between Ara-C treated, dox treated or control animals in AML without Flt3 ITD (p = 0.2833). Conclusions: The Flt3 ITD confers resistance to doxorubicin in vitro and sensitivity to Ara-C in vitro and in vivo. These results suggest AML patients with Flt3 ITD may benefit more from high-dose cytarabine regimens then anthracyclines. No significant financial relationships to disclose.
Does pre-imatinib (IM) fluorescence in situ hybridization (FISH) predict myelosuppression and outcomes in chronic myeloid leukemia (CML)?
Authors: Lima L. , Assouline S. E. , Saxe D. , Mann K. , McLemore M. , Souza L. , Arellano M. , Winton E. F. , Bernal-Mizrachi L. , Khoury H. J. 
Published: August 2020

7071 Background: IM-associated myelosuppression occurs in 4–40% of CML patients (pts) vs. 1–16% in GIST. Selective inhibition of predominantly Philadelphia chromosome (Ph+) driven hematopoiesis may explain development of myelosuppression. In the absence of clinically applicable methods to quantitate Ph+/Ph- progenitor ratio, we hypothesized that the pre-IM percentage of BCR-ABL+ cells measured by FISH predicts myelosuppression. Methods: FISH pre-IM was available in 58 CML pts with chronic phase (CP, n=52), or advanced phase (AP, accelerated =3, blast =3) at 2 institutions. Grade >3 myelosuppression occurred < 60 days from starting IM in 9 pts (400 mg/d=6, > 600 mg/d=3), leading to dose reduction (4), discontinuation (1) or continuation same dose IM despite myelosuppression (4). Cryopreserved marrow CD34+/CD38- cells from 14 pts with (7) or without (7) post-IM myelosuppression were sorted using flow cytometry and subjected to FISH analyses. Results: Median FISH was higher for myelosuppression (90%) vs. no myelosuppression (80%) pts (p= 0.03), and in AP vs. CP (97 % vs. 80%, p=0.003). Results of FISH on CD34+/CD38- cells will be reported. Table summarizes outcomes of CP pts. Median follow-up was 14 and 45 months for myelosuppression and no myelosuppression AP pts, respectively. Myelosuppression AP pts expired (CML=2, GVHD=1); 1 after complete hematologic (CHR) and minor cytogenetic response (CTGR), 1 after partial HR, and 1 resistant disease. All 3 pts without myelosuppression achieved CHR with major CTGR, and 2 had partial molecular response. 1 died from GVHD. Conclusions: Higher FISH pre-IM identifies a group of CML pts who develop myelosuppression and are less likely to respond to IM. [Table: see text] No significant financial relationships to disclose.
Inadequate BCR-ABL monitoring in imatinib-treated patients with chronic myelogenous leukemia
Authors: Stanek E. , Aubert R. E. , Sanders C. , Frueh F. W. , Yao J. , Epstein R. S. 
Published: August 2020

7077 Background: Recommendations for baseline and quarterly measurement of the BCR-ABL fusion transcript to monitor imatinib response in patients with chronic myelogenous leukemia (CML) were formally introduced in October 2006, and have been incorporated into nationally recognized treatment guidelines. Methods: To assess BCR-ABL testing rates, we conducted a retrospective cohort analysis using a >10 million-member health plan database comprised of integrated pharmacy and medical claims. The study cohort was defined as patients with an index imatinib pharmacy claim from July 1, 2006, to December 31, 2006, who had a CML diagnosis (ICD-9 205.1X; N = 504), and a minimum of 3 months continuous follow-up by claims history (N = 465). Over a period of up to four quarters from the index imatinib prescription date, BCR-ABL testing in each quarter was assessed by the presence of any of a set of 19 CPT-4 codes. BCR-ABL testing rates in each individual quarter and in consecutive quarters were measured. Results: The overall study cohort was 57% male; mean (±SD) age was 52±14 y/o, with 26% 19–44 y/o, 57% 45–64 y/o, and 15% ≥65 y/o. Median duration of f/u was 559 days (interquartile range 302–628 days), and a cohort of 359 patients had 4 quarters of f/u. At least one BCR-ABL test was recorded in 60% of patients. The rate of first quarter BCR-ABL testing was 40%, and remained at 42%-43% in quarters 2 thru 4. Consecutive quarterly testing rates were 24% through the second quarter, 18% through the third quarter, and 14% through the fourth quarter. Conclusions: In this retrospective claims database analysis, only 14% of a large cohort of CML patients treated with imatinib had BCR-ABL testing recorded in each of 4 consecutive quarters. Inadequate compliance with recommended BCR-ABL testing can delay treatment decisions, and may be associated with poor clinical outcome. [Table: see text]
Innovative phase I study of concomitant and consecutive treatment with dasatinib and MK-0457 in refractory Ph+ CML and ALL patients
Authors: Papayannidis C. , Iacobucci I. , Soverini S. , Paolini S. , Cilloni D. , Messa F. , Pane F. , Ottaviani E. , Baccarani M. , Martinelli G. 
Published: August 2020

7080 Background: MK-0457 is a pan-aurora kinase inhibitor with activity against wild-type and mutated BCR-ABL, including the T315I form, FLT3, and JAK-2. Methods: We conducted an innovative Phase I clinical study of sequential and concomitant treatment with dasatinib, previously administered for 3 months, and MK-0457. This combined activity suggests that MK-0457, in association with dasatinib, would suppress the emergence of T315I and other resistant clone, improving upon the response rate for dasatinib and the durability of response. The trial investigated two schedules of therapy: patients who achieved and maintained a major hematologic response (MHR) after 3 months of therapy with dasatinib (70 mg twice daily) received a 6-hour biweekly infusion of MK-0457 at 64 mg/m2/hr, whereas patients who failed to achieve a MHR received a 5-days continuous infusion of MK-0457 at 10 mg/m2/hr, every 4 weeks. Results: Two patients with Ph+ ALL and one patient with CML in myeloid blast crisis, previously unsuccessfully treated with imatinib, were enrolled. The first two patients, both in hematologic response after three months of treatment with dasatinib, subsequently received the 6-hour biweekly schedule, maintaining the hematological response. No hematological toxicity was described. The third patient, in progression disease, received the 5 days MK-0457 schedule. His peripheral blood count showed a severe pancytopenia, and his bad clinical conditions were compromised by a severe hemorrhagic pleural effusion. After one cycle of MK-0457, a complete recovery of the pulmonary disease and a complete hematologic response were obtained. Conclusions: The sequential and concomitant administration of dasatinib and MK-0457 represents a promising therapeutic strategy for refractory Ph+ CML and ALL. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Merck Sharp & Dohme. No significant financial relationships to disclose.
Prevalence of paroxysmal nocturnal hemoglobinuria (PNH) cells in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA), or other bone marrow failure (BMF) syndromes: Interim results from the EXPLORE trial
Authors: Galili N. , Ravandi F. , Palermo G. , Bubis J. , Illingworth A. , Castro-Malaspina H. , Raza A. 
Published: August 2020

7082 Background: In patients with PNH, lack of the glycophosphatidylinositol (GPI)-anchored terminal complement inhibitor CD59 on hematopoietic stem cells results in chronic intravascular hemolysis, kidney and pulmonary disorders, thrombosis, and shortened life span. Presence of even minor populations of PNH cells in AA or MDS patients is medically important as it may indicate a higher likelihood of response to immunosuppressive therapy. We conducted the first large multicenter, point-prevalence study (EXamination of PNH, by Level Of CD59 on REd and white blood cells [EXPLORE]) of PNH cells in patients with AA, MDS, or other BMF syndromes. Here we report an interim analysis. Methods: A central laboratory conducted high-sensitivity flow cytometry utilizing a combination of GPI-linked antibodies (CD59, CD24, and CD14) and fluorescent aerolysin (FLAER) to identify GPI anchor-deficient PNH cells in RBC and WBC resulting in 0.01% sensitivity. The primary endpoint was percentage of patients who had a PNH WBC clone ≥1%. Results: Among 5,212 patients screened, 4,500 (86.3%) were MDS patients, 413 (7.9%) were AA patients, and 356 (6.8%) had other BMF syndromes. Approximately 1/4 (24.5%) of patients with AA, 1.2% with MDS, and 4.6% with other BMF were newly found to have a significant PNH clone ≥ 1%. Many of the newly identified clones were of clinical significance as the median PNH clone size was 11.1% in AA patients, 16.3% in MDS patients, and 32.6% in patients with other BMF. Presence of PNH cells (≥ 0.01%) was common in all examined BMF types: 70% of AA patients, 55% of MDS patients and 55% of patients with other BMF. PNH cells were identified in all MDS subtypes represented in the trial. Conclusions: Interim analysis from this first large multicenter study demonstrates that PNH cells are present in a majority of patients with AA, MDS, and other BMF. A spectrum of PNH clone sizes was noted in patients with each form of BMF. Screening patients with BMF with high-sensitivity flow cytometry for PNH cells may guide treatment options for the underlying BMF and/or PNH. The EXPLORE trial continues to enroll patients with AA. (EXPLORE Clinical Study Abstract 1/6/2009) [Table: see text]
Frequency of use and outcome of surgical resection in the management of malignant mesothelioma in a community-based population: Results in 5,937 patients
Authors: Flores R. M. , Riedel E. , Donington J. S. , Krug L. , Rosenzweig K. , Adusumilli P. , Carbone M. , Rusch V. W. , Pass H. I. 
Published: August 2020

7510 Background: Multimodality therapy of mesothelioma patients treated at specialized tertiary hospitals report surgical resection rates of 42% (Flores RM et al. Prognostic Factors in the Treatment of Malignant Pleural Mesothelioma at a Large Tertiary Referral Center. J Thorac Oncol 2007;2(10):957–965.). Treatment strategies in the community are less well defined and surgical expertise is not readily available. We undertook this study to evaluate the rate of surgical resection and its association with survival in a non-tertiary based population. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was searched from 1990 - 2004. Variables analyzed included age, sex, race, year of diagnosis, laterality, vital status, stage, surgery, and reasons for no surgery. The association of resection on overall survival was estimated by the Kaplan-Meier method and examined in a Cox proportional hazards model adjusting for covariates. Results: Pathologically proven malignant pleural mesothelioma was identified in 5,937 patients: 1,166 women, 4,771 men; median age was 70 years. Surgical resection rate was 11% (n=636). Univariate analysis demonstrated a median survival of 13 months with surgical resection and a median survival of 7 months in the non-resected group (p<0.0001). Multivariate analysis demonstrated improved survival for surgically resected patients (HR 0.7, p<0.0001), controlling for age, gender, and stage. Conclusions: Surgical resection was associated with improved survival when controlling for age, stage, and gender. However, the rate of surgical resection was much lower in the community when compared to tertiary referral centers. Treatment efforts should be focused on a multidisciplinary approach which includes surgical evaluation. No significant financial relationships to disclose.
Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small cell lung cancer (NSCLC)
Authors: Grills I. S. , Mangona V. , Welsh R. , Chmielewski G. , McInerney E. , Ye H. , Kestin L. L. 
Published: August 2020

7516 Background: To compare clinical outcomes between lung stereotactic radiotherapy (SBRT) and wedge resection for stage I NSCLC. Methods: 112 cases of T1–2N0 NSCLC were treated with wedge resection (n=69) or image-guided lung SBRT (n=43) from 2/2003–8/2008. SBRT patients were treated on a phase II trial. All patients were ineligible for anatomic lobectomy; 93% undergoing SBRT were medically inoperable; 7% refused surgery. Mean FEV1 and DLCO were 1.58L and 13.9ml/min/mmHg for wedge cases vs 1.29L and 10.1ml for SBRT (p<0.01, p<0.01). Mean Charlson Co-morbidity Index and median age were 3 and 74y for wedge vs 4 and 77y for SBRT (p<0.01, p=0.04). Patients were staged using CT, 18FDG PET-CT, pulmonary function testing, and chemistries. SBRT patients had bone scan and brain MRI. Mediastinoscopies were performed for 28% of wedge cases vs.16% for SBRT (p=NS). SBRT was prescribed as 48 (T1) or 60 (T2) Gy in 4–5 fractions to the edge of the target volume. Adjuvant chemotherapy was given to 22% of SBRT vs12% of wedge patients (p=NS). Results: Median potential follow-up=2.3y. No significant differences were identified in local (LR), regional (RR), or locoregional recurrence (LRR), distant metastasis (DM), freedom from any failure (FFF), overall survival, or cause-specific survival between the two groups (Table); however, trends toward reduced LR and improved FFF were found with SBRT. Results excluding cases of synchronous primary tumors or pathologicalT4 (satellite lesion at wedge) are also shown, with FFF significantly better for SBRT. Multivariate analysis showed tumor grade to predict LR; LR to predict DM; LR and angiolymphatic invasion to predict RR and RR, (+)margin, FEV1, and pathologic diameter OS (p=0.06, p=0.08, p=0.01, p=0.04) in wedge cases. Conclusions: Both lung SBRT and wedge resection are reasonable treatment options for Stage I NSCLC patients ineligible for anatomic lobectomy. SBRT showed trends toward reduced LR and failure. Additional follow-up will be needed to verify durability of these findings. [Table: see text] No significant financial relationships to disclose.
Incorporation of bevacizumab (B) and erlotinib (Er) with induction (Ind) and concurrent (Conc) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic radiotherapy in stage III non-small cell lung cancer (NSCLC)
Authors: Socinski M. A. , Stinchcombe T. E. , Halle J. S. , Moore D. T. , Petty W. J. , Blackstock A. W. , Gettinger S. N. , Decker R. H. , Khandani A. H. , Morris D. E. 
Published: August 2020

7528 Background: Therapies directed at both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways have been shown to improve survival in NSCLC and also have radiosensitizing properties. Methods: Pts receive Ind Cb (AUC 6), P (225 mg/m2) and B (15 mg/kg) on d1 and 22. PET scans are done pre- and post-I. On day 43, pts receive weekly Cb (AUC 2 x 7) and P (45 mg/m2 x 7) with 74 Gy (2 Gy/d) of thoracic conformal radiotherapy (TCRT). Cohort I (n=5) received B at 10 mg/kg q2wks during C therapy. Cohorts II and III (both n=5) received the same dose of B as in cohort I but also received Er at 100 mg and 150 mg po Tuesday - Friday of each week of C therapy, respectively. The primary endpoint is PFS at 1 year. All histologies are allowed including squamous (SQ) (an early stopping rule is in place for pulmonary hemorrhagic (PH) complications in SQ pts). Results: Thus far, 31 eligible PS 0–1 pts have been accrued (med age 62 yrs, range 41–74, 19 non- squamous, 12 SQ, 63% IIIA, 37% IIIB). Ind CbP + B has been well tolerated (1 gr 3 hypertension). No PH during Ind has been seen (including the 12 SQ cell pts). Response after Ind, 37% PR, 59% SD, 4% PD. Tumor volumes and PET SUVs have significantly decreased comparing pre- and post-Ind studies (p=0.0001 and p=0.0002, respectively). Cohort II has been expanded as the phase II regimen. To date, 25 of 26 (96%) pts have achieved the dose of 74 Gy (1 pt stopped at 60 Gy due to ILD). During Conc therapy, the principal toxicity has been esophagitis (53.8% gr 2, 19.2% gr 3). One grade 3 PH occurred in 1 SQ pt. One gr 5 late (> 2 mos after treatment) PH occurred in a SQ pt. Overall response rate following treatment - 68.2% (95% CI, 45–86%). The PFS at 1 year is 58% (95% CI, 34–76%) with an estmated 1-year overall survival rate of 79% (95% CI, 53–92%) which compares favorably to our historical experience. Conclusions: Preliminarily, we conclude that 1) Incorporation of B and E into this treatment paradigm appears feasible, 2) Esophagitis remains the primary toxicity, 3) Phase II accrual continues but early analysis of survival appears promising. Further details regarding the TCRT parameters and toxicity will be presented. [Table: see text]