bluuebunny/crossref_metadata_2025 huggingface dataset:
A nine-gene predictor of therapy response in adult Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL)
Authors: Zuo Z. , Jones D. M. , Thomas D. A. , O'Brien S. , Ravandi F. , Kantarjian H. M. , Medeiros L. J. , Luthra R. , Chen S. S.
Published: August 2020

7014

Background: Ph+ ALL in adults shows a poor response to therapy and high frequency of relapse. This study utilized a meta-analysis of previous genome-wide gene expression studies to define and validate a nine-gene predictor of outcome in Ph+ ALL patients. Methods: Normalized gene expression data from previously published studies of 672 ALL patients were analyzed to identify genes associated with therapy response. Expression of the selected genes was assessed using Applied Biosystems low density reverse transcription quantitative PCR (RT-qPCR) arrays in bone marrow (BM) samples from 27 adult Ph+ ALL patients treated with standard chemotherapy plus a tyrosine kinase inhibitor. Therapy responses were defined at the molecular level by monitoring BCR/ABL1 levels, and categorized into 3 groups: optimal, persistent and relapse. Median follow up was 6 months (range 4–15). Median disease-free survival among the optimal and relapse groups were 12 and 5 months respectively (p = 0.002). There was no statistical difference in age, initial peripheral blood white cell and BM blast counts, and initial normalized BCR/ABL1 levels between groups. Differentially expressed genes were selected using the significance analysis of microarrays (SAM). Hierarchical clustering and principal component analysis were applied to assess the correlation between gene expression pattern and therapy response. A predictive model was built using support vector machines. Differences in survival among groups were compared by Kaplan-Meier analysis. Results: Data mining and pathway analysis of the published data identified 46 genes in 7 pathways potentially associated with therapy response (p < 0.001). RT-qPCR results from a 15 case training set, 5 in each outcome group, identified 9 genes that classified the cases with 100% accuracy. Validation using an additional 12 cases showed 91.7% prediction accuracy (ROC error = 0.056). Compared with the initial diagnostic samples, gene expression pattern in relapsed samples shifted to that resembling the persistent group. Conclusions: Using data-trimming of whole genome expression studies, we defined and validated a nine-gene signature that is an independent predictive marker for therapy response in adult Ph+ ALL patients.

No significant financial relationships to disclose.
A phase I dose-escalation study of the novel KSP inhibitor ARRY-520 in advanced leukemias
Authors: Estrov Z. , Cortes J. , Borthakur G. , Faderl S. , Garcia Manero G. , Ravandi F. , Khoury J. , Ptaszynski M. , Kantarjian H.
Published: August 2020

7022

ARRY-520 is a potent, selective KSP inhibitor that arrests cells in mitosis with the subsequent onset of apoptosis. ARRY-520 has shown potent activity in preclinical models of hematological cancers and is being evaluated in a phase I trial in patients with advanced or refractory leukemias. The primary objectives of this study are to establish the safety and the MTD of ARRY-520 given as a single dose each cycle. Secondary objectives are to characterize the pharmacokinetics (PK) of ARRY-520, to assess evidence of preliminary clinical activity, and to explore biomarkers of KSP inhibition. ARRY-520 is administered as a 1-h IV infusion as a single dose per cycle in a “3 + 3 phase I design”. Dose escalations are following a prespecified schema. PK analyses for ARRY-520 are performed on plasma samples collected during cycle 1 and cycle 2. Pretreatment and post-treatment peripheral blood samples are collected for analysis of markers of KSP activity. To date, 15 patients, with a median age of 69 yrs (range 44–84 yrs), have been enrolled in the single dose schedule, 3 patients each at doses of 2.5 mg/m2, 3.75 mg/m2, and 5.6 mg/m2 and 6 patients at 4.5 mg/m2 per cycle. All patients had disease refractory to, and/or relapsed from, 1 or more prior therapies with a median of 3 prior regimens (range 1–10). Two patients at 5.6 mg/m2 experienced a DLT of gr3 mucositis. ARRY-520 was well tolerated at doses below 5.6 mg/m2. 4.5 mg/m2 has been determined to be the MTD. ARRY-520 has shown promising signs of clinical activity at doses of 3.75 mg/m2 and above. 2 patients had a complete reduction in their peripheral blasts on day 5 of cycle 1. Of these, one patient experienced a 70% reduction in bone marrow blasts while on study. One patient without peripheral blood blasts at baseline had a 43% reduction in bone marrow blasts and four additional patients had marked reductions in WBC counts. This is the first reported use of a KSP inhibitor in refractory and/or relapsed leukemias. ARRY-520 has been well tolerated in patients on a single dose schedule. Mucositis was observed as the DLT at 5.6 mg/m2. At doses 3.75 mg/m2 and above, ARRY-520 has shown signs of clinical activity. Based on these data, an alternative dose schedule is being explored. Updated data including safety, PK, PD, and preliminary activity of ARRY 520 from this study will be presented.

[Table: see text]
Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance
Authors: Verma D. , Kantarjian H. , Jones D. , Borthakur G. , Garcia-Manero G. , Thomas D. A. , Verstovsek S. , Rios M. , Cortes J.
Published: August 2020

7030

Background: The most common BCR-ABL fusion transcripts in CML are e13a2 (b2a2) and e14a2 (b3a2). Rarely, other transcripts like e1a2 are seen. Currently, there is no published series of data on efficacy of imatinib or other tyrosine kinase inhibitors (TKIs) in CML with e1a2. Methods: We analyzed records of 1,292 CML patients treated with TKI at our institution between January 2000 and November 2008. Results: 14 CML patients with e1a2 transcripts were identified, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Median age at diagnosis was 60 (range 28–86) years, median follow-up 39.5 (range 2–109) months. Of the 9 in CP, 3 received interferon and then imatinib after interferon failure, 6 received TKI as first-line therapy (5 imatinib, 1 nilotinib): 5 achieved CHR only, 1 CCyR, 1 MCyR, 1 PCyR, and 1 did not respond to imatinib. 5 patients (2 post-interferon failure - 1 in CHR, 1 in PCyR; 3 frontline imatinib - 1 in CHR, 1 in CCyR, 1 non-responder) progressed to advanced phases (3 myeloid BP, 1 lymphoid BP, 1 AP) at a median 48 (range 4–92) months after CML diagnosis; with only 1 alive and in CMR after allogeneic SCT. AP patient received various TKIs sequentially and achieved only CHR with disappearance of clonal evolution. BP patients received Hyper-CVAD+imatinib/dasatinib or idarubicin+Ara-C; 2 did not respond, 1 had CCyR lasting 12 months with Hyper-CVAD+Imatinib and 1 had CMR after allogeneic SCT lasting 2 months. In all 14 patients, cytogenetic responses lasted 1–9 months before being lost and none (except 2) achieved MMR or CMR on imatinib or other TKI therapy. Six patients (5 CP, 1 AP) were alive at a median 39 (range 2–85) months after initial diagnosis: 4 with CHR (2 on imatinib, 1 nilotinib, 1 bosutinib), 1 with MCyR on imatinib, and 1 with CMR after allogeneic SCT. Conclusions: CML with e1a2 BCR-ABL fusion transcripts is rare and is associated with an inferior outcome to therapy with TKI, with responses being usually short-lived. These patients need to be identified as high-risk patients and monitored closely for efficacy during therapy with TKI.

No significant financial relationships to disclose.
Phase I/II study of oxaliplatin, fludarabine, cytarabine, and rituximab in patients (OFAR2) with Richter's syndrome (RS), and relapsed or refractory B-cell chronic lymphocytic leukemia (CLL)
Authors: Tsimberidou A. M. , Wierda W. G. , Plunkett W. K. , O'Brien S. , Lerner S. , Smith S. C. , Kantarjian H. M. , Keating M. J.
Published: August 2020

7031

Background: The first Phase I-II clinical trial of oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate with a decrease in myelosuppression, the dose of oxaliplatin was increased to 30 mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: The OFAR2 regimen consisted of oxaliplatin 30mg/m2, D1–4; fludarabine 30mg/m2, Ara-C 0.5 g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2–3 (dose level 1) D2–4 (dose level 2) or D2–5 (dose level 3); courses were repeated every 4 wks. Prophylaxis for tumor lysis, DNA viruses, and PCP was given. Results: A total of 55 pts have been treated to date: 12 pts enrolled in phase I (dose level 1, n=3; dose level 2, n=6; and dose level 3, n=3). DLTs were noted in 2/3 pts in dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1), therefore level 2 was the MTD. Forty-three pts were treated in the Phase II portion of the study (relapsed CLL, 35; RS, 8). The median age was 64 yrs (range, 40- 81); 50 (91%) had β2-microglobulin > 3 mg/L; platelets were < 100 x109/L in 22 pts; and 44 pts had > 1 prior therapies. FISH results were: 17p deletion, n=15; 11q del, n=7; trisomy 12, n=12; 13q del, n=8; normal, n=2; unknown, n=11. Overall, 33 pts had unmutated and 7 mutated IgVH gene; ZAP70 was positive in 30, and negative in 14. Six (46%) of 13 pts with 17p del by FISH responded to OFAR2 (nPR, 2; PR, 4). Eleven pts underwent stem cell transplantation as postremission or salvage therapy. The most common toxicity was myelosuppression. Conclusions: Preliminary results demonstrated that OFAR2 resulted in an overall response rate of 63%, had antileukemic activity in pts with 17p del and clinical outcomes appeared to be superior to those of OFAR1. Accrual is ongoing.

[Table: see text]

[Table: see text]
Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting
Authors: Bregni M. , Bernardi M. , Servida P. , Pescarollo A. , Crocchiolo R. , Treppiedi E. , Corradini P. , Ciceri F. , Peccatori J.
Published: August 2020

7037

Background: Stem cell transplantation from a HLA-compatible sibling donor is an adoptive immunotherapy for cytokine-refractory, metastatic clear-cell renal cell cancer (RCC). However, the recent introduction of targeted therapy compounds has reduced the interest in this therapeutic strategy. We have reanalyzed our series with the aim to assess long-term benefit from allografting. Methods: Twenty-five RCC patients (Table) received a reduced-intensity allograft from an HLA-identical sibling donor after a thiotepa, fludarabine, and cyclophosphamide conditioning regimen, and a cyclosporine-based GVHD prophylaxis. Allogeneic peripheral blood hematopoietic cells were collected by apheresis after filgrastim treatment of the donor. Results: Best response to allograft was evaluable in 24 patients: 1 complete remission, 4 partial remissions, 12 minor response or stable disease, 7 progressive disease. Six patients died because of transplant related mortality (TRM) at day +12, +71, +86, +151, +259, +478. Cause of death was infection in four cases, GVHD in one case, and acute renal failure in one case. Fourteen patients died for progressive disease at median 415 (36–958) days from transplant. One-year survival was 48%, and 5-yr survival was 20%. At a median observation time of 65 months, 5 patients are alive, one in CR, one in PR, and three with stable disease. At multivariate analysis, CRP value before transplant, number of CD34+ infused cells and disease status at +90 significantly correlated with survival. Survival of patients at favourable/intermediate-risk according to the MSKCC score that underwent allografting was better in comparison to the survival predicted by historical controls. Conclusions: Transplantation is able to induce long-term disease control in a fraction (20%) of relapsed RCC patients. Identifying patients who could benefit from allografting, and incorporating molecularly targeted drugs in the transplant regimen, could further decrease progression and prolong overall survival.

[Table: see text]

No significant financial relationships to disclose.
A phase II randomized study comparing pegfilgrastim (PEG) versus filgrastim (FIL) after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell support (PBSC)
Authors: Castagna L. , Bramanti S. , Levis A. , Michieli M. , Anastasia A. , Mazza R. , Sarina B. , Todisco E. , Giordano L. , Santoro A.
Published: August 2020

7038

Background: The aim of this study was to demonstrate the non-inferiority of one fixed dose of PEG compared to daily FIL, in patients (pts) receiving HDC and PBSC. Methods: Criteria for elegibility were: HDC for haematological or solid tumors; at least 3 x10^6/kg CD34+ reinfused; age >18 years; normal cardiac, renal, liver and pulmonary function; signed written informed consent. Pts were randomized to receive on day+1 subcutaneously(sc) PEG (6mg) or 5 mcg/kg/d sc of FIL until ANC >1.0 x 10^9/L. Primary end points were: absolute neutrophil count (ANC) < 0.5 x 10^9/L and the number (no.) of days to achieve an ANC > 0.5 x 10^9/L from day +1. Secondary end points were: no. of days to achieve an ANC > 1.0 x 10^9/L; no. of days with fever > 38 °C; duration of antibiotic therapy; and no. of documented infections. Results: 80 pts were enrolled (40 pts for group). The duration of ANC < 0.5 x 10^9/L, the time to reach an ANC > 0.5 x 10^9/L and the time to reach an ANC > 1.0 x 10^9/L were superimposable in the two groups (mean days 6, 11, 12 respectively ). No. significant differences between FIL versus PEG group were observed in incidence of fever (24 vs 22), no. of documented infections (12 vs 10), no. of days with fever (1.7 vs 0.97 days), duration of antibiotic therapy (5.7 vs 3.5 days). No. differences in terms of extra-hematological toxicities and time to discharge between the two groups (16 vs 14). Time to reach a platelets count > 20 x 10^9/L was significantly shorter in PEG group compared to FIL group (15 vs 11 days, p value 0.05). Conclusions: This study shows that PEG was not inferior to FIL in terms of hematological reconstitution. Additionally PEG significantly shortened duration of thrombocytopenia <20 x 10^9/L. Consequently, PEG could be safely used after PBSC infusion.

No significant financial relationships to disclose.
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]
Phase II study of induction and adjuvant bevacizumab in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) receiving induction docetaxel and cisplatin
Authors: Price K. , Kris M. G. , Rusch V. , Finley D. J. , Azzoli C. G. , Downey R. J. , Bains M. S. , Miller V. A. , Rizk N. , Rizvi N. A.
Published: August 2020

7531

Background: VEGF supports growth of NSCLC and is blocked by bevacizumab. Bevacizumab with chemotherapy is an established treatment for advanced NSCLC. We conducted this study to assess the efficacy and toxicity of induction bevacizumab (Bev) with cisplatin (C) and docetaxel (D) in patients with resectable NSCLC. Methods: All patients (pts) had resectable Stage IB-IIIA NSCLC and received up to 4 cycles of D 75 mg/m2 and C 75 mg/m2 followed by surgery. Pts with non-squamous NSCLC also received 3 cycles of Bev 15 mg/kg along with induction DC (Bev-DC). Bev was not given in pre-operative cycle 4. Pts with squamous or central tumors or hemoptysis received 4 cycles of DC only (DC). All resected pts were eligible for adjuvant Bev 15 mg/kg q3 weeks for 1 year. The primary endpoint was rate of downstaging from pre-operative clinical stage to pathologic stage. Results: From Aug 2005 - Nov 2008, 47 pts were enrolled: 27 women; median age 62; Stage 1B -15%, Stage II-17%, Stage IIIA-68%. Of 36 pts given Bev-DC, 15/30 (50%) who have completed surgery were downstaged. Of 11 pts given DC, 3/11 (27%) were downstaged. In Bev-DC group, 22/33 (67%) completed all 4 cycles of DC without a dose reduction and 28/33 pts (85%) completed all 3 planned cycles of Bev. Pts received <3 cycles due to: hemoptysis (n=3), consent withdrawal (n=1), hypertension (n=1), and sepsis (n=1). For DC, 6/11 pts (55%) completed all 4 cycles of DC without a dose reduction. 42/43 patients were resected. R0 resection rate: 29/31 for Bev-DC and 9/11 for DC. Grade 3/4 surgical complications were seen in 5/31 pts (16%) in Bev-DC and 1/11 (9%) in DC. Only 17/41 (41%) who completed surgery received adjuvant bev (median 6 cycles), and 7/41 (17%) completed all adjuvant Bev. Pts did not receive adjuvant Bev due to: POD prior to adjuvant Bev (n=9), POD during adjuvant Bev (n=6), toxicity (n=4), consent withdrawal (n=1), RT for unresectable disease (n=1), surgical complications (n=4), chemotherapy complications (n=4). No treatment related deaths. Conclusions: Induction chemotherapy with Bev-DC in NSCLC is feasible and is associated with an improved rate of downstaging compared with historical controls (33%). In patients treated with DC-Bev, grade 3/4 surgical complications were increased by 7%.

[Table: see text]
Third-generation drugs in the chemoradiation of stage III non-small cell lung cancer (NSCLC): A meta-analysis of efficacy and toxicity parameters
Authors: Aydiner A. , Can G.
Published: August 2020

7536

Background: The role of third generation drugs (paclitaxel, docetaxel, gemcitabine and vinorelbine) in the chemoradiotherapy to maximize survival and decrease toxicity in NSCLC is unclear. We performed a meta-analysis of published randomized controlled trials (RCT) comparing third generation drugs. Methods: We searched MEDLINE, EMBASE, CENTRAL, proceedings of ASCO and other Cancer Congresses to December 08 for RCTs comparing chemoradiation treatment (CRT) including any type of third generation drugs in stage III NSCLC patients who had not been treated surgically. Standard meta-analysis techniques, using random effects model, were used to compare study arms with regards to treatment response, survival and toxicity data. For treatment response odds ratio (OR), to reach complete response and overall response were calculated. For survival data, hazard ratios (HR) and confidence intervals (CI) of individual studies were calculated based on survival curves-published in the manuscript (Parmar MKB, 1998). Basically two types of comparisons were performed: (1) subgroups defined by the type of CRTs, (2) subgroups defined by the type of drugs administered. Results: We found 18 RCTs including 2725 patients. Concurrent CRT was superior to the pool of other types of CRT (overall survival [OAS] HR 0.76, 95%CI 0.6–0.96, p=0.021) and sequential CRT (OAS HR 0.59, 95%CI 0.39–0.88, p=0.01). CRT with paclitaxel was superior to CRT without paclitaxel or with another type of third generation drug with regard to complete response (OR 1.93, 95%CI 1.02–3.67, p=0.044), with no significant difference in OAS (HR 0.94, 95%CI 0.56–1.57, p=0.799). CRT with paclitaxel was less toxic to CRTs without paclitaxel or with another type of third generation drug with regard to the incidence of grade III and IV anemia (OR 0.1, 95%CI 0.03–0.36, p<0.001) and febrile neutropenia (OR 0.22, 95%CI 0.1–0.49, p<0.001). Conclusions: Paclitaxel has less haematologic toxicity when compared with the other drugs without any significant survival difference.

No significant financial relationships to disclose.
Topotecan consolidation after etoposide platinum for limited stage small cell lung cancer patients who do not receive prophylactic cranial irradiation
Authors: Ross H. J.
Published: August 2020

7553

Background: Small cell lung cancer (SCLC) accounts for approximately 15% of new lung cancer diagnoses in the US and about one third of patients present with limited stage (LD-SCLC). Concurrent chemoradiotherapy followed by prophylactic cranial irradiation (PCI) is standard and produces long-term survival in up to 25% of good performance status (PS) patients. Some patients refuse or are ineligible for PCI resulting in poorer outcome. Topotecan is active against SCLC and crosses the blood brain barrier suggesting that it might reduce brain metastases in this group. This phase II trial was designed to explore that possibility. Methods: Eligible patients had declined or were ineligible for PCI after completing standard platinum etoposide chemotherapy with concurrent radiotherapy for LD-SCLC with at least a partial response (PR), had recovered from toxicity with PS 0–1, and had no evidence of brain metastases. Patients received 1.5 mg/m2/day topotecan IV for 5 consecutive days every 21 days for four cycles. Primary endpoint was incidence of brain metastases with secondary endpoints overall and progression-free survival and toxicity. Results: Twenty patients enrolled between November 1999 and May 2006. 17 patients (85%) completed 4 cycles of topotecan. Brain metastases developed in 6 patients (30%) at a mean of 5.3 months (range 84–324 days). Median survival was 25.9 months with median PFS 462 days. At final data analysis, eight patients (40%) were alive without evidence of disease at 19 to 92.6 months. Topotecan was well tolerated with grade 3/4 hematologic toxicity in 13 patients (65%) and neutropenic fever in 2 patients. One patient had radiation pneumonitis. One patient died with progressive disease and pneumonia after two cycles of topotecan. Conclusions: Adjuvant topotecan was well tolerated. The 30% rate of brain metastases suggests the possibility that topotecan was active in the brain. Overall and progression-free survivals are promising. Additional study of adjuvant topotecan in LD-SCLC patients who do not receive PCI may be warranted.

No significant financial relationships to disclose.
A randomized phase II trial of adjuvant chemotherapy with docetaxel (DOC) plus cisplatin (CIS) versus paclitaxel (PAC) plus carboplatin (CAR) in patients with completely resected non-small cell lung cancer (NSCLC): Safety and feasibility data from trial TORG 0503
Authors: Kubota K. , Kunitoh H. , Seto T. , Shimada N. , Tsuboi M. , Okamoto H. , Masuda N. , Maruyama R. , Shibuya M. , Watanabe K.
Published: August 2020

7561

Background: Adjuvant chemotherapy is standard of care for patients with completely resected stage IB, II and IIIA NSCLC. However, the optimum chemotherapy regimen has not been determined. TORG 0503 was conducted to evaluate platinum-based third generation regimens in this clinical setting. Methods: Patients with completely resected stage IB, IIA, IIB or stage IIIA NSCLC were stratified by stage (IB/IIA vs. IIB/IIIA) and institution and randomized to receive 3 cycles of DOC (60 mg/m2, day 1) plus CIS (80 mg/m2, day 1) or 3 cycles of PAC (200 mg/m2, day 1) plus CAR (AUC 6, day 1). Both regimens were repeated every 3 - 4 weeks. Other eligibility criteria included ECOG PS 0–1, age ≥20, and =<70 years old, adequate organ function, no prior chemotherapy or radiotherapy. Patients who underwent pneumonectomy were excluded. The primary endpoint was 2-year relapse free survival (RFS), and secondary endpoints were overall survival (OS), quality of life (QOL), feasibility and toxicity. Results: 111 patients were randomized between April 2006 and July 2008, 58 patients to DOC+CIS (DC) and 53 to PAC+CAR (PA). Patients’ demographics (DC/PA): median age 63/59 years, 60%/66% male, 17%/22% PS 1, 79%/73% adenocarcinoma, 40%/40% of patients were stage IB/IIA, 60%/60% IIB/IIIA. Feasibility: 93% (54/58) of patients allocated to DC and 92% (49/53) patients in the PA arm completed 3 planned cycles of chemotherapy. Toxicities: DC vs. PA: Grade (G) 3/4 neutropenia (86%/75%), G3/4 anemia (2%/0%). G 3 febrile neutropenia (10%/4%), G2 ALT (0%/10%), G2 creatinine (17%/0%), G2–4 allergy (0%/4%), G2 alopecia (43%/47%), G2/3 fatigue (5%/10%), G2/3 anorexia (43%/22%), G2/3 nausea (47%/22%), G2/3 vomiting (31%/12%), G2 diarrhea (12%/8%), G2 constipation (2%/4%), G2/3 sensory neuropathy (3%/33%), G2/3 arthralgia (0%/31%), G2 myalgia (2%/8%). No treatment related deaths were observed in either arm. Conclusions: Both docetaxel plus cisplatin and paclitaxel plus carboplatin are safe and feasible regimens as adjuvant chemotherapy.

[Table: see text]