bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline bone mineral density testing among breast cancer patients prescribed aromatase inhibitors (AIs).
Authors: Charlson John A. , Smith Elizabeth , Laud Purushottam , Smallwood Alicia , Neuner Joan
Published: March 2020

6642

Background: Because of the adverse effects of AI’s on bone mineral density (BMD) and fracture risk, current guidelines recommend baseline BMD testing when initiating adjuvant AI’s. Methods: We used a validated breast cancer algorithm of Medicare claims to identify older US female breast cancer patients starting adjuvant AI therapy and to examine baseline BMD testing rates. The cohort included all US non-HMO Medicare D-enrolled women age ≥67 years who initiated AI therapy within one year after a 2006-2007 initial breast cancer surgery. Women receiving IV bisphosphonates consistent with metastatic breast cancer treatment (interval <90 days)were excluded. We examined BMD testing between 24 months prior and 6 months after AI initiation, adjusting for demographic and fracture risk factors, and comparing to a duration-adjusted testing rate for a 5% random sample of all cancer-free women enrolled in Medicare in 2008. Results: A majority of the cancer cohort (67.7%) had baseline BMD testing. This was substantially higher than the 2008 BMD testing rate for the non-cancer sample (15.4%, which translates into a 38.5% 30-month rate). Women of higher age and co-morbidity, as well as women of black race or lower income were less likely to be tested (see Table). Empiric use of oral bisphosphonates increased slightly with age, but this did not fully account for the testing differences by age. Conclusions: Although baseline BMD testing is high among women initiating AIs, approximately one-third do not receive guideline-recommended testing. Furthermore, those with greater risk fracture risk based on age and higher co-morbidity are less likely to have appropriate bone care. [Table: see text]
Impact of a decision support tool on quality measures.
Authors: Ellis Peter G. , Lokay Kathleen
Published: March 2020

6643

Background: UPMC CancerCenter received their ASCO QOPI certification after the Spring 2011 measurement period with a QOPI Certification Overall Quality Score of 78.2%. The results, however, demonstrated a number of metrics performing below QOPI mean scores. Physicians and staff performed an analysis of root causes for these underperforming metrics and identified a combination of steps to improve these metrics and the overall score. Methods: Interventions to ensure high capture of Core Metric #9 (staging within 30 days of diagnosis), #10 and #11(treatment intent and discussion with patient) were imbedded into the clinical pathways program (Via Oncology Pathways) used by the UPMC CancerCenter physicians beginning in February 2011. These data points were charted by physicians when utilizing the Via Pathways Portal and automatically displayed on the regimen order sets that are generated by that Portal. These order sets were used as official orders and therefore placed into the patient charts. Results: UPMC CancerCenter’s QOPI Certification Overall Quality Score improved by 7 percentage points to 85.39% for the Fall 2012 measurement period (as compared to Spring 2011). All of the 24 certification metrics for Fall 2012 were similar or improved as compared to Spring 2011. Core Metrics #9 and #10 improved by 18 and 22 percentage points, respectively Conclusions: Improvements in quality measures such as ASCO QOPI can be gained through targeted analysis of root cause and application of new interventions such as clinical pathways decision support. We feel that decision support tools such as pathways programs may be an important source of data for e-QOPI type programs and should be considered.
A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Authors: O'Brien Susan Mary , Lamanna Nicole , Kipps Thomas J. , Flinn Ian , Zelenetz Andrew David , Burger Jan Andreas , Holes Leanne , Johnson David Michael , Gu Jessie , Dansey Roger D. , Dubowy Ronald L. , Coutre Steven E.
Published: March 2020

7005

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective oral inhibitor of PI3Kδ. When combined with R in 19 relapsed/refractory patients with CLL, the ORR was 78% (Coutre, ASH 2012). Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m2 weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 wks w/o progression could continue to receive idelalisib on an extension study. Responses and progression were based on investigator assessment using IWCLL criteria (Hallek, Blood 2008). Results: Data is presented here on the first 50 of 64 pts enrolled, 48 CLL/2 SLL, median age 71 yrs (range: 65-89), M/F 70/30 (%), Rai stage III/IV 10/32 (%), nodes ≥5 cm in 16%, WHO 0/1/2 in 34/64/2 (%); del(17p) in 6 pts and del(11q) in 13 pts. 32 pts completed 48 wks (18 discontinued, 11 due to AE, 4 due to death and 3 other); 30 pts entered the extension study and 26 remain on treatment. The median time on treatment was 16 months (range 0.8-27.5). The ORRwas 96% with 4% nonevaluable; median time to response was 1.9 mos (range 1.0-6.5). There have been no on-study relapses. The Kaplan-Meier estimated PFS is 91% at 24 mos. Of note, 6/6 pts with del(17p) responded (1 CR, 5 PR) and 3 remain on treatment for more than 21 months. 13/14 (93%) pts with thrombocytopenia and 12/12 (100%) pts with anemia at baseline responded. Of 20 pts with B symptoms at baseline, 13 (65%) were asymptomatic by 8 wks. Most frequent AEs (total%/ ≥G3%) were diarrhea (including reported as colitis) (46/16), pyrexia (42/4), chills (34/0), fatigue (34/2), rash (34/10), pneumonia (30/20) and nausea (28/0). Elevated ALT/AST was seen in 60%, Gr ≥3 in 22%. Conclusions: Idelalisib + R is highly active, resulting in durable disease control in treatment-naïve older pts with CLL. These results support the further development of idelalisib in frontline CLL. Clinical trial information: NCT01203930.
Long-term safety and survival outcomes after TK-expressing donor lymphocyte infusion (TK-DLI) in allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Ciceri Fabio , Lupo-Stanghellini Maria Teresa , Oliveira Giacomo , Greco Raffaella , Vago Luca , Bondanza Attilio , Lambiase Antonio , Bordignon Claudio , Bonini Chiara
Published: March 2020

7007

Background: Suicide gene therapy (SGT) was firstly applied to allogeneic HSCT, addressing the need for modulation of graft vs host disease (GvHD) reactions while preserving graft vs leukemia (GvL) effect of alloreactive T cells. HSV-TK gene insertion in donor T-cells modulates alloreactivity by selectively destroying dividing alloreactive cells involved in GvHD. Methods: Long-term safety and survival was assessed in 128 pts entering worldwide 10 phase I-II trials that used TK-DLI to improve GvL, immune reconstitution (IR) and GvHD control. In all, 57 pts received TK DLI at our Institution: 23 to treat relapse after HLA-identical HSCT (Ciceri, 2007) and 34 to improve IR after haploidentical HSCT (Ciceri, Bonini, 2009). Results: SGT was feasible, safe and effective in promoting a dynamic and specific modulation of alloreactivity. TK-DLI clinical benefit, defined by chimerism, tumor response and/or IR, was achieved by 65 pts (51%). Grade 2 to 4 GvHD (n=28, 22%) was fully controlled by SGT. TK-DLI engrafted in 51 pts (90%) and, being detectable at low frequency up to 14 yrs, no SGT-related adverse events occurred. In HLA-identical setting (n=23; median follow-up, 15 yrs), 11 pts (48%) had disease response and 2 pts (9%) were alive in complete response (CR). In haploidentical setting (n=34; median follow-up, 7 yrs), 25 pts (73%) had IR and 9 pts (26%) were alive in CR. All pts were monitored according to guidelines on long-term survivors (Majhail, 2012). There were no major infections, while 3 pts had a second tumor. Immunity against TK-DLI was reported exclusively after HLA-identical allo-HSCT indicating that TK-DLI is not limited by SGT-specific immunity after haploidentical HSCT. Conclusions: Long-term follow-up confirms the high benefit to risk ratio of TK-DLI. A phase III trial is ongoing in haploidentical HSCT (NCT00914628). Clinical trial information: NCT00423124.
Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL).
Authors: Chang Betty Y , Furman Richard R. , Zapatka Marc , Barrientos Jacqueline Claudia , Li Daniel , Steggerda Susanne , Eckert Karl , Francesco Michelle , Woyach Jennifer Ann , Johnson Amy J , James Danelle Frances , Versele Matthias , Byrd John C. , Stilgenbauer Stephan , Buggy Joseph J.
Published: March 2020

7014

Background: Ibrutinib interacts covalently with cysteine 481 of Bruton tyrosine kinase (BTK), resulting in targeted inhibition of B cell receptor signaling. Early trials of ibrutinib mono- or combination therapy enrolled 246 CLL patients receiving a median of 14 months of ibrutinib. 20 patients (8%) experienced progressive disease (PD), including 8 patients with Richter's transformation. Here we examine changes to the CLL genome in 3 patients that acquired resistance to ibrutinib. Methods: Ibrutinib resistance was defined as patients achieving partial response (PR) or better lasting ≥ 6 months, then developing PD without Richter’s transformation. RNAseq and whole exome sequencing (WES) followed by comparative genome analysis was performed at baseline and after PD and confirmed by Sanger sequencing. RNAseq and WES data were aligned using TopHat and BWA software. Single nucleotide variations (SNVs) were identified using SAMtools mpileup. Results: Compared to patients who relapsed from conventional chemotherapy, minimal genomic changes were acquired in ibrutinib resistant patients, reflecting relative genomic stability. SNVs were discovered in 3 patients specific to the relapse sample (Table). 2 out of 3 patients had distinct SNVs that each encode a cysteine-to-serine substitution at position 481of BTK (C481S). Homologous cysteine residues in BMX, ITK, TEC and BLK were wild-type (WT). Ibrutinib inhibited recombinant C481S 25 fold less potently than WT, and could not covalently bind C481S expressed in cells. The third patient had WT BTK, but acquired a potential gain-of-function mutation encoding a R665W substitution in PLCg2, a substrate of BTK, consistent with constitutive PLCg2 activation. Conclusions: Although rare, the acquisition of C481S BTK and R665W PLCg2 mutations in the setting of resistance confirms BTK as an important pharmacologic target of ibrutinib, and suggests mechanisms of ibrutinib resistance. [Table: see text]
Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Authors: Seymour John Francis , Davids Matthew Steven , Pagel John M. , Kahl Brad S. , Wierda William G. , Miller Thomas P. , Gerecitano John F. , Kipps Thomas J. , Anderson Mary Ann , Huang David C.S. , Darden David E. , Gressick Lori A. , Nolan Cathy E. , Yang Jianning , Busman Todd A. , Graham Alison M. , Cerri Elisa , Enschede Sari H. , Humerickhouse Rod A. , Roberts Andrew Warwick
Published: March 2020

7018

Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki<0.10 nM) than for BCL-XL (Ki=48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose-escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626.
SWOG S0919: A phase II study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukemia (AML).
Authors: Advani Anjali S. , McDonough Shannon , Copelan Edward , Willman Cheryl L. , Mulford Deborah A. , List Alan F. , Sekeres Mikkael A. , Othus Megan , Erba Harry P. , Appelbaum Frederick R.
Published: March 2020

7028

Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A prior Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also reported an encouraging response rate (Blood 109: 2999, 2007). SWOG S0919 therefore evaluated the complete remission (CR) rate in a larger number of pts with relapsed AML treated with the pravastatin dose arrived at in the Phase 1 trial. Methods: Pts were treated at SWOG institutions from Aug 2009 through Nov 2012. Pravastatin was supplied by Bristol-Meyers Squibb. The protocol was approved by each institution’s review board. Eligibility: age ≥ 18 yrs, relapsed AML, cardiac ejection fraction ≥ 45%, CR/ CR with incomplete count recovery (CRi) following most recent chemotherapy lasting ≥ 3 months, no prior hematopoietic cell transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m2/d IV Days 4-6, and cytarabine 1.5 g/m2/d continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by IWG criteria. Fifty eligible pts were to be accrued. If ≥ 21 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level = 4.8% if true CR rate = 30% and power of 90% if true CR rate = 50%). Results: The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study. Thirty-six pts with a median age of 59 yr (range 23-78) were enrolled. Seventeen pts (47%) were male and the median WBC was 2800/ uL (range 700-110,600). The median time from initial dx to registration was 18 mo (range 5-136). Relapse status: 1st: 17 pts (47%), 2nd: 15 (42%), 3rd: 2 (5.5%), and 4th: 2 (5.5%). Eighteen pts have died, 3 during treatment. The response rate was 75% (95% CI 58-88%; 20 CR, 7 CRi); and the median overall survival was 10 mo. The p-value comparing 75% to 30% (null response rate) is 3.356 x 10-8. Duration of last CR (≤ 6 months) and prior high dose cytarabine exposure did not affect response to protocol treatment. Conclusions: The CR/ CRi in this relapsed population is encouraging. We plan to evaluate the efficacy of this regimen in higher-risk patients. Clinical trial information: NCT00840177.
Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis.
Authors: Kvasnicka Hans-Michael , Thiele Juergen , Bueso-Ramos Carlos E. , Hou Kevin , Cortes Jorge E. , Kantarjian Hagop M. , Verstovsek Srdan
Published: March 2020

7030

Background: Myelofibrosis(MF) is characterized by splenomegaly, burdensome symptoms, progressive bone marrow (BM) fibrosis, and shortened survival. Ruxolitinib (Rux), an oral, FDA-approved JAK1/JAK2 inhibitor, has demonstrated improvements in spleen volume, symptoms, and survival in patients (pts) with MF. This study was conducted to explore possible effects of long-term Rux treatment on BM morphology in MF. Methods: Trephine biopsies were obtained at baseline, 24 (67 pts), and 48 (17 pts) months (mo) from the cohort of MF patients treated at MD Anderson Cancer Center who participated in a phase I/II trial of Rux (NCT00509899). The clinical outcomes from this trial have been published previously [Verstovsek, NEJM 2010]. Two of the authors (JT and HMK) independently evaluated the World Health Organization (WHO)-defined BM fibrosis grade (0-3). Reviewers were blinded to pts characteristics and outcomes and consensus decided discordant scores. For demonstrative purposes, WHO BM fibrosis grading was also determined for a control cohort of pts treated with hydroxyurea (HU) for 24 (31 pts) and 48 (20 pts) mo. Changes in BM fibrosis grade vs. baseline were calculated for 24 and 48 mo, and categorized as improvement, stabilization, and worsening for each patient. Results: A higher percentage of Rux-treated pts showed stabilization or improvement of BM fibrosis at both 24 and 48 mo than the HU-treated pts. Worsening was greater in the HU-treated cohort at both time points. Conclusions: This exploratory analysis of long-term exposure to Rux in MF provides the first indication that JAK inhibitor therapy may be able to meaningfully retard advancement of BM fibrosis. A comparable effect was not seen with long-term HU therapy. Additional research is needed to further elucidate these findings. Clinical trial information: NCT00509899. [Table: see text]
Efficacy and cost of peripheral blood stem cell (PBSC) mobilization with low-dose cyclophosphamide (LD-CY) compared with plerixafor (P) in multiple myeloma (MM) patients (pts) treated with novel induction therapies.
Authors: Chaudhary Lubna , Awan Farrukh Tauseef , Cumpston Aaron , Tse William W. , Craig Michael , Hamadani Mehdi
Published: March 2020

7040

Background: Efficacy and cost effectiveness of P vs. LD-CY mobilization in MM pts treated with novel induction therapies is not known. Methods: We analyzed the mobilization outcomes of 107 consecutive pts who underwent a planned, single autograft within 1-year of starting induction therapy with novel agents (thalidomide, lenalidomide, bortezomib) between 2003-2012. Pts undergoing mobilization with LD-CY/G-CSF (1.5gm/m2) (n=74) were compared against those receiving P/G-CSF (0.24mg/kg) (n=33). Efficacy of PBSC mobilization was assessed by evaluating peak peripheral blood (PB) CD34+ cell counts, CD34+ cell yield on day1 of collection, total CD34+ cell collection, and total number of apheresis sessions. Mobilization failure was defined as failure to collect ≥2 x106 cells/kg body weight. Mobilization costs were calculated per patient in both groups. Centers for Medicare and Medicaid Services reimbursement rates and Red Book Average Wholesale Price were used for cost determination. Results: At baseline, the LD-CY and P cohorts were well balanced. Compared to LD-CY, P use was associated with higher median peak PB CD34+ cell count (68/µl vs. 36/µl, p=0.048), CD34+ yield on day 1 of collection (6.9 x106/kg vs. 2.4 x106/kg, p=0.001), and total CD34+ cell yield (11.6 x106/kg vs. 7x106/kg, p=0.001). Median numbers of apheresis sessions were 2 in each group (p=0.17). In pts with prior lenalidomide use, mobilization failure rate in the LD-CY group was higher compared to the P group (20% vs. 0%, p=0.01). P group had a higher number of pts collecting ≥10x106/kg CD34+ cells (60.6% vs. 31%, p=0.01). Rate of infectious complications, transfusion requirements and hospitalizations was similar in both groups. The average total cost of mobilization in the P group was significantly higher compared to the LD-CY group ($28,980 vs. $19,627, p-value<0.0001). Conclusions: Our data indicates that although associated with a significantly higher total mobilization cost, plerixafor produced a more robust PBSC mobilization, without any collection failures.
Frequency of rare cytogenetic abnormalities at relapse in acute myeloid leukemia (AML) with FLT3 internal tandem duplication (ITD) and normal karyotype at diagnosis: Evidence for genomic instability?
Authors: Gourdin Theodore Stewart , Ning Yi , Rassool Feyruz , Tidwell Michael , Duong Vu , Emadi Ashkan , Baer Maria R.
Published: March 2020

7049

Background: FLT3-ITD mutations are present in AML in 30% of patients, most commonly with a normal karyotype, and are associated with short disease-free survival. In vitro and in vivo studies of FLT3-ITD cell lines and patient samples have demonstrated DNA double-strand break repair by an alternative highly error-prone form of non-homologous end-joining (ALT NHEJ), resulting in illegitimate ligation of non-contiguous DNA breaks, causing DNA deletions and translocations that may contribute to disease progression. To look for clinical evidence of genomic instability, we reviewed cytogenetic changes at relapse. Methods: Charts of patients with cytogenetically normal AML with FLT3-ITD treated at the University of Maryland Greenebaum Cancer Center were reviewed along with metaphase analysis results at diagnosis and relapse. Results: Cytogenetic data were available from first and, when applicable, subsequent relapses for 12 patients with cytogenetically normal AML with FLT3-ITD who relapsed, including 5 following allogeneic hematopoietic stem cell transplantation (allo HSCT). Ten patients acquired cytogenetic changes, many of them rare translocations and inversions (Table). Conclusions: AML with FLT3-ITD and normal karyotype at diagnosis has a high frequency of rare cytogenetic abnormalities at relapse, providing clinical evidence for genomic instability. These data may support the potential therapeutic role of inhibitors of ALT NHEJ repair proteins, such as PARP1 and DNA ligase IIIa, in AML with FLT3-ITD. [Table: see text]
Impact of early molecular response to nilotinib (NIL) or imatinib (IM) on the long-term outcomes of newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): Landmark analysis of 4-year (y) data from ENESTnd.
Authors: Saglio Giuseppe , Hughes Timothy P. , Larson Richard A. , Issaragrilsil Surapol , Turkina Anna G. , Steegmann Juan Luis , Lopez Jose L. , Nakaseko Chiaki , Kalaycio Matt E. , Huguet Francoise , Kemp Charisse N. , Fan Xiaolin , Menssen Hans D. , Kantarjian Hagop M. , Hochhaus Andreas
Published: March 2020

7054^

Background: ENESTnd demonstrated the superiority of NIL to IM in pts with newly diagnosed CML-CP, such as higher rates of molecular response (MR) and reduced risk of progression to accelerated phase (AP)/blast crisis (BC). This landmark analysis of ENESTnd is based on BCR-ABL transcript levels at 3 mo, with 4 y of follow-up. Methods: Rates of major MR (MMR; BCR-ABLIS ≤ 0.1%), MR4.5 (BCR-ABLIS≤ 0.0032%), progression to AP/BC, overall survival (OS), and progression-free survival (PFS) in pts in the NIL 300 mg twice daily (BID; n = 282) and IM 400 mg once daily (QD; n = 283) arms of ENESTnd were evaluated based on 3-mo BCR-ABL levels (≤ 10% vs > 10%). Results: More pts treated with NIL than IM achieved BCR-ABL ≤ 10% at 3 mo (91% vs 67%; Table). Other factors associated with MR at 3 mo included Sokal risk, spleen size, chromosomal abnormalities, white blood cell count, and median dose intensity (for NIL). On both arms, pts with BCR-ABL ≤ 10% at 3 mo had significantly higher rates of MMR and MR4.5and significantly improved PFS and OS than pts with BCR-ABL > 10% at 3 mo. Of the pts with BCR-ABL > 10% at 3 mo, 2 on NIL (8%) and 14 on IM (16%) progressed to AP/BC on study. Half of these progressions occurred between 3 and 6 mo. Analyses of outcomes based on BCR-ABL levels at 6 mo were similar to findings based on 3-mo data. Conclusions: BCR-ABL levels ≤ 10% at 3 mo were associated with superior outcomes, including higher rates of MR4.5 by 4 y and lower risk of disease progression. More pts treated with NIL than IM achieved this early level of MR. Clinical trial information: NCT00471497. [Table: see text]
High-dose cytarabine-mitoxantrone versus hyper-CVAD in adult acute lymphoblastic leukemia and Burkitt’s lymphoma: A single center experience of two induction regimens.
Authors: Lamba Gurpreet Singh , Pawar Rahul , Marballi Abhishek , Lee Sang-Joon , Liu Delong
Published: March 2020

7076

Background: This is a retrospective analysis of 111 newly diagnosed adult ALL patients treated between January 1994 and January 2012 at Westchester Medical Center. Methods: Patients received induction chemotherapy with either high dose mitoxantrone and high-dose Ara-c (HDAM, n=62) or Hyper-CVAD (n=49). The patient characteristics are summarized in the table. OS, CR duration and time to recurrence were estimated using the Kaplan-Meier product estimate methods and comparative study was conducted based on Log-rank test. Differences in CR rates by treatment and by prognostic factors were analyzed using Chi-squared test and Fisher’s exact test. Results: The CR rate was 85% in the HDAM group and 84% in the HyperCVAD group. The median OS was 22.7 months (m), (95% CI 15.3-38.3 m) for the entire cohort, 21.4 m (95% CI 13.3 - 35.5 m) for HDAM arm and 26.8 m (95% CI 11.7 - 63.3 m) for HyperCVAD arm. The OS for patients with Philadelphia chromosome positive or t(4,11) was 13.2 m (95 % CI 9.5 – 26.8 m). In an analysis of the entire cohort for differences in CR rates based on prognostic factors, WBC < 10,000 was the only favorable factor toward CR (p=0.049). Other prognostic factors including cytogenetics, cell type, age, LDH, were not statistically significant. Conclusions: HDAM and Hyper-CVAD appear to be comparable in CR induction and overall survival in this single institution retrospective analysis. These two regimens should be compared in a large multicenter randomized study. [Table: see text]
Economic benefits of adequate molecular monitoring in patients with chronic myelogenous leukemia (CML).
Authors: Chen Lei , Guérin Annie , Wu Eric Q. , Dea Katherine , Goldberg Stuart L.
Published: March 2020

7093

Background: Molecular monitoring every 3 months using quantitative polymerase chain reaction (qPCR) of BCR-ABL mRNA transcripts on International Scale is recommended by the National Comprehensive Cancer Network and the European LeukemiaNet for patients (pts) in chronic phase of CML. A previous study has shown an underutilization of qPCR in the community setting. This study assessed the impact of the frequency of molecular monitoring on hospitalization and medical costs among CML pts receiving 1st-line tyrosine kinase inhibitor (TKI) therapies. Methods: Two U.S. administrative claims databases were combined (01/2000-06/2012) to identify adult CML pts initiated on TKIs (imatinib, dasatinib, nilotinib). Pts were followed for 12 months from their first TKI prescription and categorized into 3 cohorts based on frequency of qPCR tests (i.e., 0, 1-2, and 3-4). Number of inpatient admissions and medical service costs (measured from a US payer perspective; adjusted to 2012 U.S. dollars) were compared between cohorts. Multivariate regression models adjusted for confounding factors (e.g., age, gender, CML complexity, TKI). Results: The study included 1,205 CML pts. Over the 12-month study period, 41.0% of the pts had no qPCR test, 31.9% had 1-2 tests, and 27.1 % had 3-4 tests. Compared to pts with no qPCR monitoring, those with 3-4 tests incurred 37% fewer CML-related (i.e., a primary CML diagnosis) inpatient admissions (p=.017) during the study period, leading to a $4,000 (p=.009) reduction in CML-related inpatient costs and $5,663 (p=.005) reduction in all-cause inpatient costs, accounting for the majority of the $5,997 reduction in total medical service costs (p=.049). Pts with 1-2 tests a year showed smaller and statistically insignificant reductions from those with no test in the frequency of hospitalization and medical costs. Conclusions: Among CML pts who initiated 1st-line TKIs, pts with 3-4 qPCR tests a year incurred fewer inpatient admissions and lower medical service costs compared to pts with no test. These findings suggest that pts would benefit from regular qPCR testing and underscore the value of molecular monitoring in the delivery of quality care for Ph+ CML-CP pts on TKI therapies.
Predictors of survival in patients with transformed chronic lymphocytic leukemia (TC).
Authors: Falchi Lorenzo , Keating Michael J. , Wang Xuemei , Schlette Ellen J. , Sargent Rachel L. , Marom Edith M. , Truong Mylene , Wierda William G. , Ferrajoli Alessandra
Published: March 2020

7098

Background: Patients with CLL that develop Richter’s syndrome (RS) have a very poor prognosis. Similarly, pts with CLL that have clinical and histological features (increased large cells/prolymphocytes in CLL tissue biopsy) of increased aggressiveness (defined as accelerated phase CLL, AP) have a poor prognosis. In order to identify prognostic factors in pts with AP and RS, collectively referred to as TC, we reviewed our center experience. Methods: Pts with TC and complete evaluation including biopsy and concomitant FDG/PET were included. Pts with de novo TC were excluded as their prognosis is substantially superior versus previously treated pts. Pts with N+ or M+ concurrent solid tumors were also excluded. Since FDG/PET-derived SUV reflects tumor proliferative rate, we used SUVmax≥10 to indicate high-risk disease (Falchi, Blood. 2012;120: abstr # 927). We identified factors associated with outcome and performed a multivariable model for OS. Results: One hundred eighty-three consecutive pts with TC (99 with AP and 84 with RS) were evaluated at MDACC between 2002 and 2012. Demographic and clinical characteristics were similar between pts with AP and pts with RS. 30% and 77% of pts with AP and RS, respectively had an SUVmax≥10. Approximately half of the pts were treated with intensive chemoimmunotherapy after the TC diagnosis. CR rates were 21% and 16% and overall response rates were 37% and 26% for pts with AP and RS, respectively. At the time of this analysis 144/183 pts have died, for a median OS of 9.6 months (7.9-14.7). Age ≥65, B symptoms, LDH, β2-microglobulin, del17p, SUVmax≥10, extensive disease by FDG/PET (SUVmax≥5 on both sides of the diaphragm), PS≥2 bulky disease and high Ki67 correlated with shorter OS. In multivariable analysis SUV uptake (max≥10), PS higher than 1 and bulky nodal disease (>5 cm) retained independent significance. Conclusions: Based on our experience, an SUVmax of 10 or higher, PS higher than 1 and bulky nodal disease (>5 cm) are the most important factors predicting outcome in pts with TC. A prognostic model for survival is being developed for pts with TC.
Trends and outcomes of severe sepsis in hematopoietic stem cell transplant recipients.
Authors: Guddati Achuta Kumar , Kumar Gagan
Published: March 2020

7127

Background: Sepsis is common in hematopoietic stem cell transplant (HSCT) patients due to deficient immune system in the early part of the transplant and in patients with graft versus host disease (GVHD). There is very limited data on outcomes and trends of severe sepsis (SS) in these groups of patients. Methods: Using the Nationwide Inpatient Sample 2000-2008, patients older than 18 years, discharged with SS were identified using ICD-9-CM codes. Status of HSCT was identified using ICD-9-CM codes 41.0x. We also identified subsequent hospital admissions using ICD-9-CM codes V42.81-82 and 996.85 and GVHD using 279.5x. Hospital mortality was the primary outcome studied. Chi square test was used for comparison. Logistic regression model was constructed to examine the independent effect of HSCT on mortality in patients with SS. We adjusted for age, gender, race, insurance, hospital characteristics, Charlson's co-morbidity index and severity of sepsis using number of organ failures. Results: Of the 291,182 admissions with HSCT from 2000 to 2008, 7.5% had SS. The rate of SS was 5 times higher in HSCT when compared to non transplant group. In engraftment period, allogenic transplant had higher rates of SS when compared to autologous (13.2% vs. 5.2%, p<0.001). During engraftment, in-hospital mortality with SS was higher in allogenic transplant (55.1%) compared to autologous group (30.1%) (mortality in non-transplant was 32.9%). On adjusted analysis, compared to non transplant group, the odds of mortality was 4.69 times (95%CI 2.85-7.69) higher in allogenic transplants while it was similar in autologous group. In subsequent admissions, the odds of mortality were 2.38 times (95%CI 2.10-2.69) higher in GVHD and 1.45 times higher (95%CI 1.28-1.65) in non-GVHD patients when compared to the non-transplant group. The in-hospital mortality in HSCT decreased from the year 2000 to 2004 but has not changed ever since, while in the non-transplant group the mortality has continued to decrease. Conclusions: Higher mortality is observed in allogenic transplant patients and in those developing GVHD when compared to non-transplant patients. The mortality due to SS in HSCT patients has not changed since 2004 and may warrant more aggressive interventions.
Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small cell lung cancer: A randomized, placebo controlled phase II study CALGB 30504 (ALLIANCE).
Authors: Ready Neal , Pang Herbert , Gu Lin , Otterson Gregory Alan , Thomas Sachdev P. , Miller Antonius Arthur , Baggstrom Maria Quintos , Masters Gregory A. , Graziano Stephen L. , Crawford Jeffrey , Bogart Jeffrey , Vokes Everett E.
Published: March 2020

7506

Background: Sunitinib (S) inhibits small cell lung cancer (SCLC) targets VEGFR1-3, PDGFR, and KIT. We tested whether giving S after chemotherapy (C) for extensive stage SCLC improves progression free survival (PFS). Methods: CALGB 30504 was a randomized, double-blind, placebo (P) controlled phase II study for untreated SCLC, performance status 0-2, adequate organ function, and no S risk factors: bleeding, hypertension, or brain metastases. Enrollment was prior to C: cisplatin 80 mg/m2 or carboplatin AUC5 day 1 plus etoposide 100 mg/m2days 1-3 every 21 days 4-6 cycles. Patients without progression after C were stratified cisplatin vs carboplatin, and 4-5 vs 6 cycles C, and randomized 1:1 to P or S 37.5 mg daily until progression assessed every 6 weeks. Prophylactic cranial irradiation was offered to responders (CR or PR) to start about 4-6 weeks after C. S was held during radiation. Crossover from P to S was allowed at progression. Primary endpoint was PFS (from time of randomization) for maintenance (M) P vs S using a 1-sided log rank test with a=0.15; 80 randomized and treated patients provide »89% power to detect a hazard ratio (HR) of 1.67. Results: Between 5/09 and 12/11, 144 enrolled and 138 received C. Ninety five were randomized to P vs S; 10 did not receive M due to progression, refusal, and AE (5 each arm). Eighty five received M, 41 P and 44 S. Demographics were balanced. M toxicities grade > 3 and incidence > 5% included (%): grade 3 (S: fatigue 19, neutrophils 10, leukocytes 7, platelets 7) (P: fatigue 5); grade 4 (S: 1case GI hemorrhage, 1case lipase) P zero; grade 5 zero both arms. Efficacy (90% CI): PFS on maintenance after C was P 2.3 mo (CI: 1.7-2.6) and S 3.8 mo (2.7-4.4) (HR=1.54, CI 1.03-2.32, p=0.04). Overall survival (OS) was P 6.7 mo (5.5-9.5) and S 8.8 mo (8.0-9.8) (HR=1.10, CI 0.71-1.70, p=0.36). At progression on P, 17 received S and among 14 evaluable 10 (71%) had stable disease receiving 2-9 cycles S. Conclusions: The primary objective was met showing improved PFS for maintenance S. There was a non-significant trend toward improved OS despite crossover design. S was well tolerated. Further study of sunitinib after chemotherapy for SCLC is justified. Clinical trial information: NCT00453154.
Comprehensive genomic analysis of small cell lung cancer in Asian patients.
Authors: Umemura Shigeki , Goto Koichi , Mimaki Sachiyo , Ishii Genichiro , Ohmatsu Hironobu , Niho Seiji , Yoh Kiyotaka , Matsumoto Shingo , Takahashi Akiko , Nagai Kanji , Ohe Yuichiro , Esumi Hiroyasu , Tsuchihara Katsuya
Published: March 2020

7512

Background: Small cell lung cancer (SCLC) is an aggressive disease with poor prognosis. There is an urgent need for detecting well-defined therapeutic targets, however, little is known about the molecular events causing SCLC. This report describes findings from the integrated genomic analyses of 47 human SCLC samples in Asian population. Methods: We performed whole exome sequencing and copy number analysis on surgically resected tumor and matched normal samples from previously untreated Japanese patients with SCLC. Frequency of driver gene alterations were compared with previous two reports intended for non-Asian population (Peifer et al. Nature Gen 2012 and Rudin et al. Nature Gen 2012). Results: The demographics of 47 patients were as follows: median age 67 years (range: 42-86); female 8 (17%); history of smoking 47 (100%) and pathological stage I/II/III/IV=26/12/8/1. The average of protein-altering mutations was 193 (range: 51-633, standard deviation: 129). Genomic alterations including copy number amplifications and deletions in at least one of three frequently occurred driver genes, TP53, RB1, and MYC family, were detected in 93.6% of tumors. Mutation frequencies were 76.6%, 42.6%, and 12.8% for TP53, RB1, and MYC family respectively, which were equivalent to the previous reports. Recently reported candidate new driver genes were also recurrently confirmed in the present study: PTEN 4.3%, CREBBP 4.3%, EP300 4.3%, SLIT2 4.3%, MLL 4.3%, CCNE1 8.5% and SOX2 2.1%. Many of them were potentially targetable with currently available drugs. Conclusions: The genomic landscape of SCLC was not significantly different between Asian and non-Asian population. We perform additional targeted re-sequencing on biopsy samples obtained from metastatic SCLC to further assess the relevance of our results.
Prognostic and predictive effects of a gene expression signature for NRF2 pathway activation in lung squamous cell carcinoma (SqCC).
Authors: Cescon David W. , She Desmond , Zhu ChangQi , Sakashita Shingo , Pintilie Melania , Shepherd Frances A. , Tsao Ming Sound
Published: March 2020

7517

Background: Genomic profiling of SqCC in TCGA identified somatic alterations that activate the NRF2 transcriptional program – a master regulator of the oxidative stress response – in ~35% of tumors (NFE2L2 mutations/amplifications, KEAP1 or CUL3 mutations/deletions). This pathway has been implicated in resistance to chemotherapy. To evaluate the clinical significance of this molecular subset, we developed a gene expression classifier and tested this signature as a predictor of adjuvant chemotherapy benefit with cisplatin/vinorelbine (cis/vin) in a subset of SqCC patients with microarray data from the NCIC JBR.10 Phase III clinical trial. Methods: Logistic regression (LR) and SAM analysis were independently applied to 104 TCGA SqCC cases that had both microarray gene expression and mutation data to identify genes associated with NRF2 pathway mutational status. Overlapping genes were used to define the signature, which was then tested in 3 independent SqCC datasets (62 JBR.10; 54 UHN; 129 UM) to evaluate the prognostic and predictive values of putative NRF2 pathway activation. Results: 29 genes comprising the signature were identified by overlap between LR (291 genes) and SAM (45 genes). The signature consistently separated SqCC into 2 groups in all datasets, corresponding to putatively activated and wild type (WT) NRF2 pathway tumors. No prognostic effect of the activated signature was observed in independent datasets (UHN HR 0.86, 95%CI 0.28 – 2.67; UM HR 1.43, 95%CI 0.82 – 2.48). Similarly, in JBR10, no prognostic effect was observed in the observation arm (n=24, HR 0.66, 95%CI 0.13 – 3.29). A trend toward improved survival with adjuvant chemotherapy was observed in patients with the WT signature (HR 0.34, 95%CI 0.08 – 1.78, p=0.13), but not in patients with the activated signature (HR 1.16, 95%CI 0.19 – 6.97, p=0.87; interaction p=0.18). Conclusions: A gene expression signature based on mutational activation of the NRF2 pathway may be predictive of benefit from adjuvant cis/vin in SqCC. Patients with NRF2 pathway activating somatic alterations may have reduced benefit from this therapy. Validation of this potentially "actionable" finding in additional datasets is necessary.
Accelerated hypofractionated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM): Results of a phase I/II study.
Authors: de Perrot Marc , Feld Ronald , Leighl Natasha B. , Opitz Isabelle , Anraku Masaki , Cho BC John
Published: March 2020

7526

Background: We developed a protocol with accelerated hypofractionated hemithoracic IMRT followed by EPP for MPM. Advantages include optimal delivery of radiation to the whole tumor bed in a short period limiting the risk of viable tumor cell spread during surgery. Methods: Patients with resectable clinical T1-3N0M0 histology proven MPM were eligible for the study. 25 Gy in 5 daily fractions over 1 week was delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings. EPP was performed one week after the end of radiation. Adjuvant chemotherapy was offered to patients with ypN2 on final pathology. The primary end-point was treatment related mortality. Secondary endpoint included overall survival and disease-free survival (DFS). Initial sites of recurrence were also recorded. Results: Twenty five patients were accrued between 11/2008 and 10/2012. Patients had a median age of 64 years (range, 45-75), 76% were males, 64% had epithelioid histology. All patients completed IMRT and EPP. IMRT was well tolerated with no grade 3-5 toxicity. EPP was performed 6±2 days after completion of IMRT. Surgical complications occurred in 18 patients. One patient died from empyema at 88 days. All but one patient (stage IB) had stage III (n=11) or IV (n=13) disease on final pathology. Five out of 13 patients with ypN2 disease underwent adjuvant chemotherapy. After a median follow-up of 19 months (range, 3-51), the estimated 3-year survival reached 62%. Survival was significantly better in epithelioid compared to biphasic pathologic subtypes (83% survival at 3 years vs 19%, respectively; p=0.004). 14 patients remain disease free after a median follow-up of 17 months (range, 3-37). 2-year DFS was 85% in stage III and 37% in stage IV disease (p=0.03). Recurrences occurred in the ipsilateral chest only (n=2), ipsilateral chest and distant sites (n=2), and distant sites only (n=6). Conclusions: Accelerated hypofractionated hemithoracic IMRT followed by EPP is feasible. This treatment could improve survival in selected patients with epithelial subtype. Clinical trial information: NCT00797719.
Intratumoral gene expression of 5-fluorouracil pharmacokinetics related enzymes in stage I and II non-small cell lung cancer patients treated with uracil-tegaful after surgery.
Authors: Eguchi Keisuke , Abiko Tomohiko , Kohno Mitsuo , Sawafuji Makoto , Horio Hirotoshi , Hashizume Toshinori , Nakayama Mitsuo , Kato Ryoichi , Kawamura Masafumi
Published: March 2020

7536

Background: It is believed through meta-analysis that the adjuvant chemotherapy with oral administration of uracil-tegafur combination drug (manufactured as UFT) yielded better survival than surgery alone in early stage non-small cell lung cancer patients (NSCLC) in Japan. However, no promising bio-marker, which can predict the benefit of UFT use in NSCLC patients, has been found. This clinical trial was designed to evaluate the relationship between the intratumoral gene expression of the five-fluorouracil pharmacokinetics related enzymes such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orate phosphoribosyltransferase (OPRT) and thymidine phosphorylase (TP), and clinical outcomes in patients to whom UFT was administered for 2 years after surgery. Methods: From June 2004 to September 2007, 236 NSCLC patients who underwent complete resection of a pathological stage IA (maximum diameter of 2cm or more), IB and II (according to the 1997 UICC TNM classification) were eligible in this study. Other inclusion criteria were age of 20 to 80 years, ECOG PS of 0 or 1 and feasible oral UFT administration within 8 weeks after surgery. Total RNA was extracted from formalin-fixed lung cancer cell sample obtained with micro-dissection method. Gene expression was examined using quantified fluorescence-based real time revers transcription-polymerase chain reaction assay. Results: 131 (63%) patients completed 2 year administration of UFT. 73 (31%) patients had recurrence during 5 years follow-up and 48 (73%) patients among them were treated with chemotherapy including platinum. The 5-year disease free survival (DFS) and overall survival (OS) rates in all patients were 66.7% and 83.7%, respectively. A cox multivariate analysis revealed pathological stage (HR: 0.4463; p=0.034), TS expression status (HR: 0.469; p=0.021) and DPD expression status (HR: 1.956; p=0.048) to be prognostic for DFS but no factors to be prognostic for OS. Conclusions: This study suggested that TS and DPD mRNA expression in the tumor were possible prognostic biomarkers for postoperative adjuvant chemotherapy with UFT in stage I-II NSCLC. Clinical trial information: 15-65-1.