bluuebunny/crossref_metadata_2025 huggingface dataset:
Why do cancer patients die in the emergency department (ED)? Analysis of 283 deaths in North Carolina EDs in 2008.
Authors: Leak Ashley Nicole , Mayer Deborah K. , Travers Debbie , Wyss Annah , Waller Anna
Published: March 2020

6119

Background: Emergency departments (ED) in the US are utilized by cancer patients for symptom management, treatment side effects, oncologic emergencies, and/or end of life care. EDs have become a place where acute care needs are addressed and there are discussions about end of life care. The purpose of this study was to describe characteristics of cancer patients who died in the ED, highlighting lung cancer patients and their ED visit characteristics. Methods: A secondary data analysis of ED visit data fromthe North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT), a population database of 110 of the 112 EDs in NC in 2008. This was a descriptive, retrospective analysis providing descriptive statistics of patient demographics including: sex, age at death, insurance, cancer type, and visit categories (hour, day, month). Free text chief complaints, as recorded by the health care provider, were cleaned and categorized. Results: There were37,760 ED visits by 27,644 patients associated with cancer; 283 (1%) of these visits resulted in death in the ED. The most common chief complaints of those who died were respiratory distress (17.3%), neurological changes (13.4%), and pain (5.7%). Of all cancer deaths, 63% were male with a mean age of 66 (SD 14.2). Over a third (N= 104, 36.7%) of cancer ED visits resulting in death had a code for lung cancer listed. Medicare was the insurance provided for almost half (47.3%) of these patients. Majority of deaths occurred on a patient’s first ED visit (70.9%). Although a third (34.7%) of deaths occurred during weekends, over a third (37.5%) occurred during weekday clinic hours. Conclusions: Even though deaths in the ED were infrequent, this study provides insight into reasons patients visit the ED. Some patients were enrolled in Hospice and/or had a DNR documented. This study can inform future research associated with precipitating factors leading up to the ED visit (e.g. worsening shortness of breath, location of care prior to ED visit). This study illustrates the importance of research on discussion of end of life care needs (advanced directives, code status, use of Hospice services) with cancer patients and their family before they reach the final stage of their disease.
Survival outcomes in HER2-positive invasive lobular breast carcinoma.
Authors: Barcenas Carlos Hernando , Hess Kenneth R. , Delpech Yann , Pusztai Lajos , Hortobagyi Gabriel N. , Giordano Sharon Hermes , Esteva Francisco J.
Published: March 2020

612

Background: HER2-positive (HER2+) invasive lobular breast carcinoma (ILC) is a rare entity and survival outcomes are not well characterized. Methods: We retrospectively searched for breast cancer patients treated at MD Anderson Cancer Center between 1992 and 2010 with a diagnosis of early stage (I-III) HER2+ILC or with HER2+ invasive mixed ductal/lobular carcinoma (MIX). With the purpose of comparing survival outcomes, we looked for patients with a diagnosis of HER2-negative [HER2(-)] ILC, HER2(-)MIX, and HER2+ invasive ductal carcinomas (IDC). We obtained data on demographics, estrogen (ER) and progesterone (PR) receptor status, tumor grade, chemotherapy received and survival status. A multivariate analysis using a Cox proportional hazards regression was performed to compare disease-free survival (DFS) and overall survival (OS) between the following groups: 1) HER2+ILC vs. HER2(-)ILC; 2) HER2+MIX vs. HER2(-)MIX; 3) HER2+ILC vs. HER2+MIX; 4) HER2+ILC vs. HER2+IDC; 5) HER2+MIX vs. HER2+IDC. Results: The number of patients identified for each group was: HER2+ILC (N= 67), HER2(-)ILC (N= 1260), HER2+MIX (N= 92), HER2(-)MIX (N= 932), HER2+IDC (N= 3080). Specifically for both the HER2+ILC and HER2+MIX groups, 24% patients were stage I, 43% stage II and 33% stage III. The median age at diagnosis was 53 years (y) in HER2+ILC, and 49 y in HER2+MIX. The ER/PR were both negative in 16% of HER2+ILC patients, and in 25% of HER2+MIX. While 80% of patients in these two groups received chemotherapy, 36% of HER2+ILC patients received trastuzumab compared to 50% of HER2+MIX. The median follow up was 60 months in the HER2+ILC group and 53 months in the HER2+MIX group. DFS and OS were not statistically different between all groups compared. However, the subgroup of ER/PR negative HER2+MIX patients had a better OS compared to ER/PR/HER2 negative (triple negative) MIX patients (Hazard ratio = 0.4, 0.2 – 0.9, p= 0.026). Conclusions: HER2+ILC and HER2+MIX are rare clinical entities and their survival outcomes may not differ from the more common HER2(-)ILC, HER2(-)MIX and HER2+IDC. ER/PR negative HER2+MIX may have an OS advantage over triple negative MIX tumors.
Do patient tracking, follow-up, and referral practices contribute to breast cancer disparities in a large urban area?
Authors: Weldon Christine B. , Trosman Julia R. , Dupuy Danielle , Roggenkamp Betty , Schink Julian C. , Orsi Jennifer M. , Murphy Anne Marie
Published: March 2020

6120

Background: Chicago Black women are 62% more likely to die from breast (BC) cancer than White women. Previous data from 39 Chicago hospitals suggested significant quality deficits in breast cancer screening and treatment (Chicago Breast Cancer Quality Consortium, 2010). Patient tracking, follow up and referral practices may influence quality of care for minority women (Mojica et al, Cancer Control, 2007). Our goal is to evaluate tracking, follow up and referral practices during screening, diagnosis and treatment of BC at Chicago hospitals servicing Black women. Methods: Using the framework approach of qualitative research, we conducted interviews with providers of BC screening and care from 20 Chicago institutions with Black patients averaging 50% of patient base (15 community, 3 academic and 2 public hospitals). Informants included surgeons, medical oncologists, radiologists, mammography technicians, internists, nurses, administrators, and patient navigators. Interviews were transcribed, and thematic and statistical analyses were performed (simple frequencies and Fisher's exact test). Results: Six of the 20 sites (30%) follow up with patients who did not show for a scheduled mammography visit. Five of these sites (83%, 5/6) have a low “no-show” rate (below 20%), compared to 4 sites (29%, 4/14) with low “no-show” rates among the 14 sites without follow-up (p=0.05). Seven of the 20 sites (25%) direct diagnosed patients to their next step in care by providing referrals and guidance, while other 13 sites rely on a primary care physician or leave the patient without a clear care plan. BC patients at 6 of the 7 sites directing care (83%, 5/6) are referred to a mid- or high-volume surgeon (3+ BC surgeries / month), compared to patients from only 1 of the 13 sites not directing care (p=0.001). Nine of the 20 sites track diagnosed BC patients through their care. Five of them (56%, 5/9) also track survivors, compared to none (0%, 0/11) of the 11 sites who do not track patients (p=0.008). Conclusions: Poor tracking, follow up and referral practices for breast cancer screening and treatment are associated with suboptimal care and may contribute to outcome disparities for Black women in Chicago.
Quantitative HER2 measurement and PI3K mutation profile in matched primary and metastatic breast cancer tissues.
Authors: Huang Weidong , Lara Jonathan F. , Michaelson Richard , Sun Xiu , Conte Pierfranco , Guarneri Valentina , Barbieri Elena , Ali Suhail M. , Leitzel Kim , Weidler Jodi Marie , Lie Yolanda , Haddad Mojgan , Paquet Agnes , Sperinde Jeff , Howitt John , Eisenberg Marcia , Hurley Laura , Petropoulos Christos J. , Lipton Allan
Published: March 2020

614

Background: HER2 status of primary breast cancer (PBC) is routinely used to determine systemic treatment for metastatic breast cancer (MBC) patients. Discordance rates of HER2 status between PBC and MBC range from 5.5% to 29% based on published meta-analyses. The clinical benefit of re-assessing HER2 in MBC tissues remains controversial. In this study, we measured quantitative HER2 expression in matched PBC and MBC tissues and correlated changes of HER2 with mutations in the catalytic domain of PI3 kinase(PIK3CA). Methods: Total HER2 protein expression (H2T) was quantified by the HERmark assay in 41 matched PBC and MBC formalin-fixed, paraffin-embedded specimens. PIK3CA mutation status in exons 9 (E545K and E542K) and 20 (H1047R) was determined using a validated pyrosequencing assay. Results: MBC samples included 5 lymph node, 13 viscera, 6 brain, and 17 soft tissue lesions (N=41). 27 (66%) cases showed higher H2T in MBC than in matched PBC; and 14 (34%) cases had higher H2T in PBC than in matched MBC, indicating an overall increase of H2T in matched MBC lesions (fold change 0.25-17.57; p=0.005, paired Wilcoxon rank sum test). HER2 positive conversion (HERmark negative/equivocal in PBC, but positive in matched MBC) was found in 6 (15%) cases, while HER2 negative conversion (HERmark positive in PBC, but negative/equivocal in matched MBC) was seen in 2 (5%) cases. HER2 status was unchanged in 33 (80%) cases. PIK3CA mutations were detected in 13 (32%) of PBC and 19 (46%) of MBC samples. Among the HER2 positive conversion cases, PIK3CA mutation was identified in 50% (3/6) PBC and 67% (4/6) MBC, compared to 0% (0/2, PBC or MBC) in the HER2 negative conversion cases. Among cases with unchanged HER2 status, PIK3CA mutation was observed in 30% (10/33) PBC and 42% (14/33) MBC. Conclusions: Quantitative HER2 assessment revealed a 20% discordance in HER2 status between matched PBC and MBC tissues, with more frequent conversion from low HER2 in PBC to high HER2 in MBC. PIK3CA mutation was observed more frequently in patients who converted from HER2 negative PBC to HER2 positive MBC. These results suggest that re-assessment of biomarkers in MBC tissues may better inform the selection of therapeutic options for patients with MBC.
Use of the PRO Onc Assay (Prometheus) to measure HER2 overexpression/activation in circulating tumor cells (CTCs) in women with HER2-negative metastatic breast cancer (MBC): A Sarah Cannon Research Institute (SCRI) trial.
Authors: Hainsworth John D. , Burris Howard A. , Murphy Patrick Brian , Lamar Ruth E. , Shastry Mythili , Finney Lindsey H. , Yardley Denise Aysel
Published: March 2020

618

Background: HER2- targeted therapy has markedly improved the treatment of women with HER2- positive breast cancer. FISH testing for HER2 overexpression is the most reliable assay method; treatment decisions are usually based on HER2 expression of the breast primary tumor. Accurate determination of HER2 status by testing CTCs may improve patient management by allowing ongoing assessment of HER2 status during treatment and/or identifying additional patients (pts) for HER2- targeted therapy. Methods: The PRO Onc assay uses a multiplexed immunoassay format to provide expression and activation profiling of HER2 and other signal transduction molecules. The assay can detect overexpression and activation (phosphorylation) of HER2, with sensitivity at a single CTC level. We obtained blood specimens from 57 women with metastatic HER2- negative breast cancer who were receiving standard chemotherapy. In these women, HER2 status had previously been determined by FISH (32) or 0 – 1+ IHC testing (25). All specimens were tested for the presence of CTCs; the PRO Onc assay was performed when CTCs were identified. The HER2 overexpression cutoff (>3.0 CU) was based on the reference value (average + 4SD) determined by analyzing normal blood obtained from 42 healthy donors. Results: 31 of 57 pts (54%) had CTCs identified. 6 of 31 pts (19%) had HER2 overexpressed, and 4 pts (13%) had HER2 activation without overexpression. 7 of 10 pts with HER2 overexpression/activation by PRO Onc Assay were FISH- negative; 3 were IHC- negative. Since initial HER2 determination, these 10 pts had received a median of 3 chemotherapy regimens (range 1 - 5). Conclusions: When CTCs were present, the PRO Onc assay identified HER2 overexpression or activation in 31% of women with HER2- negative MBC. The therapeutic significance of this finding is unknown. Since the predetermined threshold of ≥10% HER2- positive assay results was exceeded, this trial will proceed to a planned second portion, in which women with HER2- negative MBC (by FISH testing) and HER2 overexpression or activation in CTCs will receive a trial of HER2- targeted therapy.
Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 3-year (yr) follow-up (f/u).
Authors: Kantarjian Hagop , Flinn Ian W. , Goldberg Stuart , Bunworasate Udomsak , Zanichelli Maria Aparecida , Nakamae Hirohisa , Hughes Timothy P. , Hochhaus Andreas , Saglio Giuseppe , Woodman Richard Charles , Blakesley Rick E. , Kemp Charisse N. , Kalaycio Matt E. , Larson Richard A.
Published: March 2020

6509^

Background: In ENESTnd, nilotinib significantly reduced progression to AP/BC and demonstrated superior rates of MMR, MR4, and MR4.5 vs imatinib with f/u of 2 yrs. Methods: 846 pts with Ph+ CML-CP were randomized to nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283). Here, we report 3-yr f/u data. Results: Both nilotinib doses continued to demonstrate significantly higher rates of MMR, MR4, and MR4.5 vs imatinib. In a landmark analysis, pts with BCR-ABL transcript levels ≤ 10% at 3 months (mo) had a higher probability of achieving MMR by 1 and 2 yrs vs pts with transcript levels > 10%. No new progressions occurred on treatment since the 2-yr analysis; rates of progression to AP/BC including events on treatment (n = 2, 3, 12) and those occurring both on treatment and after discontinuation (n = 9, 6, 19) were significantly lower for nilotinib 300 mg BID and nilotinib 400 mg BID vs imatinib, respectively. At 3 yrs, OS considering only CML-related deaths was significantly higher for nilotinib vs imatinib. The safety profiles of nilotinib and imatinib were similar to those at 2 yrs. Conclusions: 3-yr f/u confirms the superiority of nilotinib vs imatinib and an acceptable tolerability profile for the treatment of pts with newly diagnosed Ph+ CML-CP. [Table: see text]
Phase II trial of the combination of ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL).
Authors: Falchi Lorenzo , Keating Michael J. , Badoux Xavier C. , Wierda William G. , O'Brien Susan Mary , Smith Susan C. , Wen Sijin , Kantarjian Hagop , Ferrajoli Alessandra
Published: March 2020

6516^

Background: Based on the activity of ofatumumab and lenalidomide as monotherapy, we evaluated efficacy and tolerability of the combination in pts with relapsed CLL. Methods: Thirty-six pts entered this phase II study. All pts had an indication for therapy, adequate liver/renal function and received prior fludarabine. Ofatumumab IV was given weekly for 4 weeks (300mg w 1; 1,000 mg w 2-4), monthly during months 2-6, and every other month during months 7-24. Lenalidomide 10 mg PO/day started on day 9 and continued for 24 months. Responses were assessed (2008 IWG criteria) at month 3, 6 and every 6 months. Results: Thirty-four pts are evaluable. Median age was 64 yrs (34-82), 59 % of the pts had Rai stage III-IV disease, median β-2M level was 4.1 mg/dL (1.7-16), 62 % of the pts had unmutated IgHV, 26% del(17p) and 12% del(11q). Median number of prior treatments was 2 (1-8), all pts had been treated with FCR and 29% were fludarabine-refractory. The overall response (OR) rate is 65% (22 pts); 7 pts (21%) achieved a complete response (CR) including 4 MRD-negative CR, and 15 pts (44%) achieved a partial response (PR). Twelve pts are still on therapy. Median duration of response has not been reached with a median follow up of 13 months. Seven pts discontinued therapy despite ongoing response: HSCT (3 pts), toxicity (2 pts) and physician choice (2 pts); 3 pts discontinued therapy because of loss of response (at 12, 16 and 16 months). Eighty-two % of the pts are alive. No deaths occurred on therapy, 6 deaths occurred after therapy discontinuation: CLL (4), HSCT (1) and CLL/lung cancer (1). Lenalidomide daily dose was 10 mg (9 pts), 7.5 mg (4 pts), 5 mg (13 pts), <5 mg (8 pts). G3-4 toxicities included neutropenia (16 pts, 47%), thrombocytopenia (3 pts, 9%) and anemia (2 pts, 6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs. One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3 infections occurred: pneumonia (4), fever/bacteremia (5), parotitis (1), cellulitis (2), HZV (1), and CNS toxoplasmosis (1). G1-2 tumor flare reaction occurred in 8 pts (24%). Conclusions: The combination of ofatumumab and lenalidomide was well tolerated. It induced durable responses in 65% of FCR pre-treated pts with relapsed CLL.
Results of a phase II trial of azacitidine (AZA) with or without epoetin beta (EPO) in lower-risk MDS.
Authors: Gardin Claude , Thépot Sylvain , Beyne-Rauzy Odile , Prébet Thomas , Park Sophie , Stamatoulas Aspasia , Guerci-Bresler Agnes , Cheze Stephane , Tertian Gerard , Choufi B , Legros Laurence , Bastie jean Noel , Delaunay Jacques , Wattel Eric , Dreyfus Francois , Vey Norbert , Boehrer Simone , Fenaux Pierre
Published: March 2020

6523

Background: Although anemia of IPSS low and int-1 (LR) MDS initially responds to erythroid stimulating agents (ESA) in 40-50% of patients (pts), response is generally transient. Anemia recurrence with RBC cell transfusion dependency (RBC-TD) is an indicator of poor prognosis, even in absence of progression to higher risk MDS. AZA leads to RBC transfusion independence (RBC-TI) in 30–40% of LR-MDS (Lyons, JCO, 2009), but it has not been prospectively tested in LR-MDS patients resistant to ESA. It also remains unknown if the addition of ESA to AZA would be useful in such pts. Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, NCT01015352), the Groupe Francophone des Myélodysplasies (GFM) compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) to the same treatment plus EPO 60000U/week (AZA+EPO arm). Inclusion criteria were LR-MDS resistant to at least 12 weeks of ESA, with RBC-TD ≥ 4 RBC units in the previous 8 weeks. Responders in both arms were eligible for maintenance up to 12 monthly cycles, unless progression or loss of erythroid response occurred. The primary endpoint was RBC-TI (HI-E major using IWG 2000 criteria) after 6 courses. Results: Between 2009 and 2010, the 98 planned pts were included: M/F 65/28; median age 71y (41-84); 5 pts were excluded (one consent withdrawal, 2 early unrelated events and 2 with exclusion criteria). In the remaining 93 pts, IPSS risk was low in 69 and int-1 in 23 pts, with no imbalance between arms. Five pts received < 4 cycles and 16 received only 4 or 5 cycles, mainly due to toxicity or progression. RBC-TI after 6 courses was observed in 16.7% (8/48) in the AZA arm and 18 % (8/45) in the AZA+EPO arm (P=1), and in 19.5% (8/41) and 26 % (8/31) respectively, in the 72 pts who received ≥ 6 cycles (P=.57). Overall best response rate (at least HI-E minor using IWG 2000 criteria) was 35 and 33% in the AZA and AZA+EPO arms, respectively (P=0.99). Of note, only 9 pts in the AZA+EPO arm required at least one hospitalization for a SAE, compared to 22 pts in the AZA arm (P=0.015). Conclusions: Erythroid response to AZA, in LR MDS with demonstrated ESA resistance, appears lower than expected, with no improved outcome when combined with an ESA. The latter may however improve tolerance of AZA in LR MDS.
Initial salvage therapy in first relapse AML: A phase IIb study of CPX-351 versus investigator’s choice—A subset analysis by prognostic group.
Authors: Goldberg Stuart , Cortes Jorge E. , Feldman Eric Jay , Rizzieri David , Kantarjian Hagop , Limor Sora , Louie Arthur Chin , Kolitz Jonathan E.
Published: March 2020

6525

Background: CPX-351 encapsulates cytarabine and daunorubicin within liposomes at a 5:1 molar ratio, shown in vitro to maximize synergy. Liposomal encapsulation enables preferential uptake of drug within leukemic blasts followed by intracellular release enhancing efficacy in AML. A randomized Phase 2b study in 1st relapse AML completed 1-year follow up with improvement in event free (EFS) and overall survival (OS). This report describes patient outcomes with a focus on the unfavorable subset per the European Prognostic Index (EPI) (Breems DA, et al. J Clin Oncol, 2005 Mar 20;23:1969-1978). Methods: Patients (pts) ≤65yo in 1st relapse AML after an initial CR >1 month, ECOG PS= 0-2, serum creatinine< 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST < 3 x ULN, and LVEF >50% were eligible. Pts with APL, daunorubicin exposure >368 mg/m2 (or other anthracycline equivalent), active CNS leukemia, uncontrolled infections were excluded. Pts were randomized 2:1 to receive up to 2 inductions and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5) or investigators choice of intensive salvage treatment. Post remission allo-transplantation was permitted. 126 pts were stratified by EPI into favorable, intermediate, and unfavorable groups (with projected 1-year OS of 70%, 49%, and 16%). The primary efficacy endpoint was % survival at 1-year. Results: CPX-351 increased the rate of morphologic leukemia-free state (77% vs. 60%), the rate of CR + CRi (51% vs. 41%), and the median EFS (4.0 vs. 1.4 mo) and OS (8.5 vs. 6.3 mo) in the overall patient population. Significant survival improvement occurred amongst those with unfavorable EPI scores (HR=0.55, p-value=0.02) with improved 1-year survival (29% vs. 10%). CPX-351 treatment resulted in more prolonged cytopenias with increased febrile neutropenia and grade 3-4 infections, but not in the D 60 mortality (overall: 15% vs. 16%; unfavorable: 16% vs. 24%). Conclusions: CPX-351 is highly active in AML and induces remission even in patients with prior cytarabine and anthracycline exposure. Efficacy was evident in every prognostic group, particularly in the unfavorable EPI group where a statistically significant improvement in 1-year survival was observed.
Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) on relapse-free survival in patients with newly diagnosed core-binding factor acute myelogenous leukemia.
Authors: Borthakur Gautam , Cortes Jorge E. , O'Brien Susan Mary , Kadia Tapan M. , Estrov Zeev , Faderl Stefan , Ravandi Farhad , Gandhi Varsha , Plunkett William , Bass Joyce , Brandt Mark , Kantarjian Hagop
Published: March 2020

6528

Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in induction and 3-4 days in post-remission cycles) with filgrastim started on day-1 and continued till neutrophil recovery. Pts who received one non-FLAG-GO induction could enroll irrespective of their remission status. Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 of 50 (10%) were in remission at enrollment from prior induction]. Median age is 48 years (range, 19-76), median WBC count 12.3 x106/L (range, 1.3-97.2); 12 patients (24%) were >60 years of age and frequency of kit mutation is 8%. Complete remission with or without platelet recovery (CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. With 6 planned consolidations, the median number of consolidation treatments received is 5 (range, 0-6). Two-thirds of pts needed dose reduction during post-remission cycles. Seven (14%) pts [t(8;21)= 5, Inv 16=2] relapsed and with a median follow-up of 34 months (range, 15-54 months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a highly effective regimen and has resulted in high rate of relapse-free survival in pts with newly diagnosed CBF AML.
A phase II trial 90y-ibritumomab tiuxetan in combination with reduced intensity regimen of fludarabine (flu) and melphalan (mel) followed by allo-HCT in patients with refractory B-cell lymphoma.
Authors: Nademanee Auayporn , Raubitschek Andrew Antony , Tsai Ni-Chun , Simpson Jennifer , Kogut Neil Martin , Popplewell Leslie , Sahebi Firoozeh , Delioukina Maria L. , Forman Stephen J.
Published: March 2020

6545

Background: RIC allo-HCT has reduced transplant-related mortality (TRM) in patients with relapsed NHL. However, relapses do occur despite potential graft vs. lymphoma (GVL) effect. We hypothesized that adding Zevalin to Flu/Mel may improve disease control and reduce relapse post allo-HCT. Methods: Patients received In- Zevalin on day -21 followed by 90Y- Zevalin 0.4mCi/kg on day -14, flu 25 mg/m2 daily on days -9 to -5 and mel 140 mg/m2 on day -4. Rituximab (R) level was measured on Day -22 and -15 and if the level was ≥ 10 μg/ml, R was not given prior to In-Zevalin or 90Y- Zevalin to enhance biodistribution. Tacrolimus and sirolimus was used for GVHD prophylaxis. Between 10/2007 and 11/2011, 31 were treated. Median age 55 (range 27-67), median regimen =3 (range 2-8). Median time from diagnosis to HCT was 20 mo (range 5-105). Histology: DLBCL (including transformed lymphoma)=14 (45%), MCL=7 (23%), FL=5 (16%) and SLL/CLL=5 (16%). Disease status at HCT: 1CR=7, Relapse=9, ≥2CR=5, primary refractory =10. Fifteen had chemoresistant and 19 had FDG PET+ at HCT. Donors: sib=13, URD=18. Results: All patients engrafted with the median time to ANC ≥500 and platelet ≥ 20,000 was 14 (range 10-28) and 13.5 days (range 11-28), respectively. There were 10 deaths from disease progression (2) infection (5) GVHD (1) and multi-organ failure (2). TRM at day +100 and at 1 yr was 6.5% and 17%, Five with DLBCL relapsed between 3-7 mos. Grade II-IV acute GVHD was 65%, Grade III-IV was 16%, chronic GVHD was 65%. Fifteen became PET- at day +100 while 4 remained PET+ and relapsed. Twenty-one are alive at a median followup of 24 mos (range 2-46). The 2 yrs OS and PFS was 65% (95% CI, 51-75%) and 57% (95% CI, 46-67%), respectively. Univariate analysis identified disease status predict for OS and PFS while histology predict for PFS. Conclusions: This study demonstrates the feasibility of adding Zevalin to flu/mel in the allo-HCT setting for B-cell NHL and suggest that this approach could be used to provide early disease control before GVL effect takes place. Innovative approaches should be explored in DLBCL.
Effect of ROR1-targeting small molecules on chronic lymphocytic leukemia (CLL) cells.
Authors: Mellstedt Hakan , Khan Salam , Vågberg Jan , Byström Styrbjörn , Schultz Johan , Hojat Farsangi Mohammad , Mansouri Ladan , Danesh Manesh Amir Hossein , Österborg Anders , Moshfegh Ali
Published: March 2020

6557

Background: There is a great interest to develop targeting drugs for CLL, both MAbs and small molecules, to improve the outcome for the disease. ROR1, a receptor tyrosine kinase, is overexpressed on CLL cells but not on normal cells. ROR1 is constitutively phosphorylated and siRNA transfection induces leukemic cell death. The aim of the study is to produce small molecules inhibiting the cytoplasmic tyrosine kinase activity of ROR1, which could induce specific killing of leukemic cells. Methods: A high-throughput screening assay in 384-format has been developed measuring phosphorylation of a substrate peptide by human recombinant intracellular ROR-1 kinase domain. A collection of 80.000 small molecules has been screened generating two chemical series. Novel leads have been synthesized and structure-activity-relationship has been developed using the assay. Results: Three compounds were selected (KAN0173631, KAN0438063, KAN0438175T). Freshly isolated leukemic CLL cells were used as targets in addition to PBMC from healthy donors to test cytotoxicity. The three compounds induced specific apoptosis of CLL cells (Annexin V/PI and MTT) both at 24 and 48h. Efficacy index (EI), i.e. killing of leukemic cells in relation to normal PBMC was favourable. The most promising drug KAN0438063 had an EI of 40 i.e. killed 40 times more CLL cells than PBMC at an IC50 of 10µM. The compounds induced PARP cleavage and cleavage of caspases 8 and 9 as well as down regulation of Mcl-1 and Bcl-xl (Western Blot). ROR1 was dephosphorylated (Western Blot). The selective apoptotic effect was compared to other small molecules targeting non-ROR1 structures in CLL (PCI-32765, CAL-101, R406, R788, STK-156485, STK-156133) and our compounds were significantly more effective (EI) (p<0.001). Conclusions: We have developed effective and selective series of compounds targeting ROR1 with promising ADMET properties. ROR1 targeting small molecules might also be effective for other tumor cells expressing ROR1 as has been noted for e.g. pancreatic carcinoma cells. Our model molecules will be further optimized and tested in animal tumor models. These molecules represent the first small molecules targeting ROR1 – a “survival factor” in CLL.
Response rates in patients with relapsed/refractory acute myeloid leukemia with FLT3-ITDmutation using 5-azacitadine plus sorafenib.
Authors: Alattar Mona Lisa , Kantarjian Hagop , Burger Jan Andreas , Richie Mary Ann , Garcia-Manero Guillermo , Konopleva Marina , Faderl Stefan , Borthakur Gautam , Daver Naval Guastad , Kadia Tapan M. , Cortes Jorge E. , Ravandi Farhad
Published: March 2020

6558

Background: The outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Sorafenib is an inhibitor of FLT-3 kinase activity in nanomolar concentrations. We conducted this phase II study to evaluate the efficacy and tolerability of the combination of Sorafenib and 5-Aza for the treatment of patients with refractory or relapsed AML with the particular emphasis on those with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 daily x 7 together with Sorafenib 200 mg BID X 28 days; cycles were repeated in approximately 1-month intervals. Responses were assessed after first cycle and then at the discretion of the treating physician at the time of the best peripheral blood response. Results: 32 patients with AML with a median age of 61 years (range, 24-87) were enrolled. They included 13 (41%) with diploid cytogenetics, 9 (28%) with complex cytogenetics, and 10 (31%) with miscellaneous chromosomal abnormalities. FLT-3-ITD was detected prior to the initiation of treatment in 30/32 patients. Patients had received a median of 2 prior treatments (range, 1-6). 12 (38%) patients had received ≥3 prior regimens and 11 had failed therapy with a FLT3 kinase inhibitor (6 with AC220, 1 with PKC412, and 5 with sorafenib, either as monotherapy or with plerixafor); 2 had failed 2 prior FLT3 inhibitors. 10 patients were inevaluable as they never received therapy or discontinued it before response assessment at one month. The overall CR/CRi rate among the 22 evaluable patients is 50%, including 9 (41%) with CRi and 2 (9%) with CR; with a median of 3 (range, 1-9) treatment cycles. The median time to achieving CR/CRi was 3 months (range, 1-4) and the median duration of CR/CRi was 3 months (range, <1–5.5). Three patients proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. Conclusions: Combination of 5-Aza and Sorafenib is promising for the treatment of patients with relapsed and refractory AML with FLT-3-ITD mutation and may allow them to proceed to stem cell transplant.
Effect of epitopes derived from the mutated region of cytoplasmatic nucleophosmine 1 (NPM1) on CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia.
Authors: Greiner Jochen , Ono Yoko , Hofmann Susanne , Schneider Vanessa , Schmitt Anita , Zhang Lu , Mehring Elmar , Goetz Marlies , Dohner Konstanze , Mytilineos Joannis , Wiesneth Markus , Dohner Hartmut , Schmitt Michael
Published: March 2020

6567

Background: Mutations of the nucleophosmin gene (NPM1mut) are one of the most frequent molecular alterations in AML and constitute an important prognostic marker. The impact of NPM1mut on leukemogenesis and progression remains to be elucidated. Immune responses against NPM1mut might contribute to the favourable prognosis of AML patients with NPM1mut. Therefore, we examined T cell responses against NPM1mut. Methods: NPM1 wildtype as well as NPM1mut were screened for HLA-A*0201 binding T cell epitopes with the help of different algorithm programs. Ten peptides with most favourable characteristics were tested with ELISpot analysis for interferon-γ and granzyme B in 33 healthy volunteers and 30 AML patients. Tetramer assays against most interesting epitopes were performed and chromium release assays were used to show the cytotoxicity of peptide-specific CD8+ T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4+ T cells in NPM1 immunogenicity. Results: Two epitopes (#1 and #3) derived from NPM1mut induced CD8+ T cell responses in a high frequency. In healthy volunteers, immune responses were detected in 39%/18% against #1 and #3, and in 33%/44% of NPM1mut AML patients against #1 and #3. NPM1-peptide primed effector T cells showed specific lysis of pulsed T2 cells as well as leukemic blasts in chromium release assays. In tetramer assays a significant CD8+ T cell population could be detected. To obtain a robust and continuous T cell reaction, the help of CD4+ T cells is indispensable. Therefore, we investigated the increase of CD8+ T cell responses by the activation of CD4+ T cells stimulated with longer peptides called overlapping peptides (OL). Potent HLA-DR epitopes were predicted and several favourable peptides (OL 1 to 8) were synthesized. OL8 showed favourable results to activate both CD8+ and CD4+ T cells. Conclusions: Taken together, NPM1mut represents a candidate for immunotherapeutic approaches and we hypothesize that it is also potentially involved in immunogenic rejection of NPM1mut leukemic blasts. Therefore, NPM1mut is a promising target structure for specific immunotherapies in AML patients.
Phase II study of AZD2171 for the treatment of patients with myelodysplastic syndromes.
Authors: O'Mahar Shannon Eileen , Jumonville Alcee , Flynn Patrick J. , Moreno-Aspitia Alvaro , Erlichman Charles , LaPlant Betsy , Juckett Mark ,   Phase 2 Consortium (P2C)
Published: March 2020

6570

Background: Inhibition of vascular endothelial growth factor receptors (VEGFR) can block growth and trigger apoptosis in neoplastic cells. AZD2171 (cediranib) is a highly potent, orally bioavailable, VEGFR-1/2 inhibitor. We conducted a phase II study of the efficacy of AZD2171 for the treatment of MDS. Methods: Adults with MDS (IPSS Int-2 or High) were eligible if they exhibited adequate organ function and ECOG 0-2. The primary endpoint was proportion of responses according to the IWG criteria assessed at one and every 3 months. Prior investigation of cediranib at 45 mg daily in patients with acute leukemia demonstrated toxicity concerns and therefore, the starting dose of this study was lowered to 30 mg daily. Results: A total of 16 pts with MDS (median age 73 years) were enrolled at a 30 mg starting dose, and all were evaluable. Median baseline marrow blasts were 12.0 % (range 2-18); 3 pts (18.8 %) had low, 6 (37.5 %) intermediate, and 7 (43.8 %) had high risk cytogenetics. Prior therapy included azacitidine (n=7), decitabine (n=2), cytarabine (n=2), erythropoietin-stimulating agents (ESAs) (n=2), lenalidomide (n=1), or none (n=6). Patients were treated for a median of two 28-day cycles (range 1 to 11). There were no confirmed responses. Patients with baseline blasts > 5% showed no significant reduction in the blast count at 4 and 12 weeks. Median OS was 4.7 mo (95% CI: 2.6 – 11.6). Median TTP was 3.8 mo (95% CI: 1.7 – 10.8). Grade 4 hematological adverse events at least possibly related to cediranib were neutropenia (n=2) and thrombocytopenia (n=4). Grade 3 hematological adverse events at least possibly related to study treatment included: neutropenia (n=3), thrombocytopenia (n=2), and anemia (n=2). Grade 3 non-hematological adverse events included fatigue (n=4), dyspnea (n=3), dehydration (n=2), diarrhea (n=2), nausea (n=2), asthenia (n=1), and hypertension (n=1). Hypertension and proteinuria was uncommon with the 30 mg/day dose. Conclusions: With no confirmed response from 16 patients, cediranib was determined to be ineffective at a dose of 30 mg daily in our patient population. Supported by NCI N01-CM62205, NCI P30-CA014520 and the UW Carbone Comprehensive Cancer Center.
Evaluation of combination therapies with MOR00208, an Fc-enhanced humanized CD19 antibody, in models of lymphoma.
Authors: Winderlich Mark , Ness Daniel , Steidl Stefan , Endell Jan
Published: March 2020

6574

Background: MOR00208 (formerly XmAb5574) is a Fc-engineered humanized anti-CD19 antibody with superior cytotoxicity in a number of in vitro and in vivo models of lymphoma and leukemia, currently being evaluated in patients with relapsed/refractory CLL. Bendamustine (BEN), an alkylating agent, fludarabine (FLU), a purine analogue, and the CD20 antibodies rituximab (RTX) and ofatumumab (OFA) were evaluated for their ability to enhance the cytotoxicity of MOR00208. Methods: Utilizing CD19/CD20+ MEC-1 CLL cells, cytotoxicity was assessed in vitro by flow cytometry. MOR00208 was tested alone and in combination with BEN, FLU, RTX and OFA using peripheral blood mononuclear cells as effector cells. Median survival (MS) was evaluated in a murine model of disseminated lymphoma, using i.v.-administered RAMOS cells (CD19+) and treatment with MOR00208 alone and in combination with FLU. Combinatorial effects were classified according to Chou-Talalay (Pharmacol Rev. 2006 Sep;58(3):621-81). Results: MOR00208-mediated in vitro cytotoxicity was synergistically enhanced by BEN, FLU and the CD20 antibodies irrespective of their different modes of action (Combination Index < 1). In vivo, FLU alone at doses up to the maximum tolerated dose (MTD) did not prolong MS, whereas MOR00208 at 3 mg/kg increased MS by 26% compared to the isotype control. Co-administration of MOR00208 with 125 mg/kg FLU significantly enhanced MS by 65%. Despite its lack of single agent activity, FLU thus significantly enhanced the cytotoxicity of MOR00208. Conclusions: The cytotoxic in vitro activity of MOR00208 on CD19+ B cells was synergistically enhanced by all studied drugs irrespective of their effector mechanisms. In vivo, the activity of MOR00208 in an aggressive lymphoma model was potentiated in combination with FLU. These results provide a mechanistic rationale for MOR00208 drug combinations which warrant further evaluation in clinical trials.
Quantitative detection of ZAP-70 expression in chronic lymphocytic leukemia.
Authors: Zhu Peixuan , Degheidy Heba A , Marti Gerald E , Li Shuhong , Abbasi Fatima , Wiestner Adrian , Amstutz Platte T , Tang Cha-Mei
Published: March 2020

6581

Background: Intracellular ZAP-70 protein was recently recognized as prognostic marker in chronic lymphocytic leukemia (CLL). The specific objective of this study was to develop a simple and sensitive assay, for the quantitative detection of ZAP-70 protein in leukemic cells. Methods: Components of the assay system include sample preparation, immunomagnetic fluorescence assay, Signalyte-II spectrofluorometer. The leukemic cells were isolated from CLL patient blood samples and lysed to release the intracellular ZAP-70 protein. ZAP-70 protein was captured by magnetic beads coated with anti-ZAP70 capture antibody, and recognized by a fluorescent detector antibody, forming an immuno-sandwich complex. This complex was dissociated for measurement of the fluorescence signal, which was proportional to ZAP-70 concentration, using the spectrofluorometer. Results: The assay conditions were extensively optimized by selecting an optimal pair of capture/detector antibodies, conjugation of fluorescence dye, cell lysis condition and excitation/emission wavelengths. The protocol was further validated with two positive controls, Jurkat cell lysate and recombinant ZAP70 protein (rZAP70). The limit of detection was determined to be lower than 125 Jurkat cells and 39 pg of rZAP70 protein. The signal response was linear over a wide range of concentration, from 625 to 40,000 Jurkat cells per test (R2=0.9987) and from 0 to 40,000 pg rZAP70 protein per test (R2=0.9928). The results from 20 CLL patients correlated strongly with flow cytometry analysis. The concordance between the two methods for positive and negative results was 100% (7/7) and 92% (12/13), respectively, while the overall concordance between the two methods was 95%. Conclusions: The assay is a simple, reliable, and reproducible method for quantitative detection of ZAP-70 in patient leukemic cells, without the need for cell fixation or permeabilization. The entire assay could be completed in 5.5 hours. The ZAP-70 signal was linear over a wide dynamic range, which we believe enables quantitative assessment of small changes in ZAP-70 expression over the course of the disease and in response to therapeutic intervention.
Phase I study of TH-302, a hypoxia-activated cytotoxic prodrug, in subjects with advanced leukemias.
Authors: Konopleva Marina , Handisides Damian , Lorente Gustavo A. , Benito Juliana M. , Richie Mary Ann , Borthakur Gautam , Jabbour Elias , Faderl Stefan , Cortes Jorge E. , Kroll Stewart , Andreeff Michael , Kantarjian Hagop , Thomas Deborah A.
Published: March 2020

6585

Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with ALL have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PlosOne, in press). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and AML samples in vitro. Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. Methods: Eligibility: ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepatorenal function. A standard 3+3 dose escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 minutes daily on Days 1-5 of a 21-day cycle. The objectives were to determine the MTD and PK profile of TH-302 with this schedule and to assess preliminary clinical activity of TH-302. Results: 34 subjects with previously treated AML (n=26), ALL (n=6) or CML in blast phase (n=1) received TH-302 at doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=16) or 550 (n=4) mg/m². No skin or mucosal toxicity was noted in participants treated with TH-302 doses ≤240 mg/m2. At 330 mg/m2, grade 2 dermatological toxicities included skin ulcer (n=1) and hand/foot syndrome (n=1). Grade 2 mucositis (n=3) and grade 2 skin toxicity (e.g. skin rash, skin ulcers; n=3) were reported at 460 mg/m2; none were dose-limiting. Two of 3 evaluable subjects treated at the 550 mg/m2 cohort experienced DLTs of grade 3 esophagitis. Eight subjects had stable disease or better after 1 cycle. One ALL subject (at 120 mg/m2) cleared marrow blasts with persistent neutropenia. One AML subject (at 550 mg/m2) achieved CRp after 1 cycle with resolution of leukemia cutis. Conclusions: TH-302 administered daily for 5 consecutive days every 3 weeks is well-tolerated with increased incidence of skin and mucosal toxicity at higher dose levels. Clinical activity has been noted with a few objective responses, but majority of cytoreductions in the AML subset were transient. Clinical trials combining TH-302 with various chemotherapeutics with established efficacy in AML and ALL are planned.
Albumin as a prognostic factor for overall survival in newly diagnosed patients with acute myeloid leukemia (AML).
Authors: Khan Awais M. , Lancet Jeffrey E. , Kharfan-Dabaja Mohamed A. , Al Ali Najla , List Alan F. , Komrokji Rami S.
Published: March 2020

6586

Background: Hypoalbuminemia (HA) is an adverse prognostic factor in multiple neoplastic diseases. Severe hypoalbuminemia (<3.0 g/dl) at day +90 post allogeneic hematopoietic cell transplant (AHCT) was reported as an independent predictive variable for non-relapse mortality and overall survival (Kharfan-Dabaja, et al Biol Blood Marrow Transplant 2009; 15). We examined the prognostic value of serum albumin level prior to induction chemotherapy in patients with newly diagnosed AML. Methods: Data were collected retrospectively in newly diagnosed AML patients receiving induction chemotherapy (3+ 7 regimen). Primary objective was to examine the relationship between serum albumin at baseline and probability of achieving complete remission (CR) or incomplete remission (CRi) and overall survival (OS). The Kaplan–Meier method used to estimate median overall survival; chi-square test used for comparison of categorical variables and t-test for continuous variables. Log rank test used to compare Kaplan–Meier survival estimates between two groups. Results: Between November 2004 to July 2007, 135 patients who received 3+7 induction chemotherapy were included. Patient baseline characteristics were similar between patients with serum albumin < 3.5 g/dl (HA) and those with serum albumin ≥ 3.5 g/dl (no HA) with respect to age, sex, FAB subtype, history of antecedent MDS, karyotype, and chemotherapy . In patients with HA, mean age was 60 years compared to 56.5 years in non HA group. The median OS for patients with HA was 221 days (95%CI 149.5-292.5) compared to 421 days (95%CI 236.7-605) with normal serum albumin (p<0.005). (Figure-1) The CR/CRi rate was 64%% for HA and 77.6% for those with normal albumin (p=0.09). In a multivariable Cox regression analysis including age ≥ 60 years, history of MDS, karyotype, and serum albumin level at baseline; only age, karyotype and serum albumin were independent predictors of OS [Hazard ratio 0.47 (95%CI 0.31-0.71) (p<0.005) for normal serum albumin group]. Conclusions: In newly diagnosed AML, we demonstrate that hypoalbuminemia < 3.5 g/dl is an independent covariate for overall survival with conventional chemotherapy management. The prognostic value of low serum albumin should be validated in a prospective study.