bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of lapatinib and neratinib on HER2 protein levels in breast cancer cell lines.
Authors: Collins Denis , O'Donovan Norma , Walsh Naomi , Gately Kathy , Edwards Connla , Davies Anthony , O'Byrne Kenneth John , Crown John ,   Molecular Therapeutics for Cancer Ireland (MTCI)
Published: March 2020

637

Background: HER2, a member of the c-erbB receptor tyrosine kinase family, is over-expressed (HER2 gene amplification/IHC 3+, >30% cells) in approx. 25% of breast cancers. Pre-clinical studies have shown that the HER2-targeted small molecule tyrosine kinase inhibitor (TKI) lapatinib (LAP) can increase HER2 levels in cell line models and can potentiate trastuzumab-mediated antibody dependent cell-mediated cytotoxicity. To assess the potential effects of the next generation TKI neratinib (NER) on expression of HER2 in breast cancer, this study compares the effects of LAP and NER on HER2 protein levels in the HER2-amplified SKBR3 and HER2-non-amplified T47D cell lines in vitro. Methods: SKBR3 and T47D were treated with LAP or NER (0.2, 1 and 2 µM) for 12, 24 and 48 hours.HER2 protein levels were determined by ELISA, immunoblotting and high content analysis (HCA). HER2 protein was examined using two antibodies targeting the extracellular domain (ECD) and the intracellular domain (ICD) of HER2. pHER2, EGFR/pEGFR, MAPK/pMAPK and AKT/pAKT levels were determined by immunoblotting. Proliferation studies utilized an acid phosphatase-based assay. Results: ELISA analysis confirmedsignificantly lower HER2 expression in T47D (44 +/- 17 pg/µg) compared to SKBR3 (748 +/- 296 pg/µg), p = 0.015. NER proved a more potent inhibitor of pHER2 and pEGFR as analyzed by immunoblotting and in proliferation studies (NER IC50 - SKBR3 0.03 +/- 0.01 nM, T47D 199 +/- 70 nM, LAP IC50 - SKBR3 20 +/- 1 nM, T47D 1.2 +/- 0.2 µM). LAP induced an increase in both ECD and ICD-containing HER2 protein levels in SKBR3 and T47D cells. No increase in HER-2 levels was observed with NER treatment, as determined by HCA and immunoblotting. EGFR protein levels increased in response to lapatinib in both cell lines. Conclusions: Our results suggest that LAP and NER have differing effects on HER2 protein levels in the models examined. NER provides greater inhibition of HER2 signaling activity but does not increase HER2 protein levels as was observed with LAP. Further pre-clinical assessment of combinations of LAP and NER with HER2 and EGFR monoclonal antibody therapies is warranted in HER2-amplified, HER2-non-amplified and EGFR-expressing breast cancer models.
Time to brain metastasis (TTBM) from initial diagnosis of distant metastasis in breast cancer: Prediction of TTBM according to breast cancer subtypes and treatment effect.
Authors: Park Yeon Hee , Ahn Hee Kyung , Park Silvia , Maeng Chi Hoon , Lee Su Jin , Ahn Jin Seok , Im Young-Hyuck
Published: March 2020

644

Background: Brain metastasis (BM) from breast cancer (BC) is a growing problem. About 10-15% patients with metastatic breast cancer (MBC) developed BM, with a 1 year survival of 20%. Currently, one-third of MBC patients with either HER2+ve tumors or triple negative BC (TNBC) tumors develop brain metastases. We hypothesized that MBC patients may predispose to BM differently during the disease courses according to BC subtype and treatment. We analyzed TTBM from initial diagnosis of distant metastasis how BC subtypes and treatment affect on TTBM. Methods: We retrospectively investigated 189 consecutive patients who were diagnosed with BM from BC between 2000 and 2009 at Samsung Medical Center. We analyzed TTBM according to BC subtypes and treatment effect. Results: The median age of 189 BM patients from BC was 48 (range 26-87) years. The numbers of patients with hormone receptor (HR)+ve and HER2-ve, HER2+ve irrespective of HR status, and TNBC were 43 (22.8%), 88 (46.6%), and 58 (30.7%), respectively. Median TTBM of all 189 patients was 10.4 (95% CI, 7.7-13.1) months. We analyzed TTBC into four groups considering BC subtypes and treatment; HR+ve/HER2-ve (n=43), HER2+ve with trastuzumab (T) (n=59), HER2+ve without T (n=29), and TNBC patients (n=58). The median TTBMs for each group were 17.7 months, 13.8 months, 4.3 months, and 2.9 months, respectively (p=0.002). BM as an initial site of distant metastasis was much more common in HER2+ve without T and TNBC patients than in the other patients’ groups (40.2% vs 20.6%, p= 0.003). Conclusions: TTBMs were much shorter in patients with HER2+ve without T and TNBCs than in other BC patients. Different approaches for evaluation and therapeutic strategy for BM at the time of distant metastasis may be considered for these populations.
Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib.
Authors: Shah Neil P. , Kantarjian Hagop , Kim Dong-Wook , Hochhaus Andreas , Saglio Giuseppe , Guilhot Francois , Schiffer Charles Alan , Steegmann Juan Luis , Mohamed Hesham , Dejardin David , Healey Diane I. , Cortes Jorge E.
Published: March 2020

6506

Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 1st- and 2nd-line therapy for CML pts with newly diagnosed disease or resistance/intolerance to imatinib. This ongoing study in pts with imatinib-resistant/-intolerant CML provides the longest follow-up of a second-generation BCR-ABL inhibitor. Methods: Study design has been described (Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML (N=670) were randomized to dasatinib 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 pts (74%) remain on QD dosing, 85 of whom (56%) are on ≥100 mg QD dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) originally randomized to BID dosing having switched to QD dosing. For pts randomized to the 100 mg QD arm (n=167), progression-free survival (PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate of transformation to advanced disease. In exploratory analyses, 42% and 60% of pts had BCR-ABL levels ≤10% (International Scale) at 1 and 3 months (mos), respectively. In a landmark analysis, BCR-ABL ≤10% at 1 or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, nonhematologic adverse events (AEs; all grades) generally first occurred in <24 mos. Cumulative rates of AEs in the 100 mg QD arm were headache (33%), diarrhea (28%), fatigue (26%), and pleural effusion (24%). For dasatinib 100 mg QD, cytopenias (grades 3/4) generally first occurred in <12 mos. The most common hematologic AEs (grades 3/4) in the 100 mg QD arm were neutropenia (36%) and thrombocytopenia (24%). AEs were managed by dose/schedule modifications. Conclusions: Five-yr follow-up of pts who switched to dasatinib 100 mg QD after imatinib-resistance/intolerance shows high rates of PFS, and OS with an overall low rate of transformation. Exploratory analyses suggest that achievement of a fast and deep response (≤10% BCR-ABL) at 1 or 3 mos after initiation of dasatinib 100 mg QD may be associated with a higher PFS. Dasatinib 100 mg QD was generally well tolerated over 5 yrs. Six-yr data will be presented.
A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases.
Authors: Jaglowski Samantha Mary , Jones Jeffrey Alan , Flynn Joseph M. , Andritsos Leslie A. , Maddocks Kami J. , Blum Kristie A. , Grever Michael R. , Geyer Susan Michelle , Woyach Jennifer Ann , Johnson Amy J , Heerema Nyla A. , Molnar Erin , Stefanos Mona , Devlin Susan , Navarro Tasheda , James Danelle Frances , Lowe Ann M. , Hedrick Eric , Byrd John C.
Published: March 2020

6508

Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is critical for B-cell receptor (BCR) signaling in normal and malignant B lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor, antagonizes BCR signaling in CLL cells and abrogates protective features of the microenvironment. P is highly active as a single agent in CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent experience by combining P with ofatumumab (O), an anti-CD20 monoclonal antibody. We present initial safety and efficacy data from cohort 1. Methods: Pts with relapsed/refractory (R/R) CLL/SLL following ≥2 prior therapies (Tx), including a purine-nucleoside analog (PA), are treated with 420 mg P daily, in 28-day cycles, until disease progression. O is added at a dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15, and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8. Results: As of November 2011, 27 patients with either CLL/SLL/PLL (n=24) or Richter’s transformation (RT, n=3) have been enrolled and have received at least 6 cycles of treatment. The median age is 66 (range 51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range 2-10), 15 pts had bulky disease (> 5 cm); 11 pts were PA refractory. Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9 pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia have been observed. The majority of adverse events (AE) were G1/2. G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia (7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6 cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range 5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1 CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions: PCI-32765 combined with ofatumumab is well tolerated and highly active (100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of response, low relapse rate, and favorable safety profile make this combination worthy of further study. Cohorts evaluating other Tx sequences are currently underway.
Combination of the Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase Ib/II study.
Authors: O'Brien Susan Mary , Barrientos Jacqueline Claudia , Flinn Ian W. , Barr Paul M. , Burger Jan Andreas , Navarro Tasheda , James Danelle Frances , Hedrick Eric , Friedberg Jonathan W. , Brown Jennifer R.
Published: March 2020

6515^

Background: BTK is an essential mediator of B cell receptor signaling and a critical kinase for lymphoma cell survival. PCI-32765 (P), an oral, selective, irreversible inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells, and is highly active as a single agent for the treatment of R/R CLL pts. (O’Brien ASH 2011). BR produces an overall response rate (ORR) of 59% in R/R CLL (Fischer JCO 2011). We report interim data on P combined with BR. Methods: R/R CLL pts received P 420 mg orally daily for 28-day (D) cycles (C) until disease progression (PD). B was administered 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on D0 for C1 and 500 mg/m2 on D1 for subsequent courses for a maximum of 6 cycles. Response was evaluated according to IWCLL criteria. Results: 30 pts were enrolled. Median age of pts was 62 yrs (range 41-82). 46% of pts were Rai stage III/IV and the median # of prior therapies was 2 (range 1-4). 37% and 13% were considered refractory (treatment free interval <12 mo) to a purine analog containing regimen or BR, respectively. Bulky disease was present in 52%. Adverse events (AE) have been consistent with that expected with BR. Gr 3/4 neutropenia and thrombocytopenia have been noted in 47% and 10% of pts, respectively. Grade >3 non-hematologic AEs potentially related to P included rash (3 pts) and fatigue and tumor lysis reported in 2 pts each. There were no Gr 3/4 infusion reactions. There have been no discontinuations (D/C) due to AE and no deaths on study. At a median follow-up of 4.9 mos (range 2.7-8.3 mo) 16 pts have completed BR and 14 pts are still receiving BR. The ORR is 90% (27/30 pts) (CR 10%, PR 80%). 2 additional pts achieved a nodal response with residual lymphocytosis. Responses appear independent of high-risk clinical or genomic features. 90% of pts remain on study; reasons for D/C include PD (n=2) and 1 pt pursuing SCT. Conclusions: PCI-32765, in combination with BR, is highly active. The high ORR, low rate of PD, and good tolerability compares very favorably with historical controls, warranting additional investigation of this combination.
A phase II study of bortezomib added to standard daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine (Int-DAC) for consolidation in patients with previously untreated acute myeloid leukemia (AML) age 60-75 years: CALGB study 10502.
Authors: Attar Eyal C. , Johnson Jeffrey L. , Amrein Philip C. , Lozanski Gerard , Wadleigh Martha , DeAngelo Daniel J. , Kolitz Jonathan E. , Powell Bayard L. , Voorhees Peter Michael , Wang Eunice S. , Blum William G. , Marcucci Guido , Bloomfield Clara D. , Moser Barry K , Stone Richard M. , Larson Richard A. ,   CALGB
Published: March 2020

6526

Background: We conducted a clinical trial to determine the complete remission (CR) rate in older AML patients treated with bortezomib (Bz) plus daunorubicin and cytarabine induction therapy and the maximal tolerated dose (MTD) of Bz when added to Int-DAC consolidation therapy. Methods: Ninety-five adults (60-75 yrs old; median, 67) with previously untreated AML (including therapy-related and prior MDS) received Bz 1.3 mg/m2 IV on days 1, 4, 8 and 11 with daunorubicin 60 mg/m2 on days 1-3 and cytarabine 100 mg/m2 by continuous IV infusion on days 1-7. Patients who achieved a CR received 2 courses of consolidation chemotherapy with cytarabine 2 gm/m2 over 3 hours on days 1-5 (Int-DAC) with Bz administered on days 1, 4, 8 and 11. Three cohorts with escalating dose levels of Bz were tested (0.7, 1.0, and 1.3 mg/m2). Dose limiting toxicities were assessed during the first cycle of consolidation. Predictors of response, including CD74 expression, were assessed. Results: The CR frequency was 65% (62/95). An additional 4% (4/95) achieved CR with incomplete platelet recovery. The CR rate according to ELN Genetic Groups was 90% (9/10) for favorable, 71% (12/17) for Int-I, 52% (17/33) for Int-II, and 46% (5/11) for adverse. Six patients had grade 3 sensory neuropathy. There were 6 treatment-related deaths during cycle 1 of induction and 2 during cycle 2. Bz plus Int-DAC proved tolerable at the highest dose tested. The median disease-free (DFS) and overall survivals (OS) for patients on this study were 8.2 and 12.1 months, respectively. Lower CD74 expression was associated with CR/CRp (p=.04) but not with DFS or OS. Conclusions: The addition of Bz 1.3 mg/m2 IV on days 1, 4, 8, and 11 to standard “3 + 7” daunorubicin and cytarabine induction chemotherapy for AML is well tolerated and results in a remission rate at least as high as would be expected with ”3+7” alone in older patients. The maximum tested dose of Bz given in combination with Int-DAC for remission consolidation was 1.3 mg/m2 and proved to be tolerable. Further testing of this regimen in a phase III study is planned.
Immune-reconstitution after combined haploidentical and umbilical cord blood transplantation.
Authors: van Besien Koen , Jain Nitin , Schouten Viviane , Liu Hongtao , Ulaszek Jodie , Wickrema Amittha , Artz Andrew S.
Published: March 2020

6535^

Background: Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplantation. However, delayed myeloid and lymphoid immune-reconstitution with UCB transplantation leads to increased risk of infections. We recently reported a pilot study combining UCB with a HLA haploidentical donor (Liu et al. Blood. 2011). Here, we report the immune reconstitution after the haploidentical-cord blood transplantation. Methods: Pts received reduced-intensity conditioning with fludarabine/melphalan/rATG and were assessed for lymphocyte subsets, serological response to pneumococcal vaccination, Cylex Immuknow assay which measures amount of ATP secreted by CD4 lymphocytes on stimulation by PHA, and T-cell spectratyping. Results: 45 pts, enrolled between 01/2007 and 04/2011, are included in this analysis. The median absolute lymphocyte subset counts at serial time-points are shown in the Table. The median absolute values of CD3, CD4 and CD8 counts remained below the normal range throughout the 1st year post-transplant. The NK-cells and B-cells reached normal range by day 30 and day 100, respectively. Serological response to pneumococcal vaccination was seen in 7/17 (defined as seroconversion or >3 fold rise in titers of serotype 14, 19F and 23F) evaluable pts at a median 74 days after vaccination. Immuknow assay showed that 6/6 pts tested within first 30 days of transplant had low values whereas 5/8 tested >1yr had normal/high values. Of the 9 pts who were assessed for T-cell receptor repertoire by T-cell spectratyping, 7 had a polyclonal, complex T cell repertoire similar to healthy controls. CMV viremia requiring treatment occurred in 14 patients. EBV reactivation occurred in 18 pts and 5 developed PTLD 68 to 314 days after transplant. Conclusions: Haploidentical cord blood transplantation leads to rapid myeloid recovery and recovery of B-cell and NK cell numbers. T-cell recovery is more delayed, but at 1-year most pts have a polyclonal T cell repertoire and robust T-cell responses. [Table: see text]
Low day 100 transplant-related mortality (TRM) and relapse rate following clofarabine (CLO) in combination with cytarabine, total body irradiation (TBI), and allogeneic stem cell transplantation (AlloSCT) in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia.
Authors: Radhakrishnan Kavita , Ricci Angela M , Geyer Mark B , Harrison Lauren , Duffy Deirdre , Ozkaynak Mehmet Fevzi , Satwani Prakash , Cheerva Alexandra C , Talano Julie , Moore Theodore , Gillio Alfred P , Wada Randal K. , Baxter-Lowe Lee Ann , Cairo Mitchell S.
Published: March 2020

6537

Background: CAYA with ALL or AML in third complete remission (CR3), refractory relapse (RR) or induction failure (IF) have an extremely poor prognosis, <20% EFS (Gaynon, BJH, 2005;Wells, JCO, 2003). CLO, an inhibitor of DNA polymerase and ribonucleotide reductase, has significant activity in CAYA with relapsed ALL/AML (Jeha, JCO 2006,2009) and synergy with cytarabine (Faderl, Blood, 2005). We sought to determine safety, day-100 TRM, and overall survival (OS) associated with CLO, cytarabine and TBI followed by AlloSCT in CAYA with poor-risk ALL/AML. Methods: This is a multi-center phase I/II trial of a novel conditioning regimen of CLO (dose escalation: 40mg/m2 [n=3], 46 mg/m2 [n=3], 52 mg/m2 [n=19]) x5d, sequential (4 hrs later) cytarabine 1000 mg/m2 x6d and TBI (1200cGy) followed by AlloSCT from matched related or unrelated donors in CAYA with ALL/AML in CR3, RR or IF. Patients with unrelated donors received R-ATG. GVHD prophylaxis consisted of tacrolimus and MMF (Bhatia/Cairo, BBMT, 2009). Kaplan-Meier method was used to determine the probabilities of engraftment, GVHD, TRM and OS. Results: 25 pts, median age: 11.3 yrs (1.5-20.7); M:F: 19:6, ALL/AML: 22:3 (10 CR3, 3 RR, 12 IF), 10 related donors, 15 unrelated donors (9 BM/PBSCs, 6 UCB). Median TNC and CD34 dose was 4.47x108/kg and 4.84x106/kg for BM/PBSCs and 4.0x107/kg and 2.8x105/kg for UCB, respectively. Probabilities of neutrophil, platelet engraftment and grade II-IV aGVHD were 100%, 92.9% and 47.5%, respectively. CLO dose was tolerable at 52mg/m2/d x5d without dose limiting toxicity. Probability of Day 100 TRM was only 4.3%. Probability of 1-yr PFS and OS were 51% (CI95: 28-71%), and 43% (CI95: 22-63%) respectively. Conclusions: Preliminary results suggest this novel regimen followed by AlloSCT is safe and well tolerated in CAYA with poor-risk ALL/ AML with CLO dose 52 mg/m2. Results are encouraging with respect to low risk of day 100 TRM and leukemic relapse associated with this conditioning regimen in this poor-risk population.
Single center experience treating adults with FLT3-mutated acute myeloid leukemia (AML).
Authors: Halpern Anna B. , Kunnavakkum Rangesh , Joseph Loren , Stock Wendy , Odenike Olatoyosi , Godley Lucy A. , Thirman Michael J. , Artz Andrew S. , Sipkins Dorothy , Liu Hongtao , Raca Gordana , Le Beau Michelle M. , Larson Richard A.
Published: March 2020

6562

Background: Activating mutations of the fms-like tyrosine kinase-3 (FLT3) gene are common in AML. Depending upon the allele mutation fraction, these mutations have been associated with poor outcomes in prospective multi-center trials. Methods: We studied a consecutive series of adults with FLT3-mutated leukemia at our institution since we began testing in 2006 through Sept 2011. Clinical characteristics and patient (pt) outcomes were extracted through a retrospective chart review and analyzed using logistic regression and Cox proportional hazard models. Results: We identified 73 pts with a FLT3 mutation (71 with AML and 2 with myelodysplasia with <20% blasts). 62 (85%) presented to our institution at initial diagnosis; 11 (15%) were diagnosed elsewhere and seen by us only at relapse. 44 (60%) were men and 51 (70%) were white. Median age was 62 yrs (range, 19-90); 48% were <60 yrs old. 63 (86%) had an internal tandem duplication (ITD) mutation, 9 (12%) had the D835 point mutation (TKD), and 1 had both. An NPM1 mutation was also present in 26 (36%). Median white blood cell count at diagnosis was 53 x 103/µL (range, 0.8 - 466). 34 (47%) had monocytic morphology (M4 or M5). 8 (11%) pts had favorable karyotypes; 50 (68%) had normal karyotypes; 13 (18%) had unfavorable karyotypes. 58 (79%) received standard induction therapy (anthracycline + cytarabine for most; ATRA + arsenic trioxide for 3 with APL); 46/58 (79%) achieved a complete remission (CR). Including the 15 pts who received only low intensity therapies, 40/64 (63%) with an ITD and 6/9 (67%) with a TKD mutation achieved CR. 31 (42%) pts received an allogeneic transplant, 21 in first CR (CR1) and 10 after relapse. Median overall survival (OS) for the whole group was 417 days (95% CI: 291-780); it was 684 days for those diagnosed at our institution and 285 days for those seen only after relapse. Median disease-free survival (DFS) in CR1 was 417 days. Median OS for pts transplanted in CR1 was 1262 days from initial diagnosis and 416 days for those transplanted after relapse. DFS did not differ with or without a transplant (median, 526 vs 305 days; p=.64). Conclusions: FLT3-mutated AML is heterogeneous. Our single center experience is similar to that reported from multi-center trials.
Mitoxantrone and etoposide for acute myeloid leukemia in first relapse.
Authors: Im Annie P. , McLaughlin Brian Thomas , Lin Yan , Raptis Anastasios , Agha Mounzer E. , Hou Jing-Zhou , Redner Robert , Boyiadzis Michael
Published: March 2020

6563

Background: Achievement of complete remission (CR) for relapsed acute myeloid leukemia (AML) is crucial for improving prognosis and survival. However, there are no established standard therapies for AML in first relapse. Our purpose was to evaluate the efficacy and toxicity of a regimen of mitoxantrone and etoposide for relapsed AML and assess factors that may be predictive of response. Methods: Patients were identified from a database of patients with AML treated at the University of Pittsburgh Cancer Institute from 1999-2011. Subjects were patients with AML in first relapse treated with mitoxantrone 10mg/m2 and etoposide 100mg/m2 daily on days 1-5. An exploratory analysis was performed to determine CR rate, overall survival, toxicities, and predictive factors. Results: The study cohort consisted of 66 patients with AML in first relapse, median age 56.5 years (range 21-75). At time of relapse, 12 were classified as having poor cytogenetics, 39 had intermediate cytogenetics, and 5 had favorable cytogenetics (9 patients did not have karyotype analysis). 34.8% (23/66) of patients achieved CR, and 16 went on to have allogeneic hematopoietic cell transplantation. Patients with favorable, intermediate, and poor cytogenetics had CR rates of 60% (3/5), 35.9% (14/39) and 50% (6/12), respectively. Median survival was 8.1 months (95% CI 5.1-11.9). Patients who achieved CR had significantly improved survival compared to those who did not (20.0 months vs. 5.2 months, p<0.0001). Median days to neutrophil and platelet recovery were 37.5 (range 19-81) and 40 (range 21-81), respectively. There were no grade 3/4 hepatic toxicities. The 4-week and 8-week mortality rates were 4.5% and 13.6%, respectively. Duration of first remission greater than 12 months was predictive of CR (p<0.001), whereas age, cytogenetics, bone marrow blast percentage, and white blood cell count at relapse were not. Conclusions: In an unselected heterogeneous patient population with relapsed AML, mitoxantrone and etoposide was an effective regimen with acceptable toxicity, and those who achieved CR had significantly improved overall survival. Duration of first remission greater than 12 months was the only predictive factor, and response was seen among all cytogenetic risk groups.
Incidence of second and secondary malignancies in patients with CLL: A single institution experience.
Authors: Dalia Samir , Chavez Julio C. , Domingo Gelenis , Carballido Estrella M. , Aguayo-Hiraldo Paibel I. , Sweet Kendra Lynn , Crescentini Robert M. , Sokol Lubosh , Bello Celeste M. , Cultrera Jennifer L. , Shah Bijal D. , Lancet Jeffrey E. , Komrokji Rami S. , Sotomayor Eduardo M. , Pinilla-Ibarz Javier
Published: March 2020

6568

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher incidence of second malignancies than the general population with one study showing the risk at 2.2 times the general popualtion. The increased incidence is thought to be due to immunosupression which results in decreased cell surveillance and proliferation of malignant cells. Our study aims to present the rate of second malignancies by cancer type in patients with CLL at our institution. Methods: The Moffitt Cancer Center Total Cancer Care (TCC) database was used to identify patients who had a diagnosis of CLL between January 1993-December 2009. Individual charts were reviewed to confirm the diagnosis of CLL, collect demographic data, and to assess for the presence of a second malignancy under an IRB approved protocol. A second malignancy was defined as another malignancy or transformation of CLL reported in the medical record. Second malignancy data was placed in three categories; skin cancers, solid tumor malignancy, and hematologic malignancy. Results: 546 CLL patients were included in the study. Median age was 62.5 years. 84 (43%) were Stage 0 and 62 (32%) were Stage 1 RAI at diagnosis indicating earlier disease. 266 (49%) patients had a second or secondary malignancy. A total of 304 cancers were identified. 14% of patients had more than one malignancy. Melanoma was identified in 44 (16.5%) patients and non-melanoma skin cancer was identified in 54 (20%). Lung cancer was identified as the most frequent solid tumor malignancy with 36 (13.5%) cases, followed by prostate (35), breast (21), colorectal (15), and bladder (14). 10 patients had a Richter’s transformation of their CLL. 26 patients developed either myelodysplastic syndrome or acute myelogenous leukemia. Conclusions: Second malignancies are frequent in CLL patients. Immunosupression, increased UV light exposure, longer life expectancy in low risk CLL, and tertiary cancer center referral bias are likely reasons for these increased rates. Further research is needed to identify the precise mechanism which cause patients with CLL to have higher rates of second malignancies and to identify if there is an increased risk of a specific type of malignancy in patients with CLL.
Induction chemotherapy with high-dose cytarabine and mitoxantrone in elderly acute myeloid leukemia (AML) patients.
Authors: Ramanathan Muthalagu , Cerny Jan , Raffel Glen , Walsh William Vincent , Woda Bruce , Miron Patricia , Nath Rajneesh
Published: March 2020

6569

Background: Induction chemotherapy is often not used in elderly patients with AML due to poor prognosis and inferior outcomes. We present here our experience in treating 20 patients age>70yrs with an induction regimen consisting of high dose cytarabine and mitoxantrone (HiDAC/MITO). Methods: We analyzed all patients age > 70 years who underwent induction with HiDAC/MITO at our institution from January 2009 to December 2011. 20 patients received HiDAC at 3 g/m2 daily on days 1-5 and mitoxantrone 80mg/m2* once on day 2(*one patient received 60mg/m2). The end points analyzed were complete remission (CR) and induction mortality at day 30, overall survival and progression free survival. Results: Median age was 75 years (70-83). 11 (55%) patients were male and 9 (45%) patients were female. Median duration of follow up of 10 (50%) patients who are still alive at the time of this analysis is 439 days (38-1095). High risk cytogenetics was noted in 11 (55%) patients including two patients with FLT3 mutated cytogenetics. Intermediate risk cytogenetics was noted in 9 (45%) patients including 2 patients with NPM1 mutated FLT 3 WT AML. 12 (60%) patients had secondary AML. The age unadjusted charlson comorbidity index (CCI) was 3 (2-9). 15 (75%) patients attained CR and 3 (15%) patients attained a CR with incomplete platelet recovery (CRp). CR +CRp rate was 90%. Two (10%) patients were refractory to induction and 5 (25%) patients relapsed at a later time point after induction. Median duration of hospital stay was 28 days (22-60). Median time to ANC >1K was 23.5 days (18-29), excluding 2 patients who had refractory disease. Median time to platelet recovery >100K was 25 days (20-44), excluding 2 patients with refractory disease and 3 patients with CRp. Regimen related toxicity included cardiac toxicity in 4 patients and bacteremia in 11 patients. Five (25%) patients were consolidated with stem cell transplant. Median overall survival (OS) was 151 days (38-1095) and progression free survival (PFS) was 131 days (38-1049). Conclusions: HiDAC/MITO induction is well tolerated by elderly patients with AML and demonstrates an overall response (CR+CRp) rate of 90% coupled with no induction deaths.
A simple but effective model to decrease early deaths in acute promyelocytic leukemia (APL).
Authors: Jillella Anand P. , Sadek Ibrahim , Morrison Devi , Natrajan Kavita , Awan Farrukh Tauseef , Kolhe Ravindra , Kota Vamsi
Published: March 2020

6573

Background: Recent reports suggest that approximately 30% of patients with APL die during induction. This has been confirmed in large population-based studies in Sweden and the US. A recent analysis of SEER data from 13 population-based cancer registries with 1400 APL patients in the US showed that 17% of all patients and 24% of patients greater than 55 years of age die within one month of diagnosis. The most common causes of death are bleeding, infection, differentiation syndrome and multi-organ failure. Patients who survive induction have an excellent cure rate with few late relapses. Hence, decreasing early deaths is a high priority both at experienced as well as smaller centers with limited leukemia treatment experience in this highly curable disease. Methods: At Georgia Health Sciences University, between 7/2005 and 6/2009, 19 patients were diagnosed with APL. Seven patients (5 high-risk and 2 low-risk) died during induction resulting in an unusually high mortality rate of 37%. All patients who survived induction are still in remission at present. The high early death rate prompted us to develop a simple, 2 page treatment algorithm that focuses on quick diagnosis, prompt initiation of therapy, and proactive and aggressive management of all the major causes of death during induction. We also made our treatment protocol available to smaller treatment centers and helped the treating oncologists manage the patient during the first few days after diagnosis. Results: From 11/2010 to 12/2011, we treated 4 patients at GHSU and helped manage 4 patients at 2 outreach sites. The age range was 30 to 60; two patients were high-risk, 5 intermediate- and one low-risk. There were no deaths during induction and all eight patients proceeded to consolidation treatment. Conclusions: While we recognize that this is a small cohort, our own experience and a similar approach pioneered by investigators in Brazil clearly shows this to be an effective intervention to decrease early deaths in APL. We believe our experience warrants large scale implementation of our protocol in an attempt to reduce early APL mortality.
Cancer testicular antigens as a prognostic markers of chronic lymphocytic leukemia.
Authors: Chavez Julio C. , Domingo Gelenis , Dalia Samir , Dubovsky Jason A. , Berchmans Emmanuel , Powers John Joseph , Sweet Kendra Lynn , Crescentini Robert M. , Sotomayor Eduardo M. , Komrokji Rami S. , Pinilla-Ibarz Javier
Published: March 2020

6575

Background: CLL is the most common leukemia in adults and has a variable course and prognosis. Clinical staging systems and the use of biomarkers such as cytogenetics and the IGVH mutational status remain the gold standard for stratification. Cancer testis antigens (CTAs) expression analyses have shown prognostic impact in other hematological malignancies such as acute leukemias and multiple myeloma. With the analysis of CTAs we aim to discover additional molecular markers that can help us predict the clinical course and outcome in CLL patients. Methods: We analyzed the expression by RT-PCR of 39 known CTAs including members of the MAGE, GAGE, MAD-CT and SSX CTAs families in a group of 59 CLL patients seen at our institution. The Moffitt Cancer Center Total Cancer Care (TCC) database was used to correlated these findings with relevant clinical and molecular markers such as Rai stage, demographic data, initial WBC count, IGVH mutational status, CD38 expression, cytogenetics by FISH analysis and treatment outcomes. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan Meier curves with a SPSS statistical software Results: Deletion 13q was the most common gene abnormality in 35/59 (59.3%). 29/59 (49.1%) required at least one line of treatment. MAGE family CTAs were present in 53/59 (83.9%), MAD-CT in 24/59 (40.7%), SSX in 14/59 (23.7%) and GAGE in 12/59(20.3%). 35/59 (59.3%) CLL patients expressed 2 or more MAGE family CTAs. No differences were noted in the Rai staging, initial white blood cell count, B symptoms, extranodal disease, presence of CD38, or unmutated IVGH. The OS was not significantly different among all CTAs families with a tendency towards a better OS those expressing the SSX family (p=0.63). Additionally, CLL patients with single expression of MAD-CT1 (p=0.05) and MAGE-B2 (p=0.038) antigens correlated with improved survival. Conclusions: Patients with SSX family have a trend towards improved survival. When analyzed by individual antigen, MAD-CT1 and MAGE-B2 expression was associated with improved survival. Further studies with a larger number of patients are needed to assess the real value of the expression of CTAs in CLL.
Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies.
Authors: Roboz Gail J. , Khoury Hanna Jean , Shammo Jamile M. , Syto Mary , Burrows Francis , Zaknoen Sara L. , Jabbour Elias
Published: March 2020

6577

Background: TG02 is a novel multikinase inhibitor with a unique spectrum of activity, targeting both the cell cycle regulatory cyclin-dependent kinases (CDKs) 1 and 2 and the transcriptional regulators CDKs 7 and 9. TG02 also inhibits the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5. TG02 kills primary blasts from a variety of hematologic cancers and is curative in the MV4-11 model of FLT3-mutant AML. Methods: This is a first-in-man,single arm, open label, phase I dose escalation trial. The primary endpoints are dose-limiting toxicity (DLT), maximally tolerated dose (MTD ) and recommended phase 2 dose (RP2D). Patients (pts) ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules. Pts had acceptable organ function and ECOG PS 1-2. Definition of DLT was G3-4 AST or ALT ≥7 days, G4 AST or ALT, G4 hyperbilirubinemia, any other NCI CTC G3-4 events not due to underlying disease. Dose levels on arm A were 10mg to 70mg and 15mg-150 mg on arm B. Results: Forty-five pts have received at least one dose of study drug. Median age was 66 years (range, 37-87) and 80% were ECOG 0-1. Disease types enrolled included: AML (80%), high-risk MDS (22%), and CML-BC (3%). The median number of previous regimens was 3 (range, 1-12). The MTD on arm A was defined at 50 mg daily based on 2 DLTs at the 70mg dose level (G4 hyperbilirubinemia, G4 fatigue). Enrollment to arm B has competed dose levels 15 (N=3), 30 (N=3), 50 (N=3), 70 (N=3), 100mg (N=3), and enrollment at 150mg is ongoing without DLT to date. Common drug related adverse events were nausea (42%), vomiting (23%), fatigue (18%), decreased appetite (15%), constipation and diarrhea (13% each). Preliminary PK demonstrated dose proportional increases in exposure and a T1/2 , supporting once daily dosing. Conclusions: The MTD for TG02 has been determined for the daily schedule at 50mg. Enrollment continues on the intermittent schedule. Schedules of every other day and week on/week off dosing will also be evaluated.
Phase II study of the oral MEK inhibitor selumetinib (AZD6244) in advanced acute myeloid leukemia (AML).
Authors: Jain Nitin , Curran Emily , Iyengar Neil M. , Diaz-Flores Ernesto , Kunnavakkam Rangesh , Popplewell Leslie , Kirschbaum Mark H. , Erba Harry Paul , Green Margaret , Poire Xavier , Koval Greg , Shannon Kevin , Atallah Ehab L. , Dy Philip , Smith Scott E. , Doyle L. Austin , Larson Richard A. , Stock Wendy , Odenike Olatoyosi ,   University of Chicago Phase II Consortium
Published: March 2020

6582

Background: RAS-RAF-MEK-ERK pathway is activated in >75% of AML patients (pts). Selumetinib (AZD6244) is an orally bioavailable small molecule inhibitor of the MEK kinase. We report here the results of a phase II multicenter trial using selumetinib in advanced AML pts. Methods: Pts ≥18 years (yrs) with relapsed/refractory AML or ≥60 yrs old with untreated AML who were not candidates for standard chemotherapy were eligible. Pts received selumetinib 100mg twice daily. Pts were screened for KRAS, NRAS and FLT3 mutations. Analysis for p-ERK (downstream of MEK) was performed by flow-cytometry. Results: 47 pts (27 men) were enrolled. Median age was 69 yrs (range, 26-83). 85% were ≥60 yrs. Disease stage included previously untreated AML (13 pts, all were ≥ 60 yrs; 11 had prior therapy for antecedent hematologic disease), primary refractory AML (14 pts), 1st relapse (8 pts) and beyond first relapse (12 pts). Overall, 51% pts had secondary AML. Median number of prior therapies was 2 (range, 0-6). 51% had poor-risk cytogenetics. 10 pts had a FLT3 ITD, 3 pts had an NRAS mutation and one pt had a KRAS mutation. Selumetinib was well tolerated. Median number of cycles administered was 1 (range, 1-21). 49% received ≥2 cycles. Grade ≥3 adverse events possibly related to the drug included fatigue, dyspnea, and nausea occurring in 9%, 9% and 6% respectively. 1 pt has partial response, 3 pts had minor response (>50% decrease in blood and/or marrow blasts lasting >4 weeks), 2 pts had unconfirmed minor response (uMR: >50% decline in marrow blasts without a follow up confirmatory biopsy), 4 pts had stable disease (median: 16.5 weeks, range: 9-85). No pt with FLT3 ITD or NRAS mutation responded. The sole pt with KRAS mutation had uMR with hematologic improvement in platelets. Analysis of p-ERK showed baseline activation in 15/21 (71%) pts, but no difference in baseline levels in the responders vs non-responders (p=0.27). Conclusions: Administration of selumetinib in advanced AML is associated with modest antileukemic activity, which is independent of baseline p-ERK levels. Given its favorable toxicity profile, combination with drugs that target relevant signaling pathways in AML should be considered. (Sponsored by NCI grant NO1-CM-62201)
Phase II study of omacetaxine (OM) and low-dose AraC (LDAC) in older patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
Authors: Kadia Tapan M. , Jabbour Elias , Pemmaraju Naveen , Faderl Stefan , Borthakur Gautam , Thomas Deborah A. , Daver Naval Guastad , Ravandi Farhad , Kantarjian Hagop
Published: March 2020

6592

Background: Treatment of AML in patients (pts) > 70 yrs of age with intensive chemotherapy is associated with high rates of early mortality and little benefit. Newer, lower-intensity approaches with novel mechanisms are needed. OM is a semisynthetic plant alkaloid which has demonstrated activity in AML as a single agent and with chemotherapy. Methods: We studied a low intensity program combining subcutaneous (SQ) OM with SQ LDAC in pts >/= 60 yrs, with AML or MDS, a performance status (PS) of </=2, and adequate organ function. Initially, 6 pts were enrolled at the following doses: OM 1.25 mg/m2 SQ Q12 hrs x 3 days with AraC 20 mg SQ Q12 hrs x 7 days on a 4 week cycle. If safety is confirmed, the phase II portion would commence at the safe dose levels. Up to 12 courses can be given. The primary endpoint was to determine the complete remission (CR) rate. Secondary endpoints were: CR duration, DFS, OS, safety, and early mortality. Results: 17 pts were enrolled on study so far. The median age was 74 yrs (range, 64-81); the median PS was 1 (0-1). The karyotypes in these pts were: diploid in 6 (35%), complex with chromosome (chr) 5 and/or 7 abnormality (abnl) in 4 (24%), complex without chr 5 and/or 7 abnl in 2 (12%), 11q abnl in 1 (6%), poor metaphases in 1 (6%), and other in 3 (18%). Four pts with prior MDS were treated with a median of 2 prior therapies (1-3). Median bone marrow blast % at the start of therapy was 40 (15-87). The median WBC, hemoglobin, and platelets were 2.1 (0.4–24.8), 8.9 (7.7–10.7), and 45 (14–104), respectively. These pts have received a median of 1 (1-3) cycle of therapy. Of the 11 pts evaluable for response, there were 2(18%) CR, 1(9%) CRp, 1(9%) PR for an ORR of 4/11 (36%). Five pts had no response and were taken off study. Two pts died on study: 1 on day 6 and 1 on day 27. Both pts were 74 yrs with a complex karyotype. One died of pneumonia and multi-organ failure and the 2nd died from cardiac arrest. Other than the deaths, serious adverse events included grade 3 transaminitis in 1 and grade 3 heart failure in 1. Conclusions: OM and LDAC appears to be tolerable in older pts with AML. The combination appears to have activity. Stopping boundaries for futility and safety have not been breached. Enrollment is ongoing.
Treatment outcome of acute myeloid leukemia (AML) in HIV+ patients.
Authors: Dy Irene Ang , Patchett Matthew , McDonald Alicia , Wiernik Peter H.
Published: March 2020

6595

Background: AML is diagnosed more frequently in HIV+ patients than previously. The results with standard AML treatment in such patients have not been evaluated. We evaluated whether the results justify standard aggressive treatment of AML in HIV+ patients. Methods: We identified 5 HIV+ patients at our institution who were subsequently diagnosed with AML and 68 previously reported HIV+ patients with AML through PubMed from 1986-2011. The median age at the time of AML diagnosis was 40 years (range 7-70 years). Of the 26 patients with known karyotype, 7 had favorable, 7 intermediate and 12 had unfavorable cytogenetics. The majority of treated patients received standard intensive induction therapy and complete responders (CR) received consolidation therapy. HIV was pre-, post-, and concurrently diagnosed in 47, 2 and 19 AML patients respectively. The Kaplan-Meier method examined whether CD4 count, AML treatment and CR attainment affected overall survival. Cox proportional hazard modeling, adjusted for age and CD4 count determined whether AML treatment and CR attainment were associated with death from AML. Results: The final analysis included pre- and concurrently HIV diagnosed AML patients (n=66). HIV infection occurred at a median of 5 years (range 0.25-28 years) prior to the diagnosis of AML in 47 patients. The most common FAB types were M4 (22.6%) and M2 (22.6%). CR was achieved in 71.7% (n=33/46) of treated patients and 51.5% (n=17/33) of them relapsed with a median CR duration of 9.2 months. Median survival of patients with CD4 count < 200 and ≥ 200 was 7 vs. 13.4 months (p=0.03); median survival of untreated and treated patients was 1.0 vs.13.2 months (p < 0.001) and median survival of treated patients who did and did not achieve CR was 2 vs. 21 months respectively (p < 0.001). All treated patients and those who achieved CR were less likely to die from AML than untreated patients and those who failed to respond (H.R=0.05; 95% CI, 0.01-0.17 and H.R. = 0.11; 95% C.I, 0.04-0.35, respectively). Conclusions: Standard AML treatment and CR were associated with longer survival in HIV+ patients regardless of CD4 count. More than half of patients studied achieved CR. HIV+ AML patients should be offered standard AML therapy.
Comparison of fludarabine (F), cyclophosphamide (C), and rituximab (R) versus FCR plus bevacizumab (B) in relapse chronic lymphocytic leukemia (CLL).
Authors: Lee Hun Ju , Wierda William G. , Ferrajoli Alessandra , Burger Jan Andreas , Trinh Long , Lerner Susan , Keating Michael J. , O'Brien Susan Mary
Published: March 2020

6598

Background: There is significant data to show that vascular endothelial growth factor (VEGF) is important in the development and progression of CLL. Bevacizumab (B) is an anti-VEGF monoclonal antibody associated with improvement in progression free survival (PFS) when combined with chemotherapy in pts with solid malignancies. FCR is the most active chemoimmunotherapy in treatment of CLL. We report data on a phase II trial combining FCR-B and comparing the results to those seen in a trial with FCR for pts with relapsed CLL (Badoux et al. Blood, March 2011). Methods: FCR consisted of F: 25 mg/m2 and C: 250 mg/m2 on D2-4; R: 375 mg/m2 on D1 (for the first course) and 500 mg/m2 for courses 2-6, every 4 weeks for 6 courses. FCR-B consisted as above for FCR and (B) 10 mg/kg was given on D3 of each cycle. Indications for treatment and response assessment were according to 1996 NCI-WG guidelines for both groups. Results: Baseline characteristics, complete remission (CR), overall response rate (ORR), PFS and OS of relapsed CLL pts are shown (Table). Conclusions: In relapsed pts with CLL, FCR-B showed a trend toward improved PFS compared to FCR. [Table: see text]