bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]
Expression levels of nucleoside transporter hENT1 and dCK enzyme, as prognostic factors in patients with AML treated with cytarabine.
Authors: Corrales-Alfaro Carmen , Candelaria Myrna , labardini-Mendez Juan , Gutierrez-Hernandez Olga , Vidal-Millan Silvia , Espinoza Ramiro , Ojeda Juan 
Published: March 2020

6599 Background: Cytarabine has been set as the main drug included in different schemas for the treatment of AML patients. This drug requires inflow to the cell by the nucleoside transporter hENT1 and its activation rate is limited by dCK enzyme. Therefore decreased expression levels of these genes may influence response rate to this drug. Methods: AML patients > 15 years, without previous treatment were included. After informed consent signature, peripheral blood was obtained and DNA was extracted by standard methodology. Amplification of hENT1 and dCK genes was done by RT-PCR. Clinical parameters were registered. All patients received cytarabine + doxorrubicine as induction regimen (7 + 3 schema). Descriptive statistics was used. Uni- and multivariate analysis was done to determine factors influencing on response and overall survival. This protocol was approved by local IRB. Results: From January till December 2011, 22 patients have been included. Median age was 36 years (15-72 y), 52.3 % were male. According with FAB classification, M2 subtype was the most frequent (28.5 %). All patients had an adequate performance status (ECOG 1 & 2 = 34 & 66 %, respectively). Cytogenetic risk was considered as intermediate risk in 38 %, followed by unfavorable in 28 %. Complete response was achieved in 58 %. Higher hENT1 expression levels was the only factor influencing on response and survival by Spearmen correlation analysis. Conclusions: These are preliminary results but are highly suggestive that pharmacogenetic analysis regarding cytarabine inflow may be decisive in AML patients. Our results require to be confirmed with a larger sample, and a longer follow-up.
Real-world study of imatinib treatment patterns and outcomes among veteran patients with chronic myeloid leukemia.
Authors: Shi Lizheng , Chen Lei , Sharma Hari , Marynchenko Maryna , Wu Eric Q. , Liu Jinan , Yang Heidi , Guo Min Amy , Vander Velde Nancy S. 
Published: March 2020

6600 Background: Imatinib (IM) is the most commonly used drug in the treatment of chronic myeloid leukemia-chronic phase (CML-CP) patients (pts). This study investigated the treatment patterns and outcomes for veteran CML-CP pts initiated on IM. Methods: Pts (age >18 yrs) with >1 CML diagnosis codes documented (ICD-9 CM: 205.1x) between 1/1/2000 and 12/31/2010 were identified from the VISN 16 data warehouse. Pts were required to have initiated IM as the first-line therapy in CML-CP. Accelerated and blastic phases (A/BP) were identified based on WHO classification using CBC information. IM dose adjustments were assessed as dose increase from <400 mg to >600mg or from 400-600mg to >800 mg daily. Rates of IM discontinuation (no use of IM for >60 days) and switching to other drug therapy (dasatinib/nilotinib (DS/NL), hydroxyurea, and interferon-alpha) were estimated. Time to discontinuation, progression to A/BP, and survival were assessed using Kaplan-Meier analysis (K-M). Overall survival was measured from IM initiation while survival among pts with disease progression was measured from the date of progression. Results: Among the 137 pts selected, average age was 64.8 yrs and follow-up time was 4.0 yrs. 16.8% of pts had dose increase from <400mg to >600mg and 21.7% of these pts switched to other therapy after dose increase. 13.1% of pts had dose increase from 400-600mg to >800 mg with 22.2% of these pts switching to other therapy later. During the study, 83.8% of the 74 pts who discontinued IM did not use other drug therapies; and 16.2% (12 pts) switched, among which 9 pts took DS/NL. K-M showed that 25.6% and 42.4% pts discontinued IM treatment by year 1 and 2 and 8.1% and 16.0% pts experienced disease progression by year 1 and 2, respectively. Among the 28 patients who had disease progression, 32.1% continued IM use after progression and only 7.1% switched to other therapies (50% switching to DS/NL). The mortality rates were 3.0% and 9.5% by year 1 and 2 after IM initiation, and 21.7% and 42.7% by year 1 and 2 after disease progression, respectively. Conclusions: The majority of IM-treated patients, including patients with disease progression, discontinued IM use without switching to other effective therapies.
Factors associated with outcome of secondary MDS and AML: Review of 2,182 patients at MDACC.
Authors: Tambaro Francesco Paolo , Wierda William G. , Garcia-Manero Guillermo , Cortes Jorge E. , Pierce Sherry , Annunziata Mario , Ripaldi Mimmo , Borthakur Gautam , Jabbour Elias , Ravandi Farhad , Faderl Stefan , Kantarjian Hagop 
Published: March 2020

6603 Background: Secondary acute myeloid leukemia (sAML) and myelodysplastic syndromes (sMDS) have been associated with prior treatment for other malignancies, particularly chemotherapy, and associated with high-risk features and poor clinical outcomes. Methods: We identified 2,182 patients (pts) (57% male) diagnosed with AML (n=1,073; all FAB/WHO represented) or MDS (n=1,109; 984 MDS, 125 MDS/MPD, all WHO represented) and who had 1 (n=1,907), 2 (n=239), or 3 (n=36) prior malignancies (PM). Pt characteristics and outcomes were analyzed. Results: The median age was 67 yrs. Prior hematological neoplasms (25%), breast (16%), prostate (16%), skin (9%) were most common. The prior malignancy reflected prior treatment, 1,252 pts underwent surgery, 939 received radiation, and 1,211 received chemotherapy alone or in combination; 124 were untreated. Types of prior malignancy and prior treatment associated with AML and MDS will be presented. Median time to AML/MDS was 64 months (mo) and 46 mo (p=0.000) for pts with 1 or >1 PM, respectively, and correlated with type of PM (p=0.000) and previous monotherapy (surgery vs RT vs chemo) (p=0.020). For both AML and MDS, the incidence of poor-risk cytogenetics was nearly twice for pts who received prior chemotherapy compared to those who underwent surgery or radiation alone. Factors associated with survival in secondary AML and MDS are reported in the table. Conclusions: In conclusion, outcomes for pts with secondary AML and MDS are poor, especially for pts treated with prior chemotherapy. Type of prior malignancy and treatment are correlated with outcomes. Furthermore, greater number of prior malignancies correlates with inferior outcomes. [Table: see text]
A new paradigm in CLL: Minimizing toxicity by using the minimum effective dose (MED) of lenalidomide for older patients with CLL.
Authors: Lamanna Nicole , Heaney Mark L. , Maslak Peter George , Jurcic Joseph G. , Rosenblat Todd L. , Noy Ariela , Palomba Maria Lia , Weiss Mark Adam 
Published: March 2020

6609 Background: While CIT has proven active for younger patients with CLL; studies from Germany and MDACC with fludarabine or fludarabine- based regimens did not benefit the patient over the age of 65 or 70. As the median age of diagnosis is 72, the development of safe, active therapies for older patients is an unmet need in CLL. Lenalidomide is an active drug in CLL. The current clinical trial was designed to assess whether low-dose continuous lenalidomide therapy can provide long-term disease control with minimum toxicity in patients older than 65. Methods: Patients initiate lenalidomide at 2.5mg daily (28-day cycle) and only dose escalate for progressive disease (POD). Results: 18 patients have been enrolled: 12 men and 6 women, med age 70 (range 65-84) with Rai-intermediate (7 pts) or high-risk (11 pts; 61%) disease; med WBC 50.5 (6.7-326.3), HGB 10.3 (8.9-13.9), PLT 121 (44-215), β-2 microglobulin 4.9 (3.0-10.2). 16 (89%) patients had chromosomal abnormalities: 3 with 13q, 6 with tris 12, 3 with 11q, and 4 with 17p. 13 (72%) patients have unmutated IGHV. 5 (28%) patients were previously untreated; 13 (72%) had prior therapy (range 1-5; med 2). Median dose of lenalidomide is 2.5mg (range 2.5mg-10mg); median no. cycles is 7 (range 1-28). 11 patients (61%) are still on therapy (7 previously treated): 6 at 2.5mg; 4 at 5mg, and 1 at 10mg. 7 have discontinued therapy: 1 for ITP; 3 for POD including one with Richter’s, 2 for desquamating rash; and 1 withdrew consent. Only 2 patients had tumor lysis and 10 had tumor flare (8 given steroids briefly). In these older patients on long-term continuous treatment, therapy has been generally well tolerated. There have been no deaths on study. Pneumonia developed in 4 patients (3 of these had prior therapy). 1 patient with history of atrial fibrillation developed DVT/PE. Main hematologic toxicity is neutropenia seen in 11 patients but transient. Grade 3/4 thrombocytopenia and anemia was seen in 5 and 0 patients, respectively. Conclusions: Low-dose continuous lenalidomide therapy iappears to be well-tolerated and may offer long term disease control in some patients with CLL. Additional accrual and longer follow-up will be required to further assess the utility of this strategy.
Safety and efficacy of dose escalated liposomal amphotericin B in adult leukemia patients with refractory invasive fungal infections: A single institution report.
Authors: Mathew Sherry , Harnicar Stephen , Halton Elizabeth , Berman Ellin , Brentjens Renier J. , Heaney Mark L. , Jurcic Joseph G. , Lamanna Nicole , Maslak Peter George , Rosenblat Todd L. , Adel Nelly G. , Frattini Mark G. 
Published: March 2020

6613 Background: Leukemia patients are at risk for invasive fungal infections(IFI). Empiric therapy of suspected IFI is begun due to fever despite appropriate antibiotics during neutropenia or infiltrates on chest CT. Liposomal amphotericin B (L-AmB) is used for empiric anti-fungal therapy at 3-5 mg/kg. Data is lacking on the efficacy of L-AmB dose escalation in patients with CT progression and clinical decline. Methods: Patients who received 10 mg/kg of L-AmB from 2002-11. They were required to be ≥18 years old and escalated from 5 to 10 mg/kg L-Amb for at least 7 doses. Patient information was collected from pharmacy and medical records. Successful treatment was defined as resolution of fever at least 1 week after high dose L-AmB and/or improvement or stability on chest CT. Renal and hepatic toxicity was assessed. Clinical remission was defined as recovery of a normal neutrophil count. IRB approval was obtained for this study. Results: 58 patients were evaluated. At the time of presumed or probable IFI, 19 had completed induction therapy, 5 had received supportive therapy, and 34 had received 2 or more cycles of therapy. High dose L-AmB was begun for CT findings and fever, CT findings only, and fever only in 14, 26, and 17 patients, respectively. Patients received a median of 15 doses of high dose L-AmB, and all received concomitant therapy with an echinocandin except two: 1 received nothing and 1 received voriconazole. Treatment success was seen in 28 (48%) patients. Twenty-nine (50%) patients were alive at 12 weeks and 10 (17%) patients proceded to BMT. Only 11 (39%) of the responding patients achieved a clinical remission. All patients received IV hydration and electrolyte repletion. Six patients had a grade 2 increase in serum creatinine and 10 patients developed grade 2 or 3 hepatic toxicity. There were no grade 4 adverse events. Conclusions: Although it has been reported that L-AmB at 10mg/kg was inferior to 3 mg/kg in untreated patients, our study supports a safe dose escalation strategy to 10mg/kg in treating progressive presumed or probable IFI and should be considered a clinical alternative for these high risk patients.