bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.