bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed AML.
Authors: Daver Naval Guastad , Basu Sreyashi , Garcia-Manero Guillermo , Cortes Jorge E. , Ravandi Farhad , Jabbour Elias , Hendrickson Stephany , Brandt Mark , Pierce Sherry , Gordon Tauna , Pemmaraju Naveen , Andreeff Michael , Ning Jing , Kornblau Steven , Kadia Tapan M. , Dinardo Courtney Denton , Konopleva Marina , Allison James Patrick , Kantarjian Hagop M. , Sharma Padmanee 
Published: September 2018

7026 Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, ASH 2016). AZA up-regulates PD-1 in AML (Yang et al., Leukemia 2013). Methods: Pts were eligible if they had AML and failed prior therapy, had adequate performance status (ECOG ≤ 2), and organ function. AZA 75mg/m2Days 1-7 with nivolumab 3mg/kg on Day 1 and 14 was established as the recommended phase II dose. Courses were repeated every 4-5 weeks indefinitely. Responses were evaluated at the end of 3 courses. Results: 53 pts with med age 68 years (range, 44 – 90), secondary AML (43%), poor risk cytogenetics (43%), med prior regimens 2 (range, 1-7) have been enrolled. Common mutations included DNMT3A (n = 11), TP53 (n = 11), TET2 (N = 8), CEBPA (n = 8), ASXL1(n = 8). All 53 pts are evaluable for response: 11 (21%) achieved CR/CRi and 7 (14%) had hematologic improvement (HI) for an overall response rate of 35%. Additionally, 14 (26%) had ≥50% BM blast reduction, 3 (6%) had stable disease > 6 months, and 12 (23%) had progression. The CR/CRi have been durable with 9 of 11 (82%) pts with CR/CRi alive at 1 year, after censoring for SCT. Med survival for the 53 evaluable pts was 5.7 months (range, 0.9 – 16.2) and in the 27 salvage 1 pts was 9.3 months (range, 1.6 – 16.2). These compare favorably to historical survival with AZA-based salvage protocols at MDACC. Grade 3/4 and Grade 2 immune toxicities were observed in 7 (14%) and 6 (12%) pts, respectively. These responded rapidly to steroids and 12 of 13 pts were successfully rechallenged with nivolumab. Multicolor flow-cytometry data were available on pretherapy, end of cycle 1, and end of cycle 2 BM aspirates in 9 CR/CRi and 22 non-responders. Pts who achieved CR/CRi had higher pre-therapy total CD3 (P = 0.02) and higher CD8+ T-cells (P = 0.07) infiltrate in the BM. Responders demonstrated progressive increase in BM CD8+ and CD4+ infiltrate. Both responders and non-responders had increase in CTLA4+ CD8+ cells on therapy. Conclusions: Full dose AZA and nivolumab are tolerable and may produce durable responses in relapsed AML. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML. Clinical trial information: NCT02397720.
Updated results of frontline ofatumumab-hyper-CVAD in adults with CD20+ acute lymphoblastic leukemia.
Authors: Maiti Abhishek , Kantarjian Hagop M. , Ravandi Farhad , Thomas Deborah A. , Khouri Maria , Garcia-Manero Guillermo , Garris Rebecca S. , Cortes Jorge E. , Short Nicholas James , Sasaki Koji , Issa Ghayas C. , Koller Paul B. , Schroeder Heather M , Kadia Tapan M. , Verstovsek Srdan , Daver Naval Guastad , Jain Nitin , Konopleva Marina , O'Brien Susan Mary , Jabbour Elias 
Published: September 2018

7033 Background: Chemoimmunotherapy is an effective frontline therapy for acute lymphoblastic leukemia (ALL). Ofatumumab (O) binds to a proximal small-loop epitope on CD20 and is more potent in vitro than rituximab. Here we report interim results of its combination with hyper-CVAD (HCVAD) in adult patients (pts) with CD20+ ALL. Methods: Since 7/2011, we have enrolled 63 pts with Ph-negative CD20+ ALL (59 newly diagnosed, 4 previously treated). For the intensive phase, pts received 4 cycles (cy) of HCVAD (odd cy 1, 3, 5, 7) alternating with 4 cy of methotrexate-cytarabine (MTX-Ara-C, even cy 2, 4, 6, 8), and ofatumumab during cy 1-4. For maintenance, pts received POMP for ~30 months (mos), and intensification with MTX/PEGylated asparaginase on mos 6 and 18, and O-HCVAD on mos 7 and 19. Intrathecal MTX-Ara-C was used for CNS prophylaxis. Bulky mediastinal disease was irradiated when indicated. Results: Median age was 41 years (range: 18-71) and median WBC count was 4.6 x109/L (range: 0.6-201 x109/L). 22 pts (35%) had diploid cytogenetics and 8/35 pts (23%) had TP53 mutation. CD20 expression was > 20% in 38 pts (60%), 10-20% in 6 pts (10%) and 1-10% in 16 pts (25%). Median follow-up was 20 mos (range: 1-58) and median number of cy was 8 (range: 1-8). 3 pts (5%) were in CR at the time of enrollment. Of 60 pts evaluable for response, 58 pts (97%) achieved CR; 1 pt achieved CRp and 1 pt died during cy 1 from sepsis. Flow cytometric minimal residual disease (MRD) was negative in 57/62 pts (92%) overall, and in 36/57 pts (57%) at CR. Median time to negative MRD was 0.7 mos. Median time to platelet and neutrophil recovery in cy 1 was 21 and 18 days, respectively. The most common grade 3/4 non-hematological toxicities were infections during induction (49%) and consolidation (72%), elevated transaminases (35%), and hyperbilirubinemia (21%). 5 pts (7%) experienced a grade 3/4 transfusion reaction. 8 pts (13%) received stem cell transplantation in CR1. 10 pts (16%) have relapsed (8 morphological, 2 MRD only). Overall survival and 2-year CR duration rates were 80% and 81%, respectively. Survival outcomes were independent of percentage of CD20 expression. Conclusions: O-HCVAD is safe, effective and results in durable responses in pts with CD20+ ALL. Clinical trial information: NCT01363128.
Ten-year survival after randomized comparison of imatinib (IM) 400 mg vs. IM 800 mg vs. IM + IFN vs. IM + Ara C vs. IM after IFN in chronic myeloid leukemia (CML).
Authors: Hehlmann Ruediger , Lauseker Michael , Saussele Susanne , Pfirrmann Markus , Neubauer Andreas , Krause Stefan W. , Hossfeld Dieter K. , Nerl Christoph , Baerlocher Gabriela M. , Heim Dominik , Kolb Hans-Jochem , Proetel Ulrike , Kohlbrenner Katharina , Gratwohl Alois , Burchert Andreas , Voskanyan Astghik , Rinaldetti Sebastien Ly , Hochhaus Andreas , Hasford Joerg ,   SAKK and German CML Study Group
Published: September 2018

7049 Background: It is unclear whether IM 400 mg is the optimum choice for the successful treatment of CML. Treatment optimization was therefore attempted. Methods: From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase (CP) were randomized into a 5-arm study to analyze 2 IM doses and 3 combinations. 1536 patients were evaluable, 400 for IM 400 mg, 420 for IM 800 mg, 430 for IM + Interferon (IFN), 158 for IM + Ara C and 128 for IM after IFN. Recruitment to the latter two arms was stopped after a pilot phase. Results: 10-year overall survival (OS) of all patients was 82%, 10-year progression free survival (PFS) 80%. 10-year OS was 80% with IM 400 mg, 79% with IM 800 mg, 84% with IM + IFN, 84% with IM + Ara C and 79% with IM after IFN. The differences were not significant. 10-year PFS was 80% with IM 400mg, 77% with IM 800mg, 83% with IM + IFN, 82% with IM + Ara C and 75% with IM after IFN. The differences were not significant either. Survival with any treatment was not significantly different from IM 400mg at any risk level by any risk score (Euro Sokal, EUTOS, ELTS). 87 patients progressed to blast crisis (BC). The 10-year cumulative incidence of BC was 5.8% (95% CI: 4.7%; 7.1%) equally distributed across treatment arms. Most BC occurred in the first 2 years. Median survival after BC was 7.9 months across treatment arms. 275 patients have died, 23 after stem cell transplantation in first CP. Two thirds of deaths were unrelated to CML. Incidence of death due to CML by competing risk analysis with death unrelated to CML as competing risk was not different between the 5-treatment arms. 10-year relative survival probability was 92% when compared to matched general population data. Patients reaching the cytogenetic or molecular response landmarks according to European LeukemiaNet criteria ( < 10% BCR-ABL IS at 3 months, < 1% BCR-ABL IS or complete cytogenetic remission at 6 months, < 0.1% BCR-ABL IS (MMR) at 12 months) had a significantly better survival than those not reaching the landmarks regardless of therapy. Conclusions: In conclusion, outcome of CML is currently more determined by prognostic markers than by choice of therapy. IM400 mg remains an excellent choice for initial therapy of CP-CML. Clinical trial information: NCT00055874.
CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL.
Authors: Gill Saar , Frey Noelle V. , Hexner Elizabeth O. , Lacey Simon F. , Melenhorst Jan Joseph , Byrd John C. , Metzger Susan , Marcus Taylor , Gladney Whitney , Marcucci Katherine , Hwang Wei-Ting , June Carl H. , Porter David L. 
Published: September 2018

7509 Background: Immunotherapy with anti-CD19 CART cells induces complete remission (CR) in the minority of patients with CLL, but where CRs occur they tend to be durable. Based on preclinical evidence of synergy, we combined anti-CD19 CAR T cells with ibrutinib to test the hypothesis that pre- and concurrent treatment would enhance the CR rate. Methods: This is a pilot trial of anti-CD19 CAR T cells in adults with CLL/SLL who were not in CR despite at least 6 months of ibrutinib. Pts must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation. T cells were lentivirally transduced to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119). Pts were lymphodepleted 1 week before infusion. Ibrutinib was continued throughout the trial. Results: Manufacturing was successful in all pts. Ten pts (9M, 1F; ages 47-77; 0-12 regimens prior to ibrutinib) have been infused. All had abnormalities of TP53 or ATM and two pts had increasing BTK C481S clones. Median marrow CLL burden was 10% (range 10-50%). The median follow-up is 6 months (range 0.5-9). Cytokine release syndrome (CRS) developed in 9 pts; gr1 in 2, gr2 in 6 and gr3 in 1 pt. One pt developed gr4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required. At 3 months, 8 evaluable pts had achieved an MRD-ve marrow CR (89%) by 9-color flow, and all remain in marrow CR at last F/U. There was modest residual splenomegaly in 3/5 patients, and adenopathy resolved in 4/6 subjects with progression in 1/6. MRD assessment by deep sequencing will be presented. Conclusions: We observed 89% MRD-ve marrow CR in pts with high-risk CLL using a well-tolerated combination of CART cells and ibrutinib. Longer follow-up will reveal the durability of these results and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy. Clinical trial information: NCT02640209.
L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.
Authors: Maddocks Kami J. , González Barca Eva , Jurczak Wojciech , Liberati Anna Marina , Duell Johannes , Nagy Zsolt , Papajík Tomáš , Andre Marc , Kalakonda Nagesh , Dreyling Martin H. , Zinzani Pier Luigi , Ambarkhane Sumeet Vijay , Weirather Johannes , Salles Gilles A. 
Published: September 2018

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.
Updated results of single-agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).
Authors: Grommes Christian , Gavrilovic Igor T. , Kaley Thomas Joseph , Nolan Craig , Omuro Antonio Marcilio Padula , Wolfe Julia , Pentsova Elena , Hatzoglou Vaios , Mellinghoff Ingo K. , DeAngelis Lisa Marie 
Published: September 2018

7515 Background: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in Mantle cell lymphoma, CLL, Marginal Zone, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. Methods: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Twenty-five patients were enrolled (3 at 560 mg; 22 at 840 mg). Median age was 68 (range 21-85); 15 were women. Median ECOG was 1 (0: 2, 1: 15, 2: 8). 64% had PCNSL and 36% SCNSL; 68% had recurrent disease. Seventeen had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 5 both. Seven grade 4 adverse events were observed in 7 patients neutropenia (in 3 patients), lymphopenia (2), sepsis (1), and ALT elevation (1). Fourteen patients developed 20 grade 3 toxicities, including lymphopenia in 5 patients, hyperglycemia in 3, ALT elevation in 2, thrombocytopenia in 2, lung infection in 2, AST elevation in 1, neutropenia in 1, urinary tract infection in 1, colitis in 1, febrile neutropenia in 1 and fungal encephalitis in 1. The most common toxicities at any grade were hyperglycemia, thrombocytopenia and anemia of which most were grade 1/2. No grade 5 events have been observed. After a median follow-up of 414 days (range 289-674), 22/25 patients were evaluated for response (3 did not complete at least 15 days of drug treatment). Over all response was 68% (17/22; 77% (17/22) in patient that completed at least 15 days of drug treatment) with 10 CR, 7 PR, 2 SD and 3 PD as best response. The median PFS is 4.6 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 15.3 months). The median overall survival has not been reached. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 68% of CNS lymphoma patients. Clinical trial information: NCT02315326.
Preliminary results of a phase Ib study of GS-4059 in combination with entospletinib in patients with B-cell malignancies.
Authors: Fegan Christopher , Danilov Alexey Valeryevich , Hodson Daniel , Salles Gilles A. , Starodub Alexander , Mitra Siddhartha , Yang Yingsi , Walter Harriet , Morschhauser Franck 
Published: September 2018

7518 Background: GS-4059 (ONO-4059) selectively and irreversibly inhibits Bruton’s tyrosine kinase (BTK) and entospletinib selectively inhibits spleen tyrosine kinase (SYK). Methods: This ongoing phase 1b study is evaluating the safety and tolerability of GS-4059 combined with entospletinib in patients with previously treated CLL, FL, SLL, MCL, MZL, WM, or non-GCB DLBCL. The study design uses 3+3 dose escalation (Table) withexpansion cohorts at potential phase 2 doses. Results: With a median duration of treatment of 22 weeks (range 3-56), 26/32 enrolled patients continue on treatment. The median age was 70 (43–85) years and 59% were men. Patients had the following diseases: CLL (n = 9), non-GCB DLBCL (7), FL (6), WM (5), MCL (2), SLL (2), and MZL (1). The median number of prior therapies was 2 (1–5). Five patients discontinued all study treatment, 4 due to disease progression (DLBCL x 2, MCL, MZL) and one due to withdrawal of consent. There has been 1 death on study due to progressive disease. The maximum tolerated dose was not reached. 90% of patients treated reported a treatment-emergent AE (TEAE) of which 48% were grade ≥3. Grade ≥3 TEAEs that were present in more than 1 patient were neutropenia (4), anemia, thrombocytopenia, pneumonia and AST/ALT elevation (2 each). The TEAEs present in >10% of patients were fatigue (7), petechiae (5), asthenia, constipation, contusion, dyspepsia, neutropenia and rash (4 each). No patients discontinued treatment due to AEs and all 5 patients with interruption of treatment for an AE successfully re-initiated therapy. 17 patients were evaluable for best overall response with the results as follows: 11 with partial responses (2 each with CLL, DLBCL, FL, SLL, WM, 1 with MCL); 4 with stable disease; 2 with progressive disease. Conclusions: GS-4059 at up to 160 mg in combination with entospletinib up to 400 mg daily was safe and well tolerated, supporting the continued clinical evaluation of the combination for the treatment of B-cell malignancies. Clinical trial information: NCT02457598 Clinical trial information: NCT02457598. [Table: see text]
Cytogenetic and fluorescence in situ hybridization testing in veterans with chronic lymphocytic leukemia.
Authors: Halwani Ahmad Sami , Burningham Zachary , Rasmussen Kelli Marie , Patil Vikas , Low Clarke Alan , Meissner Brian , Kapustyan Tatyana , Lawrence Nicole , Walker Jodi , Keim Holger , Sauer Brian C 
Published: September 2018

7526 Background: The presence of deletion 17p (del17), determined by chromosome analysis and/or fluorescence in situ hybridization (FISH), is a strong negative prognostic marker in chronic lymphocytic leukemia (CLL). Prior to the introduction of novel agents (ibrutinib, venetoclax), the clinical utility of cytogenetics/FISH was limited by the absence of chemoimmunotherapy regimens that were proven effective in patients with del17. Testing practices for chromosomal aberrations since the introduction of novel agents have not been reported. We report cytogenetic/FISH trends in a nationwide cohort of veterans diagnosed with CLL. Methods: CLL patients diagnosed 2008-2015 and receiving care at VA were identified through the VA Clinical Cancer Registry. Electronic medical records were used to determine cytogenetic/FISH testing (lab records), treatment histories (pharmacy dispensation records), and evidence of system use (heme-onc notes). Cytogenetic/FISH testing was identified by presence of specific keywords in the test name or Logical Observation Identifiers Names and Codes (LOINC) descriptions, then validated by human annotation. The testing rates are reported for the entire cohort, at time of diagnosis, time of regimen initiation (including the 12 months preceding initiation), during the novel era (2014 – 2015) and prior (2008–2013). Results: From 2008 to 2015, 3,638 CLL patients were diagnosed and received care at VA. Documented records of treatment regimens were available for 1,562 patients who received a total of 2,929 treatment regimens. Only 24% (998) of patients were tested at any point in time during their care at the VA, 17% (622) were tested at time of diagnosis, and 19% (542) of treatment courses were preceded by cytogenetic/FISH testing. No testing differences existed following the introduction of the novel agents at diagnosis (both ~ 17%), or prior to regimen initiation (20% vs 16%). Conclusions: Our study suggests CLL patients diagnosed and receiving care at the VA are not routinely undergoing cytogenetics/FISH testing at diagnosis or prior to treatment. Changing this practice pattern will personalize treatments so that del17 CLL patients receive less toxic and more effective therapies.
Phase 2 trial of brentuximab vedotin and gemcitabine for pediatric and young adult patients with relapsed or refractory Hodgkin lymphoma (HL): A Children’s Oncology Group (COG) report.
Authors: Cole Peter D. , McCarten Kathleen , Metzger Monika , Drachtman Richard A. , Horton Terzah M. , Pei Qinglin , Bush Rizvan , Blaney Susan , Weigel Brenda , Kelly Kara M. 
Published: September 2018

7527 Background: AHOD1221 (NCT01780662) tested Brentuximab vedotin (Bv) with gemcitabine (GEM) in children or young adults with HL. The primary objective was to describe the complete response (CR) rate within 4 cycles of therapy. Methods: Eligibility criteria included age ≤30 years; no prior Bv exposure; and primary refractory HL or advanced stage disease with early relapse. Each 21-day cycle consisted of Bv on day 1 at the recommended phase 2 dose (RP2D), 1.8 mg/kg and GEM 1000mg/m2 on days 1 and 8. Patients were evaluable for response if they completed 4 cycles of Bv+GEM, had a CR after 2 cycles, or progressive disease at any time. Response was assessed after even cycles, and confirmed by central review. CR was defined by FDG-PET negativity (Deauville 1-2) regardless of residual lesion size. Results: 42 patients were treated with Bv+GEM. Median age was 17.4 years (range 5.4-28.7), and 23 (55%) were female. The majority (n=35; 83%) had primary refractory disease or early relapse <6 months after completion of primary treatment. Common (>10%) adverse events included maculopapular rash (36% in cycle 1), neutropenia (33%) and elevated serum transaminases (21%). GCSF-stimulated peripheral blood stem cell (PBSC) collection was successful in all patients (n=23) for whom it was attempted, with median total collection of 9.4x106CD34+ cells/kg (range 3.5-36.8). 23 of 40 evaluable patients experienced a CR (58%; 95% CI 42-73%) within four cycles, and 6 had a partial response (PR), for an ORR of 73% (95% CI, 59-86%). For 4 patients with PR or stable disease, all target lesions were Deauville 3 or less after cycle 4, considered a CR by modern response criteria (Cheson et al. Blood 2016;128(21): 2489). Conclusions: Bv+GEM is a highly active combination for primary refractory or high-risk relapse of HL, with a CR rate exceeding that seen after either Bv (34%) or GEM (9%) alone. PBSCs can be collected successfully following Bv+GEM, making this an effective reinduction regimen when autologous stem cell transplantation is indicated. Compared to alternate retrieval regimens, Bv+GEM offers the advantage of avoiding agents associated with late treatment sequelae. Clinical trial information: NCT01780662.