bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated results from phase II study of guadecitabine for patients with higher risk myelodysplastic syndromes or chronic myelomonocytic leukemia.
Authors: Montalban-Bravo Guillermo , Bose Prithviraj , Alvarado Yesid , Daver Naval Guastad , Ravandi Farhad , Borthakur Gautam , Takahashi Koichi , Andreeff Michael , Cortes Jorge E. , Dinardo Courtney Denton , Jabbour Elias , Kadia Tapan M. , Kornblau Steven , Ohanian Maro , Huang Xuelin , Nogueras-Gonzalez Graciela M. , Bodden Kristy , Pierce Sherry , Kantarjian Hagop M. , Garcia-Manero Guillermo
Published: September 2018

7020

Background: Improving the current response and survival outcomes of patients with higher risk MDS and CMML is fundamental. Guadecitabine is a next generation hypomethylating agent with increased length of exposure compared to decitabine and clinical activity in patients with MDS. Methods: Single arm phase 2 clinical trial of guadecitabine at a dose of 60mg/m2 sc daily for 5 days (days 1-5) every 28 days for patients with newly diagnosed MDS or CMML classified as Intermediate-2 or High risk by IPSS. Primary endpoint is complete response (CR). Responses were evaluated following the revised 2006 International Working Group criteria. Sequencing data was obtained at the time of pre-treatment evaluation by the use of a 28-gene next generation sequencing platform. Study included stopping rules for response and toxicity. Overall survival (OS) was censored at the time of transplant. Results: A total of 53 patients have been enrolled: 50 (94%) are evaluable for toxicity and 44 (83%) for response. Median age is 67 years (49-87). A total of 43 (86%) patients have MDS and 7 (14%) have CMML. A total of 21 (42%) have complex karyotype. Sequencing data was available in 48 (96%) patients with TP53 mutations being the most frequently detected in 36% patients. After a median of 6 treatment cycles (1-20), the ORR is 71% including 32% CR. Median best response occurred by 3 cycles (1-6). Seven (21%) out of 33 evaluable patients achieved a complete cytogenetic response. Ten (20%) subjects proceed to allogeneic stem cell transplantation. Median follow up was 6.3 months (0-23). Median OS is 14.1 months (CI 13.3-14.9 months) and median EFS is 8.4 months (CI 5.6-11.2 months). Forty-five (90%) patients experienced at least one AE during therapy. Most common grade 1-2 AEs included fatigue (66%), nausea (38%) and dyspnea (26%). Dose reductions due to cytopenias were required in 17 (34%) patients. Early 8-week mortality occurred in 3 (6%) patients. Conclusions: Guadecitabine is well-tolerated and active in patients with higher-risk MDS and CMML even in the presence of adverse biological features such as high frequency of complex karyotype, therapy related disease and TP53 mutations. Clinical trial information: NCT02131597.
Genomic landscape of adult mixed phenotype acute leukemia (MPAL).
Authors: Morita Kiyomi , Wang Feng , Patel Keyur , Bueso-Ramos Carlos E. , Abou Zahr Abdallah , Gumbs Curtis , Zhang Jianhua , Song Xingzhi , Mendoza Marisela , Wu Chang-jiun , Kornblau Steven , Dinardo Courtney Denton , Ravandi Farhad , Garcia-Manero Guillermo , Jabbour Elias , Andreeff Michael , Kantarjian Hagop M. , Konopleva Marina , Futreal Andrew , Takahashi Koichi
Published: September 2018

7023

Background: MPAL is a rare subgroup of acute leukemia characterized by both myeloid and lymphoid phenotypes. Genetic basis of MPAL is not well understood. Methods: We studied 31 patients (pts) with MPAL (median age 53) that met 2008 WHO criteria. Bone marrow samples were studied by targeted capture sequencing of 295 genes (median 393x), RNA sequencing, and Infinium methylation EPIC array (Illumina). Mutational landscape was compared to 194 AML, 71 B-ALL, and 6 T-ALL cases. Promoter methylation pattern was compared to the data from 194 AML (TCGA), 505 B-ALL and 101 T-ALL cases (Nordlund et al. Genome Biology. 2013). Results: Eighteen (58%) pts had myeloid-T and 13 (42%) had myeloid-B phenotype. Four pts had t(9;22), 1 had 11q23 rarrangement, and 8 had complex karyotype. MPAL had similar number of mutations with AML but had higher number of mutations than B-ALL or T-ALL. Both AML-type and ALL-type mutations were detected in MPAL, supporting the mixed phenotypic features. However, NPM1, CEBPA and GATA2 mutations were specific to AML and were not found in MPAL. Myeloid-T and myeloid-B showed distinct patterns of mutations, in which DNMT3A, IDH2, NOTCH1, IL7R, and FBXW7 mutations were enriched in myeloid-T whereas RUNX1 mutations were enriched in myeloid-B. Myeloid-T and myeloid-B also showed distinct patterns of promoter methylation. Overall, myeloid-T had more hypermethylated CpG loci than myeloid-B. Genes that have essential role in T-cell receptor (TCR) pathway ( CD3D, CD7, CD247, LCK, PRKCQ, CCR9, and TCL1A) were differentially methylated and differentially expressed between myeloid-T and myeloid-B. RNA sequencing revealed several known translocations such as, NSD1-NUP98, and KMT2A-MLLT4, in addition to the novel fusion proteins such as FOXP1-DNAJC15, RUNX1-NAP1L1, and BCL2-TM9SF3. Unbiased hierarchical clustering of MPAL, AML, B-ALL and T-ALL by promoter methylation revealed that myeloid-T had consistent similarity with T-ALL, while myeloid-B showed random similarity with either B-ALL or AML. Conclusions: MPAL is genetically heterogeneous and myeloid-T and myeloid-B shows distinct patterns of mutations, methylation and gene expressions. Therapy for MPAL may need to be tailored based on the genetic profiles.
Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with relapsed B-ALL.
Authors: Park Jae Hong , Santomasso Bianca , Riviere Isabelle , Senechal Brigitte , Wang Xiuyan , Purdon Terence , Wang Yongzeng , Halton Elizabeth , Diamonte Claudia , Li Daniel , Sadelain Michel , Brentjens Renier J.
Published: September 2018

7024

Background: CD19-specific chimeric antigen receptor (CAR) modified T cells produce high anti-tumor activity in relapsed or refractory (R/R) ALL, but can be associated with cytokine release syndrome (CRS) and neurotoxicity (NTX). Herein, we report baseline and post-treatment clinical and laboratory factors associated with severe NTX (≥Grade 3) in our phase I clinical trial of CD19-specific 19-28z CAR T cells for adult patients (pts) with R/R B-ALL (NCT01044069). Methods: 51 adult pts with R/R B-ALL were treated with 19-28z CAR T cells following conditioning chemotherapy at MSKCC. In order to identify clinical and serum biomarkers associated with severe NTX (sNTX), we examined demographic, treatment, and clinical blood parameters as well as in vivo CAR T expansion and serum cytokines, and performed univariate and multivariate analysis. Results: In this cohort of ALL pts, 20, 8, 2, 18 and 3 pts experienced Gr 0, 1, 2, 3, and 4 NTX, respectively. No pt developed grade 5 NTX. Disease burden (≥50% blasts) at the time of T cell infusion (p = 0.0045) and post-treatment ≥Gr3 CRS (p = 0.0010) were significantly associated with sNTX, but we found no association with age, weight, T cell dose, choice of conditioning chemotherapy (Flu/Cy s. Cy), and prior lines of treatment. Among the clinical and blood parameters, fever, low PLT, high ferritin and MCHC as well as elevated GM-CSF, IFNγ, IL-15, IL-5, IL-10, IL-2 at day 3 of T cell infusion at day 3 of T cell infusion were significantly associated with sNTX (all p < 0.01). While some of these cytokines were also elevated in severe CRS cases, IL-5 and IL-2 at day 3 were unique to sNTX. Furthermore, in vivo peak CAR T expansion at day 7 (p = 0.0001) significantly correlated with sNTX (p < 0.01). Lastly, multivariate analysis revealed baseline PLT < 60 or MCHC > 33.2% and morphologic disease ( > 5% blasts) has 95% sensitivity and 70% specificity of identifying sNTX pts. Conclusions: These data provide a characterization of early clinical and serum biomarkers of sNTX in adult pts receiving 19-28z CAR T cells and should help identify appropriate pts for early intervention strategy to mitigate NTX. Clinical trial information: NCT01044069.
Inotuzumab ozogamicin (IO) combined with mini-hyper-CVD as salvage therapy for patients (pts) with R/R acute lymphoblastic leukemia (ALL).
Authors: Assi Rita , Kantarjian Hagop M. , Ravandi Farhad , O'Brien Susan Mary , Kebriaei Partow , Thomas Deborah A. , Garcia-Manero Guillermo , Khouri Issa F. , Champlin Richard E. , Kadia Tapan M. , Cortes Jorge E. , Jain Nitin , Konopleva Marina , Khouri Rita , Estrov Zeev , Takahashi Koichi , Sasaki Koji , Jacob Jovitta , Garris Rebecca , Jabbour Elias
Published: September 2018

7025

Background: Outcome of pts with R/R ALL is poor. IO, a CD22 monoclonal antibody bound to a toxin, calicheamicin, has single-agent activity in R/R ALL with response rate of 80% and median survival of 7.7 months. Adding IO to low-intensity chemotherapy might further improve clinical outcomes. Methods: Pts ≥18 years with R/R ALL were eligible. Chemotherapy was of lower intensity than standard hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction (DR), no anthracycline, methotrexate at 75% DR, cytarabine at 0.5 g/m2 x 4 doses). Rituximab (if CD20+ blasts) and intrathecal chemotherapy were given for first 4 courses. IO was given on day 3 of each of the first 4 courses at a dose of 1.8 mg/m2 for cycle 1 then 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), IO was modified to 1.3 mg/m2 for cycle 1 followed by 1.0 mg/m2 for subsequent cycles. Results: Sixty pts with a median age of 35 years (range 18-87) were treated. Overall, 47 pts (80%) responded, 32 of them (54%) achieving complete response. The overall minimal residual disease negativity rate among responders was 82%. Grade 3-4 toxicities included prolonged thrombocytopenia (79%), infections during induction and consolidations (52%, and 73% respectively), and hyperbilirubinemia (13%). VOD of any grade occurred in 9 patients (15%). At a median follow-up of 19 months, the median relapse-free survival (RFS) and overall survival (OS) were 9 and 11 months, respectively. The 2-year RFS and OS rates were 33% and 38%. The 2-year OS rates for patients treated in salvage (S)1, S2, and S3 and beyond were 53%, 0%, and 34%, respectively (p = 0.005). When compared to IO monotherapy in a similar pts population, a significant improvement in OS was observed (11 and 6 months, respectively; p = 0.003). Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is effective in pts with R/R ALL. Results are encouraging and appear superior to those obtained with IO alone, particularly in pts treated in S1. The risk of VOD should be considered carefully for transplant candidates and pts with previous liver damage. Lower dose of weekly schedules of IO are being explored Clinical trial information: NCT01371630.
A phase 1b dose escalation study to evaluate safety, tolerability and pharmacokinetics of oral monotherapy with KX2-391 in elderly subjects with acute myeloid leukemia who are refractory to or have declined standard induction therapy.
Authors: Kasner Margaret T. , Ritchie Ellen K. , Cutler David , Fetterly Gerald J. , Kramer Douglas , Hangauer David , Thompson James E.
Published: September 2018

7043

Background: Treatment of elderly AML patients is complicated by poor tolerance to standard therapies and multi-drug resistance. It is imperative to explore novel agents which are tolerable and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerase. We conducted a phase I open-label safety and activity study in elderly subjects with AML who were refractory to or declined standard induction chemotherapy. Five dose levels were tested from 40 to 160 mg daily. Methods: 24 subjects were recruited from 3 institutions with an average age of 74 years (range 63-86). The majority had previously received HMAs. 1 subject was treated at 40 mg, 2 at 80 mg, 8 at 120 mg, 12 at 140 mg, and 1 at 160 mg. Of the 24 subjects enrolled, 7 (29%) were on treatment for 12 days or less; 9 (38%) from 15 to 29 days, 5 (21%) from 33 to 58 days and 3 (13%) from 77 to 165 days. One subject treated at 120 mg for 165 days had a reduction in splenomegaly from 16 cm to 4 cm BLCM, and survived 373 days. A second subject was treated at 120 mg for 154 days until disease progression. One subject was dosed at 160 mg for 12 days and remained treatment-free for about 18 months. Results: DLTs occurred in 8 subjects at: 120mg (AST/ALT, elevated bilirubin); 140 mg (Mucositis, Allergic Reaction, 2 elevated LFTs, acute kidney injury) and 160 mg (Mucositis). The most common (≥ 25%) treatment-related adverse events were nausea/vomiting; diarrhea; anorexia; fatigue/weakness; increase ALT/AST; hypokalemia; hypotension; febrile neutropenia; dyspnoea; abdominal pain; constipation; dizziness. The RPTD for KX2-391 is 120 mg given once daily. KX2-391 bone marrow concentrations are similar to the target IC50 of 142 ng/mL. Conclusions: This is the first study conducted to determine whether KX01 can be safely given to this high risk, frail AML patient population. The data from this study support proceeding with further studies including alternative dosing phase 1 studies (higher dose, shorter course followed by drug-free intervals) and phase 2 studies to assess efficacy. Clinical trial information: NCT01397799.
Prognostic and therapeutic impact of cytogenetic abnormalities in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable.
Authors: Mangaonkar Abhishek Avinash , Alkhateeb Hassan , Al-Kali Aref , Gangat Naseema , Begna Kebede , Elliott Michelle A. , Hogan William J. , Zblewski Darci , Ketterling Rhett P. , King Rebecca L. , Litzow Mark Robert , Tefferi Ayalew , Patnaik Mrinal Mahesh
Published: September 2018

7058

Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.
Does supplemental interphase FISH analysis to standard chromosom analysis improve the detection of myelodysplastic syndrome?
Authors: Lang Benjamin Joseph , Minyon Carol , Dhiman Neelam , Gupta Saurabh , Wenceslao Stella , Vuica-Ross Milena , Dobson Robin
Published: September 2018

7060

Background: Our objective was to evaluate whether the addition of interphase FISH analysis to standard chromosome analysis (CA) improves the detection of chromosomal abnormalities in patients with work up for myelodysplastic syndromes (MDS), acute myeloid leukemia, and myelodysplastic/myeloproliferative disorders and thereby increases diagnostic and prognostic information. We performed a retrospective data review of all MDS orders between January and September 2015 at our institution and evaluated concurrent tests for discrepancies between CA and FISH results. Our aim was to evaluate best practices with regard to diagnostic test utilization, specifically to assess the diagnostic and prognostic value of FISH in addition to CA for patients with potential and known MDS. Methods: Retrospective data review of concurrent test orders of CA and myelodysplastic FISH panel were reviewed. The myelodysplastic FISH panel consists of screening for monosomy 5/deletion 5q, monosomy 7/deletion 7q, CEP7, trisomy 8, and D20S108 (20q12). The results of CA and FISH results were analyzed using a chi-square test to evaluate statistical significance. Results: A total of 1121 samples were queried, of which 55 were excluded due to inability to perform CA and limited diagnostic value of accompanying standalone FISH data on the 4 markers tested in this study. Analysis of the eligible 1066 samples showed that the standalone CA had significantly higher sensitivity (p < 0.0001) in detecting abnormal cases (N = 247, 23.17%) as compared to standalone FISH analysis (N = 180, 16.89%). Overall, 173 (16.23%) cases were determined to be abnormal by both methods. CA correctly interpreted 1059 of 1066 cases (99.34%).Only 7 samples were interpreted as normal by CA but were found to be abnormal by FISH. This results in overall 0.66% (2.76% of the abnormal cases) of abnormalities that would have been missed by CA only. Conclusions: These findings suggest that FISH studies with 4 markers used in this study provide limited additional utility in cases with a complete CA.
First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.
Authors: Flinn Ian , van der Jagt Richard , Chang Julie E. , Wood Peter , Hawkins Tim E. , MacDonald David , Trotman Judith , Simpson David , Kolibaba Kathryn S. , Issa Samar , Hallman Doreen M. , Chen Ling , Burke John M.
Published: September 2018

7500

Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.
Phase IIIb randomized study of lenalidomide plus rituximab (R2) followed by maintenance in relapsed/refractory NHL: Analysis of patients with double-refractory or early relapsed follicular lymphoma (FL).
Authors: Andorsky David Jacob , Yacoub Abdulraheem , Melear Jason M. , Coleman Morton , Kolibaba Kathryn S. , Brooks Heather Dawn , Bitran Jacob D. , Fanning Suzanne R. , Lansigan Frederick , Ricker Justin L. , Foon Kenneth A. , Liu Dongfang , Llorente Mary , Li Jiahui , Sharman Jeff Porter ,   MAGNIFY Trial Investigators
Published: September 2018

7502

Background: Chemoresistant patients with FL and those who progress within 2 y after initial diagnosis have poor outcomes (Casulo. JCO. 2015) and highlight an unmet need. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of relapsed/refractory (R/R) NHL patients, including grades 1-3b or transformed FL (tFL). Patients receive 12 cycles of lenalidomide plus rituximab (R2); those with stable disease or better are randomized 1:1 to maintenance R2 or rituximab alone. The primary endpoint is progression-free survival (PFS). This analysis focuses on FL: double-refractory (DR) patients are refractory to both rituximab (as monotherapy or combination) and an alkylating agent, and early relapse (ER) patients progressed or relapsed within 2 y of initial diagnosis. Results: As of July 19, 2016, the R/R FL population (N = 117) included 32 (27%) DR and 43 (37%) ER patients, median ages of 64 and 65 y, respectively, mostly grade 1-3a FL (94%; 91%) and 2 tFL (1 DR; 1 ER); 72% and 49% were stage IV at study entry. Patients had a median of 2 prior regimens (DR 3; ER 2). Of ER patients, 31 had first-line R-chemo vs 12 with R-mono/other. Response rates are in Table 1. Median time to response was 2.8 mo for DR and 2.7 mo for ER patients, with median duration not reached. 1-y PFS for FL patients was 66% (DR 66%; ER 45%); 1-y PFS for ER patients with first-line R-chemo was 50% vs 27% in others. Common grade ≥3 treatment-emergent AEs for DR and ER patients were neutropenia (53%; 33%), leukopenia (9%; 12%), and lymphopenia (9%; 5%). Conclusions: R2 followed by maintenance showed favorable activity and tolerable safety profiles in FL patients who are double-refractory or had early relapse ( < 2 years) after initial diagnosis. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865. [Table: see text]
Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study.
Authors: Sharman Jeff Porter , Brander Danielle M. , Mato Anthony R. , Kambhampati Suman , Burke John M. , Lansigan Frederick , Schreeder Marshall T. , Lunin Scott D. , Ghosh Nilanjan , Zweibach Alexander , Shtivelband Mikhail , Travis Patrick M. , Chandler Jason Claud , Kolibaba Kathryn S. , Sportelli Peter , Miskin Hari P. , Weiss Michael S. , Flinn Ian
Published: September 2018

7504

Background: Patients (pts) with high-risk chronic lymphocytic leukemia (CLL) defined by interruptions in TP53 (either by mutation or deletion) or loss of chromosome 11q experience inferior outcomes with ibrutinib (IB) monotherapy (O’Brien ASH 2016). Ublituximab (UTX) is a novel glycoengineered mAb with enhanced ADCC targeting a unique epitope on the CD20 antigen. GENUINE is the first randomized Ph 3 trial conducted assessing the addition of a novel agent to ibrutinib in high-risk rel/ref CLL, and evaluates IB monotherapy vs. UTX + IB. Methods: Eligible pts with rel/ref CLL and centrally confirmed del17p, del11q, and/or a TP53 mutation were randomized 1:1 to receive IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cycle 1, D1 of Cycle 2-6, and Q3 Cycles thereafter). There was no limit on number of prior therapies. Prior IB exposure was excluded. The primary endpoint was overall response rate (ORR) per iwCLL 2008 criteria, with secondary endpoints including CR rate, MRD negativity, PFS, time to response (TTR) and safety. Results: 126 pts were randomized at sites in the US and Israel, with 117 pts treated (59 on UTX + IB, 58 on IB alone). Median age 67, median 3 prior therapies (range 1-8), > 70% of were male. High-risk cytogenetics were relatively balanced with ~ 50% of pts having del17p. UTX+IB was well tolerated, with infusion reactions the most prevalent AE (44%, GR3/4 5%). Neutropenia was comparable with the combination (17%, Gr3/4 7% vs. 10%, Gr3/4 9%), and other AE’s were similar or lower with UTX+IB vs. IB alone (all grades), including fatigue (17% vs. 31%), dizziness (12% vs. 21%), contusion (12% vs. 26%), anemia (10% vs. 16%), and myalgia (9% vs. 14%). At median follow-up of 12 mo, best ORR per independent central review was 80% for UTX + IB vs. 47% for IB alone (p < 0.001). While not powered for secondary endpoints, observed advantages were seen in PFS and radiographic CR rate in the UTX + IB arm. CR and MRD confirmation is ongoing. Median TTR for the combo was 1.97 mo vs. 3.8 mo for IB alone. Both arms have responses pending confirmatory assessments. Conclusions: The addition of UTX to IB demonstrated a superior response rate compared to IB alone without additional clinically significant toxicity. Clinical trial information: NCT02301156.
Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma.
Authors: Jin Michael C. , Kurtz David Matthew , Esfahani Mohammad Shahrokh , Scherer Florian , Craig Alexander F.M. , Soo Joanne , Khodadoust Michael Siavash , Saganty Ruth Sharon , Chabon Jacob J. , Schroers-Martin Joseph , Stehr Henning , Advani Ranjana H. , Rossi Davide , Gaidano Gianluca , Westin Jason R. , Diehn Maximilian , Alizadeh Ash A.
Published: September 2018

7507

Background: Somatic copy number alterations (SCNAs) are common and clinically important genomic events in lymphomas. For example, MYC and BCL2 amplifications are associated with adverse outcomes (Quesada, ASH 2016), while PD-L1 ( CD274) amplifications are associated with improved response to checkpoint inhibitors (Ansell, NEJM 2015). However, noninvasive detection of these events from circulating tumor DNA (ctDNA) remains difficult. Using CAPP-Seq, a targeted high-throughput sequencing platform, we developed a method to profile both focal and broad SCNAs from plasma. Methods: We profiled plasmas from a cohort of 75 pretreatment diffuse large B-cell lymphoma patients and 48 healthy controls. Focal SCNAs were evaluated at ultra-high depths (~10,000x), allowing for detection of lesions at ~1% ctDNA fraction. Thresholds were tuned to allow a false positive rate of 1%, which was empirically validated in an independent healthy cohort (n = 15), yielding a panel-wide false discovery rate of ~2.3% (0% in our genes of interest). Sequencing reads outside the targeted regions were separately pooled and analyzed to evaluate arm and chromosome level SCNAs. Results: We detected SCNAs in clinically relevant genes at the frequencies reported in literature, including amplifications in MYC (8.0%), BCL2 (24.0%), and BCL6 (14.7%) and deletions in TP53 (13.3%) and CDKN2A (9.3%). Remarkably, 26.7% of the cohort demonstrated amplification of both PD-L1 and PD-L2 ( PDCD1LG2). Furthermore, we discovered amplifications in PD-L2, but not PD-L1, in 13.3% of our patients. Interestingly, PD-L1 amplifications were more common in patients with relapsed lymphoma than in those with treatment-naïve disease (43.5% vs 19.2%, p = 0.02). Most PD-L1 amplifications were focal (65%) while the remainder typically involved > 80% of Chr9p. Corresponding tissue profiling data is in progress and will also be presented. Conclusions: Noninvasive sampling of lymphoma ctDNA enables detection of both focal and broad SCNAs, including amplifications of MYC, BCL2, and PD-L1. The ability to noninvasively profile copy number altered regions allows for biopsy-free discovery of clinically significant structural alterations in lymphoma patients.
Clinical and biologic covariates of outcomes in ZUMA-1: A pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (r-NHL).
Authors: Locke Frederick Lundry , Neelapu Sattva Swarup , Bartlett Nancy L. , Lekakis Lazaros J. , Miklos David Bernard , Jacobson Caron Alyce , Braunschweig Ira , Oluwole Olalekan O. , Siddiqi Tanya , Lin Yi , Timmerman John , Reagan Patrick Michael , Bot Adrian , Rossi John , Navale Lynn , Jiang Yizhou , Aycock Jeff , Elias Meg , Wiezorek Jeffrey S. , Go William Y.
Published: September 2018

7512

Background: Outcomes in activated B cell subtype diffuse large B cell lymphoma (ABC-DLBCL) and r-NHL are poor (Sehn Blood 2015, Crump ASCO 2016). ZUMA-1 is the first, multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells, axi-cel, in r-NHL. Methods: Dosing and eligibility were per Neelapu ASH 2016. The primary endpoint was objective response rate (ORR); secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Cell of origin (COO) and CD19 status were assessed centrally using Lymphoma Subtyping Test NanoString (Wallden JCO 2015) and a validated immunohistochemistry assay, respectively. Results: As of Jan 27, 2017, 111 patients (pts) were enrolled; the manufacturing success rate was 99% with an average 17-d turnaround time; 101 pts (modified intent-to-treat [mITT] population) received axi-cel. In the mITT population, the ORR was 82% (complete response [CR], 54%). With 8.7 m median follow-up, 44% remain in response and 39% in CR. The median DOR was 8.1 m and not reached (NR) for pts with CR. Median OS was NR. Results for clinical and biologic covariates are listed in the table. In pts who received tocilizumab (n = 43) and/or steroids (n = 27) for cytokine release syndrome (CRS) and/or neurologic events (NE), ORR was 84% and 78%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia (24%), and encephalopathy (21%). Rates of grade ≥3 CRS and NE were 13% and 28%, respectively. There were 3 grade 5 AEs (Neelapu ASH 2016). Conclusions: Axi-cel induced an ORR of 82% in pts with r-NHL, response is ongoing in 44% of pts at 8.7 m. Similar clinical responses were observed in pts with r-ABC-DLBCL. AEs were manageable and the use of tocilizumab/steroids did not appear to impact ORR. Drs Locke and Neelapu contributed equally. Funding source: Kite Pharma and Leukemia & Lymphoma Society Therapy Acceleration Program Clinical trial information: NCT02348216. [Table: see text]
Outcomes by CD30 expression in patients with CTCL receiving brentuximab vedotin (BV) vs physician's choice (PC) in the Phase 3 ALCANZA study.
Authors: Kim Youn H. , Prince H. Miles , Whittaker Sean , Horwitz Steven M. , Duvic Madeleine , Scarisbrick Julia , Quaglino Pietro , Zinzani Pier Luigi , Wolter Pascal , Bechter Oliver , Wang Yinghui , Palanca Wessels Maria Corinna , Wood Kenneth W. , Li Martha , Liu Yi , Lin Hui-Min , Little Meredith , Danaee Hadi , Trepicchio William L. , Dummer Reinhard
Published: September 2018

7517

Background: The Phase 3 ALCANZA study showed significant, durable responses with CD30-directed antibody-drug conjugate BV vs PC of methotrexate (MTX) or bexarotene (Bex) for CD30-positive (CD30+) cutaneous T cell lymphoma (CTCL). Uniform CD30 expression is characteristic of primary cutaneous anaplastic large cell lymphoma (pcALCL), but is variable among other subtypes including mycosis fungoides (MF). We examined activity of BV and MTX / Bex by CD30 expression in pts treated on the ALCANZA study. Methods: Adults with previously treated CD30+ MF or pcALCL were enrolled. MF pts had ≥2 skin biopsies from separate lesions, pcALCL had ≥1. Patients were scored CD30+ if ≥1 biopsy had ≥10% CD30+ lymphoid cells using an investigational Ventana diagnostic test, centrally assessed by one pathologist. We compared the proportion of MF subgroup pts (n=50 per treatment arm) with objective response lasting ≥4 months (ORR4; ALCANZA primary endpoint) and PFS in pts with all biopsies ≥10% CD30+ (CD30min ≥10%) vs ≥1 biopsy <10% CD30+ (CD30min <10%). Pts were randomized 1:1 to BV 1.8 mg/kg IV, Q3W, or PC for up to 16 three-week cycles. Results: 125/184 (68%) MF and 44/47 (94%) pcALCL pts were screened and scored CD30+. High inter-lesional variability in CD30 expression was seen in MF pts; 55/125 CD30+ MF pts (44%) had ≥1 biopsy with low (<10%) or undetectable CD30. 100/125 CD30+ MF pts were eligible and enrolled. In the BV arm, ORR4 was higher in MF pts with CD30min ≥10% vs <10%; median PFS with BV was higher in the CD30min <10% group (Table). ORR4 with BV was greater than PC over all CD30 expression ranges (CD30min <5%, 38% vs 13%; CD30 ≥5–≤20%, 35% vs 10%; CD30 >20%, 76% vs 7%, respectively). Conclusions: Notable inter-patient or inter-lesional variability in CD30 expression was seen in MF pts. Highly superior ORR4 and PFS endpoints were seen with BV over PC regardless of CD30min expression level. Clinical trial information: NCT01578499. [Table: see text]
Innovative approach to determine overall survival (OS) benefit for orphan diseases using case match control analyses (CMCA): The PROPEL experience of pralatrexate in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL).
Authors: O'Connor Owen A.
Published: September 2018

7521

Background: The challenges in conducting randomized studies in orphan diseases poses limitations on our ability to identify the most promising treatments. Randomized studies in this setting can take protracted periods of time to complete, can be very expensive while not offering the promise of significant commercial return, and could become irrelevant as the pace of scientific advancement continues. The majority of drugs approved in this setting are often approved on surrogate end-points like progression free survival (PFS) or complete response (CR) rates in single arm studies. CMCA are statistically stronger than single arm studies, and can be highly informative in this setting. Methods: We established an integrated international database of patients with R/R PTCL to clarify the OS advantage of pralatrexate using original data from the PROPEL study, an international, multicenter phase II study in patients with R/R PTCL. The propensity score was used to match cases and controls. Cases were matched based on histology, number of previous treatments received, age at diagnosis and sex. Results: With 1:1 ratio match, we identified 83 cases and 83 controls. In total, 83 patients out of 109 treated on the PROPEL study were successfully matched. OS was plotted for each of the two study populations. The survival curves for the control population were found to be nearly identical to that reported for this population from other datasets. The overall survival was 4.04 months (95% CI 2.83, 5.78), which is consistent with historical controls describing this population. The median OS in for the pralatrexate treated cohort in this analysis was 16.6 months (95% CI: 11.99-25.56). The OS was a highly statistically significant difference between these two populations, with a hazard ratio of 0.426 (95% CI: 0.296-0/61). This difference held up for each of the major histologic subsets, including PTCL-NO and angioimmunoblastic PTCL. Conclusions: This approach can be used to better understand how new drugs in orphan diseases perform in heterogeneous patient populations. Clinical trial information: NCT00364923.
Digital sorting and copy number profiling of purified, PD-L1 positive, Reed Sternberg cells in classical Hodgkin lymphoma.
Authors: Mangano Chiara , Lanzellotto Rossana , Bolognesi Chiara , Forcato Claudio , Ferrarini Alberto , Del Monaco Valentina , Petrini Edoardo , Tononi Paola , Buson Genny , Medoro Gianni , Fontana Francesca , Manaresi Nicolò
Published: September 2018

7528

Background: Classical Hodgkin Lymphoma (cHL) is one of the disease in which the check-point inhibitors have been demonstrated to be more successful. Lately, it has been reported that in malignant Reed-Sternberg Cells (RSCs), PD-1 ligands (PD-Ls) are overexpressed and that chr.9 amplification correlates with advanced stages of the disease, when the standard therapy have already failed. Unfortunately, the detection of the genetic alterations in RSCs is challenging, as one of the hallmark of cHL is the presence of a small number of malignant cells sparse in an abundant and heterogeneous immune infiltrate. Here we present a method for the isolation and the genetic characterization of purified RSCs, which overcomes the limitations posed by the low-cellularity of cHL biopsies, and could be helpful for earlier detection of genetic alterations and adoption of immunotherapy. Methods: FFPE tissue sections from cHL patients were dissociated down to single-cell suspension and stained using anti-CD30 and anti-PD-L1 antibodies. Beyond the positivity to CD30 and PD-L1, RSCs were selected according to morphological criteria such as cell size and the presence of polylobate nuclei compared to surrounding lymphocytes. Target cells were isolated using the DEPArray™ cell sorter, as single cells or in small pools of cells. Recovered cells were whole genome amplified ( Ampli1™ WGA), and genome-wide copy-number aberrations (CNAs) profiles were obtained using Ampli1™ LowPass kit on IonTorrent platform. Results: After the dissociation, RSCs maintained cell morphology and therefore, we were able to discriminate them from the heterogeneous immune infiltrate. RSCs appeared as large multinucleated cells with a big central nucleolus surrounded by a clear halo; cell diameter and ploidy were computed from the images. Pools of lymphocytes and pools of CD30+/ PD-L1+ RSCs were isolated. Sequencing results confirmed the expected flat profile for lymphocytes, while RSCs showed an aberrant profile with multiple losses and gains. Conclusions: The analysis of purified RSCs, could offer a valuable tool to uncover genetic alterations hidden by cHL immune infiltrate, for earlier adoption of more effective treatment regimens.
Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study.
Authors: Fowler Nathan Hale , Neelapu Sattva Swarup , Samaniego Felipe , Forbes Sheryl , Hagemeister Fredrick B. , Fayad Luis , Feng Lei , Turturro Francesco , Westin Jason R. , Arafat Janine , Neal Eleanor , Nastoupil Loretta J.
Published: September 2018

7531

Background: Relapsed follicular lymphoma (FL) remains a challenge and salvage regimens are associated with toxicity and limited control. Outcomes are linked to the immune microenvironment and lenalidomide and rituximab are highly active in FL. Obinutuzumab has increased ADCC compared to rituximab in preclinical models and is approved for relapsed FL. We hypothesized that the immunologic properties of obinutuzumab and lenalidomide would be synergistic. The study objective was to determine the MTD of lenalidomide with obinutuzumab in relapsed FL and describe the efficacy of the combination. Methods: This open label phase I/II study enrolled Gr 1-3a FL. Transformation was excluded. Lenalidomide was given on D 2-22 with 1000mg obinutuzumab on D1, 8, 15, and 22 of cycle 1 and on D1 for up to 12 cycles (28 days/cycle). Obinutuzumab was given every 2 months thereafter for up to 30 months in pts who responded following doublet therapy. During dose escalation, 3 cohorts were planned with 10, 15 and 20mg of lenalidomide. Phase II planned to enroll 30 pts at MTD with efficacy and safety as primary endpoints. Results: All 36 pts with FL enrolled (6 in dose escalation and 30 at MTD), and are eligible for efficacy and safety analysis. The median age was 65 with a median of 2 prior therapies. No DLTs were observed in phase I, and 20 mg of lenalidomide was used for phase II. To date, the most common all grade non-heme toxicities were fatigue(83%), diarrhea(67%) and rash(53%). Grade 3+ toxicities included neutropenia (23%), infection (11%) and fatigue (8%). The overall response rate was 100% with 78% (95%CI 60.85-89.88%) of pts attaining complete response (CR/Cru). All pts with rituximab refractory FL (13) responded. At a median follow up of 14 months, 10 pts progressed. The estimated 24 month PFS is 61% (95% CI 43-87%). Conclusions: Lenalidomide and obinutuzumab is highly active with durable remissions in relapsed FL, with all pts responding and 78% achieving CR. The majority of pts remain on therapy and the combination appeared safe. Correlatives are ongoing to identify biomarkers of response and frontline studies of the combination are currently enrolling. Clinical trial information: NCT01995669.
Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA.
Authors: Soo Joanne , Kurtz David Matthew , Scherer Florian , Craig Alexander F.M. , Jin Michael C. , Westin Jason R. , Rossi Davide , Gaidano Gianluca , Advani Ranjana H. , Diehn Maximilian , Alizadeh Ash A.
Published: September 2018

7538

Background: Patients with diffuse large B cell lymphoma (DLBCL) exhibit significant differences in clinical outcome based on cell-of-origin (COO). Patients are categorized as having germinal-center-like (GCB) or activated-B-cell-like (ABC) disease based on RNA microarray and histopathological analyses of tumor biopsies. We recently described an accurate sequencing-based method for determination of COO in DLBCL utilizing stereotyped differences in mutations (Scherer et al., 2016). Here, we further explore the mutational patterns in patients with differing molecular subtypes of DLBCL based on sequencing of circulating tumor DNA. Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) to pretreatment plasma samples and matched germline from a cohort of 115 patients with DLBCL. We then identified somatic alterations, which were used to determine COO molecular subtypes as previously described. Finally, we compared mutational patterns in patients with GCB and non-GCB DLBCL. Results: We detected a significantly greater number of total mutations (GCB: 1766 ± 160 mutations per Mb of targeted sequencing; non-GCB: 1364 ± 150 mutations per Mb of targeted sequencing; p < 0.05) and coding mutations (GCB: 145 ± 21 mutations per Mb of targeted sequencing; non-GCB: 28 ± 8.5 mutations per Mb of targeted sequencing; p < 0.001), particularly in immunoglobulin (Ig) regions (p < 0.05). In addition, GCB and non-GCB samples exhibited distinct mutational patterns within Ig regions. GCB samples were enriched for mutations in regions of switch mu (Sμ) (p < 0.01) and IGHV2-70 (p < 0.01), while non-GCB samples were enriched for mutations in regions of IGHG3 (p < 0.03), IGHV4-34 (p < 0.03), and IGLL5 (p < 0.05). GCB samples were also significantly enriched for coding mutations in SOCS1 (p < 0.01), a gene not included in our original COO classifier. Conclusions: Patients with GCB and non-GCB DLBCL exhibit distinct mutational patterns across both Ig and non-Ig loci of the genome. These differences in mutational patterns can be used to classify molecular subtypes noninvasively, potentially providing further utility to noninvasive genotyping and liquid biopsies.
Anti-infective prophylaxis with aciclovir and cotrimoxazole to reduce the rate of infections and therapy-associated deaths in elderly patients with DLBCL undergoing R-CHOP immunochemotherapy.
Authors: Murawski Niels , Amam Josif , Altmann Bettina , Ziepert Marita , Haenel Mathias , Viardot Andreas , Neubauer Andreas , Held Gerhard , Truemper Lorenz , Schmidt Christian , Kanz Lothar , Hallek Michael , Schmitz Norbert , Heintges Tobias , Koelbel Christian , Poeschel Viola , Pfreundschuh Michael
Published: September 2018

7539

Background: To study if anti-infective prophylaxis with aciclovir and cotrimoxazole is effective in preventing infections in pts. receiving R-CHOP, we compared infections and treatment-related deaths in two prospective DSHNHL trials with different anti-infective strategies. Methods: 61-80-yo. pts. in RICOVER-60 study [Lancet Oncol 2008; 9:105-116] received 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab. Anti-infective prophylaxis consisted of ciprofloxazine (500 mg/d) during days of severe leukocytopenia ( < 1000 / mm3). In OPTIMAL > 60, pts. were randomized to 6xCHOP-14 or 6xCHLIP-14 (conventional substituted by liposomal vincristine) in combination with rituximab, 8 applications q 2 wks. or 12 applications between days -4 and 238 /2x2 factorial design). In OPTIMAL > 60, anti-infective prophylaxis consisted of cotrimoxazole (2 double strength doses twice every week p. o.) and aciclovir (4 x 400 mg/d p.o.) in addition to ciprofloxazine. Results: In RICOVER-60, grade 3&4 infections in 232 patients (IPI = 1 and bulky disease or IPI > 1) receiving 6xCHOP-14+8R were 6% (76/1200) per cycle and 28% (60/218) per patient. With intensified anti-infective prophylaxis in OPTIMAL > 60 there were no differences with respect to infections between the 4 treatment arms. Grade 3&4 infections were 4% (83/1987) per cycle (p = 0.007) and 18% (64/365 pts. with toxicity documentation) per patient (p = 0.004). Treatment-related deaths (defined as all non-lymphoma associated deaths during and within 2 months after the end of chemotherapy) went down from 15/232 (7%) in RICOVER-60 to 7/385 (2%; p = 0.003) in OPTIMAL > 60. Conclusions: Anti-infective prophylaxis with cotrimoxazole and aciclovir in addition to ciprofloxazine significantly reduced the rates of severe infections and treatment-related deaths in elderly patients receiving R-CHOP supporting the use of this anti-infective strategy in all DLBCL patients receiving R-CHOP. Clinical trial information: NCT01478542.