bluuebunny/crossref_metadata_2025 huggingface dataset:
Update on lower-dose dasatinib 50 mg daily as frontline therapy in newly diagnosed chronic phase chronic myeloid leukemia (CML-CP).
Authors: Naqvi Kiran , Jabbour Elias , Skinner Jeffrey A , Anderson Kristin N , Yilmaz Musa , Jain Nitin , Ferrajoli Alessandra , Bose Prithviraj , Thompson Philip A. , Alvarado Yesid , Takahashi Koichi , Burger Jan Andreas , Borthakur Gautam , Estrov Zeev , Pemmaraju Naveen , Paul Shilpa , Dellasala Sara , Cortes Jorge E. , Kantarjian Hagop M.
Published: March 2020

7052

Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. We previously reported dasatinib 50 mg daily to be active and better tolerated than the approved 100 mg daily dose (CANCER. 2018 Jul 1;124(13):2740-2747). We present an update on the efficacy and toxicity profile of lower dose dasatinib 50 mg orally daily in patients with early CML-CP. Methods: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884). Results: From March 2016 to March 2018, 81 patients have been enrolled. Median age is 47 years (20-84). Patients categorized by Sokal risk are: low 53; intermediate 22 and high 6. Median follow-up is 18 months (9-31). Cumulative response rates over time are shown below: At 3 months, 96% patients achieved early molecular response ( BCR-ABL PCR ≤10%). Median time to CCyR was 4.6 months, MMR 6.0 months, MR4.0 11.4 months and MR4.5 12.2 months. Eighteen patients had treatment interruption: pleural effusion 4 (possibly related 3, unrelated 1 due to pneumonia); gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 1; asthma exacerbation 1; pneumonitis 1; lower extremity edema 1; myalgias 1, and pregnancy 2. Four patients had dose reductions: pleural effusion 3; myalgias 1. Four patients had dasatinib dose increased to 100mg: lack of CCyR at 6 months, 3; lack of MMR at 12 months, 1. Four patients are off study: no response 2, pneumonitis 1, and insurance 1. None of the patients have transformed or died. Conclusions: These updated results continue to support dasatinib 50 mg daily as an effective and safe dose for early CML-CP. Clinical trial information: NCT02689440. [Table: see text]
Discrepancy of blast percentage between the bone marrow aspirate and biopsy and its impact on survival outcomes in patients with myelodysplastic syndromes excess blast (MDS-EB).
Authors: Yogarajah Meera , Nguyen Phuong L. , He Rong , Alkhateeb Hassan , Shah Mithun Vinod , Patnaik Mrinal Mahesh , Gangat Naseema , Hogan William J. , Tefferi Ayalew , Litzow Mark Robert , Al-Kali Aref
Published: March 2020

7053

Background: The revised International Prognostic Scoring System (IPSS-R) aids in prognosticating MDS. The percentage (%) of blasts in the bone marrow is one of the major determinants of the scoring system. The aspirate blast % is utilized as the standard of care, but there could be discrepancies in the blast % reported by the aspirate and the biopsy. We aim to study the possible use of bone marrow biopsy blasts in MDS-EB in calculating IPSS-R. Methods: The MDS database was reviewed for cases of MDS-EB after due IRB approval. We calculated IPSS-R scores based on the aspirate blast % (IPSS-RAsp) and biopsy blast % (IPSS-RBx). The biopsy blast % was reported morphologically or by the CD34 stain. Whenever a range was reported the highest value was utilized as the blast %. Suboptimal aspirates were excluded from the study. The overall survival (OS) was determined by IPSS-RAsp, IPSS-RBx and IPSS-R highest blast (IPSS-RHi). OS estimates were calculated by Kaplan-Meier curves and log-rank testing using JMP v.13. Uno’s concordance statistic was used to compare all 3 risk scoring systems. Results: Of 1322 patients, 431 (33%) cases were identified with MDS-EB; out of which 173 cases had both blasts reported in the biopsy and the aspirate. Out of 173 cases, 35 (20%) had MDS-EB1, and 61 (35%) had MDS EB-2 based on both biopsy and aspirate (concordant cases). Seventy seven (45%) patients changed from EB-1 to EB2 or vice versa based on the biopsy blast (44/77 (57%) cases were upstaged). The OS outcomes based on the IPSS-RBx biopsy showed a clear and meaningful separation with median OS decreasing with increased risk but IPSS-RAsp and IPSS-RHi did not (Table). We compared the 3 models for observed OS differences using the Uno model and there was no statistically significant difference. Conclusions: IPSS-RBx (but not IPSS-RAsp and IPSS-RHi) identified prognostic groups for OS with median OS decreasing with increased risk. The small sample size may have led to an insignificant effect on model power by Uno model. This finding needs to be validated by other centers. [Table: see text]
Proposal of an endpoint for a phase III clinical study of essential thrombocythemia: Balancing between short term effects and long term benefits.
Authors: Mesa Ruben A. , Zimmerman Craig , Kang Lih Lisa , Qin Albert , Lee Chungwei , Shih Weichung (Joe) , Zagrijtschuk Oleh , Komatsu Norio , Xiao Zhi-Jian , Hou Hsin-An , Chen Chih-Cheng , Verstovsek Srdan
Published: March 2020

7055

Background: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN), covering broad spectrum of clinical scenarios, from asymptomatic patients with only isolated high platelets to highly morbid patients in late stage disease. Due to heterogenous patient population, designing clinical studies in ET is difficult, and after anagrelide there was no new drug approval to treat ET during the past 15 years, thus, high unmet medical to treat patients with ET remains. Interferons alpha (IFNa) are known to have beneficial effects in MPN (Kiladjian et al, 2016). P1101 is a next generation monopegylated IFNa, developed specifically to treat MPNs, including ET. Methods: External published clinical data in ET were analyzed to design optimal clinical study. Proposed endpoints are meant to cover all relevant clinical aspects of ET, and suffice for a regulatory relevant pivotal clinical study. Results: Composite primary endpoint scale is based on modified ELN criteria. Short term study endpoints should have clinical meaningfulness at time of measurement but also predict the later outcomes. The scale consists of: normalization of platelets (<400 G/L) and leukocytes (<9.5 G/L); normalization in size or non-progression of palpable spleen; lack of major cardiovascular event during the observation period; and improvement of Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS). MPN-SAF TSS is a 10 items questionnaire, allowing concise, valid, and accurate assessment of MPN symptom burden over time (Emanuel et al, 2012). For TSS-10 score, to qualify for response, following rules were elaborated: 10 points or higher reduction for patients with baseline score of ≥20, for patients with baseline score 15-19 – 5 points reduction, baseline scores 10-14 – reduction below 10 points, and for TSS baseline score <10 – stay <10. Bone marrow analysis is not to be a mandatory test for assessment of overall benefit of therapy. Extensive genetic workup is planned to document any change in observed genetic and chromosomal abnormalities, including level of circulating mutant CALR. This would allow for objective evaluation of IFNa’s ability to modify the disease. Long term observation, going beyond the 12 month of initial observation, is planned. Conclusions: Authors conclude that proposed endpoint scale covers well all clinically relevant aspects of ET, in order to make clinically relevant conclusions on durable benefits and risks of P1101 therapy.
A phase II study of cpi-0610, a bromodomain and extraterminal protein inhibitor (BETi) alone or with ruxolitinib (RUX), in patients with myelofibrosis (MF).
Authors: Kremyanskaya Marina , Hoffman Ronald , Mascarenhas John , Bose Prithviraj , Gupta Vikas , Schiller Gary J. , Liew Elena , Lebedinsky Claudia , Senderowicz Adrian Mario , Mertz Jennifer , Trojer Patrick , Verstovsek Srdan
Published: March 2020

7056

Background: BETi have been shown to regulate NF-κB, MYC, BCL2, and TGF-β signaling, important drivers of marrow fibrosis. Preclinical studies have suggested that combined BETi and JAK2 inhibition synergistically reduce MF-related splenomegaly, bone marrow fibrosis and the malignant allele burden (Kleppe, 2018). CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). Arms 1 and 2 are stratified: transfusion dependence (TD) yes: A/no: B. The primary objectives are to evaluate the effect of CPI-0610 on transfusion dependence (TD, 1A and 2A) and spleen volume (1B, 2B and 3). A Simon two-stage design: if 2 responses are seen will advance to the 2nd stage. Results: 4 pts enrolled in Arm 1, 14 pts in Arm 2, no pts accrued to Arm 3 yet. Median age: 69 years (46-83), gender: 9 male pts; 11 pts received ≥1 prior therapy besides RUX. JAK2/MPL/CALR mutations: 17/18 pts, ≥3 mutations: 10 pts, ASXL1 mutations: 11 (61%) pts. Hemoglobin <10 g/dL at baseline: 11 (61%) pts. 6 pts received ≥ 24 weeks of CPI-0610 treatment at this analysis. 2 TD pts in Arm 2 became transfusion independent, both remain on treatment free of transfusions. Hgb increase of ≥1.5 g/dL from baseline was observed with successive cycles of therapy in anemic pts: 2/2 pts in Arm 1 (100%) and 3/9 pts in Arm 2, (33%). Spleen volume reduction, by MRI (6-44%) was observed in all 10 evaluable pts irrespective of their driver mutation. Symptom improvement and reductions of cytokine levels were observed. In Arm 1: 2/2 evaluable pts had marrow fibrosis improvement with Hgb increase; additionally, thrombocytosis resolved in 2/2 pts (baseline ≥791 103/uL). Most common adverse events were mild diarrhea, nausea/vomiting; and reversible and non-cumulative thrombocytopenia. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Collectively, these data indicate that CPI-0610 +/- RUX might have disease modifying effects. Updated data will be provided. Clinical trial information: NCT02158858.
TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
Authors: Siddiqi Tanya , Dorritie Kathleen Anne , Soumerai Jacob Drobnyk , Stephens Deborah Marie , Dubovsky Jason A , Gillenwater Heidi H. , Gong Lucy , Thorpe Jerill , Yang Lin , Wierda William G.
Published: March 2020

7501

Background: Eradication of MRD in CLL patients may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1/2 TRANSCEND CLL 004 study. Methods: Eligible pts had CLL/SLL, received ≥2 prior lines of therapy (including Bruton’s tyrosine kinase inhibitors [BTKi] unless medically contraindicated), and had ECOG PS ≤1. Post lymphodepleting chemotherapy, pts received liso-cel infusion at either dose level (DL)1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by iwCLL 2008 criteria. MRD was assessed by flow cytometry in blood (10−4) and by NGS in bone marrow (BM; 10−6). Results: At data cutoff, 16 pts received liso-cel: DL1, n = 6; DL2, n = 10. 75% of pts had high-risk features ( TP53 mutation, complex karyotype, or del17p); 100% had prior ibrutinib and 50% had prior venetoclax. Median (range) number of prior lines of therapy was 4.5 (2‒11). There was 1 DLT of grade (G) 4 hypertension (DL2). The most common G3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). 1 pt had G3 cytokine release syndrome (CRS); 3 pts had G3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable pts was 87% (13/15). 7 pts (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). 10/15 pts (67%) achieved undetectable MRD (uMRD) in blood by day 30 and in 7/8 pts (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR+ T cell level was 16 days (4‒30). Conclusions: In this study of heavily pretreated pts with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs), were manageable. Pts rapidly achieved CR/CRi and uMRD. Additional follow-up will be presented. Clinical trial information: NCT03331198.
First-line therapy of T-cell lymphoma: Allogeneic or autologous transplantation for consolidation—Final results of the AATT study.
Authors: Shmitz Norbert , Truemper Lorenz , Ziepert Marita , Bouabdallah Kamal , Cartron Guillaume , Nickelsen Maike , Milpied Noel Jean , Gisselbrecht Christian , Wulf Gerald , Maury Sébastien , Gyan Emmanuel , Jaccard Arnaud , De Leval Laurence , Gaulard Philippe , Rosenwald Andreas , Friedrichs Birte , Reimer Peter , Wilhelm Martin , Altmann Bettina , Tournilhac Olivier
Published: March 2020

7503

Background: In patients (pts) with peripheral T-cell lymphoma (PTCL) results of first-line therapy remain poor; guidelines recommend consolidation with autologous transplantation (autoSCT) in transplant-eligible pts. AATT (Autologous or Allogeneic Transplantation in T-cell lymphoma) sought to improve first-line therapy and compared alloSCT with autoSCT. Methods: This was a prospective randomized trial comparing autoSCT with alloSCT in younger pts (18-60 yrs) with newly diagnosed PTCL who had achieved CR, PR, or SD after 4 courses of CHOEP and 1 course of DHAP. Pts were to receive BEAM followed by autoSCT or myeloablative conditioning (fludarabine, busulfan, cyclophosphamide) followed by alloSCT from a matched related or unrelated donor. Primary endpoint was 3-year event-free survival (EFS). The study was stopped prematurely after a pre-planned interim analysis (JCO 33, 2015, suppl 8507a). Results: 103 pts randomized upfront to autoSCT (n=54) or alloSCT (n=49) formed the full analysis set. Median age was 50 years, 63% were male. 36 pts (35%) could not proceed to transplantation mostly due to early progression. Median observation time for EFS was 42 months. 3-year EFS and overall survival (OS) did not significantly differ between alloSCT and autoSCT (EFS: 43% (95% CI29-57%) vs. 38% (25-52%), p=0.58, OS: 57% (43-71%) vs. 70% (57-82%) (p=0.41). Comparing pts who actually received autoSCT (n=41) or alloSCT (n=26) EFS, PFS, and OS also showed no significant difference. No patient relapsed but eight pts (31%) died of treatment-related mortality (TRM) after alloSCT compared to 13 relapses (36%) but no TRM observed after autoSCT. Comparison of pts with aaIPI 2/3 vs. 0/1 showed significant differences for all endpoints. Conclusions: AlloSCT or autoSCT given to consolidate response in pts with PTCL showed no significant survival differences. While exerting a strong GvL-effect alloSCT resulted in substantial TRM. For younger pts with PTCL autoSCT remains the preferred consolidation, in particular, because pts. relapsing after autoSCT can be successfully salvaged with alloSCT. Clinical trial information: 2007-001052-39.
Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: Results from a randomized HOVON-Nordic Lymphoma Group phase III study.
Authors: Lugtenburg Elly J. , Brown Peter , van der Holt Bronno , D'Amore Francesco , Koene Harry R , de Jongh Eva , Fijnheer Rob , Loosveld Olaf , Böhmer Lara H , Pruijt Hans , Verhoef Gregor , Hoogendoorn Mels , Bilgin Yavuz , Nijland Marcel , Lam King H , de Keizer Bart , de Jong Daphne , Zijlstra Josee M
Published: March 2020

7507

Background: This randomized phase III trial assessed whether intensification of rituximab (R) during the first 4 cycles of R-CHOP can improve outcome of diffuse large B-cell lymphoma (DLBCL) patients compared with standard R-CHOP. Patients in complete remission (CR) after induction treatment were randomized between rituximab maintenance and observation. Intensification of rituximab was not more effective than standard R-CHOP, showing same CR-rates and progression free survival after induction (ASCO 2016 # 7504). Here, we report the results of the second randomization for rituximab maintenance therapy. Methods: Patients in CR after R-CHOP were randomized between 24 months of rituximab maintenance 375 mg/m2 intravenous every 8 weeks (n = 199 ) or observation (n = 199). CT scans were performed at 6, 12, 18 and 24 months in both arms. The primary endpoint was disease free survival (DFS) from maintenance randomization. Secondary endpoints were overall survival (OS) and adverse events (AEs). ( www.trialregister.nl NTR1014). Results: Median age was 65 years (range 31-80), 48% were 66 years or older and 49% were male. The majority of patients (54%) had a high-intermediate or high aa-IPI score. After a median follow-up of 79.9 months (maximum 125.7 months), the 5-year DFS rate was 79% for rituximab maintenance versus 74% for observation. This difference was not statistically significant, with a hazard ratio of 0.83 (95% confidence interval 0.57-1.19, p= 0.31, adjusted for age and aa-IPI). The secondary endpoint OS was also not significantly different (85% versus 83% at 5 years). No clinical subgroup benefited from rituximab maintenance. Toxicity was mild. Among patients who received rituximab maintenance CTCAE grade 3 and 4 AEs were reported in 17% and 6% of patients, respectively. Infection was the most frequent AE, a grade 3 infection occurred in 6% of patients. Neutropenia was seen in 1% (grade 3) and 3% (grade 4) of patients. Conclusions: Rituximab maintenance therapy provides no additional benefit for DLBCL patients in first CR after R-CHOP. Clinical trial information: www.trialregister.nl NTR1014.
Outcomes in chronic lymphocytic leukemia (CLL) patients with NOTCH1 signaling pathway mutations.
Authors: Helbig Daniel R. , Abu Zeinah Ghaith F , Bhavsar Erica B. , Allan John N.
Published: March 2020

7524

Background: NOTCH1 is one of the most frequently mutated genes in CLL and has emerged as a marker of poor prognosis. Additional mutations in the NOTCH1 signaling pathway, specifically MED12, FBXW7, and SPEN, have been identified in CLL but their clinical significance has yet to be fully determined. We evaluated the clinical outcome of time to first treatment (TTFT) to compare patients with mutations to those who are wild type for NOTCH1, MED12, FBXW7, and SPEN, hypothesizing that patients with these mutations will behave similarly to NOTCH1 mutated patients and have a shorter TTFT. Methods: We conducted a single center retrospective database review of 506 patients diagnosed with CLL from 1980 to 2018 who underwent whole exome profiling between 2015 to 2018 with a lymphoid specific 75-gene next generation sequencing (NGS) panel (Genoptix Inc). The TTFT was estimated using Kaplan-Meier methods, and the difference between groups was compared using the log-rank test. Multivariate analysis (MVA) was performed with Cox proportional hazards regression. Results: Of the 506 patients who underwent NGS testing, 121 (23.9%) had at least one mutation in the NOTCH1 signaling pathway. These patients were diagnosed at an older age (62.0 years vs. 60.0 years, p=0.04) and had higher rates of CD38 positivity (40.9% vs. 22.9%, p≤0.001), Trisomy 12 (36.0% vs. 15.8%, p≤0.001), and IGVH unmutated status (71.3% vs. 44.1%, p≤0.001). They also had a shorter TTFT with a median of 3.93 years compared to 5.02 years in patients without any mutation in the NOTCH1 signaling pathway (p=0.002). In MVA, IGVH unmutated status and CD38 positivity remained independently predictive for TTFT. Conclusions: We identified three mutations in genes associated with regulation of NOTCH1 signaling that appear to signify poor prognosis, predict for a shorter TTFT, and associate with similar baseline factors that NOTCH1 does such as Trisomy 12 and IGVH unmutated status. NOTCH1 mutated patients have poor response to chemoimmunotherapy and are associated with aggressive disease biology. Future research is needed to determine whether mutations in MED12, FBXW7, or SPEN may also predict for poor response to frontline chemoimmunotherapy or novel agents currently used in CLL.
Diversity of genetic alterations of primary central nervous system lymphoma in Hispanic versus non-Hispanic population.
Authors: Barakat Mohamad , Albitar Maher , Whitney Robin L. , Chen Calvin , Kuo Yu-Hung , Silveira William , Bukari Mohammed SANI , Arekapudi Subramanyeswara Rao , Dhaliwal-Binning Karamjit , Abdulhaq Haifaa
Published: March 2020

7535

Background: Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma, distinguished by poor prognosis. Previous studies have identified MYD88, CD79b and PIM1 as the most common genetic mutations in PCNSL. However, the extent to which mutations vary by ethnicity is unknown. The purpose of this study was to describe differences in genetic mutations and survival by Hispanic ethnicity in PCNSL. Methods: We retrospectively reviewed records of 30 patients with PCNSL diagnosed between January 2007- December 2017. We examined mutations in 275 genes by DNA analysis and 1382 genes by RNA analysis utilizing next generation sequencing. Results: Among the thirty patients, median age was 60 years, 60% were male, and 60% were Hispanic. Twenty-four patients had activated B-cell (ABC) and 5 patients had germinal center (GC) type per Hans criteria. Among 29 patients with complete mutation data, 125 different mutated genes were detected. Missense mutations were the most common (75%) followed by frame shift mutations (25%). The most commonly affected genes were: MYD88 (44%), CARD11 (21%), CD79b (17%), PIM1 (17%), KMT2D (17%) and ETV6 (14%). CD79b mutation was more common in GC type vs. ABC type (60% vs. 8%, P=.01). MYD88 mutation was less frequent in Hispanic patients (27% vs 66%, P=.02), while there were no statistically significant differences in CARD11 (22% vs 18%, P=.79), KMT2D (22% vs 9%, P=.36), CD79B (16% vs 19%, P=.92) and PIM1 (16% vs 19%, P=.92). There were more Hispanic patients with >3 mutated genes (89% vs 55 %. P=.03). Two-year progression-free survival (PFS) and overall survival (OS) were 46% and 50%, respectively. Both outcomes were superior among Hispanic vs. non-Hispanic patients (2-yr PFS 60% vs 27%, P=.09), (2-yr OS 60% vs 36%, P=.23), but this was not statistically significant. MYD88, CARD11, PIM1, and KMT2D were not associated with significant differences in 2-year OS or PFS. However, patients with CD79b mutations had superior 2-yr PFS (P=.04). Conclusions: We identified highly recurrent genetic alterations in PCNSL. Our data suggest that some heterogeneity in the most frequent mutations in PCNSL may be related to ethnicity. However, the superiority in 2-yr PFS and OS did not reach statistical significance in our Hispanic patients. Further studies on a larger patient population may further help to describe the differences in incidence, tumor biology, and outcomes in Hispanic patients.
Comparison of clinical scoring systems in aggressive B-cell lymphomas (BCL): An individual patient-level analysis across international trials (SEAL).
Authors: Ruppert Amy S. , Dixon Jesse G. , Salles Gilles A. , Wall Anna K. M. , Cunningham David , Poeschel Viola , Haioun Corinne , Tilly Herve , Ghesquieres Herve , Ziepert Marita , Flament Jocelyne , Flowers Christopher , Shi Qian , Shmitz Norbert
Published: March 2020

7544

Background: Great heterogeneity in survival exists for patients (pts) newly diagnosed with aggressive BCL. Three scoring systems based on simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the international prognostic index (IPI), revised-IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We studied BCL pts treated with R-CHOP to determine which scoring systems best identifies subgroups with poor outcomes that might benefit from new approaches. Methods: Individual pt data from 7 multicenter trials (1998-2009) of pts with BCL (86% DLBCL) treated front-line with R-CHOP (or variant) were analyzed to determine whether IPI, R-IPI, or NCCN-IPI best discriminated overall survival (OS). The concordance index (c-index) from a proportional hazards model, stratifying on trial and induction therapy, quantified predictive accuracy of each scoring system. Results: 2561 pts (median age 63 yrs, 56% male) were classified into IPI, R-IPI, and NCCN-IPI risk groups (Table). With a median follow-up of 5 yrs, NCCN-IPI had the greatest absolute difference in OS estimates between the highest and lowest risk groups at 1, 3, and 5 yrs, and best discriminated OS (c-index = 0.631, Table). Conclusions: In an independent and large cohort of pts, NCCN-IPI performs best in risk-stratifying pts with aggressive BCL, readily distinguishing pts at high and low risk for treatment failure using clinical parameters (5-yr OS between 48 and 92%). Improvement over the simpler IPI appears incremental, and IPI may remain a valuable alternative. Work integrating molecular features of the tumor into the (NCCN-) IPI is in progress to define high risk groups where targeted novel approaches are needed most. [Table: see text]
Molecular profiling of primary central nervous system lymphoma as compared to activated B-cell subtype of diffuse large B-cell lymphoma.
Authors: Barakat Mohamad , Albitar Maher , Xu-Monette Zijun , Young Ken H , Abdulhaq Haifaa
Published: March 2020

7549

Background: The cell of origin of primary central nervous system lymphoma (PCNSL) remains controversial. Data using immunohistochemistry (IHC) and Hans algorithm suggested that both germinal-center B-cell–like (GCB) and activated B-cell-like (ABC) subtypes can be seen in PCNSL. We explored the potential of DNA and RNA molecular profiling in characterizing the biology of PCNSL and compared this profile with ABC subtype of diffuse large B-cell lymphoma (DLBCL). Methods: RNA and DNA were extracted from 30 formalin-fixed paraffin-embedded (FFPE) tissue samples from PCNSL patients and 30 FFPE tissue samples from cases with lymph node DLBCL of ABC subtype. Subtyping of DLBCL cases was performed using IHC and gene expression profiling. We sequenced the DNA using a 275 gene panel (Qiagen) and the RNA using a 1382 gene panel (Illumina). Next Generation Sequencing on Illumina platform was used for detecting mutations and expression profiling. The levels of RNA expression were normalized to that of PAX5. Mutations detected by RNA sequencing were compared to those detected by DNA sequencing. Results: There was no significant difference between DLBCL-ABC and PCNSL in mutation rate of MYD88, CD79B, CARD11 or KMT2D: 33.3%, 10%, 10%, and 13.3%, respectively, in DLBCL-ABC vs 30%, 10%, 10%, and 10%, respectively, in PCNSL. However, NOTCH2 mutations were significantly different and detected in 16.7% of DLBCL-ABC as compared with 3% in PCNSL (P=.001). An algorithm that uses expression profiling of 46 different genes and distinguishes DLBCL-ABC from GCB showed that all PCNSL cases classified as ABC. The GCB classical marker LMO2 was expressed at very low level in both DLBCL-ABC and PCNSL, but was at relatively higher level in PCNSL (P=.002, Kruskal-Wallis ANOVA). There was significantly higher expression of the adhesion molecule CXCR4 (P=.008), activation molecules BTK (P=.0003) and PLCG2 (P=.002), and BCL6 (P=.002) in PCNSL as compared with DLBCL-ABC. There was no significant difference between the two groups in MYC, Ki67, BCL2, CD44, or CD274 (PD-L1) expression. Conclusions: DNA and RNA molecular profiling of PCNSL suggests similarity to DLBCL-ABC subtype. However, PCNSL is unique by expressing higher levels of the adhesion molecule CXCR4 and the activation molecules BTK and PLCG2. The lack of increased expression of MYC and Ki67 suggests that PCNSL is unlikely to be similar to Burkitt lymphoma.
Efficacy of frontline treatment regimens in follicular lymphoma: A network meta-analysis of phase III randomized controlled trials.
Authors: Wang Yucai , Zhou Shouhao , Yang Fang , Nowakowski Grzegorz S. , Habermann Thomas Matthew , Wang Michael , Witzig Thomas E.
Published: March 2020

7556

Background: The frontline treatment for advanced follicular lymphoma has evolved with the introduction of maintenance therapy, bendamustine (Benda), obinutuzumab (G), and lenalidomide (Len). We conducted a network meta-analysis of phase 3 randomized controlled trials (RCTs) to identify the regimens with superior efficacy. Methods: Data were extracted from 7 RCTs (FOLL05, StiL NHL1, BRIGHT, PRIMA, GALLIUM, StiL NHL7, and RELEVANCE). Progression-free survival (PFS) was compared between 11 regimens with different immunochemotherapy and maintenance strategies. To incorporate direct and indirect comparisons, random-effects Bayesian network meta-analyses were conducted after adjusting for study-wise variation. The posterior inference was derived based on Markov chain Monte Carlo methods and implemented using JAGS v4.3.0. Pairwise comparison of hazard ratios (HRs) and 95% credible intervals (CIs) were calculated. Results: PFS HRs of other regimens compared to the reference regimen are summarized in the Table. Compared to Rituximab(R)-Benda, R-CHOP had inferior PFS, R-CHOP-R, G-CHOP-G, and R-Len-R had similar PFS, while R-Benda-R, R-Benda-R4 and G-Benda-G had better PFS. Compared to R-CHOP-R, G-CHOP-G and R-Len-R had similar PFS, while R-Benda-R, R-Benda-R4 and G-Benda-G had better PFS. In addition, the PFS for G-Benda-G was similar to R-Benda-R4 (HR 0.94, 95% CI 0.78-1.09) but better than R-Benda-R (HR 0.82, 95% CI 0.75-0.97). Conclusions: Compared with the commonly used R-Benda and R-CHOP-R regimens, G-CHOP-G, R-Benda-R and R-Benda-R4 had better PFS, while the chemotherapy-free regimen R-Len-R had similar PFS. [Table: see text]
Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).
Authors: Topp Max S. , van Meerten Tom , Wermke Martin , Lugtenburg Elly J. , Minnema Monique C. , Song Kevin W. , Thieblemont Catherine , Jiang Yizhou , Plaks Vicki , Kerber Anne , Kersten Marie Jose
Published: March 2020

7558

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved in the EU and US for patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of pts, respectively; 26% of pts received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol. 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs). Methods: Eligible pts with R/R LBCL were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. Pts in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE. Results: As of 9/14/2018, 21 of 40 planned pts received axi-cel with a minimum follow-up of 1 mo (median, 2.6 mo). The median age was 63 y (range, 36 – 73), 67% were male, 81% had disease stage III-IV, 76% were R/R to ≥ second-line therapy, and 10% had relapsed post-autologous stem cell transplantation. Seventy-six percent of pts received steroids and 81% received tocilizumab. Most pts (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of pts; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of pts, respectively. No pt had Grade ≥ 3 CRS; 33% of pts had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 pt died due to disease progression. The ORR per investigator assessment was 76% with 48% of pts achieving a CR. Pharmacokinetic data will be presented. Conclusions: Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in pts treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy. Clinical trial information: NCT02348216.
Association of high baseline metabolic tumor volume with response following axicabtagene ciloleucel in refractory large B-cell lymphoma.
Authors: Dean Erin , Lu Hong , Lazaryan Aleksandr , Krivenko Gabriel S , Bachmeier Christina A , Chavez Julio C. , Davila Marco L. , Khimani Farhad , Liu Hien D , Pinilla-Ibarz Javier , Shah Bijal D. , Jain Michael D. , Balagurunathan Yoganand , Locke Frederick Lundry
Published: March 2020

7562

Background: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 targeted Chimeric Antigen Receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). High tumor burden, by sum of the product of diameters (SPD) in ≥ 6 reference lesions, was associated with lower durable responses rates in the ZUMA-1 trial (Locke F.L. ASCO. 2018). Although metabolic tumor volume (MTV) predicts worse outcomes with chemotherapy in lymphoma (Guo B. PLoSOne. 2019), its prognostic significance remains unclear with axi-cel therapy. Methods: MTV was measured by MIM Software using a 41% SUVmax threshold with manual lesion contour adjustment and radiologist review. Low and high MTV groups were defined based on median cutoff value. Cytokine release syndrome (CRS) was graded by Lee et al. ( Blood. 2014). Neurotoxicity (NT) was graded by CTCAEv4. Toxicities, overall response rate (ORR), and complete response rate (CR) were evaluated via Fisher’s test; PFS and OS via Kaplan-Meier and log-rank test. Results: 48 patients with LBCL, or its variants, that received axi-cel at Moffitt from June 2015 to October 2018 were included. 31 were male, and median age was 63 years (range, 28-76). CRS occurred in 43/47 (91.5%) and NT in 32/47 (68.1%) patients. Grade 3-4 CRS in 2/47 (4.3%) and NT in 12/47 (25.5%). Median follow up for survivors was 8.9 months (range, 1.4- 36.8 months). CR was achieved in 31/48 (64.6 %) and ORR in 39/48 (81.3%). Median for the low MTV group was 35.1 mL (range, 4.24-132.8 mL), and for the high MTV group 455.5 mL (range, 162.2-1221.4 mL). High MTV was not predictive of G1-4 NT or G3-4 NT (OR = 1.14, P = 0.99; OR = 1.66, P = 0.52). Similarly, high MTV was not predictive of G1-4 CRS or G3-4 CRS (OR = 0.29, P = 0.348; OR = 1.05, P = 0.99). Low MTV was predictive of ORR (OR = 11.50, P = 0.026) and CR (OR = 9.8, P = 0.002). Patients with high MTV had inferior PFS (HR = 3.296, 95% CI 1.42-7.64, P = 0.008) and OS (HR = 6.68, 95% CI 2.56-17.32, P = 0.003). Conclusions: High baseline MTV is associated with decreased and less durable response following axi-cel. As survival data mature, future analyses will aim to assess the role of MTV as an independent prognostic tool in axi-cel recipients with LBCL.
A phase I study of a selective PI3Kδ inhibitor YY-20394 in patients with relapsed or refractory B-cell malignancies.
Authors: Qiu Lugui , Qi Junyuan , Song Yuqin , Jiang Bo , Tu Meifeng , Ping Lingyan , Li Zengjun , Zhu Jun , Xu Yuanyuan , Bao Hanying , Xu Zusheng
Published: March 2020

7563

Background: YY-20394, an oral highly selective PI3Kδ inhibitor was studied in a phase I trial for patients with relapse or refractory B-cell malignancies. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YY-20394. Methods: YY-20394 was given orally once daily (QD) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Only 1 subject was treated with starting dose 20 mg once daily, then subsequent cohorts used a 3+3 design and evaluated doses of 40, 80, 140 and 200 mg QD. Once a recommended Phase II (RP2D) dose is determined, a separate dose expansion part will enroll up to 12 patients at the RP2D. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria. Results: 22 patients were enrolled as of Jan 14th 2019. The patients including diffuse large B-cell lymphoma (DLBCL), n=2; follicular lymphoma (FL), n=8; follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL), n=3; mantle cell lymphoma (MCL), n=3; lymphoplasmacytic lymphoma (LPL), n=1; marginalzone B-cell lymphoma (MZBL), n=1 and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), n=4, received YY-20394 20 mg (n=1), 40 mg (n=3),80 mg (n=11),140 mg/day (n=3) or 200 mg/day (n=4) respectively. All the patients had heavy treatment and had received an average of 3.5 lines of therapy before participating in the current study including BTK inhibitor therapy and CAR-T treatment. All the patient have completed cycle 1 safety observation and no dose-limiting toxicities occurred. The most common nonhematologic TEAEs (all grades/grade≥3) were LDH elevation (36.4%/0%), pneumonia (18.2%/18.2%) and hyperuricemia (13.6%/4.5%). Gr≥3 hematologic TEAEs were neutropenia (13.6%), lymphocythaemia (9.1%), leukocytosis (4.5%) and leukopenia (4.5%). Of 19 patients evaluable for response, the overall objective response rate was 68% ((4CR + 9 PR)/19), with 86% ((3CR + 3PR)/7) in FL. The median duration of response is not available so far, the treatment for 11 subjects was still ongoing. The duration of response in 4 subjects with ongoing treatment has already over 8 months. PK parameters AUC0-24h and Cmax were dose proportional with median Tmax 2 hours. Conclusions: YY-20394 is well tolerated and with promised objective response rates in patients with relapsed or refractory B-cell malignancies. Clinical trial information: NCT03757000.
Effect of epigenetic modifier-based combinations on efficacy in patients with peripheral T-cell lymphoma (PTCL): Deciphering impact of mutations in epigenetic operations on response.
Authors: O'Connor Owen A. , Sokol Lubomir , Shustov Andrei R. , Falchi Lorenzo , Lue Jennifer Kimberly , Montanari Francesca , Amengual Jennifer , Sawas Ahmed , Deng Chanchung , Khan Karen , Jacobs Alice , Rada Aishling , Kim Hye A. , Soderquist Craig R. , Park David , Menezes Daniel
Published: March 2020

7565

Background: Recurring mutations in epigenetic functions in PTCL, coupled with marked activity of epigenetic drugs, raises a question regarding whether these mutations might portend greater vulnerability to one drug over another. For example, do mutations in genes governing DNA methylation suggest these patients might benefit from a hypomethylating (HMA) agent? Preclinical data from our group suggests marked synergism between histone deacetylase inhibitors (HDACi) and HMA, as well as HDACi and pralatrexate (PDX), irrespective of mutations in epigenetic genes. Phase 1 studies (romidepsin [R] plus PDX or R plus 5-azacytidine [Aza]) are completed, and the Phase 2 studies are near completion. This clinical trial scenario affords a unique opportunity to decipher the impact of a HMA on response as a function of TET2, IDH2, DNMT3 and other mutations in PTCL. Methods: Patients with R/R lymphoma were eligible for the phase 1, whereas the phase 2 only enrolled patients with PTCL, either R/R or treatment-naïve individuals. Exploratory endpoints included next generation sequencing (NGS) and methylation arrays. Results: In toto, 89 patients have been enrolled on both trials across all histology’s, 58 have PTCL. NGS and efficacy data is available for the majority of patients, with some from the PDX + R study in process. The ORR among the PTCL patients for PDX+R and Aza+R has been 71% and 73% respectively. Eight of 9 angioimmunoblastic TCL patients responded. Among those with TET2 mutations, 7 of 8 responded to the Aza based treatment, while only 3 of 6 (50%) who were TET2 negative responded. Similarly, of 3 patients with DNMT3 treated with Aza based therapy, all 3 responded. Remarkably one patient with a TET2 mutation experienced progression to PDX+R, and CR to Aza+R. Among the PTCL patients treated with Aza, the global demethylation score (GDMS) demonstrated marked demethylation among all patients, with no correlation between the score and likelihood of response. Conclusions: We will share the completely annotated analysis correlating clinical metrics to the spectrum of epigenetic mutations and GDMS and across all histology’s and treatments. Clinical trial information: NCT01998035; NCT01947140.
Outcomes of patients with t(11;14) multiple myeloma: An International Myeloma Working Group (IMWG) multicenter study.
Authors: Durie Brian G. , Goldschmidt Hartmut , Mateos Maria-Victoria , Gonzalez Veronica , Du Juan , Kim Kihyun , Merlini Giampaolo , Mangiacavalli Silvia , Min Chang Ki , Dimopoulos Meletios A. , Kastritis Efstathios , Ludwig Heinz , Esteves Graca , Handa Hiroshi , Escalante Fernando , Fernández de Larrea Rodríguez Carlos , Delforge Michel , Cameron Chris , Rajkumar S. Vincent , Kumar Shaji
Published: March 2020

8015

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in approx. 15% of patients (pts) with MM, is considered a standard risk abnormality, but recent data suggest that the prognosis may be inferior to what had been expected. This is of particular relevance as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be effective in t(11;14) pts. Methods: This was a multicenter study designed and conducted by the IMWG, to identify the outcomes of pts with t(11;14) using a retrospective cohort of pts. Pts with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months (mos) of diagnosis, and with treatment details available and if alive, a minimum of 12 mos of follow up, were enrolled. Results: The current analysis includes 848 pts with a median age of 64.4 years; 60.0% are male. The median follow-up from diagnosis for the entire cohort was 45.7 mos; 84.7% of the pts were alive at the last follow up. ISS stage distribution included: Stage 1 (35.3%), Stage II (38.9%) and stage III (25.8%). The distribution of FISH abnormalities included: del 13q (14.5%), 1q amp (12.1%), del 17p or monosomy 17 (6.1%). Pts received initial therapy with different regimens: IMiD-24.3%, PI-41.0%, both-20.8% and 13.8% had no novel agent. The drug classes by line of therapy are shown in table. An early stem cell transplant (SCT) was used in 40.8% of pts. The median time to next treatment (TTNT) after initial treatment was 15.0 (95% CI: 12.2 to 17.7) mos. The median overall survival from diagnosis for the entire cohort was 82.5 (95% CI: 73.5 to 95.8) mos. Conclusions: This is the first study to examine the outcomes of a large group of myeloma pts with t(11;14) abnormality. Pts receiving a combination if a PI and an IMiD appear to have the best survival outcomes and thse receiving an early SCT appear to have excellent survival with median OS approaching 10 years. Additional pts are being accrued to this study and additional analysis examining the variables affecting response duration and survival will be presented. [Table: see text]
Ixazomib, lenalidomide, and dexamethasone for patients with POEMS syndrome.
Authors: Dispenzieri Angela , Lacy Martha , Mauermann Michelle , LaPlant Betsy , Go Ronald S. , Kapoor Prashant , Leung Nelson , Hwa Yi Lisa , Fonder Amy , Buadi Francis , Hayman Suzanne R. , Lust John Anthony , Dingli David , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji , Gertz Morie A.
Published: March 2020

8019

Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. Most of the information regarding treatment has been gleaned from retrospective data. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We designed a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF > 200 pg/ml, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp A, 13 cycles for patients (pts) who had relapsed or refractory disease; Gp B, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant. Primary endpoint was VEGF complete response (CR = normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response, clinical responses including neurologic response were also studied. To date, 13 pts enrolled since 10/31/2016—4 to Gp A and 9 to Gp B. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 1/21/2019. Results: Median age was 55; 73% were male. So far, overall 64% met primary endpoint of VEGF CR (Table). The median follow-up of survivors is 12.4 mo (6, 24). 1 pt came off study for non-responsive disease and died thereafter. 38% of patients had grade 3+hematologic AE; 72% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection and hypotension in 2 each; atrial fibrillation, diarrhea, edema, dyspnea, and thromboembolism in 1 each. 4 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Clinical trial information: NCT02921893. [Table: see text]