bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical benefit of luspatercept in patients (pts) with lower-risk MDS (LR-MDS) and high transfusion burden in the phase III MEDALIST study.
Authors: Zeidan Amer Methqal , Garcia-Manero Guillermo , Dezern Amy Elizabeth , Fenaux Pierre , Greenberg Peter L. , Savona Michael R. , Jurcic Joseph G. , Verma Amit , Mufti Ghulam J. , Buckstein Rena , Santini Valeria , Laadem Abderrahmane , Zhang Jennie , Rampersad Anita , Sinsimer Daniel , Louis Chrystal Ursula , Linde Peter G. , List Alan F. , Sekeres Mikkael A. 
Published: May 2020

7554 Background: Anemic pts with LR-MDS and high baseline RBC transfusion burden (HTB) have very few treatment options and constitute a pt population with significant clinical unmet need. In this secondary analysis of the MEDALIST trial (NCT02631070), we sought to evaluate the clinical benefit of luspatercept in this pt population. Methods: MEDALIST is a randomized, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of luspatercept in pts with anemia due to LR-MDS with ring sideroblasts (RS) (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or PBO subcutaneously every 3 weeks. HTB was defined as ≥ 6 RBC units transfused/8 weeks. Results: 153 pts were randomized to luspatercept and 76 to PBO. As of July 1, 2019, 23/66 (34.8%) and 12/66 (18.2%) HTB pts receiving luspatercept achieved a ≥ 50% and ≥ 75% reduction from baseline in RBC transfusion burden over ≥ 24 weeks, respectively, vs 3/33 (9.1%; P = 0.0063) and 1/33 (3.0%; P = 0.0363) pts receiving PBO. 6/66 (9.1%) luspatercept-treated HTB pts and 1/33 (3.0%) PBO-treated HTB pt achieved RBC-transfusion independence (TI) ≥ 8 weeks in Weeks 1–24 ( P = 0.2699). The median (range) time to achieve RBC-TI with luspatercept was 50.0 days (1.0–100.0) and median (range) duration of RBC-TI in the luspatercept arm was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 in the luspatercept arm vs 12.4 in the PBO arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) PBO-treated HTB pts reported ≥ 1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) pts, respectively, reported ≥ 1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) PBO-treated pts reported ≥ 1 serious AE. Incidence of grade 3–4 TEAEs in HTB pts was similar between arms (53.0% luspatercept vs 54.5% PBO). Conclusions: Luspatercept treatment resulted in clinically significant reductions in transfusion burden and reduced number of transfusion events in HTB pts with LR-MDS with RS, with an acceptable safety profile consistent with the overall population. Clinical trial information: NCT02631070 .
Chronic myelomonocytic leukemia genomic signature correlates with the degree of bone marrow fibrosis: A single-institutional retrospective study.
Authors: Ally Feras , Jariwala Amar , Aoun Patricia A. , Telatar Milhan , Pillai Raju K. , Ali Haris , Snyder David , Louie Carrie , Afkhami Michelle 
Published: May 2020

7559 Background: Chronic myelomonocytic leukemia (CMML) has features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. The median overall survival (OS) in most series is 20-40 months. CMML is a relatively rare entity, and there is limited understanding of prognostic molecular markers. CMML associated with bone marrow fibrosis grade 1, appear to have shorter progression free survival. In this study we investigated the correlation of mutations with bone marrow reticulin fibrosis in patients with CMML. Methods: We investigated a cohort of 41 consecutive patients diagnosed with CMML 0, 1, 2, and CMML-AML from 2014 to 2019 at our institute. The median age of 41 patients was 68 years (range, 34-82). 27% were females and 73% were males. This cohort consists of 8 (20%) patients with CMML0, 19 (46%) with CMML1, 8 (20%) with CMML2 and 6 (15%) with CMML-AML. Genomic DNA was extracted from the bone marrow aspirates and targeted mutation NGS libraries were prepared from 200 ng of genomic DNA using the SureSelect target enrichment system (Agilent Technologies Inc.). The gene panel consists of 73 genes focused on myeloid neoplasms. The data were curated on the basis of our molecular pathology and national databases. Additionally, clinical data and bone marrow (BM) reticulin fibrosis grades (n = 27 available) were retrieved from the patient’s medical record. Results: The mutational profile frequency in our cohort showed that the most common mutations were TET2 (31%), ASXL1 (31%), and SRSF2 (23%), with frequencies very similar to those reported in the literature. Of the 27 cases with an available reticulin stain, only low grade fibrosis (MF-0, n = 18. MF-1, n = 9) were identified in our cohort. The frequencies of mutations in ASXL1, U2AF1, TP53, JAK2 and RUNX1, positively correlated with low grade fibrosis (MF-1). Additionally, patients with higher frequencies of SRSF2, TET2, and SETBP1 mutations showed no fibrosis (MF-0). Conclusions: This study is the first to correlate the degree of fibrosis with the frequency of mutations in CMML. We found similar mutations spectrum reported in the literature in patients with CMML. The mutational profile associated with CMML cases appears to affect the degree of the bone marrow fibrosis at the time of diagnosis.
Is autologous transplantation (autoHCT) in relapsed diffuse large B-cell lymphoma (DLBCL) patients achieving only a PET/CT positive partial remission (PR) appropriate in the CAR-T cell era?
Authors: Shah Nirav Niranjan , Ahn Kwang Woo , Litovich Carlos , Fenske Timothy , Hamadani Mehdi 
Published: May 2020

8000 Background: In relapsed, chemosensitive DLBCL patients (pts), autoHCT consolidation is a standard therapy option. With the approval of anti-CD19 CAR T-cells in 2017, relapsed DLBCL pts with residual PET/CT avid disease after salvage therapies are increasingly being offered CAR T-cells in lieu of autoHCT. According to Center for International Blood and Marrow Transplant Research (CIBMTR) data in 2018, the number of autoHCT for DLBCL in the U.S. decreased by ~45% from prior years, likely due to application of CAR T-cells for both chemorefractory DLBCL and chemosensitive DLBCL pts not achieving a complete remission. Using the CIBMTR database, we report outcomes of autoHCT in relapsed chemosensitive DLBCL pts achieving only a PET/CT+ PR prior to HCT. Methods: 249 relapsed DLBCL pts undergoing an autoHCT from 2003-13 with a PET/CT+ PR prior to transplant were identified. The study cohort was divided into two groups: (a) early chemo-immunotherapy failure (ECF) defined as pts with primary refractory disease (PRefD) or relapse within 12 months of diagnosis, (b) late chemoimmunotherapy failure (LCF) defined as pts relapsing ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. Results: 182 pts had ECF and 67 pts had LCF. The median age of ECF pts was 57 years versus (vs) 63 years for LCF (p < 0.01). ECF pts more frequently had stage III-IV at diagnosis (74% vs 54%, p = < 0.01). 79% of ECF pts had PRefD. The most common conditioning regimen was BEAM in both cohorts. The adjusted 5-year probabilities for PFS and OS (ECF vs LCF) was not different between the 2 cohorts: 41% vs 41% (p = 0.93) and 51% vs 63% (p = 0.09), respectively. Cumulative incidence of relapse at 5 years in similar order was 48% vs 57%, p = 0.27. On multivariate analysis compared to the LCF, pts with ECF had an increased risk of death (HR = 1.61, 95%CI 1.05-2.46, p = 0.03) but no increased risk in PFS or relapse. Conclusions: Using the CIBMTR registry, we report outcomes of relapsed DLBCL pts in a PR with residual PET/CT avid disease at time of autoHCT. While OS favored LCF pts, the adjusted 5-year PFS (41%) was comparable in both cohorts. This 5 year PFS is comparable to results reported in historical trials of auto-HCT for DLBCL. With no randomized data demonstrating superiority of CAR T-cell therapy in chemosensitive PR patients, these findings strongly support that autoHCT should remain the current standard of care for this patient population.
ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM).
Authors: Tam Constantine Si Lun , Opat Stephen , D'Sa Shirley , Jurczak Wojciech , Lee Hui-Peng , Cull Gavin , Owen Roger G. , Marlton Paula , Wahlin Bjorn E. , Tedeschi Alessandra , Castillo Jorge J. , Siddiqi Tanya , Buske Christian , Leblond Veronique , Chan Wai Y. , Schneider Jingjing , Ro Sunhee K. , Cohen Aileen , Huang Jane , Dimopoulos Meletios A. 
Published: May 2020

8007 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in WM patients. Methods: Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at ~12 months after last patient enrolled. Results: In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, except in the ZANU arm there were more elderly patients (aged >75 years, 33.3% vs 22.2%) and more anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events (AEs) leading to discontinuation or death were lower with ZANU. The rate of neutropenia was higher with ZANU (Table); however, grade ≥ 3 infection rates were similar (17.8% vs 19.4%). Conclusions: ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared to IBR. Clinical trial information: NCT03053440 . [Table: see text]
Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: An international, multicenter propensity matched study.
Authors: Chin Collin K , Lim Kenneth JC , Lewis Katharine L , Jain Preetesh , Qing Yun , Feng Lei , Cheah Chan , Seymour John Francis , Ritchie David , Burbury Kate , Tam Constantine Si Lun , Fowler Nathan Hale , Fayad Luis , Westin Jason , Neelapu Sattva Swarup , Hagemeister Fredrick B. , Samaniego Felipe , Flowers Christopher , Nastoupil Loretta J. , Dickinson Michael 
Published: May 2020

8021 Background: Transformation of untreated indolent B-cell lymphoma (Tr-iNHL) is associated with poor outcomes. Current practices are extrapolated from prospective studies of de novo large B-cell lymphoma (DLBCL) or small retrospective studies. High dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) is used as consolidation in first remission (CR1) in some centers but the evidence-base is weak. Methods: CLL/SLL, MCL as primary diseases and non-DLBCL transformations were excluded. Propensity score analysis (PSM) using the “greedy match” algorithm was used to match the baseline covariates to adjust for potential selection bias. Landmark analysis was performed with time zero at 3 months after completion of front line chemotherapy (FLC). Kaplan-Meier method and the Cox proportional hazards model were was used for time-to-event analysis including progression-free survival (PFS) and overall survival (OS). Results: 319 transplant eligible patients (age <75, LVEF >45%, no severe lung disease, CR by PET or CT >3 months after FLC) who received >/= standard RCHOP intensity FLC were identified across three centers in Australia & US. 283 (89%) patients had follicular lymphoma, 30 (9%) marginal zone lymphoma, 6 (2%) other subtypes. 49 patients underwent HDC and ASCT in CR1, a matched cohort of 98 pts based on age, stage, HGBL-DH and ECOG PS at diagnosis was generated with a 1:2 ratio using PSM. After a median follow-up of 3.6 (min: 0.1, max: 18.3) years, ASCT was associated with significantly superior PFS on multivariable analysis (MVA) (HR 0.51, 0.27-0.98; P=0.043). Univariate analysis demonstrated a trend towards inferior OS in the ASCT cohort (HR 2.36; 0.87-6.42; P=0.092) with more deaths in the ASCT arm due to PD (8% v 4%). Of the 40 patients (41%) with relapsed disease in the non-ASCT cohort–15 patients underwent salvage HDC & ASCT with 7/15 (47%) ongoing CR; 10 patients underwent CAR-T therapy (5 relapse post ASCT, 4 refractory disease, 1 relapse post FLC) with 6/10 (60%) ongoing CR; 3 patients underwent allogeneic SCT (2 relapse post ASCT, 1 relapse post FLC) with 2/3 (67%) ongoing CR. Conclusions: Although ASCT in CR1 may improve initial duration of disease control in de novo Tr-iNHL, the impact on OS is less clear with effective salvage therapies in the CAR-T era.
Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: Interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).
Authors: Lee Hun Ju , Choi Michael Y. , Siddiqi Tanya , Wierda William G. , Barrientos Jacqueline Claudia , Lamanna Nicole , Goldenberg Alec , Isufi Iris , Tuscano Joseph M. , Subbiah Suki , Weihe Elizabeth Kristine , Ianopulos Xen , Breitmeyer James Bradley , Hsu Frank J. , Wang Michael , Jamieson Catriona HM , Kipps Thomas J. 
Published: May 2020

8036 Background: ROR1 is an onco-embryonic tyrosine kinase receptor that is re-expressed at high levels on many hematologic and solid cancers but not on normal adult tissues. ROR1 binds Wnt5a, resulting in increased tumor growth and survival, cancer cell stemness and epithelial mesenchymal transition. Cirmtuzumab (Cirm) is a humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in MCL or CLL. Methods: As of Jan 29, 2020, 12 pts with relapsed refractory (RR) MCL were enrolled into Part 1 Dose Escalation (DE). All MCL pts had stage 3/ 4 at original diagnosis, 25% had bulky tumor at study entry, 58% had intermediate/high risk MIPI scores and the majority (83%) had ≥ 2 prior regimens. 34 pts with CLL [12 treatment naïve (TN) and 22 RR pts] enrolled into Part 1 DE (n = 18) or Part 2 Expansion (n = 16). At least 79% of CLL pts were high risk as determined by unmutated IGHV, 17p/p53 loss, and/or del 11q. DE pts received Cirm IV q2wks x 3-5 doses then q4wks plus Ibr (starting D28). Following DE, Cirm 600mg IV q2wks x3 then q4wks plus Ibr (420mg/day CLL or 560mg/day MCL) was chosen for Expansion. Results: Safety : only grade 1/ 2 AEs were reported as possibly related to Cirm alone, whereas the safety profile attributed to Ibr or Ibr / Cirm was similar to published data, with no new or unexpected events. Efficacy for MCL: 83% ORR, 33% (4) CR, 50% (6) PR, 17% (2) SD. CRs were achieved at a median of 3.6 mos in heavily pretreated pts, including 2 with bulky disease > 5cm. Prior therapy of the 4 CR pts: 2 pts failed R-Ibr (7-10 mos) and R-hyperCVAD, 1 pt, auto-SCT and allo-SCT, 1 pt, auto-SCT and CAR-T. Efficacy for CLL : 88% ORR (92% TN, 86% RR), 3% (1) CR, 85% (22) PR/ (7) PR-L, 12% (4) SD. In addition, 3 PR pts with CLL met criteria for “Clinical CR, bone marrow biopsy not performed”. The pt achieving a CR had RR disease with del 11q; this pt remains in remission > 6 mos after stopping all therapy. At a median follow-up of 9.9 mos, 100% of CLL pts are free of disease progression and > 82% remain on study. Conclusions: Cirm in combination with Ibr is a well-tolerated and active regimen for RR MCL and TN or RR CLL. In this evaluation of 46 pts, the ORR and PFS continue to improve with longer follow-up and additional pts, supporting continued investigation of this regimen in ROR1 expressing tumors. This study is ongoing and enrolling an Expansion arm for MCL pts and an open-label randomized Phase 2 in CLL pts comparing Ibr alone to Cirm /Ibr. Clinical trial information: NCT03088878 .
Haemophagocytic lymphohistiocytosis (HLH) in patients with large B-cell lymphoma treated with standard of care (SOC) axicabtagene ciloleucel (Axi-cel).
Authors: Ahmed Sairah , furqan fateeha , Strati Paolo , Westin Jason , Fayad Luis , Hagemeister Frederick B. , Lee Hun Ju , Iyer Swaminathan Padmanabhan , Nair Ranjit , Nastoupil Loretta J. , Parmar Simrit , Rodriguez Maria Alma , Samaniego Felipe , Steiner Raphael , Wang Michael , Pinnix Chelsea Camille , Flowers Christopher , Horowitz Sandra B. , Hawkins Misha , Neelapu Sattva Swarup 
Published: May 2020

8057 Background: HLH is a rare but serious complication of chimeric antigen receptor (CAR) T cell therapy, characterized by severe immune activation, and immune mediated multi-organ failure. Diagnosis is difficult in the context of cytokine release syndrome (CRS) and optimal treatment and outcomes are unclear. Methods: Retrospective, descriptive analysis of patients with relapsed/refractory LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 - 10/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) defined as time from axi-cel infusion to progression/death or last follow-up. Diagnosis of HLH per HLH-2004 and CART cell therapy toxicity guidelines (Neelapu, 2018) Results: One hundred and five patients with relapsed/refractory LBCL included, 6 diagnosed with HLH. No significant difference in baseline characteristics, disease stage, international prognostic index or inflammatory markers at baseline between groups, with exception of platelet count which was lower in HLH group 116 [37-129] versus 141 [9-391] (p = 0.07). Development of HLH was early after CART cell infusion at a median 11 days [7 – 78 days] with 3 patients having bone marrow hemophagocytosis; all 6 had abnormalities in liver function tests, fibrinogen, triglycerides, and at least 1 ferritin level > 10,000. CART toxicity in HLH cohort: 4 patients experienced grade 0-1 CRS, and 1 with grade 2 CRS while 3 HLH patients experienced grade 3-4 IEC-associated neurotoxicity syndrome ( ICANS), and 2 patients had grade 0-1 ICANS. Five HLH patients treated with high dose steroids, and tocilizumab; anakinra administered in 2 patients. Four of 6 patients had resolution of HLH with treatment and didn’t require escalation to HLH specific therapy however 1 patient was treated with steroids/etoposide. PFS and overall survival (OS) were significantly shorter in HLH group, PFS 1 months vs 8 months, respectively (p < 0.001) and median OS 2 months vs not reached, respectively (p = 0.001) follow up 10 months (95% CI 8-12 months). One patient died of acute respiratory failure, 2 patients died of HLH and multi-organ failure without progressive disease (PD). Of 3 remaining patients, all had radiographic PD at day 30, 2 of whom died of PD. Conclusions: HLH is likely an underreported complication of CART cell therapy, and patients with HLH have significantly worse outcomes. In this series the majority of patients died of PD, not the syndrome itself. More information is necessary to design treatment strategies that won’t compromise CART outcomes.
Alternative anti-CD20 antibody versus desensitization for lymphoma patients with drug hypersensitivity reactions requiring discontinuation of rituximab, obinutuzumab, or ofatumumab.
Authors: Ghione Paola , Joffe Erel , De Paola Nadia , Mainardi Timothy , Noor Sarah J. , Bobillo Sabela , Myskowski Patricia L. , Palomba M. Lia , Moskowitz Alison J. , Mato Anthony R. , Sha Fushen , Von Keudell Gottfried , Straus David J. , Noy Ariela , Younes Anas , Hamlin Paul A. , Brentjens Renier J. , Tejedor-Alonso Miguel Angel , Horwitz Steven M. , Zelenetz Andrew David 
Published: May 2020

8062 Background: Immunotherapy with anti CD20 is often associated with mild easily manageable infusion reactions. In rare cases, patients experience severe drug hypersensitivity reactions (DHR) serum sickness or anaphylaxis. These in turn may lead to discontinuation of the drug. In our experience, switching to a different anti-CD20 agent is a feasible alternative to discontinuation or desensitization protocols. Methods: From our pharmacology database we identified all the patients that received rituximab and/or obinutuzumab, and/or ofatumumab, and/or all the patients who received a flat dose of less than 50 mL of the same drugs and were followed at our institution. From the medical record, we identified all the cases where the anti-CD20 antibody was changed due to allergy, serum sickness or other types of DHR, and all those who received minimal doses of anti-CD20 in the context of a desensitization protocol. DHRs were evaluated either by an allergist, or by retrospective review following the World Allergy Organization guidelines. Our primary comparison, was to assess the proportion of pts able to completed planned infusion of abs using either approach (Fisher’s exact Test). Results: Among 343 patients receiving at least two different anti-CD20 antibodies or a flat dose of < 50 mL, we identified 44 patients experiencing severe DHRs needing intervention. At the time of the reaction, 16 (36%) received the anti-CD20 as single agent, 24 (54%) in combination with chemotherapy, 4 (9%) in combination with ibrutinib or lenalidomide. In 9 (20%) patients the reaction was defined as anaphylactoid (8 rituximab; 1 obinutuzumab) and in 8 (18%) patients, all receiving rituximab, as serum sickness. Episodes of DHR were addressed with either desensitization (n = 29) or change of anti-CD20 agent (n = 25), 9 patients received both of these approaches, one patient switched anti-CD20 antibodies twice. Overall, 21 desensitizations were successful (72.4%), 8 failed; 23 changes of anti-CD20 were successful (92%) and 2 failed (p = 0.09). Conclusions: In patients with DHR use of an alternative anti-CD20 antibody is safe and is an alternative or complementary approach to anti-CD20 desensitization.