bluuebunny/crossref_metadata_2025_split huggingface dataset:
S824 A PHASE 3 RANDOMIZED, OPEN‐LABEL, MULTICENTER STUDY OF ISATUXIMAB, POMALIDOMIDE, AND LOW‐DOSE DEXAMETHASONE VS POMALIDOMIDE AND LOW‐DOSE DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)
Authors: Attal M. , Richardson P.G. , Rajkumar S.V. , San‐Miguel J. , Beksac M. , Spicka I. , Leleu X. , Schjesvold F. , Moreau P. , Dimopoulos M.A. , Huang J.S.‐Y. , Minarik J. , Cavo M. , Prince H.M. , Mace S. , Corzo K.P. , Campana F. , Le‐Guennec S. , Dubin F. , Anderson K.C. 
Published: June 2019

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.
PS953 SURVIVAL OUTCOME OF SECOND ALLOGENEIC‐HCT IN ADULT ALL PATIENTS WHO RELAPSED AFTER PREVIOUS ALLOGENEIC‐HCT
Authors: Yoon S.Y. , Yoon J.‐H. , Kim C. , Lee J. , MIn G.J. , Eom K.‐S. , Kim H.‐J. , Lee J.W. , Lee S. 
Published: June 2019

Background:Allogeneic hematopoietic cell transplantation (allo‐HCT) is a potentially curative option for adult patients with acute lymphoplastic leukemia (ALL). However, no standard therapy is elucidated for patients who relapsed after allo‐HCT.Aims:We analyzed patients treated with second allo‐HCT and tried to find out risk factors for survival outcomes.Methods:We retrospectively analyzed 35 adult ALL patients (median 35 years old, range 16–66) treated with second allo‐HCT in second remission from 2010 to 2017, all of them relapsed after previous allo‐HCT (median 12.8 months, range 2.9–99.4). After second remission, most patients underwent second allo‐HCT from available donor within 6 months, but some patients with Ph‐positive ALL responding to salvage tyrosine kinase inhibitors or with isolated EMR were delayed for second allo‐HCT.Results:Of 35 patients, 3 patients were T‐ALL, 16 were Philadelphia chromosome (Ph)‐negative, and 16 were Ph‐positive B‐ALL. Extramedullary relapse (EMR) were observed in 11 patients, and 5 of them were isolated EMR without hematological relapse. At the time of second allo‐HCT, 17 were in complete remission (CR) and 18 were in CR without full hematological recovery. Among 16 Ph‐positive ALL patients, 9 were in complete molecular response, 2 were in major molecular response, and 5 were in poor molecular response. After median follow‐up of 38.2 months (range 7.5–86.3), 3‐year overall survival (OS) and disease‐free survival (DFS) were 31.9% and 26.0%, respectively. Cumulative inicidence of non‐relapse mortality (NRM) and relapse (CIR) at 3 years were 29.1% and 45.4%, respectively. Acute GVHD was observed in 17 (12 with grade I‐II, 4 with grade III, 1 with grade IV) and chronic GVHD was observed in 14 (mild 7, moderate 4, severe 3) out of 31 patients who were alive at least 100 days after HCT. We identified late relapse > 6 months and early allo‐HCT within 6 months (48.1% vs. 12.5% ; HR = 0.27, 95%CI 0.1–0.7, p = 0.014) and chronic GVHD (49.0% vs. 27.8% ; HR = 0.28, 95%CI 0.1–0.8, p = 0.021) showed favorable 3‐year OS in the entire cohort. Among patients with Ph‐positive subgroup, post‐HCT complete molecular response was related with superior OS (66.7% vs. 0.0% ; HR = 0.09, 95%CI 0.01–0.69, p = 0.021).Summary/Conclusion:Our data suggested that second allo‐HCT might be a feasible choice for some patients relapsed after previous allo‐HCT as a curative treatment option when allo‐HCT is performed earlier in late relapse case. Safe salvage therapy and additional post‐HCT preemptive therapy should be considered for better transplant outcomes.
PS980 GRIK5 DRIVES SELF RENEWAL PATHWAYS IN HUMAN ACUTE MYELOID LEUKEMIA CELLS
Authors: Xia J. , Garg S. , He L. , Jagdhane P. , Carsten M.‐T. , Caroline P. 
Published: June 2019

Background:Acute myeloid leukemia (AML) is characterized by a block in differentiation and uncontrolled proliferation of immature hematopoietic precursor cells. Self‐renewing leukemia stem cells (LSCs) are supposed to initiate and promote the disease. In our previous study, we had identified a set of genes associated with high LSC frequency in normal karyotype AML. Among these, we identified the Glutamate receptor ionotropic, kainate 5 (GRIK5) coding for a transmembrane protein, which is known to be expressed in the central nervous system as a ligand‐gated ion channel receptor.Aims:In this study, we aimed to understand the functional role of GRIK5 in normal HSPCs and AML cells. In particular, we investigated how GRIK5 drives self‐renewal pathways in AML and whether GRIK5 might represent a novel cell surface target for anti‐leukemic therapy.Methods:We performed knockdown (KD) experiments using small hairpin (sh) RNAs to determine whether GRIK5 was essential for proliferation, differentiation, and survival of primary human cord blood CD34+ HSPCs, leukemic cell lines, and primary human‐derived AML xenograft cells. Furthermore, lentivirally transduced HSPCs and leukemia cells were analyzed in vitro for proliferative output, viability, immunophenotype, and colony formation potential. RNA sequencing (RNA‐Seq) and whole cell mass spectrometry followed by enrichment analysis were used to identify key signaling pathways affected by GRIK5 KD.Results:We found that knockdown of GRIK5 expression strongly impaired leukemic cell proliferation and totally abrogated human leukemic engraftment in immunocompromised mice. In the healthy system, however, GRIK5 KD predominantly reduced the proliferative output of more committed progenitors, while more immature HSPCs were less affected. RNA‐Seq data points towards a major involvement in several key self‐renewal pathways.Summary/Conclusion:Here we found that the surface receptor GRIK5 is overexpressed in the majority of AML samples compared to healthy HSPCs. GRIK5 plays a pivotal role in proliferation, differentiation, and engraftment capacity of primary human leukemia cells in xenotransplantation assays and might, therefore, be used as a novel therapeutic target for anti‐leukemic therapies.
PS1066 AXICABTAGENE CILOLEUCEL (AXI‐CEL) IN REFRACTORY LARGE B CELL LYMPHOMA: OUTCOMES IN PATIENTS ≥ OR < 65 YEARS OF AGE IN THE PIVOTAL PHASE 1/2 ZUMA‐1 STUDY
Authors: Neelapu S.S. , Jacobson C.A. , Oluwole O.O. , Munoz J. , Deol A. , Miklos D.B. , Bartlett N.L. , Braunschweig I. , Jiang Y. , Kim J.J. , Zheng L. , Rossi J.M. , Locke F.L. 
Published: June 2019

Background:Axi‐cel is an autologous anti‐CD19 chimeric antigen receptor (CAR) T cell therapy approved in the European Union and United States for the treatment of patients with relapsed or refractory large B cell lymphoma with ≥ 2 prior systemic therapies. In the 2‐year follow‐up of ZUMA‐1, the objective response rate was 83%, with a complete response rate of 58%, and 39% of patients were in ongoing response (Locke et al. Lancet Oncol. 2019).Aims:To assess efficacy and safety outcomes of axi‐cel in patients ≥ or <65 years of age from ZUMA‐1.Methods:Eligible patients with refractory large B cell lymphoma underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti‐CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator‐assessed objective response rate. Additional key endpoints were adverse events, overall survival, and levels of CAR gene‐marked cells in peripheral blood. Efficacy was evaluated for Phase 2 patients; safety was evaluated for all treated patients (Phases 1 and 2). Patients were analyzed by age ≥ 65 years vs <65 years.Results:As of August 11, 2018, 108 patients were treated. Patients ≥ 65 years (n = 27) vs <65 years (n = 81) had a median age of 69 years vs 55 years, respectively, and were 81% vs 63% male; 70% vs 36% had an International Prognostic Index score of 3–4, 59% vs 57% had an Eastern Cooperative Oncology Group performance status of 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow‐up was 27.1 months for Phase 2 patients (n = 101). The objective response rate for patients ≥ 65 years (n = 24) and <65 years (n = 77) was 92% and 81% (complete response rate, 75% and 53%), respectively, with ongoing responses in 42% and 38% of patients (ongoing complete response, 42% and 35%). The 24‐month overall survival rate was 54% for patients ≥ 65 years and 49% for patients <65 years. Most patients experienced Grade ≥ 3 adverse events (100% of patients ≥ 65 years; 98% of patients <65 years), and 4% of each group (1/27 patients ≥ 65 years and 3/81 patients <65 years) died due to adverse events as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of patients ≥ 65 years vs <65 years, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μL) or area under the curve (562 vs 448 days × cells/μL) was similar in patients ≥ 65 years vs <65 years, respectively.Summary/Conclusion:The 2‐year follow‐up of ZUMA‐1 demonstrates that axi‐cel can induce high rates of durable responses with a manageable safety profile for patients ≥ and <65 years. Axi‐cel offers substantial clinical benefit for older patients with refractory large B cell lymphoma who otherwise have limited treatment options.
PS1114 PATIENTS WITH GAUCHER DISEASE SHOW AN IMMUNE‐DYSREGULATION PATTERN SECONDARY TO A DEFECT OF APOPTOSIS
Authors: Miano M. , Madeo A. , Cappelli E. , Fioredda F. , Palmisani E. , Terranova P. , Lanza T. , Vené R. , Vernarecci C. , Beccaria A. , Maggiore R. , Guardo D. , Dufour C. , Micalizzi C. , Di Rocco M. 
Published: June 2019

Background:Gaucher Disease (GD) is a congenital disorder secondary to GBA1 gene mutations that cause a defective function of the catabolic enzyme β‐glucocerebrosidase (GBA) and a progressive accumulation of its substrate‐ glucocerebroside (GC) in various organs, in particular in mononuclear phagocite system. Bone infiltration, hepatosplenomegaly and cytopenia represent the most common features of the disease. Since clinical manifestation can be subdolous, in some cases, phenotype can overlap with Autoimmune Lymphoproliferative Sindrome (ALPS). Nonetheless, GD patients were also shown to have hyperinflammatory features‐ secondary to machrophages engorgement and actviation‐ and an aspecific impaiment involving B, T and NK cells. In addition, some patients also showed more specific ALPS‐like immune‐dyregulation features suggesting an underlying apoptosis defect.Aims:To evaluate specific ALPS‐like immunological and serological pattern (Double Negative T‐cells, TCR alfa/beta B220, B‐memory cells, T‐regs/HLA‐DR ratio, IL‐10, IL‐18,) in a cohort patients with GD and to test apoptosis pathway function in those showing ALPS‐like features.Methods:All patients were diagnosed with GD by enzyme assay on lymphocytes culture or fibroblasts and by characterization of pathogenetic variants of GBA1. Lymphocytes subsets and ALPS‐related serum biomarkers (IL‐10, IL‐18, sFAS, Vit.B12) were analyzed in 41 GD patients followed‐up at Istituto Giannina Gaslini. Furthermore, in those patients who showed an ALPS‐like phenotype, apoptosis function was analyzed after FAS–induced stimulation of EBV‐immortalized B‐cells and Western blot analysis of CASP10, CASP8, and PARP proteins.Results:10/41 (24%) patients showed an ALPS‐like immunological pattern which was more frequent in naïve patients (p = 0.003) and in patients with an earlier onset of the diesease (p = 0.010). EBV‐immortalized B‐cells of 7 out of these 10 patients were further studied and all of them showed a defective FAS‐induced apoptosis and caspases activation. Fig 1 shows apoptosis evalutation of the selected population.Summary/Conclusion:To the best of our knowledge, this study shows for the first time that untreated subjects with early‐onset GD present an immune‐dysregulation pattern secondary to a defect of apoptosis as seen in ALPS patients. These results suggest that diagnostic work‐up of both diseases must take into consideration their clinical and biochemical overlap. Further studies are needed to evaluate the potential role of cell‐membrane lipids impairment on FAS receptor structure as a cause of such defect.image
PS1119 PNH CLONE SIZE BY FLOW CYTOMETRY AND ITS CORRELATION TO PIG GENE MUTATION
Authors: Jeong D. , Park H.S. , Choi S. , Seo H. , Kim S.‐M. , Im K. , Lim K. , Yun J. , Kim J.‐A. , Kim K. , Kim J.H. , Lee D.S. 
Published: June 2019

Background:Routine diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is based on flow cytometric measurement of PNH clone in RBC and granulocyte. However there is no well‐established consensus on the clinically significant size of PNH clone.Aims:So we investigated whether quantitative results of PNH clone size measured by flow cytometry (FCM) correlate with mutant burden of PIG gene.Methods:A total of 89 specimens from 63 patients whose PNH clone size was ≥0.1% by FCM was enrolled. We performed ultra‐deep sequencing for PIGA, PIGM and PIGX genes on these 89 consecutive specimens. Also, we followed up 6 patients who were treated with Eculizumab and analyzed their laboratory changes including hemoglobin, lactate dehydrogenase level, PNH flow cytometry and PIG gene mutant burden. Treatment response was evaluated every 6 months.Results:Sixteen out of 63 patients had >10% granulocyte PNH clone and they all had PIG gene mutation. Fifteen (93.8%) had PIGA mutation and one (6.3%) PIGM mutation. Patients with >15% RBC PNH clone (n = 12) all had PNH‐related symptoms (p <0.001). Granulocyte clone size showed better correlation with VAF than RBC clone size (Granulocyte r = 0.61, p = 0.01, RBC r = 0.39, p = 0.14). On the other hand, RBC clone size was better reflective of PNH‐related symptoms with a cut‐off of 15% (p <0.001). We found no significant laboratory parameter for prediction of Eculizumab treatment response.Summary/Conclusion:Patients with >10% granulocyte PNH clone by FCM were always accompanied by PIG gene mutation. Those with >15% RBC PNH clone by FCM all had PNH‐related symptoms. Weak correlation between granulocyte clone size and VAF of PIG gene mutation implies that granulocyte clone reflects the real PNH clonal burden.image
PS1193 CHARACTERISTICS AND OUTCOMES OF THE TREATMENT PATIENTS WITH T315I MUTATION CML
Authors: Vlasova J. , Morozova E. , Barabanshikova M. , Gindina T. , Alyanskiy A. , Darskaya E. , Afanasyev B. 
Published: June 2019

Background:Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR‐ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors except ponatinib.Aims:To evaluate the results of different treatments in CML patients with mutation T315I.Methods:Retrospective analysis of 79 BCR‐ABLT315I ‐positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo‐HSCT) was made in 20 pts, 59 pts received only pharmacological therapy (41 pts received TKI as monotherapy or in combination with other drugs, 10‐ α‐IF, other 8 pts received hydroxyurea or chemotherapy). At the time of allo‐HSCT 6 pts were in CP 1, 7‐ CP≥2, 6 pts had AP and 3 pts were in BC. Median (Me) age at the time of mutation detected was 42 years (13–75) (38 years in HSCT‐group). In allo‐HSCT group 13 pts had unrelated donors, 13(65%) pts received more than 2 lines TKIs before HSCT. The number of points on EBMT scale: 3–4 points ‐ 16 pts, 5–7 points ‐ 6 pts. Conditioning regimen in 13 (70%) pts had reduced intensity. Me time to HSCT after T315I detection was 7 months (0–72).Results:Me follow‐up time after T315I detection was 21 months (1–100). 5‐years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All pts in BC (n = 7), 3 in HSCT group and 4 in non‐HSCT group, died within first year after T315I indication wherein Me survival time was 1,3 month. 5‐years OS in non‐HSCT group (n = 59) was 42% with Me survival time 2,8 years. 5‐years OS after allo‐HSCT (n = 20) was 37% with Me survival time 5 months. However, 7 pts live more than 2 years after allo‐HSCT, 2 ‐ more than 6 years. All living patients after allo‐HSCT are in deep molecular response. Pts in the 2nd CP have OS 47% (CI 95% 29–53%), p = 0.46. There was no significant difference in 5‐years OS between TKI (n = 41) and non‐TKI (n = 18) pharmacological therapy (non‐HSCT) groups (42% and 47% respectively, p = 0,53). In the group that received α‐interferon in the combination with other drugs (n = 10), the 5‐year OS is higher than in the group that did not receive interferon therapy (n = 49), 72% vs 45%, respectively (p = 0.21).Summary/Conclusion:Detection of T315I mutation in TKI‐resistant patients is extremely unfavorable factor for survival, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo‐HSCT is an effective method of treatment for this group of patients in case of good selection taking into consideration transplant risk, especially for patients in CP ≥2. The administration of pharmacological therapy in the 1st CP is an effective method of treatment, which allows to control the disease for a long time.
PS1223 INTERIM ANALYSIS OF A WT‐1 AND PRAME ‘FAST‐DC’ VACCINE SHOWS SAFETY AS ACTIVE IMMMUNOTHERAPY FOR THE PREVENTION OF AML RELAPSE
Authors: Fløisand Y. , Bigalke I. , Josefsen D. , Geiger C. , Pinkernell K. , Kvalheim G. 
Published: June 2019

Background:Patients with acute myeloid leukemia (AML), not eligible for allogeneic hematopoietic stem cell transplantation (HSCT), have a significant risk of disease relapse due to lack of long‐term disease control.Aims:To investigate the possibility of relapse prevention after initial chemotherapy, a safety and feasibility Phase I/II trial (NCT02405338) is currently being conducted using dendritic cells (DCs), generated with a rapid production protocol of 3 to 4 days. The manufacture uses RNA electroporation encoding the full‐length protein antigens PRAME (Preferentially expressed antigen in Melanoma) and WT‐1 (Wilm's Tumor‐1 Antigen) as well as a cocktail containing a TLR‐7/8 agonist for maturation. Data presented here reflect results of an interim analysis at the 1 year follow up time point, while vaccination continues until all patients reach the end of the trial at a follow up of 2 years.Methods:A total of 20 subjects (median age 59, range 24 to 73) with AML (risk groups good, intermediate, poor: 13, 5, 2), in morphologic complete remission or complete remission with incomplete hematologic recovery after induction or consolidation therapy, not eligible for allogeneic HSCT, were entered in the trial. Subjects had to be positive for WT‐1 with or without positivity for PRAME. DC vaccinations were carried out monthly, with a higher frequency within the first 6 weeks. AML diagnoses were established with a median of 9.8 months before the first vaccination (range 4.5 to 17.5 months), and the last chemotherapy infusion was performed at a median of 6.9 months (range 2 to 14.8 months).Results:The manufacture of the DC vaccine in these chemotherapy‐pretreated subjects was feasible for all 20 patients and aliquots of 5 to 10 x 106 cells were used per vaccination. The vaccinations were well tolerated with no serious adverse events (SAEs) related to the treatment. The most common adverse events (AEs) were injection site related, accounting for 35% of all AEs and were mild in nature (Grade 1). A total of 3 grade 3 adverse events, unlikely or not related to the treatment, were recorded: one Herpes zoster infection, one upper respiratory tract infection and 3 decreases in platelet counts. All three platelet count decreases were due to relapses of the leukemia.After a 12‐months treatment period, the overall survival was 89% (18 of 20 patients, 95% confidence interval: 61 to 97%) and the progression free survival was 60% (12 of 20 patients, 95% confidence interval: 36 to 78%). Most relapses, 5 out of 8, occurred within the first 80 days after the start of the vaccination, out of which the 2 deaths were in patients with relapses on days 45 and 64, which could point to a starting relapse upon entering the study.Summary/Conclusion:In summary, at a follow up time of 1 year, DC vaccination against WT‐1 and PRAME appears to be safe and feasible for use in the prevention of AML relapse.