bluuebunny/crossref_metadata_2025_split huggingface dataset:
S827 CLINICAL RESPONSES AND PHARMACOKINETICS OF FULLY HUMAN BCMA TARGETING CAR T CELL THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
Authors: Li C. , Zhou J. , Wang J. , Hu G. , Du A. , Zhou X. , Hong Z. , Meng L. , Chen L. , Mao X. 
Published: June 2019

Background:Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high‐dose BCMA‐targeting CAR‐T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re‐infusion of CAR‐T cells is not effective. To solve this dilemma, we have developed a novel BCMA‐targeting CAR‐T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4–1BB co‐stimulatory and CD3z activation domains.Aims:The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti‐myeloma activity, cytokines, CAR‐T cell persistence, and pharmacokinetics.Methods:ChiCTR1800018137 is a single‐center and single‐arm trial of CT103A in patients with RRMM. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR‐T) received CT103A in 3+3 dose‐escalation trial (three doses at 1, 3, 6 × 106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 ‐ 5) of MM therapy.Results:At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table1), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0‐28 reached levels comparable to reported CD19 CAR‐T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 ‐ 2. In the 6 × 106 /kg dose group, DLT had been observed in one patient.Summary/Conclusion:Data from this early‐stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR‐T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM.image
S862 THE ROLE OF GATA2 IN HSC GENERATION THROUGH ENDOTHELIAL‐TO‐HEMATOPOIETIC TRANSITION.
Authors: Koyunlar C. , Gioacchino E. , Hoogenboezem R. , de Looper H. , Bosch D. , Klavert J. , Havermans M. , van Strien P. , Bindels E. , Delwel R. , Dzierzak E. , Touw I. , de Pater E. 
Published: June 2019

Background:GATA2 is the most frequently mutated gene in childhood AML. These patients have germline mutations in one allele of GATA2 and have a high predisposition for MDS/AML. Also, in mouse, Gata2 is required for embryonic HSC generation and survival and complete deletion of Gata2 is lethal at embryonic day (E)10, while Gata2 haploinsufficiency results in a severe reduction in the formation of HSCs. The first HSCs are formed at E10.5 through a process called endothelial‐to‐hematopoietic transition (EHT) from specialized hemogenic endothelial cells of the dorsal aorta in the aorta‐gonad‐mesonephros (AGM) region.Aims:As all patients suffering from GATA2 haploinsufficiency syndromes have innate GATA2 mutations, our hypothesis is that embryonic haploinsufficiency of GATA2 is responsible for the phenotype of the patients. Therefore, we want to understand how Gata2 haploinsufficiency affects the generation of HSCs through EHT.Methods:We sorted phenotypic HSPCs (CD31+cKit+ cells) from WT and Gata2

+/‐
E11 AGMs and performed transcriptome analysis. Also, with whole‐mount antibody staining performed on the WT and Gata2

+/‐
AGMs, we analysed CD31+cKit+ cell populations.Results:Surprisingly, we found that the hematopoietic transcriptional program is not abrogated in Gata2

+/‐
mouse E11 CD31+cKit+ cells. However, Gata2

+/‐
HSPCs still express the endothelial program indicating that the hematopoietic cells are stuck in the endothelium and cannot complete EHT. We found that Gfi1b is downregulated in Gata2

+/‐
HSPCs. As Gfi1b is known to be required for downregulation of the endothelial program for EHT during primitive hematopoiesis, we hypothesize that Gata2 directly regulates Gfi1b and that this regulation is required for normal EHT.Summary/Conclusion:In conclusion, we showed Gata2

+/‐
HSPCs are transcriptionally different from WT HSPCs. We are currently studying if a specific HSPC subtype can overcome Gata2 haploinsufficiency and will still undergo EHT as this may have implications for the hematopoietic cells that eventually populate the hematopoietic tissues.
S910 A NEW MEMBRANE‐BOUND IL‐21/4–1BBL‐EXPANDED NK PRODUCT EXHIBITS ACTIVITY AGAINST ACUTE MYELOID LEUKEMIA ACTIVITY IN VIVO
Authors: Zhao X.‐Y. , Jiang Q. , Jiang H. , Hu L.‐J. , Zhao T. , Yu X.‐X. , Huang X.‐J. 
Published: June 2019

Background:Adoptive NK cells infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients.Aims:The aim of this study was to explore that two weeks of clinical grade expansion could provide sufficient numbers and purity of NK cells for clinical application with an enhanced ant‐leukemia response in vitro.Methods:NK cells were expanded in the large‐scale expansion platform based on membrane‐bound interleukin‐21/4–1BBL K562 feeder cells (mbIL21/4‐1BBL). The phenotype as well as responsitveness of NKcells were evaluated before and post NK cells expansion. NCG mouse model were used to assess the in vivo persistence and in vivo anti‐leukemia effect of NK products. Finally, 20 minimal residual disease persistent or relapse (MRD+) AML were enrolled to evaluate the safety of adoptive expanded NK products infusion.Results:In this study, using the large‐scale expansion platform, we first demonstrated that 2 weeks of expansion could satisfy clinical use in number (∼4.1 × 109 NK cell) and purity (median 81%) from 2 × 107 peripheral blood mononuclear cells based on membrane‐bound interleukin‐21/4‐1BBL K562 feeder cells (mbIL21/4‐1BBL), with expansion folds of 1318 and 2876 at 2 and 3 weeks, respectively. The CD107α production as well as TNF‐α secretion capacity of NK products against AML cell lines, or primary AML blasts, were comparable between 2 weeks and 3 weeks expanded NK products, both of which were higher than those resting NK cells before expansion. The MbIL21/4‐1BBL expanded NK product xenografted into immunodeficient leukemia mice could be found in bone marrow, spleen, liver, lung and peripheral blood, persisting for at least 2 weeks and reducing the AML burden in vivo. NK cells infusions once, or three times every other days exhibited similar tumor control. Compared with the case‐paired 20 minimal residual disease persistent or relapse (MRD+) AML patients with regular consolidation therapy, 20 AML MRD+ patients who accepted the expanded NK treatment showed better leukemia‐free survival and overall survival.Summary/Conclusion:In conclusion, this study demonstrated that mbIL‐21/4‐1BBL expanded NK cells exhibited anti‐leukemia activity against AML in vitro and in a mouse model, and the infusion of expanded NK product was potentially efficacious for AML patient without adverse effects.
PS913 ROLE OF CHOROID PLEXUS STROMA IN TUMOUR CHEMORESISTANCE: A SANCTUARY FOR LEUKAEMIA CELLS IN THE CENTRAL NERVOUS SYSTEM
Authors: Fernández‐Sevilla L.M. , Valencia J. , Flores M.A. , Fraile‐Ramos A. , Jiménez E. , Sacedón R. , Ramírez M. , Varas A. , Vicente Á. 
Published: June 2019

Background:Central Nervous System (CNS) relapses are still one of the main causes of morbimortality in childhood acute lymphoblastic leukaemia (ALL) patients despite the reduction achieved by CNS‐directed prophylactic chemotherapy. Although CNS colonization by ALL cells has been already associated to both increased survival and enhanced chemoresistance of blasts to intrathecal therapy, the mechanisms of protection and tumour cell maintenance in this compartment, as well as the interactions established between ALL and CNS cells, still need to be better understood.Aims:We propose in vivo and in vitro studies aimed at determining the location of leukaemia cells in the choroid plexus (CP) and the relevance of their interaction with stromal fibroblastic cells to create a tumour supportive microenvironment. Also, we explore the contribution of stromal cells to the ALL chemoresistance.Methods:Brain histopathology evaluation of immunodeficient NSG mice transplanted with human primary ALL cells or the Nalm‐6 cell line was performed by using electron and fluorescence microscopy. Leukemic co‐cultures with human CP cells in the presence or absence of different concentrations of chemotherapeutic drugs were used for viability assays. Changes in CP microenvironment were further tested by RT‐qPCR, flow cytometry, ELISA and CBA assays.Results:The histological analysis of a xenograft model of ALL revealed the presence of leukaemic cells not only in the cerebral ventricles floating in the cerebrospinal fluid, but also interacting with the CP epithelium and within the CP stroma of those animals with CNS infiltration. The proximity of ALL cells to CP capillaries suggests they may easily enter through this fenestrated endothelium. Evaluation of interactions between leukaemic cells and stromal cells showed an upregulated expression of very late antigen‐4 (VLA‐4) in ALL cells and vascular cell adhesion molecule (VCAM1) in CP fibroblasts. Furthermore, in these co‐cultures, ALL cells exhibited a reduced cell proliferation and an enhanced cell viability following treatment with chemotherapeutic agents. However, the blockade of VCAM1‐VLA‐4 interaction was found to impair those effects suggesting that VCAM1‐VLA‐4 interactions are, at least in part, responsible of protecting leukemic cells from cell death.Summary/Conclusion:Choroid plexus is proposed as a possible sanctuary for leukemic cells. There, ALL cells may remain attached to fibroblasts in a dormant state and protected from intrathecal chemotherapy treatment, thus favouring later relapses.
PS929 KLF4 EXERTS A TUMOR SUPPRESSOR FUNCTION IN PATIENTS’ B‐ALL CELLS GROWING IN MICE AND IS RE‐UPREGULATED BY AZACYTIDIN
Authors: Liu W.‐H. , Senft D. , Vösle K. , Carlet M. , Herold T. , Jeremias I. 
Published: June 2019

Background:The transcription factor KLF4 is known for its important role in stem cells, such as induced pluripotent stem cells, but its function for B‐ALL remains unclear.Aims:Here, we aimed at deciphering the role of KLF4 for survival, growth and treatment response in patients’ B‐ALL cells and asked whether KLF4 might represent a putative therapeutic target to treat B‐ALL.Methods:As clinic‐close in vivo model, patients primary B‐ALL cells were transplanted into immunocompromised mice for amplification; resulting patient‐derived xenograft (PDX) cells were lentivirally transduced to express to physiologic levels, either wildtype KLF4 or a mutant control KLF4 lacking the DNA binding domain. An inducible transgene expression system was established and fluorochromes used in pairwise competitive in vivo assays.Results:To functionally study the role of KLF4 at a molecular level in patients’ B‐ALL cells, we aimed for an inducible expression system in ALL PDX models. For the first time ever, as far as to our knowledge, we were able to establish such an inducible system in PDX B‐ALL cells which allowed to study the re‐expression of KLF4 at different disease stages.Upon spontaneous tumor growth, KLF4 re‐expression significantly reduced B‐ALL PDX cell proliferation in vivo and induced cell cycle arrest and apoptosis. The reduced cell fitness of KLF4 expressing cells was reflected by impaired homing of wtKLF4‐expressing cells into the in vivo environment upon secondary transplantation. When KLF4 was expressed during systemic poly‐chemotherapy, PDX B‐ALL tumor burden was reduced significantly faster in cells expressing KLF4. In a MRD model, mice carrying PDX B‐ALL samples were treated with conventional chemotherapy over several weeks to reduce tumor burden by several orders of magnitude; when KLF4 was re‐expressed during tumor re‐growth after treatment, it rapidly and completely abrogated pre‐treated PDX B‐ALL cells. Our data show that re‐upregulating KLF4 impairs spontaneous growth, especially after treatment, and sensitizes B‐ALL cells towards conventional treatment. KLF4 might thus represent an interesting therapeutic target in B‐ALL.We next searched for drugs which might be able to upregulate KLF4 levels in B‐ALL. We found that Azacitidine (Aza) in low, clinically relevant concentrations upregulated KLF4. Crispr‐Cas9 induced KLF4 knockout in PDX B‐ALL cells disabled Aza‐induced upregulation of KLF4 and significantly reduced AZA‐induced cell death, suggesting that Aza‐induced cell death in B‐ALL was mediated, at least in part, by KLF4. Thus, Aza uses upregulation of KLF4 in order to eliminate B‐ALL cells and KLF4 upregulation explains, at least in part, the mode of action of Aza.Summary/Conclusion:We conclude that KLF4 plays a tumor suppressor function in B‐ALL which might be utilized therapeutically, especially to prevent relapse. Due to its ability to re‐upregulate KLF4, Azacitidine might be tested in ALL in the future.
PS949 INOTUZUMAB OZOGAMICIN (INO) TREATMENT IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA (R/R ALL): OUTCOMES OF PATIENTS TREATED IN SALVAGE ONE WITH A LONG DURATION OF FIRST REMISSION
Authors: Stelljes M. , Jabbour E. , Advani A. , DeAngelo D.J. , Marks D.I. , Stock W. , O’Brien S. , Cassaday R.D. , Wang T. , Neuhof A. , Vandendries E. , Kantarjian H. 
Published: June 2019

Background:In R/R ALL, data are limited supporting targeted therapies like InO as first salvage in patients (pts) who achieved a long duration of first complete remission (CR1). InO, a calicheamicin‐conjugated antibody, targets CD22 on ALL blasts.Aims:Here we report outcomes in pts with ALL in first salvage (S1) who had a long CR1 before receiving InO vs standard of care chemotherapy (SC).imageMethods:Adults with CD22+ R/R ALL, stratified by salvage and length of remission (CR1 ≥ or <12 mos), were randomized to receive InO (n = 164) or SC (n = 162). Methods were previously described (Kantarjian et al, NEJM 2016), with data shown up to the last patient last visit (January 4, 2017). Outcomes including complete remission (CR)/CR with incomplete hematologic recovery (CRi) and overall survival (OS) were determined for S1 pts who achieved CR1 ≥ 12 mos and CR1 ≥ 18 mos.Results:For S1 pts with CR1 ≥ 12 mos or CR1 ≥ 18 mos, InO and SC arms had generally comparable baseline characteristics. For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos, fewer pts had received a prior stem cell transplant in the InO vs SC arm (10.4% vs 25.0% and 9.7% vs 21.4%). For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos respectively, InO vs SC treatment led to a higher CR/CRi rate (85.4% vs 27.5% [P < 0.0001] and 83.9% vs 32.1% [P < 0.0001]) and improved OS (HR = 0.547 [P = 0.0086] and 0.504 [P = 0.0163]), with veno‐occlusive liver disease reported in 12.5% and 12.9% of InO pts.Summary/Conclusion:Improved outcomes were seen with InO vs SC among S1 pts who had a long first complete remission (CR1 ≥ 12 mos or CR1 ≥ 18 mos), supporting the benefit of InO vs SC in this population.
PS951 MORE OR LESS? IMPACT OF DOSE NUMBER ON OUTCOMES OF PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH INOTUZUMAB OZOGAMICIN
Authors: Marks D.I. , DeAngelo D.J. , Jabbour E. , Advani A. , O’Brien S. , Wang T. , Neuhof A. , Vandendries E. , Kantarjian H. , Stock W. , Stelljes M. , Cassaday R. 
Published: June 2019

Background:In INO‐VATE (NCT01564784), patients with relapsed/refractory acute lymphoblastic leukemia who were treated with inotuzumab ozogamicin (InO) vs standard chemotherapy had significantly greater remission rates and longer overall survival (OS), with more patients proceeding to stem‐cell transplant (SCT).Aims:Here we report outcomes by number of InO cycles (Cyc) received.Methods:Methods are detailed in Kantarjian, NEJM 2016. Outcomes are reported based on number of InO Cyc received (≤3 or >3 Cyc with no SCT and ≤2 or >2 with SCT [consistent with current recommendations]) in patients who achieved complete remission (CR)/CR with incomplete hematologic recovery. Data cutoff: Jan 4, 2017.Results:Among patients who responded but did not proceed to SCT, MRD‐negativity was achieved by 88% of 32 patients receiving >3 Cyc vs 61% of 18 patients receiving ≤3 Cyc (P = 0.037). Patients who had >3 Cyc had a longer duration of remission (HR 0.35, P = 0.0005) and improved survival outcomes vs those who had ≤3 Cyc (Table). The rate of serious adverse events (AE) and the percentage of patients discontinuing treatment due to AEs was numerically lower with >3 Cyc vs ≤3 Cyc.Among patients who responded and proceeded to SCT, the percentage achieving MRD‐negativity (81% vs 69%, P = 0.123) and the duration of remission (HR 1.37, P = 0.848) were similar for those who had >2 Cyc (36 patients) vs ≤2 Cyc (35 patients). Patients with ≤2 Cyc had improved survival outcomes and non‐relapse mortality (NRM) vs those with >2 Cyc (Table). 17.1% of patients receiving ≤2 Cyc and 33.3% of patients receiving >2 Cyc developed veno‐occlusive disease (Table).Summary/Conclusion:These results are in agreement with current recommendations that patients proceeding to SCT should receive ≤2 Cyc, whereas those not proceeding to SCT may benefit from receiving up to 6 cycles of therapy.image
PS954 TIME FROM RANDOMIZATION TO FIRST SUBSEQUENT INDUCTION/SALVAGE THERAPY IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH INOTUZUMAB OZOGAMICIN IN THE PHASE 3 INO‐VATE TRIAL
Authors: Jabbour E. , Stelljes M. , Advani A. , DeAngelo D.J. , Wang T. , Neuhof A. , Vandendries E. , Kantarjian H. 
Published: June 2019

Background:Additional salvage regimens are burdensome for relapsed/refractory acute lymphoblastic leukemia (ALL) patients (pts) due to therapy‐associated toxicities, which may affect quality of life with poor efficacy. In INO‐VATE (Kantarjian et al, NEJM 2016), pts receiving inotuzumab ozogamicin (InO) vs standard chemotherapy (SC) had significantly greater remission rates and longer overall survival; after study treatment discontinuation, overall fewer subsequent induction/salvage therapies (STs, mainly burdensome chemotherapies) were used in the InO group vs SC.Aims:To investigate the treatment of InO on the time to the first ST (TST) in the INO‐VATE trial.Methods:Study design was published. Adults with CD22+ ALL who were due to receive 1st or 2nd salvage treatment were randomized 1:1 to InO (n = 164) or SC (n = 162). TST was time from randomization to the start of the first ST. Pts who did not receive any ST were censored. Data cutoff: Jan 4, 2017.Results:Fewer InO pts had ST vs SC pts (Table). Among the censored pts, 83/108 (76.9%) in the InO vs 54/69 (78.3%) in the SC group died, 23/108 (21.3%) vs 5/69 (7.2%) were alive at the end of the study, and 2/108 (1.9%) vs 10/69 (14.5%) were no longer being followed for survival. TST was longer in pts receiving InO vs SC. Overall median (95% CI) TST was 18.8 (14.7–NA) vs 3.9 (2.4–5.1) months; hazard ratio (HR) = 0.34, 97.5% CI: 0.23–0.49, 1‐sided P < 0.0001. For pts (InO: 85, SC: 126) who never received hematopoietic stem cell transplantation (HSCT) on study, fewer InO pts had ST vs SC pts; TST was significantly longer in InO vs SC. For pts (InO: 70, SC: 18) who had HSCT directly after salvage, TST was extended in InO vs SC.Summary/Conclusion:In this study, treatment with InO provided the benefit of extended TST, effectively allowing patients a longer time period until an ST was needed in both patients who proceeded to as well as those who did not proceed to HSCT.image
PS963 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN ADULT PHILADELPHIA‐POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: DOES MINIMAL RESIDUAL DISEASE BEFORE TRANSPLANTATION MATTER FOR LONG TERM OUTCOME?
Authors: Velez I. Ormazabal , Alvarez A. Figuera , Olmedillas J.L. Steegmann , De la Cámara Llanza R. , Moya A. García‐Noblejas 
Published: June 2019

Background:Allogeneic hematopoietic stem cell transplantation (HSCT) is still the goal standard of care in Philadelphia‐positive acute lymphoblastic leukemia (Ph+ ALL) in adults with curative intention, though the introduction on tyrosin kinase inhibitors (TKI). Because some controversy on the importance of minimal residual disease (MRD) exists, we decided to evaluate our experience.Aims:The primary endpoint was evalute the impact of positive MRD on survival, as well as the incidence of disease‐free survival (DFS) and overall survival (OS). Secondary endpoints refined acute graft vs. host disease (aGvHD) and chronic GvHD (cGvHD) incidence, relapse incidence (RI), and non‐relapse mortality (NRM).Methods:Between 1993 and 2018, 45 HSCT were performed in 43 patients with Ph+ ALL in our hospital (2 double alloHSCT; 2,4%). Median age was 42 years (17–66), 55,8% of the patients were male and 44,2% were <40 years. Disease status before transplant was divided in 74,4% CR1 (n = 32), 18,6% CR2 (n = 8) and 7% active disease (n = 3). MRD was available in 37 cases: 32,4% (n = 12) were positive and 54,1% (n = 20) negative by PCR, and 5,4% (n = 2) has positive and 8,1% (n = 3) negative cytogenetic, respectively. CNS was infiltrated in 8 cases (18,6%) and extramedular disease was detected in 13 cases (30,2%). TKI was employed in 24 cases (55,8%).Results:With a median follow up of 6 years (2 months‐23 years), the whole cohort DFS an OS rates were 51,2% and 55,8%, respectively. MRD positive before HSCT was related with worse outcome (p < 0,05%).The incidence of grade II‐IV aGvHD was 28,2% (n = 11) and cGvHD 30,8% (n = 12). Four patients (10,3%%) developed extensive cGvHD.Relapse incidence was 25,6% (n = 11) with a median time of 16 months (3–62). The incidence of NRM was 34,9% (n = 15). The causes in order of frequency were pneumonia or respiratory failure (n = 6; 31,6%) an septic shock (n = 3; 15,8%).Summary/Conclusion:In our cohort was highlghted the importance of achieving negative MRD before HSCT. An important goal in the near future should be the achievement of MRD negative before HSCT with the employment of current potent TKIs.