bluuebunny/crossref_metadata_2025 huggingface dataset:
PF817 INTENSIVE PLAN OF THERAPEUTIC PLASMA EXCHANGE IN PATIENT WITH EXTREME HYPERTRLIGLYCERIDEMIA DUE TO L‐ASPARAGINASE IN THE CONTEXT OF SMILE PROTOCOL IN T/NK NASAL LYMPHOMA TREATMENT
Authors: Sobejano E. , López‐Parra M. , Villar O. López , Higuero V. , Presa D. , Azibeiro R. , Rey B. , Fonseca M. , Avendaño A. , Carrilo J. , Rivera D. , de Ramón C. , Redondo A. , Yeguas A. , Baile M. , Mateos M.L. Martin , de la Calle V. Gonzalez , Díaz M. González , Vidriales M.
Published: June 2019

Background:

A 42 year‐old male patient was diagnosed in July 2018 of extranodal T / NK lymphoma, nasal type, EBV + CD56 +, IIA Stage, IPI 1, with right thigh mass and inguinal adenopathies. He received chemotherapy according to the SMILE protocol, that included dexamethasone, methotrexate, ifosfamide, etoposide and L‐asparaginase, starting in August 2018 together with local radiotherapy in the mass concomitantly. As a personal medical history, he was under treatment with Rosuvastatin for familial hypercholesterolemia and hypertriglyceridemia, that was well controlled.

Aims:

To prove that carry out an aggressive prophylactic apheresis schedule, allows to reduce the complications derived from hypertriglyceridemia due to L‐ASA and to administer full chemotherapy that entails greater possibilities of cure.

Methods:

One T/NK Nasal Lymphoma patient with familial dyslipidemia suffered multiple events of extreme hypertriglyceridemia (TAGs>1200) that required a total of twenty‐two therapeutic plasma exchanges (TPE) to be able to administer Lasparaginase.

Results:

During the first cycle after the 5th dose of L‐asparaginase the patient presents extreme hypertriglyceridemia (9016 mg /dl) and two TPE was done with very good response, TAGs of 511 mg/dl and 251 mg/dl after the 1st and 2nd apheresis, respectively. Due to it was an unexpected event, conservative management was performed and he did not receive the last two doses of L‐Asa. Due to the importance of L‐ASA,we optimized oral treatment and carried out an intense apheresis program since second cycle and every L‐ASA doses was received. The patient achieve completed metabolic response after the 3rdcycle. On the day +20 of the 6th cycle, coinciding with the last dose of L‐asa, it was decided not to make prophylactic plasma exchanges for TAG values of less than 1500 mg/dl (1361 mg /dl). 48 hours later he went to the emergency department and was diagnosed of acute acalculous pancreatitis in the context of hypertriglyceridemia secondary to L‐ASA (TAGs 7168 mg / dl). Two plasma exchanges were performed on days +23 and +24, with good response (decrease from 7168 to 580 TAGs).

Summary/Conclusion:

In patients with a family history of dyslipidemia maintain prophylactic apheresis until the administration of L‐asparaginase has been fully completed, maintaining <1000 TAG level is essential to improve the results.

Moreover, an exhaustive follow‐up should be carried out in these patients, confirming 24 hours after the end of treatment that the TAGs value continues to be <1000 mg/dl and the patient is not at risk of developing pancreatitis.
S820 FRONTLINE BRENTUXIMAB VEDOTIN WITH CHEMOTHERAPY FOR STAGE 3/4 CLASSICAL HODGKIN LYMPHOMA: 3‐YEAR UPDATE OF THE ECHELON‐1 STUDY
Authors: Gallamini A. , Straus D. , Dlugosz‐Danecka M. , Alekseev S. , Illes A. , Picardi M. , Lech‐Maranda E. , Feldman T. , Smolewski P. , Savage K. , Bartlett N. , Walewski J. , Ramchandren R. , Zinzani P. , Connors J. , Jolin H. , Liu R. , Fenton K. , Josephson N. , Radford J.
Published: June 2019

Background:

The phase 3 ECHELON‐1 study (NCT01712490) demonstrated that brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (A+AVD) was superior to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), in terms of modified progression‐free survival (PFS) per independent review and per investigator, for the frontline treatment of stage 3/4 classical Hodgkin lymphoma (cHL) (Connors JM, et al. N Engl J Med 2018;378: 331–344). The RATHL, and SWOG S0816 studies utilized positron‐emission tomography (PET) scan‐adapted strategies performed after cycle 2 (PET2), demonstrating short‐ and long‐term toxicities in PET2‐positive (PET2+) patients switched to bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), or escalated BEACOPP, and frequent relapses in PET2‐negative (PET2‐) patients. Long‐term follow‐up of patients with stage 3/4 disease who were aged ≤60 years in the RATHL and SWOG S0816 studies demonstrated 3‐year PFS of 79.8% (PET2‐, 82.1%), and 5‐year PFS of 74% (PET2‐, 76%), respectively.

Aims:

Here we present a 3‐year update of the ECHELON‐1 study to compare the effects of frontline A+AVD vs ABVD in patients with stage 3/4 cHL, including PFS per investigator and outcomes by PET status for the intention‐to‐treat (ITT) population.

Methods:

Patients with stage 3/4 cHL were randomized 1:1 to receive up to six cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was conducted, patients with Deauville score of 5 at PET2 were allowed to switch to an alternative therapy. All analyses of PFS are exploratory and per investigator assessment.

Results:

At a median follow‐up of 37 months, analysis of PFS in the ITT population favored the A+AVD treatment arm (Table), with a 3‐year PFS of 83.1% for A+AVD vs 76.0% for ABVD; the 3‐year PFS values for PET2‐ patients aged <60 years were 87.2% vs 81.0%, respectively. A trend toward benefit for PET2+ patients aged <60 years treated with A+AVD was also observed, with a 3‐year PFS of 69.2% vs 54.7% with ABVD.

Data from subgroups, together with safety follow‐up, including for peripheral neuropathy, will be presented.

Summary/Conclusion:

Follow‐up at 3 years demonstrates that frontline treatment of stage 3/4 cHL with A+AVD provides a durable treatment benefit compared with ABVD that is independent of PET2 status. While direct comparisons cannot be made, efficacy with A+AVD appears favorable in the context of findings with PET‐adapted strategies, without requiring interim PET assessment, escalation of therapy, or bleomycin.

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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.

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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.
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).

image

Methods:

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.

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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.

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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.
PS978 DISCOVERY OF NOVEL C/D BOX SNORNAS THAT ARE REQUIRED FOR LEUKEMIA CELL PROLIFERATION
Authors: Kienast A. , Rohde C. , Zhou F. , Liu Y. , Gerloff D. , Thiede C. , Pabst C. , Radtke F. , Zoller J. , Müller‐Tidow C.
Published: June 2019

Background:

The vast majority of the human genome is transcribed, but the function of many transcripts remain obscure. It is likely, that cancer specific transcripts exist that are overlooked by conventional pipeline analysis.

Aims:

We tried to identify novel non coding RNA transcripts with C/D box snoRNA properties based on sequence homology. We specifically analysed AML patient samples

Methods:

To understand the role of snoRNAs in leukemogenesis, we analyzed the snoRNA expression pattern in an initial cohort of 63 AML patients (Zhou, 2017) and an additional cohort of 90 AML patients. Abundant regions with coverage were annotated using snoRNABase (LBME), the recently published updated snoRNAome (Jorjani, 2016) and tracks from ENSEMBL, UCSC, RNAcentral and DASHR databases. Regions without annotation were analyzed for C/D box motifs to discover putative C/D box snoRNAs. For further analysis only regions with at least one reads per million (RPM) in at least one patient sample were included.

Results:

Next generation sequencing data revealed that 248 of the 269 known C/D box snoRNAs (92%) were expressed in one or more patient samples. For the H/ACA box snoRNAs we could identify 103 of 112 (92%). In addition to this established functionally well annotated core‐set of C/D box snoRNA we confirmed another set of 76 C/D box snoRNA to be expressed in AML patient samples. These 76 snoRNA recently have been described as novel C/D‐box snoRNA based on the analysis of ENCODE small RNA‐seq data. Importantly, our in silico analysis identified 45 novel putative C/D box snoRNAs which had not been described so far. All of these putative C/D box snoRNAs contain the box C/D motifs and were mostly located in introns of known genes. In further analyses, we observed increased expression of putative snoRNAs was found in patients with intermediate molecular risk (7 snoRNAs, p≤0.05) and in patients with a poor response to chemotherapy (9 snoRNAs, p≤0.05). The novel snoRNAs were more prominently expressed in in NPM1 wildtype AML compared to NPM1 mutant AML. Overall, 13 putative C/D box snoRNA were downregulated during myeloid differentiation of HL60 cells. To study the function of the snoRNA we performed a CRISPR/Cas9 knockout of five regions in Kasumi1 and U937 cell lines. The knockout of four out of five novel snoRNAs impaired proliferation and colony growth.

Summary/Conclusion:

Multiple novel C/D box snoRNAs were identified from primary AML specimens. These show a specific expression pattern in myeloid differentiation in distinct AML subtypes. The functional relevance of these snoRNAs suggests that so far overlooked non coding RNA sequences are of high importance in AML.
PS1019 HIGH CYTOMEGALOVIRUS VIRUS LOAD INDUCES A POTENT TUMOR‐SPECIFIC CD8+ T CELL RESPONSE AND PROTECTS PATIENT IN ACUTE MYELOID LEUKEMIA FROM RELAPSE AFTER SINGLE CORD BLOOD TRANSPLANTATION
Authors: Dong M. , Sun Z. , Liu H.
Published: June 2019

Background:

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Interestingly, in recent studies, CMV infections have been shown to have potential anti‐leukemia effects in acute myeloid leukemia (AML) patients after HSCT. However, studies of CMV infection on relapse after single cord blood transplantation (CBT) are limited, and the effect of the virus load on relapse has not been assessed.

Aims:

We hypothesize that the role of MCV on outcomes in CBT are related to virus load. In this study, we retrospectively analyzed the effect of CMV infection on two‐year outcomes in 151 patients with AML after CBT according to the virus load. Additionally, the mechanism of the possible interaction with lymphocyte subsets was also analyzed.

Methods:

We comparatively analyzed the outcomes of the high virus load group (CMV DNA copies ≥ 1 000/mL) and the low virus load group (CMV DNA copies <1 000/mL or negative CMV DNA copy) of two years after CBT. Furthermore, in order to explore the mechanism of CMV on relapse, a smaller cohort of 26 patients with immune reconstruction data at 1, 3, 6, 9 and 12 months after transplantation were simultaneously studied, and nine healthy physical examination populations were recruited as healthy controls.

Results:

The results showed that the high CMV virus load group had a lower two‐year cumulative incidence of relapse (Figure A, 2.2% vs. 15.2%, p = 0.008) without an increase in non‐relapse mortality (Figure B, 20.9% vs. 22.4%, p = 0.970) than the low CMV virus load group. Furthermore, the two groups had similar overall survivals (76.8% vs. 72.4%, p = 0.746). Moreover, the proportion and absolute number of CD8+ T cells were increased in the high CMV virus load group in different months after transplantation (Figure C and D).

Summary/Conclusion:

In conclusion, a high CMV virus load in AML patients after CBT indicated a lower incidence of relapse, and this anti‐leukemic effect might be mediated by the CMV‐driven expansion of CD8+ T cells.

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PS1031 DECITABINE VERSUS INTENSIVE CHEMOTHERAPY IN ELDERLY UNTREATED ACUTE MYELOID LEUKEMIA
Authors: De La Fuente A. , Tormo M. , Beneit P. , Gil C. , Castillo T. Bernal , Lopez J. Serrano , Gonzalez K. Javier , Mayol A. Sampol , Valls J. Davila , Chamorro C. Martinez , Ordoñez S. Suarez , Benavente C. , Bergua J. , de Laguna S. Jimenez Bravo , Espadana A. , Sanchez P. Martinez , Amigo M.L. , LLoris M.J. Sayas , Puente P. Herrera , Boluda B. , Fernandez R. , Brunet S. , Oiartzabal I. , Gama A. Muñoz , Sangerman M. Arnan , Martinez‐Cuadron D. , Polo S. Vives , Jorda R. Coll , Boyero R. Garcia , Figuera A. , Lopez A. Diaz , Gonzalez B. Gonzalez , Montesinos P.
Published: June 2019

Background:

The combination cytarabine + anthracycline (IC) remains the standard of care for 60 year and above AML patients (Lowenberg et al. N Engl J Med 2009). Decitabine (Dec) has been EMA approved for first line AML patients not fit for intensive chemotherapy (Kantarjian et al JCO 2012). IC vs Dec have been not previously compared.

Aims:

The aim of this study is to analyze effectiveness and tolerability of IC vs Dec as first lines in 60 and above AML patients and to identify risk factors.

Methods:

We carried out the analysis on previously untreated AML ≥60yrs old patients included in PETHEMA AML epidemiological registry (NCT02607059) and in the MDA‐AML‐2017–05 (AEMPS code). Selection criteria for the study were as follows: Age >60, diagnosis of AML under WHO criteria, treated with IC or Dec during the period 01/01/2012 to 31/12/2016. Response was assessed using the ELN‐2010 criteria, toxicity by the CTCAE v4.0 scale, OS by Kaplan‐Meier, as well as mortality within the first 8 weeks (M8wks).

Results:

A total of 756 of previously untreated AML patients were analyzed (625 treated with IC and 131 with Dec), baseline characteristics are summarized in table 1. A higher incidence of risk factors was observed in the Dec cohort. Safety: A total of 1051 IC and 716 Dec cycles were analyzed, mean 2.4 and 6.1, febrile neutropenia 74% and 47%, M8wks was 22.5% and 25.5% (p = 0.15) and composite complete response (CCR) 64% and 18% (p < .001). for IC and Dec respectively. In this study serum creatinine>1.3 mg/dL (p = 0.02, p < 0.01), ECOG≥2 (p < 0.01) and adverse cytogenetic (p < 0.01) were adverse prognostic factors for OS in both cohorts, and WBC pre‐Dec >10.000/μL (p < 0.01) in Dec and Secondary AML (p = 0.02) in IC cohort. IC resulted superior for OS (11 vs 8 months p = 0.04) but this was not significant in 70 and above (7 vs 8 months p = 0.94) or after matching by mentioned risk factors.

Summary/Conclusion:

IC and Dec are not used for the same patients due to physicians judgement. Even the outcome seams superior with IC we observe similar OS after matching by risk factors age, creatinine, ECOG, or cytogenetic. The ongoing EORTC phase III randomized trial (INDACTION) will compare a Dec‐based vs IC front‐line approach for older patients with AML.

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PS1049 COMPARATIVE RANDOMIZED STUDY OF PROTOCOL HAM VERSUS PROTOCOL FLAG IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA
Authors: elsergany A.R. , ismaeel M.I. , ibrahim M.A. , Ghazy H.F. , aladle D.A.
Published: June 2019

Background:

Acute myeloid leukemia (AML) is the commonest type of acute leukemias in adults resulting from clonal proliferation of bone marrow precursor cells with disruption of hemostasis. Patients initially respond to induction therapy but the majority of patients suffer relapse and refractoriness with very poor subsequent prognosis.

Aims:

To compare two widely used salvage regimens in treatment of relapsed/refractory AML, HAM (cytarabine, Mitoxantrone, Colony stimulating factor) versus FLAG (cytarabine, fludarabine, Colony stimulating factor) protocols.

Methods:

Prospective randomized study included 90 patient diagnosed as relapsed/refractory AML were selected from Oncology Center, Mansoura University, Egypt, from January 2014 to December 2017. Patients received salvage therapy either HAM or FLAG protocol, then outcomes regarding to efficacy, side effects and overall survival were assessed.

Results:

Ninety patients were included in our study, 43 patients received HAM protocol versus 47 received FLAG protocol. Complete remission (CR) was 42.6% in HAM group versus 48.8% in FLAG group (p = 0.5). On the other hand, hepatic impairment was 46.8% in HAM group versus 30.3% in FLAG group (p = 0.2). Also, renal impairment was 6.4% in HAM group versus 18.6% in FLAG group (p = 0.07). In addition, Event free survival (EFS) was higher in FLAG vs. HAM arms (9 versus 4 months, p = 0.2). Lastly, overall survival (OS) in HAM group was shorter than in FLAG group (3 vs. 5 months, P = 0.09)

Summary/Conclusion:

Both HAM and FLAG protocols are adequate salvage chemotherapy in relapsed/refractory AML, with different toxicity profile as HAM has more hepatotoxicity while FLAG is more nephrotoxic, CR was slightly higher with FLAG with more survival benefit compared with HAM protocol.
PS1072 SURVIVAL OF B‐CELL LYMPHOMAS IN THE PRE‐ AND POST‐RITUXIMAB ERAS: 30 YEARS REAL‐WORLD DATA
Authors: Gouda M.
Published: June 2019

Background:

Rituximab is an anti‐CD20 monoclonal antibody that has been approved by FDA in 1997 for treatment of B cell lymphomas. Most data about the effect of Rituximab on survival come from either randomized controlled trials or retrospectively from local centers’ experiences.

Aims:

The aim of this study was to report on the real‐world experience in the United States for patients with B‐cell lymphomas using data available in the SEER (National Cancer Institute Surveillance, Epidemiology, and End Results) program's database. SEER incorporates data from 18 cancer registries all over the United States and includes data dating back to 1973. These nationwide and historical data enabled the comparison between cases diagnosed 1983–1997 (15 years before Rituximab approval) and cases diagnosed 1998–2012 (15 years after Rituximab approval).

Methods:

Data were obtained using SEER∗Stat version 8.3.5 where (SEER 18 Regs Nov 2017 Submission) database was used as the main data source. B‐cell Non‐Hodgkin lymphoma cases diagnosed between 1983 and 2012 were included. Survival analyses were made using IBM SPSS version 25.0 and SEER∗Stat software. Comparison between groups was done using Log‐rank test while relative survival was calculated using Ederer II method.

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Results:

A total number of 230577 cases were included in the analysis. B‐Cell lymphomas showed a median survival of 94 months (95% CI: 93–95) compared to 50 months (95% CI: 48.7–51.3) in the post and pre rituximab eras, respectively. Log rank test showed statstically significant difference in survival between the two groups (p < 0.001) (Figure1). This difference was consistent among all stage groups (Table 1).

Summary/Conclusion:

Rituximab's approval has led to a dramatic improvement in survival of patients with B‐Cell lymphomas. Data from United States confirms that this improvement was consistent in all disease stages.
PS1079 CLINICAL OUTCOME OF INTENSIFIED CHEMO‐TARGETED THERAPY IN ACTIVATED B CELL NON HODGKIN LYMPHOMA
Authors: Sohaib A. , Hashim T. , Abouelfetouh M. , Elkhouly E. , Alhanafy A. , Samaka R.
Published: June 2019

Background:

Diffuse large B cell lymphoma (DLBCL) accounts for approximately a third of all NHL and is the most common lymphoma subtype in all parts of the world. Advances in DNA array has resulted in further subclassification of DLCBL into germinal center type and activated B cell type (ABC). Activated B cell type has a worse prognosis than germinal center type

Aims:

To assess the role of intensified chemotherapy for patients with activated B cell type of DLBCL if it would result in better outcome. Primary end point is response rate and secondary end points are PFS and toxicity, OS

Methods:

This is a randomized phase II study done on 82 patients. Cases are randomized into two arms. Control arm received R‐CHOP (47 patients) and test arm received R‐CHEOP (35 patients). All cases are tested for BCL‐6, MUM‐1 and CD10 to confirm being of ABC type according to Hans algorithm. GCSF was used for prophylaxis in the test arm in the form of daily 1 vial of neupogen for 3 days after the cycle. Evaluation is done by Cheson et. al. criteria. Toxicity was described according to CTCAE V4

Results:

Both groups were comparable as regard age, gender, performance status, stage and LDH. Median age was 52 years for the control arm and 46 years for the test arm. Results are analyzed at a median follow up of 15 months. Complete remission at end of treatment was 70.2% for the control arm and 91.4% for the test arm (p = 0.019) while interim assessment showed 58% median tumor shrinkage for the control arm and 79% for the test arm (p < 0.001). Median PFS was 25 months for the control arm and not reached for the test arm (p = 0.022) while median overall survival was 28 months for the control group and not reached for the test arm (p = 0.145). At one year of follow up, overall survival was 74.46% for the control arm and 91.4% for the test arm. Toxicity was comparable in both groups regarding neutropenia (p = 0.356), oral mucositis (p = 0.419), diarrhea (p = 0.54), vomiting (p = 0.504), thrombocytopenia (p = 0.308), anemia (p = 0.453), neuropathy (p = 1)

Summary/Conclusion:

R‐CHEOP showed more tumor shrinkage than R‐CHOP in activated B cell lymphoma with comparable toxicity. PFS was better in the first year of follow up but more time is needed to calculate mature survival data

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PS1094 MANAGING CYTOKINE RELEASE SYNDROME (CRS) AND NEUROTOXICITY WITH STEP‐FRACTIONATED DOSING OF MOSUNETUZUMAB IN RELAPSED/REFRACTORY (R/R) B‐CELL NON‐HODGKIN LYMPHOMA (NHL)
Authors: Yoon S.‐S. , Matasar M. , Sehn L.H. , Assouline S. , Bartlett N.L. , Bosch F. , Diefenbach C.M. , Flinn I. , Hong J.Y. , Kim W.S. , Nastoupil L. , Schuster S.J. , Shadman M. , Bender B. , Chu W. , Hernandez G. , Kwan A. , McCall B. , Sison I. , Wang C. , Wei M.C. , Yin S. , Yousefi K. , Budde E.L.
Published: June 2019

Background:

T‐cell directed therapies (e.g. CAR‐T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion‐related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T‐cells to engage and eliminate malignant B‐cells.

Aims:

To report safety results from an ongoing Phase 1/1b study (NCT02500407) of mosunetuzumab in patients (pts) with R/R B‐cell NHL.

Methods:

Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step‐fractionation), then a fixed dose on Day 1 of every 21‐day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy.

Results:

As of October 23, 2018, 114 pts who received step‐fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%), with only 1 treatment‐related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step‐fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL‐6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts.

Summary/Conclusion:

Step‐fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk‐benefit profile.

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PS1101 PERIOPERATIVE MANAGEMENT AND OUTCOMES IN CHILDREN WITH CONGENITAL BLEEDING DISORDERS: A RETROSPECTIVE REVIEW AT A SINGLE HEMOPHILIA TREATMENT CENTER
Authors: Park Y.S. , Chon H.N.
Published: June 2019

Background:

Establishing hemostasis for surgical procedures in children with inherited bleeding disorders is challenging. Providers are often hesitant to undertake surgeries in children with bleeding disorders out of fear of bleeding complications. However, appropriate presurgery/preprocedure factor replacement can decrease pre‐, peri‐, and postoperative bleeding complications and allow almost any necessary surgical procedure to proceed.

Aims:

We review the results of surgical procedures in children with inherited bleeding disorders at our center and review the preoperative management and hemorrhagic complications.

Methods:

We conducted a retrospective electronic medical record review from October 2006 to November 2018. Primary focus was review of factor replacement strategies and bleeding complications. Data were collected from patients under 18 years of age.

Results:

In total, 152 procedures were performed in 99 children at our center. The distribution of bleeding disorders is as follows; hemophilia A 79, hemophilia B 15, Von Willebrand disease 3 and FVII deficiency 2. The median age of the patients was 13 years (range, 0∼18). Duration of hospitalization was median 8 days (range, 0∼44) and period from surgery to discharge was median 7 days (range, 0∼42). Nineteen procedures (12.5%) in 8 children were performed in the presence of high titer inhibitors to coagulation factor. Procedures included synovectomy (84/152, 55.3%), orthopaedic procedures except synovectomy (22/152, 14.5%), central venous catheter placement or revision (9/152, 5.9%), otolaryngology procedures (7/152, 4.6%), circumcision (6/152, 3.9%), laparoscopic appendectomy (5/152, 3.3%) and miscellaneous (19/152, 12.5%). All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%).

The complete list of

all 168 surgical procedures is shown in Table 2.All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%).

Summary/Conclusion:

Surgical procedures are safe in children with bleeding disorders with adequate planning and factor replacement. Bleeding remains a problem in a subset of patients and requires ongoing hematological involvement and oversight. Delayed bleeding following tonsillectomy was especially common and suggests a need for close follow‐up and ongoing factor coverage for this group of patients.