47° Congress of the Italian Society of Hematology
Rome, Italy, October 7-9, 2019
ABSTRACT BOOK
Volume 104
OCTOBER
2019 - S2
www.haematologica.org
ISSN 0390-6078
Editor-in-Chief
Luca Malcovati (Pavia)
Managing Director
Antonio Majocchi (Pavia)
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47° Congress of the Italian Society of Hematology
Rome, Italy, October 7-9, 2019
CONSIGLIO DIRETTIVO
Paolo Corradini, Presidente
Emanuele Angelucci, Vice Presidente
Sergio Siragusa, Vice Presidente
Mario Boccadoro
Michele Cavo
Nicola Di Renzo
Gianluca Gaidano
Francesca Patriarca, Tesoriere
Giulia Perrone, Segretario
Giuseppe Rossi
Alessandro M. Vannucchi
COMITATO SCIENTIFICO
Pier Luigi Zinzani, Presidente
Anna Falanga
Gian Luca Forni
Mauro Krampera
Pellegrino Musto
Adriano Venditti
Umberto Vitolo
SEGRETERIA PERMANENTE SIE SEGRETERIA ORGANIZZATIVA
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47° Congress of the Italian Society of Hematology
Rome, Italy, October 7-9, 2019
Con il contributo non condizionante di
ABBVIE
AMGEN
CELGENE
GILEAD SCIENCES
JANSSEN ITALIA
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JAZZ HEALTHCARE ITALY
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ASTRAZENECA
BLUEBIRD BIO
DIASORIN
ISTITUTO GENTILI
MUNDIPHARMA PHARMACEUTICALS
SHIRE
ATARA BIOTHERAPEUTICS
NEOVII BIOTECH GMBH
TILLOMED ITALIA
WERFEN
47° Congress of the Italian Society of Hematology
Rome, Italy, October 7-9, 2019
Best Abstracts
...1
Oral Communications
session 1. C-001-C-005 Non Hodgkin Lymphoma 1 . . . 7session 2. C-006-C-010 Myeloma and Monoclonal Gammopathies 1. . . 9
session 3. C-011-C-015 Acute Myeloid Leukemia 1. . . 11
session 4. C-016-C-018 Myeloproliferative Neoplasms 1 . . . 14
session 5. C-019-C-025 Chronic Lymphatic Leukemia. . . 17
session 6. C-026-C-030 Allogeneic and Autologous Transplantation . . . 19
session 7. C-031-C-035 Chronic Myeloid Leukemia . . . 22
session 8. C-036-C-040 Anemia and Thalassemia . . . 25
session 9. C-041-C-045 Hodgkin Lymphoma . . . 27
session 10. C-046-C-050 Infections . . . 29
session 11. C-051-C-055 Hemostasis, thrombosis, thrombocytopenia and platelet diseases . . . 32
session 12. C-056-C-060 Acute Lymphatic Leukemia . . . 34
session 13. C-061-C-065 Chronic Lymphatic Leukemia 2 . . . 37
session 14. C-066-C-070 Myeloproliferative Neoplasms 2 . . . 39
session 15. C-071-C-075 Myelodysplastic Syndromes . . . 42
session 16. C-076-C-080 Allogeneic and Autologous Transplantation 2 . . . 44
session 17. C-081-C-085 Non Hodgkin Lymphoma 2 . . . 46
session 18. C-086-C-090 Myeloma and Monoclonal Gammopathies 2. . . 49
session 19. C-091-C-095 Acute Myeloid Leukemia 2. . . 51
session 20. C-096-C-100 Quality of Life, Pain Therapy and Home Care, Supportive Care. . . 53
Posters
session 1. P-001-P-011 Non-Oncological Hematology . . . 56session 2. P-012-P-020 Non Hodgkin Lymphoma 1 . . . 60
session 3. P-021-P-030 Myeloma and Monoclonal Gammopathies 1 . . . 64
session 4. P-031-P-040 Myeloma and Monoclonal Gammopathies 2 . . . 68
session 5. P-041-P-051 Myeloproliferative Neoplasms 1. . . 72
session 6. P-052-P-058 Hodgkin Lymphoma 1 . . . 74
session 7. P-059-P-065 Allogeneic and Autologous Transplantation 1 . . . 80
session 8. P-066-P-072 Allogeneic and Autologous Transplantation 2 . . . 84
session 9. P-073-P-084 Acute Myeloid Leukemia 1 . . . 87
session 10. P-085-P-094 Acute Lymphatic Leukemia. . . 92
session 11. P-095-P-103 Quality of Life, Pain Therapy and Home Care, Supportive Care 1 . . . 96
session 12. P-104-P-117 Chronic Lymphatic Leukemias and Lymphoproliferative Syndromes . . . 100
session 13. P-118-P-129 Cytogenetics, Molecular Genetics and Myelodislastic Syndromes . . . 106
session 14. P-130-P-138 Non Hodgkin Lymphoma 2 . . . 111
session 15. P-139-P-148 Myeloma and Monoclonal Gammopathies 3 . . . 116
session 16. P-149-P-158 Myeloproliferative Neoplasms 2. . . 120
session 17. P-159-P-168 Myeloproliferative Neoplasms 3. . . 124
session 18. P-169-P-176 Hodgkin Lymphoma 2 . . . 127
session 19. P-177-P-184 Allogeneic and Autologous Transplantation 3 . . . 131
session 20. P-185-P-196 Acute Myeloid Leukemia 2 . . . 134
session 21. P-197-P-210 Chronic Myeloid Leukemia. . . 140
session 22. P-211-P-218 Quality of Life, Pain Therapy and Home Care, Supportive Care 2 . . . 147
session 23. P-219-P-229 Infections . . . 150
Published Only
sessions PU-001-PU-053. . . . 155Main Program
. . . 175Authors Index
. . . aTable of Contents
BEST ABSTRACTS
B001
LENTIGLOBIN GENE THERAPY IN PATIENTS WITH TRANSFUSION-DEPENDENT β -THA-LASSEMIA AND NON-β0/β0 GENOTYPES: OUTCOMES FROM THE COMPLETED PHASE 1/2 NORTHSTAR AND ONGOING PHASE 3 NORTHSTAR-2 STUDIES
F. Locatelli, M. Walters, J. Kwiatkowski, S. Hongeng, J. Porter, J. Rasko, M. Sauer, A. Thrasher, I. Thuret, G. Schiller, H. Elliot, B. Deary, Y. Chen, G. Tao, R. Colvin, A. Thompson
IRCCS Bambino Gesù Children’s Hospital, UCSF Benioff Children’s Hospital, Children’s Hospital of Philadelphia, Mahidol University Ramathibodi Hospital, University College London Hospitals, University of Sydney Royal Prince Alfred Hospital, Medizinische Hochschule Hannover, UCL Great Ormond Street In-stitute of Child Health, Hôpital de la Timone, David Geffen School of Medicine at UCLA, bluebird bio, bluebird bio, bluebird bio, bluebird bio, bluebird bio, Northwestern University Feinberg School of Medicine
LentiGlobin contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) en-coding β-globin with a T87Q substitution. LentiGlobin gene therapy has been evaluated in patients with transfusion-dependent β-tha-lassemia (TDT) and non-β0/β0 genotypes in the Phase 1/2 Northstar study (NCT01745120) and Phase 3 Northstar-2 study (NCT02906202, in this trial using a refined manufacturing process).
HSCs were mobilized using G-CSF and plerixafor, collected through apheresis, and transduced with the BB305 LVV. Patients received sin-gle-agent, pharmacokinetic-guided, myeloablative busulfan and were then infused with transduced cells. Patients were followed for both safety and efficacy. Statistics are shown as median (min-max).
As of 14 September 2018, 10 and 16 patients with TDT and non-β0/β0 genotypes have been treated in Northstar (follow-up: 36.0 [29.3-48.1] months; age: 16-34 yrs) and Northstar-2 (follow-up: 9.3 [0.7-20.4] months; age: 8-34 yrs), respectively. All patients with >2 months fol-low-up engrafted. Platelet engraftment was achieved at 39.5 (19-191) and 44.5 (20-84) days in Northstar and Northstar-2, respectively.
In Northstar, 8/10 patients with non-β0/β0 genotypes achieved trans-fusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without red blood cell [RBC] transfusions for ≥12 months). Duration of TI was 38.0 (21.2-43.6) months; all responses are ongoing. Weighted average Hb during TI was 10.2 (9.3-13.2) g/dL. In patients who achieved TI, liver iron content decreased by 38% and 68% at Month 48 (n=2).
In Northstar-2, 10/11 patients with ≥3 months follow-up stopped RBC transfusions with Hb of 11.1-13.3 g/dL comprising 7.7-10.6 g/dL HbAT87Q at last visit. The primary endpoint of TI was achieved by 2/3 patients and 5/6 patients with ≥1-year follow-up had improved myeloid:erythroid ratios (0.18-0.45 to 0.77-1.1).
The most common non-hematologic grade ≥3 adverse events post-infusion (≥3 patients with non-β0/β0 genotypes in either study) were stomatitis, febrile neutropenia, irregular menstruation, epistaxis, pyrexia, and liver veno-occlusive disease (which resolved with defi-brotide).
In summary, 80% of patients with non-β0/β0 genotypes treated with LentiGlobin in Northstar achieved TI. Available data using a refined manufacturing process in the ongoing Northstar-2 study indicate that patients can achieve near-normal Hb. The safety profile is consistent with myeloablative busulfan conditioning.
B002
IBRUTINIB TREATMENT DOESN’T INDUCE TP53 CLONAL EVOLUTION IN CHRONIC LYMPHOCYTIC LEUKEMIA
L. Cafforio, L.V. Cappelli, I. Del Giudice, C. Ilari, S. Raponi, M.S. De Propris, P. Mariglia, A. Piciocchi, V. Arena, M. Vignetti, F.R. Mauro, A. Guarini, R. Foà
Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome; Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome; Hematology, Department of Transla-tional and Precision Medicine, Sapienza University of Rome; Hematology, De-partment of Translational and Precision Medicine, Sapienza University of Rome; Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome; Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome; Hematology, Department of Transla-tional and Precision Medicine, Sapienza University of Rome; GIMEMA Data Center, GIMEMA Foundation; GIMEMA Data Center, GIMEMA Founda-tion; GIMEMA Data Center, GIMEMA FoundaFounda-tion; Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome Depart-ment of Molecular Medicine, Sapienza University of Rome; Hematology, De-partment of Translational and Precision Medicine, Sapienza University of Rome, Italy
Ibrutinib (I) is active in chronic lymphocytic leukemia (CLL) pa-tients (pts) with TP53 defects. To explore the dynamics of TP53 mu-tations (TP53-m) under I treatment, 58 (37 IGHV unmutated, 21 mutated) pts underwent a longitudinal TP53 monitoring by deep se-quencing. Forty-four treatment-naïve (TN) pts received I+rituximab (IR) front-line (GIMEMA LLC1114 trial-NCT02232386; median I ex-posure: 2.7 years; range: 1.2-3.7); 14 relapsed/refractory (R/R) pts re-ceived I single agent after 1.5 (range: 1-4) lines of chemoimmunotherapy (median I exposure: 2.5 years; range: 2.1-4). Samples were sequenced on a MiSeq Illumina (mean coverage 5000X). Variant allele frequency (VF) was corrected to cancer cell fraction (CCF) by the % of CD19+/CD5+ cells. Of 44 TN pts at baseline, 27 (61%) were TP53-wild-type (WT) and 17 (39%) carried 23 TP53-m (1.4 m/pt; range: 1-5): 17 (74%) were clonal (CL) (mean VF: 58.8%; range: 18-94) and 6 (26%) subclonal (SCL) (mean VF: 5.3%; range: 2.1-9.2). Overall, 7 (30.5%) CL TP53-m persisted stable on treatment, 9 (39%) CL decreased, 3 (13%) (1 CL+2 SCL) increased and 4 (17.5%) (1 CL+3 SCL) were lost. No TP53-m was acquired under I. The mu-tational patterns per pt are shown in the Figure. Of 14 R/R pts, prior to I 4 (29%) were WT and 10 (71%) carried 31 TP53-m (3.1 m/pt; range: 1-11): 11 (35.5%) were CL (mean VF: 31.9%; range: 10.5-78.8) and 20 (64.5%) SCL (mean VF: 2.9%; range: 0.9-6.8). After I treat-ment, 8 (26%) TP53-m (4 CL+4 SCL) persisted stable, 8 (26%) (4 CL+4 SCL) decreased, 4 (13%) (2 CL+ 2 SCL) increased, 11 (35%) (2 CL+9 SCL) were lost and 2 novel SCL emerged. No TP53-m arose in the 4 WT pts over time. Overall, in both TN and R/R pts most TP53-m re-mained stable or decreased (69.5% and 52%, respectively), some in-creased (13% and 13%) and some were lost (17.5% and 35%) (p=NS). Notably, while no novel mutation arose in TN pts, 2 occurred in R/R pts. Although the lymphocyte count significantly decreased during IR/I exposure (TN: 40.7 vs 11.5x109/L, p=0.019; R/R: 39.7 vs 7.1x109/L,
p=0.0034), the mean CCF of the existing TP53-m remained stable on treatment (TN: 60.7% vs 42.7%; R/R: 20.5 % vs 20.2%). In conclusion, I in any line of therapy decreases the TP53 CL and SCL complexity; the emergence/expansion of TP53-m is rare. In TP53 WT pts, I never induced novel TP53-m after >2 years exposure. The significant
de-47° Congress of the Italian Society of Hematology
crease of lymphocytosis with stable CCF proves the I effectiveness on both TP53-m and WT cells, regardless of previous therapies.
Figure. TN patients: log fold change (FC) of the cancer cell fraction (CCF) of TP53 mutations at each time point (T), reported in months,
vs T0. Each color corresponds to a group of patientswith a common
pattern: 1) CLTP53-m present from T0 and persisting CLwith a sta-ble CCF (n=5); 2) CLTP53-m present from T0 and persisting CL with decreasing CCF (n=7); 3) CL or SCLTP53-m present from T0 with in-creasing CCF(n=2); 4) SCLTP53-mdisappearing (n=1) (greenstars correspond totimepoints where the mutations disappear); 5) ab-sence of any detectable TP53-m over time (n=27). Two patients with a complex mutational architecture are not shown.
B003
GILTERITINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3-MUTATED RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA: RESULTS FROM THE PHASE 3 ADMIRAL TRIAL
A.E. Perl, G. Martinelli, J.E. Cortes, A. Neubauer, E. Berman, S. Paolini, P. Montesinos, M.R. Baer, R.A. Larson, C. Ustun, F. Fab-biano, A. Di Stasi, R. Stuart, R. Olin, M. Kasner, F. Ciceri, W. Chou, N. Podoltsev, C. Recher, H. Yokoyama, N. Hosono, S. Yoon, J. Lee, T. Pardee, A.T. Fathi, C. Liu, X. Liu, E. Bahceci, M.J. Levis
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS, Meldola, Italy; University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Universitätsklinikum Giessen und Marburg GmbH, Marburg, Ger-many; Memorial Sloan-Kettering Cancer Center, New York City, NY, USA; L. and A. Seràgnoli Institute of Hematology, Bologna University Medical School, Bologna, Italy; Hospital Universitari i Politècnic La Fe, Valencia & CIBERONC, Instituto Carlos III, Madrid, Spain; University of Maryland Greenebaum Com-prehensive Cancer Center, Baltimore, MD, USA; University of Chicago, Chicago, IL, USA; University of Minnesota, Minneapolis, MN, USA; Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy; University of Alabama at Birming-ham, BirmingBirming-ham, A, USAL; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; University of California San Francisco, San Francisco, CA, USA; Thomas Jefferson University, Philadelphia, PA, USA; IRCCS San Raffaele Scientific Institute, Milano, Italy; National Taiwan Uni-versity, Taipei City, Taiwan; Yale University School of Medicine, New Haven, CT, USA; Institut Universitaire du Cancer Toulouse – Oncopole, Cedex, France; Sendai Medical Center, National Hospital Organization, Sendai, Japan; Uni-versity of Fukui, Fukui, Japan; Seoul National UniUni-versity, Seoul, Republic of Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Wake Forest Baptist Medical Center, Winston-Salem, NC, USA; Massachussetts General Hospital, Harvard Medical School, Boston, MA; Astellas Pharma Global Development, Northbrook, IL, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA Introduction: Gilteritinib is a potent/selective oral FLT3 inhibitor. Based
upon interim analysis response rates from the ADMIRAL phase 3 study of gilteritinib vs salvage chemotherapy (SC) in patients (pts) with re-lapsed/refractory (R/R) FLT3-mutated (FLT3mut+) AML
(NCT02421939), gilteritinib was approved as single-agent therapy in this population. We present the final results of this pivotal trial.
Methods: Adults with confirmed FLT3mut+ AML (ITD or
FLT3-TKD D835/I836 mutations) refractory to induction chemotherapy, or in untreated first relapse, were randomized (2:1) to receive continuous 28-day cycles of 120-mg/day gilteritinib or prerandomization-selected SC: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/ etoposide/cytarabine (MEC), or fludarabine/cytarabine/ granulocyte colony-stimulating factor/idarubicin (FLAG-IDA). Prior FLT3 inhibitor use, other than midostaurin or sorafenib, was excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary end-points. Safety/tolerability was also examined.
Results: A total of 371 pts were randomized: 247 to gilteritinib and
124 to SC (MEC, 25.7%; FLAG-IDA, 36.7%; LoDAC, 14.7%; AZA, 22.9%). Median age was 62 years (range, 19-85). Baseline FLT3 muta-tions were: FLT3-ITD, 88.4%; FLT3-TKD, 8.4%; both FLT3-ITD and FLT3-TKD, 1.9%; unconfirmed, 1.3%. Overall, 39.4% of pts had re-fractory AML and 60.6% had relapsed AML. Patients assigned to gilter-itinib had significantly longer OS (9.3 months) than SC (5.6 months; hazard ratio for death=0.637; p=0.0007); 1-year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (nominal p=0.0001); CR rates were 21.1% and 10.5%. Common adverse events (AEs) in all random-ized pts were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Exposure-adjusted serious treatment-emergent AEs were less common with gilteritinib (7.1/patient-year) than SC (9.2/patient-year).
Conclusions: In pts with R/R FLT3mut+ AML, gilteritinib
demon-strated superior efficacy compared with SC and had a favorable safety profile. These results change the treatment paradigm for R/R FLT3mut+ AML and establish gilteritinib as the new standard of care.
B004
CARFILZOMIB, LENALIDOMIDE, DEXAMETHASONE (KRD) WITH OR WITHOUT TRANS-PLANTATION IN NEWLY DIAGNOSED MYELOMA PATIENTS: SUBGROUP ANALYSIS IN THE FORTE TRIAL
F. Gay, C. Cerrato, M.T. Petrucci, R. Zambello, E. Rivolti, S. Ballanti, P. Omedé, M. Gentile, A. Bernardini, F. Narni, A. Capra,
G. De Sabbata, A. Gozzetti, P. Galieni, R. Rizzi, N. Pescosta,
M. Cea, S. Molica, A. Cafro, C. Musolino, A. Spadano, V. Montefusco, P. Musto, M. Cavo, M. Boccadoro
GIMEMA/ European Myeloma Network, Italy
Background: Four 28-day induction cycles of KRd followed by
autol-ogous stem-cell transplantation (ASCT) and 4 KRd consolidation (KRd_ASCT_KRd), and with 12 KRd cycles (KRd12) induced high and comparable response rate and minimal residual disease (MRD) nega-tivity in newly diagnosed myeloma (NDMM) patients. Both regimens were superior to carfilzomib-cyclophosphamide-dexamethasone (KCd) induction followed by ASCT and KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). We evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific patient subgroups.
Methods: 474 NDMM patients ≤65 years were randomized to
KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10-5) after consolidation with
KRd_ASCT_KRd vs KRd12 in patients with Revised International Stag-ing System (R-ISS) 1 and R-ISS 2/3. High-risk patients may sometimes respond rapidly, but relapse early. Therefore, we also analyzed early relapse rate (<18 months from randomization) in the two arms. We conducted a multivariate logistic regression analysis to assess factors predictive of early relapse.
Results: Median follow-up was 25 months. On intention-to-treat
analysis, KRd_ASCT_KRd and KRd12 had similar rates of ≥VGPR, ≥CR, sCR, MRD negativity in the overall population (Table 1A). Similarly, MRD negativity and response rates in the two arms were comparable in patients with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table 1B). Of note, MRD negativity rate in high-risk patients was ~50%. In the over-all population, early relapses were significantly lower with
KRd_ASCT_KRd vs KRd12 (12 patients [8%] vs 26 patients [17%]; p=0.015), mainly related to a significantly lower rate of early relapse in high-risk patients (R-ISS Stage 2/3) (11 patients [12%] vs 22 patients [23%]; p=0.05, respectively). Very few patients with R-ISS Stage 1 re-lapsed, with no difference between KRd_ASCT_KRd and KRd12 (0 vs 2 patients). In multivariate regression analysis, patients receiving KRd_ASCT_KRd had a reduced risk of early relapse vs those treated with KRd12 (OR 0.42; p=0.021); R-ISS Stage 2 (OR 3.6; p=0.001) and R-ISS Stage 3 (OR 4.85; p=0.003) increased the risk of early relapse vs R-ISS 1.
Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in
in-ducing high-quality responses, and ~50% of high-risk patients achieved MRD negativity. In addition, ASCT was beneficial in high-risk patients, reducing the risk of early relapse.
Table 1.
B005
SECOND PRIMARY MALIGNANCY IN MYELOFIBROSIS PATIENTS TREATED WITH RUXOLITINIB
N. Polverelli, E. Elli, E. Abruzzese, G.A. Palumbo, G. Benevolo, M. Breccia, M. Tiribelli, M. Bonifacio, A. Tieghi, B. Martino, N. Sgherza, M. D’Adda, M. Bergamaschi, M. Crugnola, F. Cavazzini, C. Bosi, G. Binotto, A. Isidori, D. Bartoletti, G. Auteri, R. Latagliata, L. Gandolfi, L. Scaffidi, D. Cattaneo, K. Codeluppi, M. Trawinska, D. Griguolo, A. Cuneo, M. Krampera, G. Semenzato, F. Di Raimondo, R.M. Lemoli, M. Cavo, N. Vianelli, D. Russo, A. Iurlo, F. Palandri
Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Bres-cia, Brescia; Hematology Division, San Gerardo Hospital, ASST Monza, Monza; Division of Hematology, Ospedale S. Eugenio, Roma; Department of Scienze Mediche, Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, Univer-sity of Catania, Catania; Division of Hematology, Città della Salute e della Scienza Hospital, Torino; Division of Cellular Biotechnologies and Hematology, University Sapienza, Roma; Division of Hematology and BMT, Azienda San-itaria UniversSan-itaria Integrata di Udine, Udine; Department of Medicine, Section of Hematology, University of Verona, Verona; Department of Hematology, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia; Division of Hematology, Azienda Ospedaliera “Bianchi Melacrino Morelli”, Reggio Calabria; Division of Hematology, Casa Sollievo Sofferenza, San Giovanni Rotondo; Division of Hematology, ASST Spedali Civili of Brescia, Brescia; Clinic of Hematology, De-partment of Internal Medicine (DiMI), IRCCS AOU San Martino-IST, Gen-ova; Division of Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma; Division of Hematology, University of Ferrara, Ferrara; Division of Hematology, AUSL di Piacenza, Piacenza; Unit of Hematology and Clinical Immunology, University of Padova, Padova; Hematology and Stem Cell Trans-plant Center Marche Nord Hospital, Pesaro; Institute of Hematology “L. and A. Seràgnoli”, Sant’Orsola-Malpighi University Hospital, Bologna; Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has been recently associated with the oc-currence of second primary malignancies (SPMs), mainly lymphoid neo-plasms and non-melanoma skin cancers (NMSCs). Herein, we analyzed incidence and risk factors of SPMs in 589 MF pts treated with RUX in 20 European Hematology Centers. Cumulative incidence of SPMs was calculated according to Fine and Gray model with death without SPM as competitive event. Uni and multivariate analysis were carried out by Fine-Gray proportion hazard regression for competing risks. The
char-acteristics of the MF cohort were the following: median age 65y (15-88); male gender 58%; PMF 51%; JAK2, CALR and MPL mutation 83%, 11% and 2% of 530 evaluable pts; median RUX exposure 36 mos (1-86), prior cytoreduction use in 362 pts (HU 98%), previous neoplasms in 40 pts (43 events).
Seventy pts (12%) developed 74 SPMs after RUX start, with a cumu-lative incidence of 2.3%, 4.5% and 14.3% at 1, 2 and 5y, respectively. Incidence rate of SPMs was 3.91 100 pts/y. Clinical features were com-parable between pts with or without SPMs. NMSCs were the most common SPMs accounting for 38 events in 34 pts, other neoplasms in-volved urological district (13), lung (9), GI tract (6), hematopoietic tissue (2, 1 CML and 1 Langherhans cell histiocytosis), others (6). In 17 out of 213 deceased pts (8%), SPM was the ultimate cause of death. SPM di-agnosis did not affect OS, even after excluding NMSC, with projected survival of 81 and 84% at 2y for pts with or without SPM (p=0.96). By univariate analysis, age at RUX start >55y (p=0.035), CALR mutation (p=0.023), HU time-exposure (p=0.003) and male sex (p<0.001) were associated with increased incidence of SPMs; in multivariate analysis, CALR mutation, HU use and sex maintained statistical significance (HR 3.78, CI95% 1.61-8.87 p=0.002, HR 1.07, CI95% 1.02-1.13 p=0.01 and HR 2.63, CI95% 1.08-6.43, p=0.034 respectively). After exclusion of NMSCs, HU lost any statistical significance (HR 1.01, CI95% 0.94-1.08); on the contrary, mutational status and sex confirmed their prog-nostic value (HR 2.99, CI95% 1.28-7.02 p=0.011 and HR 2.67, CI95% 1.17-6.09 p=0.019, respectively). Notably, RUX time-exposure, and starting/cumulative dose were not associated with SPMs. In conclusion, mutational status and male sex represent the major predictive factors for SPMs occurrence in RUX-treated pts. HU time-exposure was strongly associated with NMSCs.
Figure 1. Cumulative incidence of SPMs according presence of CALR mutation (a), HU exposure >5y (b) and male sex (c).
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ABSTRACT WITHDRAWN
B007
CD19 REDIRECTED CAR NK CELLS ARE EQUALLY EFFECTIVE BUT LESS TOXIC THAN CAR T CELLS IN ACUTE LYMPHOBLASTIC LEUKEMIA
S. Caruso1, C. Quintarelli1,2, S. Sivori3, S. Carlomagno4, M. Falco5,
I. Boffa1, D. Orlando1, M. Guercio1, Z. Abbaszadeh1, M. Sinibaldi1,
S. Di Cecca1, A. Camera1, B. Cembrola1, K. Bovetti1, A. Pitisci1,
M. Andreani1, L. Vinti1, F. Del Bufalo1, M. Algeri1, G. Li Pira1,
A. Moseley6, B. De Angelis1, L. Moretta7, F. Locatelli1,8
1Department of Onco-Haematology and Cell and Gene Therapy, Bambino Gesù
Children’s Hospital, IRCCS; 2Federico II University of Naples, Department of
Clinical Medicine and Surgery; 3University of Genoa, Department of
Experi-mental Medicine (DIMES) and Centre of Excellence for Biomedical Research (CEBR) ; 4University of Genoa, Department of Experimental Medicine
(DIMES); 5Istituto G Gaslini, Laboratorio di Immunologia Clinica e
Sperimen-tale, Dipartimento di Ricerca e Diagnostica; 6Sandhill Therapeutics; 7Department
of Immunology, Bambino Gesù Children’s Hospital, IRCCS; 8Department of
Pediatrics, Sapienza, University of Rome, Italy
Based on the clinical success observed in B-cell lymphoproliferative disorders with CD19-directed chimeric antigen receptor engineered T cells (CAR-T), we hypothesized that combining the CAR specificity with the innate allo-reactivity of KIR-mismatched NK (Natural Killer) cells might provide a powerful tool for adoptive cell therapy. The use of a third-party bank of CAR-NK cells offers the advantage of an im-mediate availability in the allogeneic setting. We developed a feeder-free culture resulting in a 3.2-log expansion of CAR-NK cells after 20 days of culture. Expanded NK cells preserve a high percentage of CD56+CD57- cells (85±13%), associated with high proliferative capa-bility. NK cells transduction was 38%±15% and it was stable up to 60 days after in vitro culture CAR-NK cells display significant anti-leukemia activity towards CD19+ leukemia and lymphoma cell lines (LCL 721.221, DAUDI and BV173) and primary blasts obtained from Bcp-ALL patients. Co-culture experiments, using a 1:1 E/T ratio, showed that, while the antitumor activity was already remarkable for NK cells (60±30%, 71±33% and 54±23% of residual LCL 721.221, DAUDI and BV173 cells, respectively; p<0.05 vs T cells), it reached the highest level when CAR-NK cells were used as effectors (7±9%, 16±30% and 22±16% of residual LCL 721.221, DAUDI and BV173 cells, respectively; p<0.05 vs NK cells). Importantly, INF-a production was significantly lower upon CAR-NK activation compared to CAR-T cells (DAUDI 384±194 ng/ml vs 1860±678 ng/ml, p=0.002). CAR-NK cells exert high degree of tumor control on primary Bcp-ALL blasts (2.1±2% of residual blasts vs 5.4±1.6%; p=0.04). In an in vivo leukaemia xenograft mice model, we evaluated whether CAR-NK cells are associated with a lower toxicity profile compared to CAR-T cells. While the in vivo an-tileukemia activity was superimposable between CAR-T and CAR-NK cells, mice treated with two i.v. infusions of 10x106 CAR.CD19 NK cells had a 100% overall survival at 50 days compared to 20% of mice receiving 10x106 CAR.CD19 T cells; p=0.01, which succumbed due to a xenograft reaction. These in vitro and in vivo data demonstrate the fea-sibility of clinical scale feeder-free expansion of NK cells or CAR-NK cells for treatment of CD19+ ALL. We suggest that ex-vivo expanded, feeder-free NK cells could be universally applied for ‘off-the-shelf’ im-muno-gene-therapy, and that their innate allo-reactivity can be safely harnessed to potentiate allogeneic cell therapy.
B008
A PHASE 2 OPEN-LABEL PROOF OF CONCEPT STUDY OF THE ORAL, SMALL MOLECULE FACTOR D INHIBITOR, ACH-4471, IN UNTREATED PATIENTS WITH PAROXYSMAL NOC-TURNAL HEMOGLOBINURIA (PNH)
A. Risitano, A. Kulasekararaj, J.W. Lee, R. Notaro, R.A. Brodsky, M. Huang, M. Geffner, P. Browett
Università Federico II di Napoli, King’s College Hosptial-NHS Foundation Trust, London, Catholic University of Korea, Seoul, Azienda Ospedaliera Uni-versitaria Careggi, Firenze, Johns Hopkins University School of Medicine, Bal-timore, Achillion Pharmaceuticals, New Haven and Blue Bell, University of Auckland
Background: Factor D (fD) is a highly specific serine protease that
cleaves factor B as a rate-limiting step of the alternative pathway (AP) of complement. Thus, fD is a promising target in diseases of excess AP activation, such as PNH.
Aims: We hypothesize that ACH-4471, a novel, oral, small molecule
fD inhibitor, represents a potential PNH treatment option.
Methods: Data are presented for this Phase 2, dose-finding, proof of
concept trial in PNH patients not receiving anti-complement treatment. Ten adult PNH patients were included with anemia (Hgb < 12 g/dL and adequate reticulocytosis), PNH Type III RBC/granulocyte clone size > 10%, LDH > 1.5X ULN, platelets > 50,000 µL. ACH- 4471Starting doses ranged from 100-150 mg TID, with dose escalation based on response to a maximum of 200 mg TID. The primary efficacy parameter was the change in LDH vs baseline at Day 28. Secondary efficacy parameters were Hgb relative to baseline at Days 28 and 84 and LDH vs baseline at Day 84. Safety, tolerability, PK/PD and patient reported outcomes (PRO) were also measured. After 12 weeks of treatment, patients en-tered a separate long-term extension study.
Results: Ten patients received ACH-4471. Two discontinued; one for
personal reasons unrelated to safety and the other, for a serious adverse event of elevated ALT/AST coincident with breakthrough hemolysis, which resolved without sequelae. The remaining 8 patients completed treatment and entered a long-term extension study. Baseline mean LDH for these 8 patients was 5.6X ULN and was 1.5X ULN and 2.15X ULN at Days 28 and 84, respectively. Baseline mean Hgb was 9.7 g/dL with a mean increase of 1.2 g/dL and 1.8 g/dL at Day 28 and Day 84, respec-tively. Mean reticulocyte counts and total bilirubin also decreased to the normal range with treatment. No C3 deposition on PNH RBC was observed. Mean baseline FACIT-FATIGUE score at baseline was 37 and increased by 10 and 13 points at Day 28 Day 84, respectively.
Conclusions: Proof of concept has been demonstrated with ACH-4471,
with meaningful improvements in LDH, Hgb and PRO. These improve-ments were observed in monotherapy, confirming that upstream com-plement inhibition at the level of fD can prevent MAC-mediated intravascular hemolysis and C3-mediated extravascular hemolysis in the absence of terminal pathway blockade (i.e., anti-C5 agents). Further improvements in efficacy is expected with next-generation, oral fD in-hibitors, with increased potency and twice daily administration.
B009
A BAL-DRIVEN ANTIMICROBIAL TREATMENT IMPROVES CLINICAL OUTCOME IN HEMA-TOLOGIC MALIGNANCIES PATIENTS WITH LUNG INFILTRATES DETECTION: A PROSPEC-TIVE MULTICENTER STUDY OF THE SEIFEM GROUP
F. Marchesi, C. Cattaneo, M. Criscuolo, M. Delia, M. Dargenio, M.I. Del Principe, A. Spadea, N.S. Fracchiolla, L. Melillo, K. Perruccio, C. Alati, D. Russo, M. Garzia, P. Zappasodi, M.G. Cefalo,
D. Armiento, S. Cesaro, N. Decembrino, A. Mengarelli, A. Busca, L. Pagano
Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy; Hematology Division, ASST-Spedali Civili di Brescia, Italy); Dipartimento di Scienze radiologiche, Radioterapiche ed Emato-logiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy; Hematology and Bone Marrow Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Italy; Hematology and Stem Cell Transplantation Unit, ‘Vito Fazzi’ Hospital Lecce, Italy; Hematology, partment of Biomedicine e Prevention, Tor Vergata University, Rome, Italy; De-partment of Hematology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Hematology, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria, Ospedale Santa Maria della Misericordia, Perugia, Italy; Hematology Unit, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy; Bone Marrow Transplant Unit, University of Brescia and ASST-Spedali Civili, Brescia, Italy; Hematology, San Camillo-Forlanini Hospital, Rome, Italy; Division of Hematology, Foundation IRCCS Policlinico San Matteo, University of Pavia, Italy; Hematology, San Eugenio Hospital, Rome, Italy; Hematology, Campus Bio-Medico University Hospital, Rome, Italy; Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Pediatric Hematology Oncology, IRCCS Policlinico San Matteo, University of Pavia, Italy; Stem Cell Transplant Center, AOU Citta’ della Salute e Della Scienza, Turin, Italy; Institute of Hematology, Fondazione Policlinico A. Gemelli - IRCCS, Università Cattolica Sacro Cuore, Rome, Italy
BAL is useful for characterization of lung infiltrates (LI) in patients (pts) with hematologic malignancies (HM), but prospective studies eval-uating its efficacy in response to antimicrobial treatment (tx) and sur-vival are lacking. We conducted a prospective observational study in 18 hematology institutes participating to SEIFEM group from Jan-1 to Sept-30, 2018. Adult and pediatric severely immunocompromised HM pts with LI detection were enrolled according to the following criteria: 1) presence of a host risk factor for IFD (EORTC/MSG 2008); 2) absence of any microbiological and/or serological documentation at diagnostic work-up (including serum galactomannan, GM); 3) fever or respiratory distress not responding to broad-spectrum antimicrobial tx.
Figure 1. Overall survival (A) and attributable mortality rate (B) by comparing a BAL-driven antimicrobial treatment (red line) with an empirical apporach (blue line).
According to investigators, the pts fulfilling these criteria underwent BAL. Out of 3.055 pts admitted on wards in the study period, 434 (14%) had LI and 177 (6%) were enrolled and evaluable for analysis. Median age was of 60 years (1-83). Most pts had a AML/MDS (81), fol-lowed by lymphoma (41), ALL (27), and other HM (36). Median ANC count was of 460/mm3, and 106 patients (60%) had experienced a
pro-longed and severe neutropenia (ANC <100/mm3for a median of 12
days). BAL was feasible in 145 cases (82%) in a median time of 4 days from LI detection, whereas in the remaining cases BAL was not per-formed for clinical decision. A putative causal agent was detected in 111 cases (76%): in 41 cases BAL was positive for GM, in 36 for bacte-ria, in 5 for Pneumocystis and in the remaining cases for viruses. In 87 cases (61%) the results of BAL allowed to guide the antimicrobial tx. We observed a significant better outcome of LI at day +30 from its de-tection in the pts in which a BAL-driven antimicrobial tx was possible (improve/resolution rate: 71% vs 60%; p=0,04). Moreover, we observed a significant better outcome in terms of 120d-OS (78% vs 64%; p=0,046) and 120d-AM (11% vs 25%; p=0,018) for pts in which a BAL-driven antimicrobial tx was possible (Figure 1). The multivariate analy-sis showed that only younger age and a BAL-driven antimicrobial tx were significantly related to lower 120d-AM. We did not observe any severe AE, but only 5 cases of grade 1-2 AE occurred after the proce-dure. In conclusion, in our on-study patient population: 1) BAL allows to detect a putative agent of LI in about 75% of cases; 2) BAL is feasible in almost all cases; 3) a BAL-driven antimicrobial tx allows to improve clinical outcome and survival.
B010
RANDOMIZED STUDY FOR THE TREATMENT OF PRIMARY IMMUNE THROMBOCYTOPENIC PURPURA (PITP) IN NEWLY DIAGNOSED UNTREATED ADULT PATIENTS. COMPARISON OF STANDARD DOSE PREDNISONE VERSUS HIGH-DOSE DEXAMETHASONE. PRELIMINARY RESULTS. GIMEMA PROTOCOL ITP0207
M.G. Mazzucconi, F. Paoloni, C. Santoro, A. Sau, N. Vianelli, I.D. Vin-celli, M. Ruggeri, E. Rivolti, L. Gugliotta, G. Gaidano, M. Napolitano, N. Cascavilla, C. Carbone, V. Pavone, V. De Stefano, G. Avvisati, M. Iodice, E. Baldacci, P. Fazi, F. Rodeghiero; on behalf of the GIMEMA Working Party “Anemie e Piastrinopenie”
Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Università, Policlinico Umberto I; Data Center-GIMEMA Foundation - Franco Mandelli Onlus; Ematologia, Dipartimento di Medicina Traslazionale e di Pre-cisione, Sapienza Università, Policlinico Umberto I; Azienda USL Pescara, Unità Operativa Ematologia Clinica; AOU di Bologna, Policlinico S. Orsola Malpighi, UOC Ematologia; Dipartimento di Emato-Oncologia Azienda Ospedaliera Bianchi Melacrino Morelli; AULSS 8 Berica - Ospedale di Vicenza - UOC Ematologia; AUSL di Reggio Emilia - Arcispedale Santa Maria Nuova, IRCCS - SC Ematologia; AUSL di Reggio Emilia - Arcispedale Santa Maria Nuova, IRCCS - SC Ematologia; S.C.D.U. Ematologia, DIMECS e Dipartimento On-cologico – Università del Piemonte Orientale Amedeo Avogadro; AOU Policlinico P. Giaccone - UO Ematologia; Istituto di Ematologia, IRCCS Ospedale Casa Sollievo della Sofferenza; Azienda Ospedaliera Spedali Civili Brescia, U.O. Ematologia; Unità Operativa Ematologia, Azienda Ospedaliera, Pia Fondazione di Culto e Religione Card. G. Panico; Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Area Ematologica; Policlinico Universitario Campus Bio Medico - UOC Ematologia e Trapianto di Cellule Staminali; Data Center-GIMEMA Foundation - Franco Mandelli Onlus; Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Università, Policlinico Umberto I, Data Center-GIMEMA Foundation - Franco Mandelli Onlus AULSS 8 Berica - Ospedale di Vicenza - UOC Ematologia
Background: Corticosteroids are the mostly used first-line treatment
in adult patients (pts) with pITP, but the best initial approach to this disease is still matter of debate. Comparison between standard doses of prednisone/prednisolone (PDN) and pulsed high-dose dexametha-sone (HD-DXM) seems to be advisable.
Aim: To evaluate therapy intensification with HD-DXM in newly
di-agnosed untreated adult pITP pts for response improvement at 6 months after initial response, in comparison with standard PDN doses. Study design Open label, randomized, multicentre phase III study: ARM A, PDN 1 mg/Kg/d P.O. for 4 consecutive weeks, then tapering within 14 days; ARM B, DXM, 40 mg/d P.O. for 4 consecutive days, every 14 days, for 3 consecutive courses. Initial response ARM A, at d42 from PDN start;ARM B, at d46 from HD-DXM start. Final response At d180 from initial response for both arms. Response criteria: complete response (CR), platelet (plt) count ≥100x109/L. Partial response, (PR), plt
count >50<100x109/L. Minimal response (MR), plt count >20<50x109/L.
No response (NR), plt count ≤20x109/L or >20x109/L and<50x109/L plus
bleeding. Patients Untreated adult pITP pts (>18 <80y), plt count <20x109/L or >20x109/L and <50x109/L plus bleeding. Results 113
eligi-ble pts were enrolled, 59 in ARM A, 54 in ARM B, M 43, F 70, median age 45y (18.2-79.5), median plt count 8.5x109/L (1-51). Initial response
ARM A, CR 35/56 (62.50%), PR 7/56 (12.50%), MR 2/56 (3.57%), (OR, 78.57%) NR 12/56 (21.43%). ARM B, CR 31/49 (63.27)%, PR 11/49 (22.45%), MR 4/49 (8.16%) (OR, 93.88%), NR 3/49 (6.12%): difference between the 2 ARMS concerning global responses is statistically signif-icant (p=0.0284). Final response ARM A, 13 pts not evaluable, CR 22 (51.16%), PR 3 (6.98%), MR 1 (2.33%) (OR, 60.47%), NR 12 (27.91%), loss of response 5 (11.63%); ARM B, 10 not evaluable, CR 18 (46.15%), PR 4 (10.26%), MR 1 (2.56%) (OR, 58.97%), NR 3 (7.69%), loss of re-sponse 13 (33.33%). Median follow-up was 46.0 mos (IQR 16.9-80.4). Considering the 49 responding pts, at 48 mos, 80.71% (95%CI: 68.65-94.89) was alive in response, difference between two arms was not sta-tistically significant: 89.84% (95%CI: 77.34-100) in ARM A vs 70.41% (95%CI: 51.22-96.79) in ARM B (p=0.1069). Conclusions Initial re-sponse is significantly better in ARM B, but this result is not confirmed at day 180 (p=0.8907) and during follow-up. HD-DXM, indeed, seems to be able to induce a prompt initial response, reducing bleeding risk.
B011
STANDARDIZATION OF 18F-FDG PET/CT ACCORDING TO DEAUVILLE CRITERIA FOR MRD EVALUATION IN NEWLY DIAGNOSED TRANSPLANT ELIGIBLE MULTIPLE MYELOMA (MM) PATIENTS: JOINED ANALYSIS OF TWO PROSPECTIVE RANDOMIZED PHASE III TRIALS
E. Zamagni, C. Nanni, L. Dozza, T. Carlier, P. Tacchetti, A. Versari, S. Chauvie, A. Gallamini, M. Attal, B. Gamberi, D. Caillot, F. Patriarca, M. Macro, M. Boccadoro, L. Garderet, S. Fanti, A. Perrot, F. Gay, P. Sonneveld, L. Karlin, C. Bodet-Milin, P. Moreau, F. Kraeber-Bodéré, M. Cavo
Seragnoli Institute of Hematology, Bologna University School of Medicine; Nu-clear Medicine, AOU Policlinico S.Orsola-Malpighi, Bologna, Seragnoli Institute of Hematology, Bologna University School of Medicine, Nuclear Medicine de-partment, Nantes University Hospital and CRCINA INSERM UMR 1232, France; Seragnoli Institute of Hematology, Bologna University School of Medi-cine, Nuclear MediMedi-cine, S. Maria Nuova Hospital, IRCSS Reggio Emilia, Italy; MedicalPhysics Unit, Santa Croce e Carle Hospital, Cuneo, Italy; Research and Innovation Department A Lacassagne Cancer Center, Nice, France; Hematology Department, University Hospital, Toulouse France; Hematology Unit, Azienda Ospedaliera ASMN, IRCCS, Reggio Emilia, Italy; Hematology Department, University Hospital, Dijon France; Hematologic Clinic, Udine University, Italy; Hematology Department, University Hospital, Caen, France; Myeloma Unit, Division of Hematology, University of Torino, Italy; Hematology Department, University Hospital Saint-Antoine, Dijon, France; Nuclear Medicine, AOU Poli-clinico S.Orsola-Malpighi, Bologna, Italy; Hematology Department, University Hospital, Nancy, France; Myeloma Unit, Division of Hematology, University of Torino, Italy; Hematology Department Rotterdam The Netherlands; Hematology Department, University Hospital, Lyon, France; Nuclear Medicine department, Nantes University Hospital and CRCINA INSERM UMR 1232, France; Hematology Department, University Hospital, Nantes, France; Nuclear Medi-cine department, Nantes University Hospital and CRCINA INSERM UMR 1232, France; Seragnoli Institute of Hematology, Bologna University School of Medicine, Italy
18F-FDG-PET/CT is currently considered as the standard technique to define minimal residual disease (MRD) status outside the bone mar-row (BM) in multiple myeloma (MM) patients. In this regard, standard-ization and definition of cut-offs for positivity/negativity is of highly importance.
Aim of the present study was to standardize PET/CT evaluation by centralized imaging and revision and to define criteria for PET negativ-ity after therapy, in a joined analysis of a sub-group of patients (pts) with newly diagnosed transplant-eligible MM, enrolled in 2 independ-ent European randomized phase III trials (EMN02/HO95 and IFM2009) (Cavo M et al., Blood 2017 abs; Attal M et al., NEJM 2017).
236 patients were enrolled and followed for a median of 62.9 months (mos). By study design, PET/CT scans were performed locally at base-line (B) and prior to the start of maintenance (PM), uploaded in a central website and re-interpreted a-posteriori in a blinded independent central review process, by a panel of expert nuclear medicine physicians. The five-point Deauville scores (DS) (1-5) were applied to the following pa-rameters: bone marrow (BM), focal lesions (FLs), extramedullary disease (EMD). At B, 80% of the pts had FLs, with a median (m) SUVmax of 5.
mBM SUVmax was 3. FLs DS (FS) and BM DS (BMS) > 3 (higher than the liver) were present in 79.8% and 35.5% of the pts, respectively. EMD was present in 11% of the pts. PM, mFLs and BM SUVmax were 3.6 and 2.3, respectively, with 53.5% and 71.2% of the pts obtaining a FS and BMS ≤2 and 79% and 91.4% ≤ 3, respectively. In univariate analysis, at Landmark time PM, attaining a FS and BMS ≤ 3 was the strongest predictor for prolonged PFS (FS≤ 3 vs >3: m40 vs 26.6 mos, HR 0.6, p=0.0019; BMS≤ 3 vs >3: m39.8 vs 26.6 mos, HR 0.47, p= 0.024, respectively) and OS (FS≤ 3 vs >3: estimate at 63 mos 73% vs 63.6% mos, HR 0.51, p= 0.028; BMS≤ 3 vs >3: estimate at 75.5% vs 49.7%, HR 0.28, p=0.002, respectively) and could be identified as the most rep-resentative cut-off values for PET negativity. In Cox multivariable analy-sis, FS and BMS ≤3 at PM were independent predictors of prolonged PFS (HR 0.58 and 0.41, respectively) and OS (HR 0.36 and 0.24, respec-tively).
In conclusion, reduction of FDG uptake lower than the liver after therapy, both in the FLs and in the BM, was an independent predictor for improved PFS and OS and can be proposed as the standardized cri-teria to define PET negativity, confirming the value of Deauville scores in MM.
B012
R-CHOP PRECEDED BY BLOOD-BRAIN BARRIER PERMEABILIZATION WITH ENGINEERED TUMOR NECROSIS FACTOR (TNF) IN RELAPSED OR REFRACTORY PRIMARY DIFFUSE LARGE B-CELL LYMPHOMA OF THE CNS (RPCNSL): FINAL RESULTS OF THE INGRID TRIAL
T. Calimeri, G.M. Conte, M. Ponzoni, F. Fallanca, D. Cattaneo, E. Scarano, F. Curnis, M. Sassone, M. Foppoli, F. Gagliardi, A. Chiara, S. Perrone, C. Cecchetti, P. Lopedote, F. Ciceri, N. Anzalone, A. Corti, A.J.M. Ferreri
IRCCS San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, ASST Fatebenefratelli Sacco University Hospital, Italy
PCNSLs are usually treated with high-dose methotrexate-based com-binations that require hospitalization and extensive expertise. R-CHOP could overcome these difficulties, but CNS availability of related drugs is poor. TNF induces blood-brain barrier (BBB) permeabilization and enhances CNS access of drugs. Coupling TNF with NGR, a peptide that targets CD13+ tumor vessels, improves its biological effects. Here, we report results of activity, safety and BBB permeabilization of NGR-hTNF combined with R-CHOP in pts with rPCNSL enrolled in a phase II trial (NCT03536039). HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 6 courses of R-CHOP21 preceded by NGR-hTNF (0.8 g/m2). Primary endpoint was overall response rate (ORR). Treatment
would be declared active with ≥12 responses. Secondary endpoints were changes induced by NGR-hTNF, both in vessel permeability as-sessed by DCE-MRI and 99mTc-DTPA-SPECT, and in anticancer drug levels in CSF and plasma, and CD13 expression on diagnostic tumor samples. 28 pts (median age 58 yo, range 26-78; 14 males) were en-rolled; 21 (75%) pts had intermediate-high IELSG score. Pts were heav-ily pretreated: 25 had received ASCT, WBRT or both; 15 had refractory disease. NGR-hTNF/RCHOP was active: the predetermined activity threshold (≥12 responses) was achieved, with confirmed tumor re-sponse in 21 pts (75%; 95%CI= 59-91), which was complete in 11. At a median follow-up of 12 (4-20) months, 8 pts remain relapse free and 9 are alive. Treatment was well tolerated; toxicities were quickly solved without dose reductions or interruptions. G4 toxicities were neutrope-nia (44% of courses), thrombocytopeneutrope-nia (20%), anemia (2%), and FN (1%). 15 SAE were recorded in 13 pts: seizures (3), DVT (2), infections (5), syncope (2), constipation, FN, and LVEF reduction. There were 7 g1-2 TNF infusion reactions. DCE-MRI and SPECT studies showed an increase of vascular permeability after NGR-hTNF infusion in tumor and perilesional areas. Specificity of this effect was suggested both by CD13 expression in all tumor samples, and absence of changes in CSF/plasma drug levels after NGR-hTNF infusion. NGR-hTNF/RCHOP is active and safe in pts with rPCNSL. CD13, the target of TNF, was ex-pressed in tumor tissue and, consistently, NGR-hTNF enhanced vascu-lar permeability specifically in tumor and perilesional areas. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts.
ORAL COMMUNICATIONS
Non Hodgkin Lymphoma 1
C001
OUTCOMES IN FIRST RELAPSED-REFRACTORY YOUNGER PATIENTS WITH MANTLE CELL LYMPHOMA: RESULTS FROM THE MANTLE-FIRST STUDY
C. Visco, A. Di Rocco, M. Tisi, L. Morello, A. Evangelista, V.R. Zilioli, C. Rusconi, S. Hohaus, R. Sciarra, A. Re, C. Tecchio, A. Chiappella, A.M. Niebla, R. McCulloch, G. Gini, T. Perrone, L. Nassi, E. Pennese, P.M. Stefani, M.C. Cox, V. Bozzoli, A. Fabbri, V. Polli, S. Ferrero, I.A. De Celis, A. Sica, L. Arcaini, M. Balzarotti, S. Rule, U. Vitolo
Department of Medicine, Section of Hematology, University of Verona; Sapienza University, Cellular Biotechnologies and Hematology; Cell Therapy and Hema-tology, San Bortolo Hospital; HemaHema-tology, Humanitas Clinical and Research Center; Clinical Epidemiology, Città della Salute e della Scienza and CPO Piemonte; Hematology, ASST Grande Ospedale Metropolitano Niguarda; In-stitute of Hematology, Policlinico Gemelli Foundation, Catholic University of the Sacred Heart; Haematology Oncology, Fondazione IRCCS Policlinico San Mat-teo; Hematology, Spedali Civili, Brescia; Hematology, Citta’ della salute e della scienza university hospital; Hematology, Vall d’Hebron Institut de Recerca; Haematology, University of Plymouth and Derriford Hospital; Hematology, De-partment of Clinical and Molecular Sciences, Marche Polytechnic University; Hematology, University of Bari; Hematology, Azienda Ospedaliero-Universitaria Maggiore della Carità; Hematology, UOSD “Centro Diagnosi e Terapia dei Linfomi”, PO Santo Spirito; Hematology, Treviso Hospital; Hematology, AOU Sant’Andrea; Hematology, P.O. V. Fazzi; Hematology, Azienda Ospedaliera Universitaria Senese & University of Siena; Hematology, Ospedale degli In-fermi; Molecular Biotechnologies and Health Sciences, University of Torino/AOU Città della Salute e della Scienza di Torino; Hematology, AUSLL/IRCCS Santa Maria Nuova Hospital; Hematology, Policlinico di Napoli, Italy
Introduction: Patients with mantle cell lymphoma (MCL) that fail
in-duction treatment represent a difficult-to-treat population with poor outcome. There is a paucity of large-scale treatment data in relapsed or refractory (r/r) MCL.
Methods: MANTLE-FIRST, an international, retrospective study,
eval-uated outcomes in patients with MCL which had progressive disease or first relapse when treated upfront with high dose cytarabine (HDAC), followed by autologous stem cell transplantation when ap-propriate. Overall survival (OS), and progression-free survival (PFS) were estimated from the time of salvage therapy. The previously de-fined threshold of 24 months was used to define patients as early- or late-POD.
Results: Overall, 258 patients with r/r MCL were included, with a
me-dian follow-up from time of relapse or progression of 38 months (range 1-122). Second line regimens consisted of rituximab bendamustine (R-B, 22%), R-B and cytarabine (R-BAC, 29%), Ibrutinib (18%), or other regimens (31%). Overall response was 79% in ibrutinib and R-BAC treated patients, as compared to R-B (62%), or other regimens (30%). Complete response were significantly higher with R-BAC (63%) than with R-B (43%, p=0.02), ibrutinib (34%, p=0.002), or other regimens (22%, p<0.0001). Median OS and PFS for all patients were 34±5 and 13±8 months, respectively. PFS curve according to second line therapy is shown in Figure 1. For patients with early-POD (n=126), outcomes were poor, irrespectively of second line therapy (median OS 10±1 months), unless for those reaching allogeneic transplant (n=27, median OS 63±24 months). Ibrutinib was associated with longer PFS and OS (10±1 and 30±13, respectively), compared to immunochemotherapy (6±2 and 12±2 months, p=0.09 and p=0.08). For late-POD (n=132), me-dian OS was 74±9 months, and PFS was 34±5. Ibrutinib and R-BAC (not reached) and R-B (73±21) had similar significant OS advantage, compared to other regimens (41±11, p=0.03). At multivariate analysis, factors significantly associated to a reduction of the risk of death were CR after second line regimens (HR 0,19), allogeneic transplant (HR 0,40), ibrutinib second line therapy (HR 0,47), and late-POD (HR 0,49).
Conclusions: MANTLE-FIRST is the largest patient-level pooled
analy-sis of HDAC treated patients with first r/r MCL. Our analyanaly-sis shows that Ibrutinib is the best performer in early-POD patients, R-BAC is
as-sociated with higher CR rate, while allogeneic transplant remains the only curative option.
Figure 1.
C002
ABSTRACT WITHDRAWN.
C003
LENALIDOMIDE/RITUXIMAB (R2) VERSUS RITUXIMAB/PLACEBO EFFICACY BY POD24 STATUS AND TIME TO NEXT TREATMENT IN PATIENTS WITH RELAPSED/REFRACTORY IN-DOLENT NHL (AUGMENT)
A. Pinto, J. Gribben, M. Trneny, K. Izutsu, N.H. Fowler, X. Hong, H. Zhang, F. Offner, A. Scheliga, G. Nowakowski, F. Re, L.M. Fogliatto, P. Scheinberg, I. Flinn, C. Moreira, M. Czuczman, S. Kalambakas, P. Fustier, C. Wu, J.P. Leonard
Istituto Nazionale Tumori Fondazione G. Pascale IRCCS, Centre for Haemato-Oncology Barts Cancer Institute, Charles University General Hospital, National Cancer Center Hospital , The University of Texas MD Anderson Cancer Center, Fudan University Shanghai Cancer Center, Tianjin Medical University Cancer Institute and Hospital, UZ Gent, INCA Instituto Nacional De Câncer, Mayo Clinic, Azienda Ospedaliero Universitaria di Parma, Hospital de Clinicas de Porto Alegre, Hospital A Beneficência Portuguesa de São Paulo, Sarah Cannon Research Institute/Tennessee Oncology, Instituto Português de Oncologia Do Porto Francisco Gentil Epe, Celgene Corporation, Celgene Corporation, Meyer Cancer Center Weill Cornell Medicine and New York Presbyterian Hospital
Relapse is common in indolent lymphoma, and relapse ≤2y from ini-tial chemoimmunotherapy (ie,POD24) in follicular lymphoma (FL) pa-tient (pts) has been associated with worse prognosis and survival. Objectives here were twofold: To examine the impact of POD24 status in relapsed/refractory (R/R) FL pts and to analyze time to next treatment (TTNT) in R/R FL and marginal zone lymphoma (MZL) pts receiving lenalidomide+rituximab (R2) vs rituximab/placebo (R/placebo). The AUGMENT phase III study evaluated pts with R/R FL gr 1-3a and MZL after ≥1 prior systemic therapy (not rituximab refractory). Randomiza-tion was 1:1 to R2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c]+rituximab [R] IV 375 mg/m2/wk, c1, d1, 8, 15, 22 and c2-5, d1) and
R/placebo (same schedule). The primary endpoint was PFS by 2007 IWG. POD24 was defined post-hoc as PD/relapse ≤2y from initial an-tilymphoma treatment, which included immuno and/or chemotherapy. Secondary/exploratory analyses were time to next antilymphoma/ chemotherapy treatment (TTNLT/TTNCT), response to next treat-ment, and PFS2. PFS2 was time from randomization to first PD/death (any cause) after next or start of 3rd antilymphoma treatment. As of 22June2018, 178 pts were randomized to R2 (FL, n=147; MZL n=31) and 180 to R/placebo (FL, n=148; MZL, n=32). Median PFS was superior for R2 vs R/placebo (39.4 vs 14.1 mo; HR=0.46; p<0.0001). Of the FL pts, 56 (38%) R2 and 57 (39%) R/placebo pts were POD24. Median PFS was improved in FL pts receiving R2 vs R/placebo, irrespective of POD24 status (HR=0.41 [95% CI, 0.24-0.68] with POD24 and HR=0.43 [95% CI, 0.28-0.65] with no POD24). Best responses were similar in
