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Αιματολογική Κλινική ΕΚΠΑ

ASH Highlights: Θεραπευτικές Εξελίξεις σε Λέμφωμα Hodgkin - Επιθετικά Λεμφώματα - Λέμφωμα Μανδύα - Οξείες Λευχαιμίες. Θεόδωρος Π. Βασιλακόπουλος Αναπληρωτής Καθηγητής Αιματολογίας. Αιματολογική Κλινική ΕΚΠΑ. ΛΕΜΦΩΜΑ HODGKIN.

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Αιματολογική Κλινική ΕΚΠΑ

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  1. ASH Highlights: Θεραπευτικές Εξελίξεις σε Λέμφωμα Hodgkin -Επιθετικά Λεμφώματα - Λέμφωμα Μανδύα - Οξείες Λευχαιμίες Θεόδωρος Π. Βασιλακόπουλος Αναπληρωτής Καθηγητής Αιματολογίας Αιματολογική Κλινική ΕΚΠΑ

  2. ΛΕΜΦΩΜΑ HODGKIN

  3. ECHELON-1: Phase III Trial of First-line Brentuximab Vedotin + AVD Chemotherapy in Advanced Classical Hodgkin Lymphoma Integrating New Hematology Findings Into Practice: Independent Conference Coverage ofASH 2017,*December 9-12, Atlanta, Georgia

  4. ECHELON-1: Study Design • International, randomized, open-label phase III trial EOT: CT/PET scan End of cycle 2: PET scan (Deauville 5: could switch to tx of physician’s choice) Stratified by region (Americas vs Europe vs Asia), IPS (low/int/high) Brentuximab Vedotin + AVD* IV Days 1 and 15 of six 28-day cycles (n = 664) Follow-up: every 3 mos for 3 yrs, every 6 mos thereafter Adult pts with newly diagnosed stage III/IV cHL, ECOG PS 0-2, (N = 1334) ABVD† IV Days 1 and 15 of six 28-day cycles (n = 670) *BV + AVD: BV 1.2 mg/kg + standard AVD†ABVD: standard ABVD • Primary endpoint: modified PFS per IRC • Defined as first of: progression, death from any cause, PET6 with Deauville score 3-5 after frontline tx and subsequent anticancer tx • Secondary endpoints: response, OS, PET negativity per IRC, safety Connors JM, et al. ASH 2017. Abstract 6. Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print].

  5. ECHELON-1: Baseline Pt Characteristics Connors JM, et al. ASH 2017. Abstract 6. Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  6. ECHELON-1: Primary Endpoint Connors JM, et al. ASH 2017. Abstract 6, Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  7. ECHELON-1: Modified PFS by the Investigator Connors JM, et al. ASH 2017. Abstract 6, Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  8. ECHELON-1: Modified PFS by IRC vs by Investigator • Concordance of results obtained by IRC and investigator review Connors JM, et al. ASH 2017. Abstract 6. Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  9. ECHELON-1: Modified PFS by the Investigator

  10. ECHELON-1: Secondary Efficacy and Survival Outcomes • Interim OS calculated with 67 out of 112 planned deaths for analysis • HR for BV + AVD vs ABVD: 0.72 (95% CI: 0.44-1.17; P = .19) *Per IWG 2007 criteria. †P = .03 per chi-square test. Connors JM, et al. ASH 2017. Abstract 6. Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  11. ECHELON-1: Clinically Important Treatment-Emergent AEs *Other AEs in ≥ 20% of pts: alopecia, anemia, decreased weight, nausea. Connors JM, et al. ASH 2017. Abstract 6. Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  12. ECHELON-1: AEs of Special Interest • Primary G-CSF prophylaxis led to comparable safety profiles between BV + AVD and ABVD • At last f/u, 67% of BV + AVD pts with PN had resolution or ≥ 1-grade improvement • Pts with ongoing PN at last f/u: 64%, grade 1; 29%, grade 2; 7%, grade 3 *Primary prophylaxis with G-CSF by Day 5 of study tx. †Encompasses preferred terms ‘neutropenia’ and ‘neutrophil count decreased.’ Connors JM, et al. ASH 2017. Abstract 6.

  13. ECHELON-1: Deaths • Fewer deaths observed with BV + AVD vs ABVD during treatment and follow-up • Among BV + AVD pts, 6/7 neutropenia-associated deaths occurred in those who had not received G-CSF primary prophylaxis Connors JM, et al. ASH 2017. Abstract 6. Connors JM, et al. N Engl J Med. 2017;[Epub ahead of print]

  14. ECHELON-1: Conclusions • In pts with previously untreated advanced cHL, first-line BV + AVD showed significantly improved modified PFS by IRC vs ABVD • Risk of PD, death, or need for further anticancer tx reduced by 23% (HR: 0.77; log-rank P = .035) - Similar results obtained by investigator review • BV + AVD associated with higher rates of PN, neutropenia but lower rates of interstitial lung disease, pulmonary toxicity–related deaths vs ABVD • Investigators conclude that bleomycin-free BV + AVD is a more effective first-line therapy than ABVD with a manageable safety profile for pts with untreated advanced cHL • Recommend primary prophylaxis with G-CSF for all pts receiving BV + AVD Connors JM, et al. ASH 2017. Abstract 6.

  15. Analysis of Nivolumab Continued Beyond Progression in Patients With R/R Classical Hodgkin LymphomaOutcomes from the Phase 2, Checkmate 205 Study Integrating New Hematology Findings Into Practice: Independent Conference Coverage ofASH 2017,*December 9-12, Atlanta, Georgia Jonathon B Cohen, Andreas Engert, Stephen Ansell, Anas Younes, Marek Trneny, Kerry J Savage, RadhakrishnanRamchandren, Graham Collins, Michelle A. Fanale, Philippe Armand, Pier Luigi Zinzani, Jan Paul De Boer, Margaret A. Shipp, Armando Santoro, John M Timmerman, Mariana Sacchi, Oumar Sy and John Kuruvilla Blood 2017; 130: 650

  16. Nivolumab Beyond Progression in cHL: Study Design • CheckMate 205: single-arm, multicenter, multicohort, open-label phase II trial • Protocol amendment (July 2014): pts with perceived clinical benefit, stable PS, and nonrapid PD permitted to receive nivolumab beyond investigator-assessed progression Until PD (≥ 10% increase in tumor burden) TBP Pts: Pts continuing nivoafter PD (n = 70) Adult pts with R/R cHL after autoHSCT failure without BV (cohort A), with BV after transplant (cohort B), or with BV before and after transplant (cohort C) (N = 243) Nivolumab* 3 mg/kg IV Q2W Current analysis: Pts with PD (n = 105) Non-TBP Pts: Pts discontinuing nivo after PD (n = 35) *Until PD or unacceptable toxicity; pts could d/c for alloHSCT. • Prespecified exploratory endpoint: tumor burden change • Other exploratory endpoints: OS, time to next therapy, safety Cohen JB, et al. ASH 2017. Abstract 650. ClinicalTrials.gov. NCT02181738.

  17. Nivolumab Beyond Progression in cHL: Baseline Pt Characteristicsa • Pts receiving continued nivolumab had better ECOG PS and fewer B symptoms at baseline *Individual pts could have multiple findings.†Sum of product of diameters ≥ 50% increase from nadir.‡Investigator-assessed unequivocal progression per protocol.§Appearance of any new lesion > 1.5 cm along any dimension (even if size of other lesions diminishing). Cohen JB, et al. ASH 2017. Abstract 650. Cheson BD, et al. J Clin Oncol. 2007;25:579-586.

  18. Nivolumab Beyond Progression in cHL: Conclusions • In R/R cHL pts continuing nivolumab after disease progression, 53% experienced target lesion reduction • Lesion reduction > 25% in 31% of pts • Responses generally stable • Median time from initial PD to next therapy longer for TBP vs non-TBP pts • Nivolumab well tolerated and associated with no new safety signals • Investigators conclude that in R/R cHL pts experiencing progression on nivolumab, continuing treatment may offer long-term benefit to those with stable PS per conventional response criteria • Proposed updates to conventional response criteria (LYRIC, RECIL) may improve evaluation of long-term efficacy with checkpoint inhibitor therapy Cohen JB, et al. ASH 2017. Abstract 650.

  19. Phase I/II Study of Brentuximab Vedotin + Nivolumab for Patients With R/R Classical Hodgkin Lymphoma Integrating New Hematology Findings Into Practice: Independent Conference Coverage of ASH 2017,*December 9-12, Atlanta, Georgia Alex F. Herrera, Alison J. Moskowitz, Nancy L. Bartlett,  Julie M Vose, Radhakrishnan Ramchandren,  Tatyana AFeldman, Ann S LaCasce, Stephen M Ansell,  Craig H. Moskowitz, Keenan Fenton, Carol Anne Ogden,  David Taft, Qu Zhang, Kazunobu Kato, Mary Campbell  and Ranjana H. Advani Blood 2017; 130: 649

  20. Brentuximab Vedotin + Nivolumab for R/R cHL: Study Design • Multicenter, single-arm, open-label phase I/II trial 62 adult pts with cHL, relapsed or refractory to frontline chemotherapy; no prior BV, salvage tx for R/R HL (including salvage RT), autoHSCT or alloHSCT, or immunotherapy targeting PD-1, CTLA4, or CD137 paths EOT CT/PET Brentuximab vedotin 1.8 mg/kg IV on Day 1 of cycles 1-4 + Nivolumab 3 mg/kg IV on Day 8 of cycle 1, then Day 1 of cycles 2-4 Eligible for autoHSCT after EOT response assessed Interim CT during cycle 2. AEs were recorded from Day 1 to 100 days after last nivo dose. • Co-primary endpoints: CR per Lugano 2014 criteria after EOT, safety • Other endpoints: ORR, DoR, post-autoHSCT PFS, overall PFS, biomarker analyses Herrera AF, et al. ASH 2017. Abstract 649.

  21. Brentuximab Vedotin + Nivolumab for R/R cHL: Baseline Pt Characteristics *1 pt treated with BEACOPP after d/c ABVD because of inadequate interim response. Herrera AF, et al. ASH 2017. Abstract 649

  22. Brentuximab Vedotin + Nivolumab for R/R cHL: Response • All observed SD and PD cases in pts with Deauville score 5 • 80% ORR, 40% CR among 17 pts completing study tx + salvage tx (n = 12 with autoHSCT) *Coprimary endpoint. †In pt achieving CR with Deauville score 5, biopsy of FDG-avid residual area on PET was not consistent with residual HL. Herrera AF, et al. ASH 2017. Abstract 649.

  23. Brentuximab Vedotin + Nivolumab for R/R cHL: Autologous HSCT Following EOT Stem Cell Mobilization and Engraftment • 54 pts received autoHSCT after BV + nivolumab • n = 42 with BV + nivolumab only • n = 12 with additional salvage therapy following EOT • Treatment with BV + nivolumab did not appear to effect stem cell mobilization, collection yields, or engraftment • No increased toxicity observed during and after transplantation *Includes 42 pts with BV + nivolumab, 2 pts with additional salvage tx Herrera AF, et al. ASH 2017. Abstract 649.

  24. Brentuximab Vedotin + Nivolumab for R/R cHL: Additional Outcomes • Median follow-up: 8 mos • Pts remaining in follow-up: • 41/42 with autoHSCT after BV + nivo only • 16/17 with autoHSCT following additional salvage therapy after BV + nivo • DoR: Not Reached • 6-mo PFS: 89% (95% CI: 75% to 95%) Comparison with 45 patients treated with BV-ICE (Mosko7witz, Lancet Oncol, 2015 Herrera AF, et al. ASH 2017. Abstract 649.

  25. Brentuximab Vedotin + Nivolumab for R/R cHL: Conclusions • In this updated analysis, BV + nivolumab was associated with an ORR of 83% (CR: 62%) in pts with R/R cHL • BV + nivolumab was well tolerated with no discontinuations due to IRRs or irAEs • Most IRRs were low grade • irAEs were observed in 82% of pts, with < 10% requiring systemic steroid tx • Pts successfully proceeded to ASCT following treatment with BV + nivolumab with no adverse effects on stem cell mobilization and collection • BV + nivolumab associated with increases in biomarkers of circulating T-cell number, innate and adaptive immune activation, and memory T-cell function • Investigators conclude that the chemotherapy-free combination of BV + nivolumab associated with encouraging clinical activity in R/R cHL • Further evaluation warranted (eg, the ongoing phase III Checkmate 812 trial) Herrera AF, et al. ASH 2017. Abstract 649. ClinicalTrials.gov. NCT03138499.

  26. ΕΠΙΘΕΤΙΚΑ Β-ΛΕΜΦΩΜΑΤΑ

  27. JULIET: Phase II Primary Analysis of CAR T-Cell Therapy Tisagenlecleucel (CTL019) in Adult Patients With Relapsed/Refractory DLBCL Integrating New Hematology Findings Into Practice: Independent Conference Coverage ofASH 2017,*December 9-12, Atlanta, Georgia Stephen J. Schuster, Michael R. Bishop, Constantine S. Tam,  Edmund K. Waller, Peter Borchmann, Joseph P.McGuirk, Ulrich Jaeger,  Samantha Jaglowski, Charalambos Andreadis, Jason R. Westin,  Isabelle Fleury, VeronikaBachanova, Stephen Ronan Foley, P. Joy Ho,  Stephan Mielke, John M. Magenau, Harald Holte, Koen Van Besien,  Marie Jose Kersten, Takanori Teshima, Kensei Tobinai, Paolo Corradini,  Oezlem Anak, Lida Bubuteishvili Pacaud, Christopher del Corral,  Rakesh Awasthi, Feng Tai, Gilles Salles and Richard Thomas Maziarz Blood 2017; 130: 577

  28. Primary Analysis of Tisagenlecleucel in R/R DLBCL (JULIET): Background • Pts with R/R DLBCL have poor responses to available salvage therapy • ORR 26% to 39% (CR: 7% to 27%), mOS ~ 4 to 6 mos[1,2] • Curative options lacking for ~ 90% of R/R DLBCL pts who are ineligible for, fail to respond to, or relapse after standard high-dose CT followed by autoHSCT[3] • Tisagenlecleucel (CTL019): anti-CD19 CAR T-cell therapy[4] • First FDA approved CAR T-cell therapy; indicated for R/R B-cell precursor ALL up to 25 yrs of age[5] • In phase II study of R/R CD19+ B-cell lymphomas, 6 of 14 (43%) DLBCL pts achieved CR, with 86% maintaining the response at median follow-up of 28.6 mos[6] • Current primary analysis of phase II JULIET study evaluated efficacy, safety of tisagenlecleucel in pts with R/R DLBCL[7] • Interim analysis reported ORR of 59% (CR: 43%)[8]

  29. JULIET Primary Analysis: Baseline Pt Characteristics • 90% of pts received bridging chemotherapy, 93% of pts received lymphodepleting chemotherapy Schuster SJ, et al. ASH 2017. Abstract 577.

  30. JULIET: Best ORR (Primary Endpoint) • Study met primary endpoint with ORR of 53% (95% CI: 42% to 64%) • Significantly greater than null hypothesis ORR ≤ 20% (P < .0001) • No relationship apparent between tisagenlecleucel dose and 3-mo response - Responses observed across entire dose range Schuster SJ, et al. ASH 2017. Abstract 577.

  31. JULIET: AEs of Special Interest • No deaths due to cytokine release syndrome, cerebral edema, or tisagenlecleucel • No relationship observed between tisagenlecleucel dose and neurologic events Schuster SJ, et al. ASH 2017. Abstract 577.

  32. JULIET: Cytokine Release Syndrome • Higher tisagenlecleucel doses associated with higher probability of CRS • CRS manageable per protocol-specific algorithm *n = 57 pts with CRS. Schuster SJ, et al. ASH 2017. Abstract 577.

  33. JULIET: Conclusions • Phase II JULIET trial met its primary endpoint with a best ORR of 53% (CR: 40%) in R/R DLBCL pts receiving tisagenlecleucel • Significantly higher than the null hypothesis ORR ≤ 20% (P < .0001) • Responses generally stable; most CR pts maintaining depth of response through 6 mos • Most common AEs included CRS, neurologic events, prolonged cytopenia, infections • No deaths attributed to CRS, cerebral edema, or tisagenlecleucel • Tisagenlecleucel safely infused in both inpatient and outpatient clinics • Investigators conclude that tisagenlecleucel associated with durable clinical benefits, manageable safety profile in R/R DLBCL and global distribution of CAR T-cell therapy is feasible • Study results included in international regulatory submissions Schuster SJ, et al. ASH 2017. Abstract 577.

  34. Randomized Phase II Trial of Polatuzumab Vedotin Addition to Bendamustine + Rituximab in Patients With Transplant-Ineligible Patients with R/R DLBCL Integrating New Hematology Findings Into Practice: Independent Conference Coverage ofASH 2017,*December 9-12, Atlanta, Georgia Laurie H. Sehn, Alex F. Herrera, Matthew J. Matasar,  Manali Kamdar, Andrew K. McMillan, Tae Min Kim,  Won Seog Kim, Mark Hertzberg, Muhit Ozcan, Elicia Penuel,  Ji Cheng, Jamie M. Hirata, Grace Ku and Christopher Flowers Blood 2017; 130: 2821

  35. Polatuzumab Vedotin + BR in R/R DLBCL: Background • ~ 50% of pts with R/R DLBCL are ineligible for transplant due to advanced age, comorbidities, and other factors[1] • Transplantation-ineligible R/R DLBCL associated with a poor prognosis and minimal likelihood of prolonged disease control • Polatuzumab vedotin: humanized anti-CD79b mAb conjugated to MMAE[2] • CD79b: B-cell–specific surface antigen expressed in NHL[3] • Durable responses and acceptable safety profile reported in phase Ib/II study of PV addition to BR or BG in transplantation-ineligible pts with R/R DLBCL and FL[4] • Among pts with R/R DLBCL, ORR of 50% with PV + BR and ORR of 57% to 83% with PV + BG • Current analysis evaluated efficacy and safety of PV addition to BR vs BR alone in phase II cohorts of transplantation-ineligible R/R DLBCL pts[5] 1. Friedberg JW. Hematology Am Soc Hematol Educ Program. 2011;2011:498-505. 2. Dornan D, et al. Blood. 2009;114:2721-2729. 3. Polson AG, et al. Blood. 2007;110:616-623. 4. Matasar M, et al. EHA 2017. Abstract S468. 5. Sehn LH, et al. ASH 2017. Abstract 2821.

  36. Polatuzumab Vedotin + BR in R/R DLBCL: Baseline Characteristics Sehn LH, et al. ASH 2017. Abstract 2821.

  37. Polatuzumab Vedotin + BR in R/R DLBCL: Response • Median follow-up per reverse Kaplan-Meier: PV + BR, 11.1 mos; BR, 10.9 mos *Cell of origin assessed via gene expression assay in pts with available tissue (n = 50): activated B-cell, n = 25 (50%); germinal center B-cell, n = 22 (44%); unclassified, n = 3 (6%); pending analysis, n = 13. Response and cell of origin data available for 37 pts, including 1 pt per arm in CR with unclassified results. Sehn LH, et al. ASH 2017. Abstract 2821.

  38. Polatuzumab Vedotin + BR in R/R DLBCL: Survival • OS favored PV + BR in subgroups stratified by BL characteristics • OS favored PV + BR after adjusting for BL chars in multiple Cox models stratified by DoR Sehn LH, et al. ASH 2017. Abstract 2821.

  39. Polatuzumab Vedotin + BR in R/R DLBCL: Safety *Grade 5 AEs during tx in PV + BR arm: pulmonary edema, massive hemoptysis, pneumonia; in BR arm, pneumonia, sepsis, septic shock, cerebrovascular accident. During follow-up in PV + BR arm: distributive shock, pneumonia, herpetic encephalitis, renal failure (all in setting of PD); in BR arm: multiple organ dysfunction and cerebral hemorrhage (both in setting of PD), unexplained death. Sehn LH, et al. ASH 2017. Abstract 2821.

  40. Polatuzumab Vedotin + BR in R/R DLBCL:Conclusions • Addition of polatuzumab vedotin to BR was associated with a significantly increased response rate in R/R DLBCL pts vs BR alone • CR by IRC at PRA (primary endpoint): 40% vs 15% (P = .012) • Preliminary biomarker data suggested that PV + BR improved response rates in pts with activated B-cell or germinal center B-cell subtypes • PV addition associated with improved DoR, EFS, PFS, and OS • Median OS with PV + BR vs BR: 11.8 vs 4.7 mos (HR: 0.35; P = .0008) • OS benefit with PV + BR was consistent across subgroups and after adjusting for BL characteristics in multiple Cox regression models • Investigators conclude that polatuzumab vedotin addition to BR was associated with clinically meaningful responses, prolonged survival, and acceptable safety profile in transplant-ineligible R/R DLBCL pts Sehn LH, et al. ASH 2017. Abstract 2821.

  41. Long-Term Results of PET-Guided Radiation Therapy in Patients with Advanced-Stage Diffuse Large B-Cell Lymphoma Treated with R-CHOP in British Columbia 702 patients 498 PET-neg 204 PET-pos 109 RT 95 no RT (63 not amenable to RT or clear PD) Median follow-up for living patients: 3.3 yrs Freeman CL, Savage KJ, Villa D, Scott DW, Srour L, Gerrie AS, Brown MJ, Slack GW, Farinha P, Skinnider B, Aquino Parsons C, Pickles T, Tonseth P, Wilson D, Connors JM and Sehn LH Blood 2017; 130:823

  42. ΛΕΜΦΩΜΑΜΑΝΔΥΑ

  43. Extended Follow-up of Mantle Cell Lymphoma Patients Treated With First-line Lenalidomide + Rituximab Integrating New Hematology Findings Into Practice: Independent Conference Coverage ofASH 2017,*December 9-12, Atlanta, Georgia Jia Ruan, Peter Martin, PaulChristos, Leandro Cerchietti,  Bijal D. Shah, StephenJ. Schuster, Wayne Tam, Amelyn Rodriguez,  David Hyman, Maria Nieves Calvo Vidal, Lidia Roman Gonzalez,  Sonali M. Smith, Jakub Svoboda, Richard R. Furman,  Morton Colemanand John P. Leonard Blood 2017 130:154

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