Best of ASH A selection by Fritz Offner UZ Gent

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1 Best of ASH 2014 A selection by Fritz Offner UZ Gent

2 Best of ASH Checkpoint inhibition in immunotherapy : antipd-1 in lymphoma 2. Evolution in CAR-T and bispecific antibodies in B-ALL 3. Treatment of AML may finally be at the dawn of targeted treatment : oral IDH-2 inhibitors can induce durable remission in refractory AML 4. Ashwell-Morell receptor controls hepatic Tpo production in a Jak-Stat dependent pathway

3 Best of ASH Checkpoint inhibition in immunotherapy : antipd-1 in lymphoma 2. Evolution in CAR-T and bispecific antibodies in B-ALL 3. Treatment of AML may finally be at the dawn of targeted treatment : oral IDH-2 inhibitors can induce durable remission in refractory AML 4. Ashwell-Morell receptor controls hepatic Tpo production in a Jak-Stat dependent pathway

5 Preliminary Results of a Phase I Study of Nivolumab in Patients with Relapsed or Refractory Lymphoid Malignancies Alexander M. Lesokhin 1, Stephen M. Ansell 2, Philippe Armand 3, Emma C. Scott 4, Ahmad Halwani 5, Martin Gutierrez 6, Michael M. Millenson 7, Adam Cohen 8, Stephen J. Schuster 8, Daniel Lebovic 9, Madhav Dhodapkar 10, David Avigan 11, Bjoern Chapuy 3, Azra H. Ligon 12, Scott J. Rodig 12, Deepika Cattry 1, Lili Zhu 13, Joseph F. Grosso 13, Su-Young Kim 13, Margaret A. Shipp 3, Ivan Borrello 14, John M. Timmerman 15 1 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; 2 Mayo Clinic, Rochester, MN; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Oregon Health and Science University and the Knight Cancer Institute, Portland, OR; 5 University of Utah Huntsman Cancer Institute, Salt Lake City, UT; 6 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; 7 Fox Chase Cancer Center, Philadelphia, PA; 8 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 9 University of Michigan Hematology, Ann Arbor, MI; 10 Yale Cancer Center, New Haven, CT; 11 Beth Israel Deaconess Medical Center, Boston, MA; 12 Brigham and Women s Hospital Clinical Cytogenetics Laboratory, Boston, MA; 13 Bristol-Myers Squibb, Princeton, NJ; 14 Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 15 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 5 6 T H A N N U A L A S H M E E T I N G D E C E M B E R S A N F R A N C I S C O, C A Courtesy of A Lesokhin

Introduction PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response via PD-1 on immune effector cells.

6 Introduction PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response via PD-1 on immune effector cells. 1 PD-L1 expressed on malignant cells and/or in the tumor microenvironment suppresses tumor infiltrating lymphocyte activity and interferes with host antitumor immunity. 2 IFNγ IFNγR MHC T-cell receptor Tumor cell PD-L1 PD-L2 PD-1 PI3K NFκB Other Shp-2 T cell PD-1 Nivolumab Nivolumab is a fully human IgG4 monoclonal antibody with anti-pd-1 activity. Courtesy of A Lesokhin 1 Francisco LM et al. J Exp Med 2009;206: Andorsky DJ et al. Clin Cancer Res 2011;17:

7 Background PD-1 blockade results in durable responses in multiple solid tumor types. 1 PD-L1 expression associated with higher frequency of response Early studies in hematologic tumors show PD-1 blockade has produced encouraging responses. Armand et al. J Clin Oncol 2013; 31: Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. Berger et al. Clin Cancer Res 2008; 14: Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Courtesy of A Lesokhin 1 Topalian SL, et al. J Clin Oncol 2014; 32:

8 Study Design Relapsed or Refractory HM (N=105) No autoimmune disease No prior organ or stem cell allografting No prior checkpoint blockade Dose Escalation Nivolumab 1mg/kg 3mg/kg Wks 1,4 then q2w (N=13) B-Cell Lymphoma (n=8) CML (n=1) Multiple Myeloma (n=4) Dose Expansion (3mg/kg) Hodgkin Lymphoma (n=23) (N=69) B-Cell Lymphoma (n=23) T-Cell Lymphoma (n=23) Multiple Myeloma (n=23) Endpoints Primary Safety and Tolerability Secondary Best Overall Response Investigator assessed Objective Response Duration of Response PFS Biomarker studies Courtesy of A Lesokhin

9 Baseline Characteristics By Tumor Type Characteristic (N=82*) FL (n=10) B-Cell Lymphoma/ PMBL (n=31) T-Cell Lymphoma (n=23) Multiple DLBCL (n=11) Other (n=8) MF (n=13) PTL (n=5) Other (n=3) Myeloma (n=27) Median age, y (range) 57 (37-69) 67 (37-74) 68 (61-74) 59 (30-78) 73 (47-81) 73 (51-76) 63 (32-81) Prior autologous stem cell transplant, n (%) 2 ( 20) 2 (18) 0 (0) 0 (0) 2 (40) 0 (0) 15 (56) No. prior systemic treatments, n (%) 2 1 (10) 2 (18) 2 (25) 0 (0) 2 (40) 0 (0) 8 (30) 3 3 (30) 3 (27) 3 (38) 2 ( 15) 1 (20) 0 (0) 4 (15) 4 1 (10) 3 (27) 0 (0) 4 (31) 1 (20) 1 (33) 6 (22) 5 2 (20) 2 (18) 3 (38) 6 (46) 1 (20) 1 (33) 8 (30) *A single patient had CML (data not shown) 2 patients had PMBL (data not shown) 2 patients had other non-cutaneous T-cell lymphomas (data not shown) PMBL, Primary mediastinal B-cell lymphoma; FL, Follicular B-cell lymphoma; DLBCL, Diffuse large B-cell lymphoma; MF, Mycosis fungoides; PTL, Peripheral T-Cell lymphoma; CML, Chronic myelogenous leukemia Courtesy of A Lesokhin

10 Drug-related Adverse Events Overview Nivolumab (N=82) n (%) Any Grade Related AE 51 (62) Any Grade Drug-related AE Occurring in 5% of Patients n (%) Fatigue 11 (13) Pneumonitis 9 (11) Pruritus 7 (9) Rash 7 (9) Pyrexia 6 (7) Anemia 5 (6) Diarrhea 5 (6) Decreased appetite 5 (6) Hypocalcemia 5 (6) Safety profile similar to other nivolumab trials The majority of pneumonitis cases were Grade 1 or 2 No clear association between pneumonitis and prior radiation (28 patients), brentuximab vedotin (9 patients) or gemcitabine AE, adverse event Courtesy of A Lesokhin

11 Best Overall Response Objective Response Rate, n (%) Complete Responses, n (%) Partial Responses, n (%) Stable Disease n (%) B-Cell Lymphoma* (n=29) 8 (28) 2 (7) 6 (21) 14 (48) Follicular Lymphoma (n=10) 4 (40) 1 (10) 3 (30) 6 (60) Diffuse Large B-Cell Lymphoma (n=11) T-Cell Lymphoma (n=23) Mycosis Fungoides (n=13) Peripheral T-Cell Lymphoma (n=5) 4 (36) 1 (9) 3 (27) 3 (27) 4 (17) 0 (0) 4 (17) 10 (43) 2 (15) 0 (0) 2 (15) 9 (69) 2 (40) 0 (0) 2 (40) 0 (0) Multiple Myeloma (n=27) 0 (0) 0 (0) 0 (0) 18 (67) Primary Mediastinal B-Cell Lymphoma (n=2) 0 (0) 0 (0) 0 (0) 2 (100) *includes other B-cell lymphoma (n=8) includes other cutaneous T-cell lymphoma (n=3) and other non-cutaneous T-cell lymphoma (n=2) Courtesy of A Lesokhin

12 Percent Change from Baseline Diffuse B-Cell Lymphoma Patient Responses * ** Diffuse Large B-Cell (n=11) Median Response Duration, wks (range) 17 (6.0, 44.1+) Diffuse Large B-Cell Lymphoma Upper Limit Approximately 540% Upper Limit Approximately 238% Ongoing Responders/ Total Responders Median Follow-up wks (range) * ** 1/4 23 (3.0, 69.0+) Time since First Dose (Weeks) Courtesy of A Lesokhin

13 Percent Change from Baseline Follicular Lymphoma Patient Responses Follicular (n=10) Median Response Duration wks (range) Not Reached (16.1+, 80.6+) Follicular B-Cell Lymphoma Ongoing Responders/ Total Responders Median Follow-up wks (range) Time since First Dose (Weeks) 4/4 Not Reached (9.9+, 88.1+) Courtesy of A Lesokhin

14 Percent Change from Baseline All T-Cell Lymphoma Patient Responses Mycosis Fungoides Cutaneous T-Cell Lymphoma Other Cutaneous T-Cell Lymphoma MF (n=13) PTCL (n=5) Median Response Duration wks (range) Not Reached (0.1+, 13.0+) Not Reached (10.6, 32.0+)) Time since First Dose (Weeks) Other Non-cutaneous T-Cell Lymphoma Peripheral T-Cell Lymphoma Ongoing Responders/ Total Responders 2/2 1/2 Median Follow-up wks (range) Not Reached (2.9+, 41.9+) 35 (4.9+, 39.9+) Courtesy of A Lesokhin

15 PD-L2 Translocation in a Cutaneous T-cell Lymphoma Patient with the translocation had a partial response of 13 weeks duration. Translocation of PD-L2 supports blockade of the receptor rather than the PD- L1 ligand.

16 PD-L1 Expression in the Follicular Lymphoma Microenvironment PAX5+ (red)/ PD-L1- (brown) follicular lymphoma cells PAX5 -/ PD-L1+ (brown) infiltrating macrophages PD-L1 is largely restricted to infiltrating macrophages Double staining helps distinguish tumor from macrophage expression of PD-L1.

17 Conclusions In patients with relapsed or refractory hematologic cancers, nivolumab has an acceptable safety profile. Nivolumab demonstrated activity across multiple hematologic malignancies, with a 40% response rate in follicular and 36% response rate in diffuse large B-cell lymphoma. Stable disease in the absence of objective responses was seen in MM. Genetic alterations of 9p24.1 were uncommon in this small NHL series. Single 9p24.1/PD-L2 translocation in a responding patient PD-L1 protein expression in infiltrating macrophages in follicular lymphoma Multicenter, phase 2 studies are ongoing in diffuse large B-cell and follicular B-cell lymphomas. MM, Multiple myeloma; NHL, Non-Hodgkin lymphoma

18 Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma Preliminary Safety, Efficacy and Biomarker Results of a Phase I Study Philippe Armand 1, Stephen M. Ansell 2, Alexander M. Lesokhin 3, Ahmad Halwani 4, Michael M. Millenson 5, Stephen J. Schuster 6, John Timmerman 7, Ivan Borrello 8, Martin Gutierrez 9, Emma C. Scott 10, Deepika Cattry 3, Bjoern Chapuy 1, Azra H. Ligon 11, Scott J. Rodig 11, Lili Zhu 12, Joseph F. Grosso 12, Su Young Kim 12, and Margaret A. Shipp 1 1 Dana-Farber Cancer Institute, Boston, MA ; 2 Mayo Clinic, Rochester, MN; 3 Memorial Sloan Kettering Cancer Center, New York, NY; 4 University of Utah Huntsman Cancer Institute, Salt Lake City, UT; 5 Fox Chase Cancer Center, Philadelphia, PA; 6 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 7 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; 8 Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 9 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; 10 Oregon Health and Science University, Portland, Oregon; 11 Brigham and Women s Hospital, Boston, MA; 12 Bristol-Myers Squibb, Princeton, NJ Courtesy of Ph Armand

Background Pathology of chl: rare malignant Reed-Sternberg cells within an extensive inflammatory/immune cell infiltrate. Genetic analyses: frequent 9p24.

19 Background Pathology of chl: rare malignant Reed-Sternberg cells within an extensive inflammatory/immune cell infiltrate. Genetic analyses: frequent 9p24.1 amplification with upregulation of PD-1 ligands and JAK2. Hypothesis: chl may have a genetically driven dependence on PD- 1. Courtesy of Ph Armand Juszczynski et al PNAS 2007; 104: Green et al Blood 2010; 116: 3268; Chen et al. Clin Cancer Res 2013; 19:3462

20 Rationale and Design Based on potential vulnerability to PD-1 blockade, chl included as independent expansion cohort in Phase 1b study of nivolumab in hematologic malignancies. Relapsed or Refractory HM (N=105) No autoimmune disease No prior organ or stem cell allograft No prior checkpoint blockade Dose Escalation Nivolumab 1mg/kg 3mg/kg Wks 1,4 then q2w (n=13) Dose Expansion (3mg/kg) Hodgkin Lymphoma (n=23) NHL/MM (n=69) Endpoints Primary Safety and Tolerability Secondary Best Overall Response Investigator assessed Objective Response PET + CT Duration of Response PFS Biomarker studies Courtesy of Ph Armand

21 Baseline Characteristics Characteristic N (%) Total 23 (100) Age 35 (20-54) chl histology Nodular sclerosis 22 (96) Mixed cellularity 1 (4) Prior ASCT 18 (78) Prior Brentuximab Vedotin 18 (78) Prior systemic therapies 2 to 3 8 (35) 4 to 5 7 (30) 6 8 (35) Courtesy of Ph Armand

22 Safety Any AE Related AE Grade 3 Related AE Grade 4 Related AE Discontinued for Related AE Patients, n (%) 22 (96) 18 (78) 5 (22) 0 (0) 2 (9) No drug-related grade 4 AEs or drug-related deaths AEs leading to discontinuation: MDS with grade 3 thrombocytopenia (6 prior treatments including ASCT) Grade 3 pancreatitis Other grade 3 related AEs: Lymphopenia Increased lipase GI inflammation Safety profile similar to that in solid tumors Pneumonitis, colitis and stomatitis (post autologous stem cell transplant) Courtesy of Ph Armand

23 Efficacy Total (N = 23) n (%) ASCT Failure Brentux Failure (N = 15) n (%) ASCT-Naïve Brentux Failure (N = 3) n (%) Brentux Naïve (N=5) n (%) Overall Response 20 (87) 13 (87) 3 (100) 4 (80) Best Response CR 4 (17) 1 (7) 0 3 (60) PR 16 (70) 12 (80) 3 (100) 1 (20) SD 3 (13) 2 (13) 0 1 (20) PD week PFS 86% 85% n/c 80% Courtesy of Ph Armand

24 Best Response SD (13%) PR (70%) CR (17%) Courtesy of Ph Armand

25 Response Kinetics Courtesy of Ph Armand

26 Patients Response Duration Courtesy of Ph Armand

27 9p24.1/PD-L1/PD-L2 Locus Integrity and Protein Expression PD-L1/2 locus integrity Red=PD-L1 Green=PD-L2 Yellow= Red + Green Cyan=Centromere Immunohistochemistry PD-L1 (brown) PAX-5 (red) PD-L2 (brown) pstat3 (red) Courtesy of Ph Armand

28 Conclusions Nivolumab can be safely administered to patients with relapsed/refractory classical Hodgkin Lymphoma. Response rate 87% (20/23) in heavily pre-treated patients. All studied tumors harbored genetic abnormalities at 9p24.1 leading to over-expression of PD-1 ligands. Classical HL appears to be a tumor with genetically determined vulnerability to PD-1 blockade. FDA has granted nivolumab breakthrough therapy designation in Hodgkin Lymphoma. A Phase 2 study is ongoing in patients who relapsed after ASCT. PD-1 blockade could become an important part of the treatment of patients with chl in the future.

29 Nivolumab : Response rate 87% (20/23), 17% CR in heavily pre-treated patients with HD. (Armand #288) Response 3/10 follic NHL, 3/11 DLBCL, 2/5 PTCL, 3/13 CTCL, 0/27 MM. (Lesokhin #289) Pembrolizumab : in HD with BV failure 53 %OR, 20% CR (Moskowitz #290) Ipilimumab (anti CTLA4) : Conclusions #3964 Davids 3/29 pts following allotx was 2 CR HD, 1 PR MCL.

30 Best of ASH Checkpoint inhibition in immunotherapy : antipd-1 in lymphoma 2. Evolution in CAR-T and bispecific antibodies in B-ALL 3. Treatment of AML may finally be at the dawn of targeted treatment : oral IDH-2 inhibitors can induce durable remission in refractory AML 4. Ashwell-Morell receptor controls hepatic Tpo production in a Jak-Stat dependent pathway

31 The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling in vivo and in vitro Renata Grozovsky Antonija J. Begonja Kaifeng Liu Gary Visner John H. Hartwig Hervé Falet Karin M. Hoffmeister Program of Excellence in Hematopoietic Glycoscience, Hematology Division, Brigham and Women s Hospital, Boston Children s Hospital, Harvard Medical School, Boston, MA

32 Ashwell-Morell receptor (AMR) clears platelets Thrombopoietin (TPO) Hepatocyte Megakaryocyte Sialic acid Galactose Platelet Courtesy of K Hoffmeister

33 Ashwell-Morell receptor (AMR) clears platelets Thrombopoietin (TPO) Hepatocyte Megakaryocyte X Sialic Galactose acid Platelet Loss of sialic acid = desialylation Aging Courtesy of K Hoffmeister

Ashwell-Morell receptor (AMR) clears platelets Hepatocyte Galactose Platelet Desialylation Aging Megakaryocyte Ashwell-Morell receptor (AMR) Galactose receptor exclusively

34 Ashwell-Morell receptor (AMR) clears platelets Hepatocyte Galactose Platelet Desialylation Aging Megakaryocyte Ashwell-Morell receptor (AMR) Galactose receptor exclusively expressed in hepatocytes Trimer Deletion of one subunit leads to receptor inactivation Identified in 1974, but its physiological role is not fully understood Courtesy of K Hoffmeister

35 Hypothesis Clearance of desialylated platelets by the Ashwell-Morell receptor regulates TPO production in the liver. Courtesy of K Hoffmeister

Fold Desialylated human platelets stimulate Thrombopoietin (TPO) production in HepG2 cells pg/ml Human Platelets Control Sialic acid Desialylated Platelet ingestion

36 Fold Desialylated human platelets stimulate Thrombopoietin (TPO) production in HepG2 cells pg/ml Human Platelets Control Sialic acid Desialylated Platelet ingestion Desialylated Human hepatoma (HepG2) cells % Platelet ingestion, TPO mrna, TPO protein Control TPO mrna TPO protein Desialylated Desialylated Control Control Courtesy of K Hoffmeister

37 What is the signaling pathway activated by desialylated platelets? Galactose Ashwell-Morell receptor (AMR)? Nucleus Thrombopoietin (TPO)

38 What is the signaling pathway activated by desialylated platelets? Galactose Ashwell-Morell receptor (AMR) P JAK2 P STAT3 P STAT3 Nucleus Thrombopoietin (TPO) Courtesy of K Hoffmeister

39 pjak2/jak2 (fold) Desialylated human platelets activate JAK2-STAT3 signaling in HepG2 cells pstat3/stat3 (fold) JAK2 phosphorylation STAT3 phosphorylation Platelets: Control Desialylated Platelets: Control Desialylated Time (h): Time (h): P-JAK2 P-STAT3 Control Desialylated Desialylated Control Time (h) Time (h) Courtesy of K Hoffmeister

40 Pharmacological JAK1/2 inhibitors Galactose Ashwell-Morell receptor (AMR) P JAK2 P STAT3 AZD1480 TG BMS P STAT3 Nucleus Thrombopoietin (TPO)

41 Pharmacological JAK1/2 inhibitors Galactose Ashwell-Morell receptor (AMR) JAK2 X STAT3 AZD1480 TG BMS Nucleus X Thrombopoietin (TPO)

42 Does uptake of desialylated platelets by the Ashwell-Morell receptor increase hepatic TPO production in vivo?

43 Mouse strains of platelet clearance by the Ashwell-Morell receptor Control (WT mice) Sialic acid X Galactose Platelet Platelet survival (t1/2) Platelet count Platelet sialic acid content 47 h 1,420 k/µl 100% Baseline clearance AMR deficient (Asgr2 / mice) X X 64 h 2,150 k/µl 60% No clearance Sialyltransferase null (St3gal4 / mice) 18 h 428 k/µl 15% Maximal clearance Courtesy of K Hoffmeister

44 Clearance of desialylated platelets by the AMR correlates with TPO expression in mice Liver TPO mrna expression (fold) Control AMR Deficient (Asgr2 / ) Sialyltransferase null (St3gal4 / ) Courtesy of K Hoffmeister

45 Can uptake of desialylated platelets modulate TPO production in wild type mice? Courtesy of K Hoffmeister

46 Desialylated platelet transfusion stimulates hepatic TPO production in wild type mice Fold Sialic acid Control platelets Galactose Desialylated platelets Asgr2 / Platelet Liver TPO mrna expression Platelet Transfuse St3gal4 / Platelet AMR deficient Sialyltransferase null Wild type Control Liver mrna Time (h) Courtesy of K Hoffmeister

47 Administration of JAK1/2 inhibitors block TPO mrna increase in wild type mice Wild Type JAK inhibitors Transfuse control or desialylated platelets Harvest Livers JAK inhibitors 12h 0h 24h 48h 60h Vehicle Liver TPO mrna expression (fold) Vehicle + JAK inhibitor + JAK inhibitor control platelets desialylated platelets Courtesy of K Hoffmeister

48 Summary Clearance of aging, desialylated platelets by the Ashwell- Morell receptor stimulates TPO production via JAK2-STAT3 signaling. This novel regulatory feedback mechanism of hepatic TPO production has clinical implications, as JAK1/2 inhibitor administration often causes thrombocytopenia in patients with myeloproliferative neoplasms (MPN). Sialic acid Loss of sialic acid: aging pjak2 pstat3 Ashwell Morell Receptor Grozovsky et. al., Nat Medicine. Dec Courtesy of K Hoffmeister

Immunotherapy Approaches in Lymphoma

Immunotherapy Approaches in Lymphoma John Kuruvilla MD FRCPC 1 Disclosures for John Kuruvilla MD Research Support Employee Leukemia and Lymphoma Society US, Rasch Foundation Roche, N/A Consultant Abbvie,