Hematologische tumoren hoever is IO therapie? Monique Minnema, hematoloog UMC Utrecht Cancer Center 2 de multidisciplinair IO symposium

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1 Hematologische tumoren hoever is IO therapie? Monique Minnema, hematoloog UMC Utrecht Cancer Center 2 de multidisciplinair IO symposium

2 Vraag 1: Behandelt u patiënten met Morbus Hodgkin? 1. ja 2. nee

3 Vraag 2: Wordt in uw ziekenhuis allogene stamceltransplantatie toegepast? 1. ja 2. nee

4 Wat hebben we bereikt? Hematologie : bakermat van de immuuntherapie allogene stamcel/beenmerg transplantatie - CAR- T cells (Prof Kersten) - Blinatumumab; - Voorlopige goedkeuring EMA 2015

5 Blinatumomab - bispecifieke T cell-engager (BiTE) antistof - connector - indicatie: volwassenen recidiverende of refractaire precursor-b acute lymfoblasten leukemie (ALL), Philadelphiachromosoom-negatief

6 Figure 3. Kaplan-Meier curves for relapse-free survival (A), overall survival (B), Safety and activity of blinatumomab for adult patients with relapsed or refractory B- precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study, Lancet Oncology 2015

7 Checkpoint inhibitors - Nivolumab - Pembrolizumab - Ipilimumab

8 Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study JCO, 2016,

9 Diagnose; Identificatie van Reed-Sternberg cellen in een mixed inflammatory achtergrond 20% 30% zijn EBV+ Behandeling: - Multi chemotherapie - Radiotherapie Zeer succesvol! Curatie 80% eerste lijn Classical Hodgkin Lymphoma Recidief; Autologe SCT Brentuximab-Vedotin (anti CD30-MMAE) Allogene SCT Reed-Sternberg cell in an extensive inflammatory background

10 PD-L1 Expressie in chl 1. 87% (33 of 38 cases) of primary chl show PD-L1 expression by the Reed-Sternberg cells 2. 11% (7 of 66 cases) of primary non-hodgkin lymphomas show PD- L1 expression by the neoplastic B-cells NHL Chen BJ et al. Clin Cancer Res. 2013;19:

11 Chromosoom 9p24.1 mutaties in 97% chl 9p24.1/PD-L1/PD-L2 mutaties verhogen de aanwezigheid van de PD-1 liganden Roemer M et al. JCO; Apr 11, 2016.

12 Mechanismen van PD-1 Ligand Expressie in chl 1. Genetics 2. STAT Signaling 3. Viral Signaling CD274 (PD-L1) PDCD1LG2 (PD-L2) JAK2 Cytokine pstats EBV LMP1 There are multiple, reinforcing mechanisms to drive PD-1 ligand expression in chl PD-1 Ligand Green MR et al. Clin Cancer Res. 2012;18(6):

13 ORR=87% ORR=objective response rate; PD-1=programmed death receptor-1. Ansell S et al. N Engl J Med. 2015;372:

14 Checkmate 205 studie Multi cohort fase II studie A. Recidief Hodgkin na behandeling Auto-SCT en na Brentuximab-vedotin B. Recidief Hodgkin na Auto-SCT maar Brentuximab naïef C. Recidief Hodgkin na behandeling Auto-SCT en ooit Brentuximab D. Newly diagnosed advanced stage (niet in NL) Exclusie o.a. Na allogene SCT Auto immuunziekten > 10 mg prednison

15 Checkmate 205 studie Behandeling: Nivolumab 3 mg/kg elke 2 wk tot Ziekte progressie; per ; doorgaan indien kliniek goed Toxiciteit Patiënt verzoek Evaluatie PET- CT scans vgl Lugano criteria

16 N = 80, ORR 66,3% Median FU 8.9 mnd Lancet oncology july 2016

17 Relatie PD-L1 expressie & respons

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19 Onderdeel Keynote 013 studie - Myelodysplastic Syndrome, Multiple Myeloma, Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Primary Mediastinal B-Cell Lymphoma,

20 Methods Phase 1b multicenter, multi-cohort trial in patients with hematologic malignancies Pembrolizumab 10 mg/kg q2w was administered to patients with chl previously treated with brentuximab vedotin (BV) who had relapsed after (71%), refused, or were ineligible for ASCT N=31 Exclusion AIZ, allo-sct < 5 jaar Study objectives included safety, rate of CR, and ORR Median follow-up 9.7 months

21 KEYNOTE 013: Pembrolizumab in Relapsed/Refractory chl Results Safety (most common treatment-related adverse events) Percentage of Patients (n=31) Hypothyroidism (16%) Diarrhea (13%) Nausea (13%) Pneumonitis (10%) ORR n, (%) 20 (65%) (90% CI, 48-79) Complete remission 5 (16%) Partial remission 15 (48%) Stable disease 7 (23%)

22 Conclusie 1. PD-L1/PD-L2 toename zijn typisch bij klassiek Hodgkin Lymfoom en geassocieerd met PD-L1 en PD-L2 expressie door Reed Sternberg cellen 2. JAK2 copy gain en toename JAK-STAT signaling, en EBV infectie geven additionele mechanismen voor PD-L1 expressie in RS cellen 3. PD-1 blockade wordt goed getolereerd in fase I/II trials, en lijkt een effectieve behandeling voor patienten met een recidief Hodgkin Lymfoom met een respons percentage van ongeveer 65% 4. FDA goedkeuring May 17, A new Warning and Precaution was issued for complications of allogeneic HSCT after nivolumab. Transplantrelated deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions 5. Geen EMA goedkeuring

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24 Ipilimumab na allogene SCT muis model geen inductie graft versus host disease itt PD-1 remmers Patiënten; - > 3 mnd na allogene SCT - recidief, progressie of persistent leukemie, lymfoom, myeloom, MDS of MPN - geen immuun suppresiva - geen VG met gr III of IV GvHD - T cel chimerisme > 20% donor Therapie: 3 10 mg/kg, 4 giften, elke 3 wk, maintenance 5 giften elke 12 wk totaal 28 patienten, median time vanaf allo; 675 dg ( )

25 Adverse Events and Outcomes of Treatment. 4 6 Davids MS et al. N Engl J Med 2016;375:

26 Leukemia cutis

27 Conclusie: IO therapie zeer geschikt ook voor haem maligniteiten Uniek micro-environment belangrijk Hodgkin Lymfoom prototype voor Checkpoint inhibitor therapie? Stimulatie polyklonale T cellen post allogene SCT met risico s