NK/T cell lymphoma Recent advances. Y.L Kwong University Department of Medicine Queen Mary Hospital

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1 NK/T cell lymphoma Recent advances Y.L Kwong University Department of Medicine Queen Mary Hospital

2 Natural killer cell lymphomas NK cell lymphomas are mainly extranodal lymphomas Clinical classification 1. Nasal 2. Non-nasal 3. Disseminated (leukaemia / lymphoma)

3 Typical lesion lethal midline granuloma

4 Typical lesion lethal midline granuloma

5 Non-nasal NK/T-cell lymphomas

6 Cutaneous NK cell lymphoma Arm Scrotum

7 Cutaneous NK cell lymphoma

8 Extranasal NK-cell lymphoma

9 CNS NK cell lymphoma

10 Cutaneous NK cell lymphoma

11 Cutaneous NK cell lymphoma and mosquito bite hypersensitivity

12 Cutaneous NK cell lymphoma, nasal type

13 Cutaneous NK/T cell lymphoma, nasal type Disseminated NK cell lymphoma

14 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

15 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

16 Problems of treatment 1. NK/T-cell lymphomas are radiosensitive. However, about 50% of patients treated with radiotherapy alone will relapse, of whom about half relapse systemically, indicating that the disease is not really localized. Therefore, NK/T-cell lymphoma should never be treated with radiotherapy alone 2. Conventional chemotherapy designed for B cell lymphomas does not work very well for NK cell lymphomas. Anthracyclines have not been shown to be necessary in NK cell lymphomas 3. NK cells express the highest amount of P- glycoprotein, leading to the multidrug resistance phenotype

17 NK/T-cell lymphomas treated by CHOP Chim et al, Blood 2004

18 SMILE protocol for NK cell lymphomas (K. Oshimi) 2 g/m 2 Methotrexate Folinic acid Daily MTX level 1.5g/m 2 Ifosfamide mesna 40mg/d Dexamethasone 100mg/m 2 etoposide 6000u/m 2 /d L-asparaginase G-CSF Days

19 SMILE protocol for NK cell lymphomas (K. Oshimi) 2 g/m 2 Methotrexate Folinic acid Daily MTX level 1.5g/m 2 Ifosfamide mesna 40mg/d Dexamethasone 100mg/m 2 etoposide 6000u/m 2 /d L-asparaginase G-CSF Days

20 SMILE: phase II results

21 SMILE: results outside clinical trial

22 SMILE in 87 cases of NK/T-cell lymphomas Overall survival: newly-diagnosed Kwong et al, Blood 2012

23 Survivals of NK/T-cell lymphomas SMILE (all stages) CHOP (stage I/II)

24 Non MDR related chemotherapy Promace-CytaBOM (III) DHAP (I) SMILE (II)

25 Non MDR related chemotherapy Promace-CytaBOM (III) + RT SMILE (II)

26 Second generation non-mdr dependent regimens Kwong & Tse, Blood 2013

27 Second generation non-mdr dependent regimens Kwong & Tse, Blood 2013

28 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

29 Circulating EBV DNA 1. Plasma EBV DNA 2. Whole blood EBV DNA Cellular EBV DNA + plasma EBV DNA

30 Plasma versus whole blood for EBV DNA Plasma whole blood Conceptual DNA plasma plasma and WBC Origin tumor tumor and EBV + B-cells Contamination none EBV + B-cells PCR competitor Nil WBC genomic DNA Standard WHO none Comparison Quantification per ml variable (per mg DNA) Inter-laboratory possible impossible

31 For quantification of circulating EBV DNA as a monitoring for EBV+ lymphomas Plasma EBV DNA is the suitable starting material Whole blood should not be used

32 Plasma versus PBMNC for EBV DNA

33 Plasma versus PBMNC for EBV DNA

34 Source of positive specimens (%) Plasma versus PBMNC for EBV DNA Positive in PBMC Positive in Plasma Indeterminate Positive in PBMC + Plasma EBV+ disease (N=105) EBV+ disease in CR (N=18) No EBV+ disease (N=402)

35 Quantification of circulating EBV DNA for prognostication and assessment of minimal residual disease

36 Plasma EBV DNA

37 Plasma EBV DNA

38 Presentation EBV DNA for SMILE treated NK/T-cell lymphoma

39 Impact of negative EBV DNA after SMILE (I) on OS Kwong et al Leukemia 2014

40 Impact of dynamic EBV DNA changes on DFS Kwong et al Leukemia 2014

41 Conclusions 1. Presentation EBV DNA reflects tumor load, but does not impact on survivals 2. Negative EBV DNA after SMILE (I) reflects superior response to chemotherapy, and therefore impacts on OS 3. For patients already in CR, nondetectable EBV DNA means optimal suppression of tumor cells, and therefore impacts on DFS

42 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

43 Deauville five-point scale for interim PET 1. No uptake. 2. Uptake mediastinum. 3. Uptake > mediastinum but liver. 4. Uptake moderately increased compared to the liver at any site. 5. Uptake markedly increased compared to the liver at any site or/and new sites of disease.

44 Deauville criteria for end of treatment PET 1. Category 1: score 1, 2, 3 likely to represent complete metabolic response (CMR) 2. Category 2: score 4 with reduction of intensity from baseline, but no new lesions, representing partial metabolic response (PMR) at interim but residual metabolic disease (RMD) at end of treatment 3. Category 3: score 5 with no significant reduction in uptake or new lesions at interim, or score 4 or 5 with increase in uptake in previous foci and/or new FDGavid foci consistent with lymphoma, representing no metabolic response or progressive metabolic disease (NMR/PMD)

45 Role of interim PET/CT in SMILE therapy

46 Role of interim PET/CT in SMILE therapy Khong et al J Nucl Med 2014

47 Role of interim PET/CT in SMILE therapy Multivariate analysis OS Deauville 5-point score P < Multivariate analysis PFS Deauville 5-point score P < 0.001

48 Impact of mid-treatment PET/CT on OS Khong et al J Nucl Med 2014

49 Impact of mid-treatment PET/CT on PFS Khong et al J Nucl Med 2014

50 Impact of end-of-treatment PET/CT on OS Khong et al J Nucl Med 2014

51 Impact of end-of-treatment PET/CT and EBV DNA

52 Combined EBV DNA and PET/CT at end of treatment Prognostic impact Kim et al Lancet Haematol 2015

53 Combined EBV DNA and PET/CT at end of treatment Prognostic impact Kim et al Lancet Haematol 2015

54 EBV DNA and PET/CT scan Interim results should be evaluated Inability to achieve a molecular or radiologic remission is associated with poor treatment outcome Prospective data needed to define what the best approach is for poor interim results

55 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

56 Prognostic factors for ENKT EBV DNA PET/CT KIPI PINK PINK-E

57 Prognostic factors for ENKT EBV DNA PET/CT KIPI PINK PINK-E

58 PINK / PINK-E : prognostication Age Stage Non-nasal type Distant lymph-node involvement Detectable EBV DNA Established and validated with data from non-anthracycline regimens

59 PINK : prognostication OS DFS Kim et al Lancet Oncol 2016

60 PINK : prognostication OS DFS Kim et al Lancet Oncol 2016

61 PINK - E : prognostication OS DFS Kim et al Lancet Oncol 2016

62 PINK - E : prognostication OS DFS Kim et al Lancet Oncol 2016

63 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

64 Concurrent chemotherapy and radiotherapy

65 Survival of patients induced by concomitant chemotherapy and radiotherapy, and consolidated by L-asparaginse containing regimens

66 SMILE in 87 cases of NK/T-cell lymphomas Overall survival: IPI for prognostication P=0.001 Low High Low-Inter High-Inter Kwong et al Blood 2012

67 The outcome of concomitant or sequential chemotherapy and radiotherapy is comparable Concomitant Chemotherapy & Radiotherapy Sequential Chemotherapy & Radiotherapy

68 The outcome of concomitant or sequential chemotherapy and radiotherapy is comparable Concomitant Chemotherapy & Radiotherapy Sequential Chemotherapy & Radiotherapy

69 NK/T-cell lymphoma, CCRT or CT+RT Background 1. RT conventionally used for stage I/II disease 2. Ineffective CT added to RT did not improve outcome 3. Relapse rate of RT alone reaches 50% 4. CCRT gave apparently better results, in the era of CHOP / CHOP-like regimens 5. In the era of L-asparaginase-containing regimens, results of CT much improved 6. Unclear if CCRT has any significant advantage over CT + RT

70 CT, RT or CCRT for stage I / II Objective 1. Evaluate the efficacy of CT + RT in comparison with CCRT Method 1. Retrospective multi-center study 2. Stage I/II patients 3. Different combinations of CT, RT and CCRT 4. All CT regimens were non-anthracycline ones, most containing L-asparaginase

71 CT, RT or CCRT for stage I / II Results 303 patients from 22 participating centers M: 207 F: 96 Stage I: 207 Stage II: 96 CT : 11% RT : 6% CT + RT : 18% CCRT + CT : 57% RT + CT : 3% CCRT : 6%

72 CT, RT or CCRT for stage I / II Kwong et al Ann Oncol 2018

73 CT, RT or CCRT Kwong et al Ann Oncol 2018

74 CT, RT or CCRT Kwong et al Ann Oncol 2018

75 CT, RT or CCRT for stage I / II Kwong et al Ann Oncol 2018

76 CT, RT or CCRT for stage I / II Conclusions 1. When effective CT is used, the results of CT + RT are comparable with CCRT 2. The position of RT in stage I/II patients is not critical, because most patients will have reached a complete response before receiving RT 3. Efforts should be made to eliminate RT from the treatment algorithm

77 Recent advances in NK/T-cell lymphomas 1. Advent of L-asparaginase containing regimens 2. Plasma EBV DNA quantification in monitoring of response 3. PET/CT as an integral part of the management 4. Prognostication of NK/T-cell lymphoma 5. Optimal sequencing of chemotherapy and radiotherapy 6. Immunotherapy of NK/T-cell lymphomas

78 Immunotherapy for NK/T-cell lymphoma CD56 CD30 CD56 Batlevi et al, Nat Rev Clin Oncol 2016

79 Immunotherapy for NK/T-cell lymphoma CD56 CD30 Batlevi et al, Nat Rev Clin Oncol 2016

80 Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016

81 Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016

82 Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016

83 Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016

84 Immunotherapy for NK/T-cell lymphoma Batlevi et al Nat Rev Clin Oncol 2016

85 Case presentation: refractory NKTCL M / 37 Nasal NK/T-cell lymphoma 2007: regional hospital ProMACE-CytaBOM + RT 2013: relapse PIGLETS x : relapse SMILE x 3

86 M / : Massive epistaxis Hemorrhagic shock Aspiration pneumonia Activated factor VII to stop bleeding Tracheostomy to protect airway

87 Case presentation: refractory NKTCL

88 EBV DNA response Pembrolizumab Kwong et al, Blood 2017

89 Targeting of PD1 in NK/T-cell lymphomas Kwong et al, Blood 2017

90 Targeting of PD1 in NK/T-cell lymphomas Kwong et al, Blood 2017

91 Targeting of PD1 in NK/T-cell lymphomas Kwong et al, Blood 2017

92 Targeting of PD1 in NK/T-cell lymphomas CD3 Kwong et al, Blood 2017

93 Targeting of PD1 in NK/T-cell lymphomas CD4 Kwong et al, Blood 2017

94 Targeting of PD1 in NK/T-cell lymphomas CD8 Kwong et al, Blood 2017

95 Targeting of PD1 in NK/T-cell lymphomas EBER Kwong et al, Blood 2017

96 Pseudo-progression during PD1 blockade in NK/T-cell lymphoma Kwong et al, Blood 2017

97 Targeting of PD1 in NK/T-cell lymphomas CASE 2

98 Targeting of PD1 in NK/T-cell lymphomas F / 80 Stage IV NK/T-cell lymphoma CR after L-asparaginase regimen Short CR with disseminated relapse On referral, ECOG score: 4

99 Targeting of PD1 in NK/T-cell lymphomas

100 Targeting of PD1 in NK/T-cell lymphomas

101 Targeting of PD1 in NK/T-cell lymphomas

102 Targeting of PD1 in NK/T-cell lymphomas Nivolumab 40 mg No toxicity in the first cycle Second dose nivolumab 40 mg Tumour lysis syndrome Cytokine release syndrome (with hypofibrinogemia, respiratory impairment)

103 Targeting of PD1 in NK/T-cell lymphomas

104 Targeting of PD1 in NK/T-cell lymphomas All skin lesions disappeared after the tumor lysis syndrome Skin biopsy: complete pathologic remission

105 Targeting of PD1 in NK/T-cell lymphomas Before

106 Targeting of PD1 in NK/T-cell lymphomas Before After

107 Targeting of PD1 in NK/T-cell lymphomas Before

108 Targeting of PD1 in NK/T-cell lymphomas Before After

109 Targeting of PD1 in NK/T-cell lymphomas Before

110 Targeting of PD1 in NK/T-cell lymphomas Before After

111 Targeting of PD1 in NK/T-cell lymphomas H&E CD3 CD4 CD8 EBER pre

112 Targeting of PD1 in NK/T-cell lymphomas H&E CD3 CD4 CD8 EBER pre post

113 Targeting of PD1 in NK/T-cell lymphomas 1. To date, one of the most effective salvage methods for R/R NK/T-cell lymphomas 2. Beware of a. Pseudo-progression b. TLS (in high tumor load cases) C. CRS (in high tumor load cases) 3. Ongoing trials of pembrolizumab and nivolumab 4. Future directions: whether PD1 blockade can substitute RT, and whether PD1 blockade alone is adequate for good-risk patients

114 Recent advances in NK/T-cell lymphomas 1. Frontline chemotherapy should contain L- asparaginase 2. Plasma EBV DNA quantification is useful in disease monitoring. Aim for negative plasma EBV DNA after 2 3 cycles of treatment 3. PET/CT is an integral part of the management. Aim for DS 3 at interim 4. Prognostication of NK/T-cell lymphoma with the PINK / PINK-E scores is needed 5. When effective chemotherapy is used, it does not matter when radiotherapy is used (? even omitted) 6. PD1 blockade is highly effective

115 Acknowledgment NKTSG K. Oshimi, M. Yamaguchi, R. Suzuki ALSG W.S. Kim, S.T. Lim Haematology Team, Queen Mary Hospital

116 Acknowledgement

117 Hematology, Medical Oncology and Hematopoietic stem cell transplantation Queen Mary Hospital, Hong Kong