NK/T cell lymphoma Recent advances Y.L Kwong University Department of Medicine Queen Mary Hospital
Natural killer cell lymphomas NK cell lymphomas are mainly extranodal lymphomas Clinical classification 1. Nasal 2. Non-nasal 3. Disseminated (leukaemia / lymphoma)
Typical lesion lethal midline granuloma
Typical lesion lethal midline granuloma
Non-nasal NK/T-cell lymphomas
Cutaneous NK cell lymphoma Arm Scrotum
Cutaneous NK cell lymphoma
Extranasal NK-cell lymphoma
CNS NK cell lymphoma
Cutaneous NK cell lymphoma
Cutaneous NK cell lymphoma and mosquito bite hypersensitivity
Cutaneous NK cell lymphoma, nasal type
Cutaneous NK/T cell lymphoma, nasal type Disseminated NK cell lymphoma
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
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
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
NK/T-cell lymphomas treated by CHOP Chim et al, Blood 2004
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 1 2 3 4 8 14
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 1 2 3 4 8 14
SMILE: phase II results
SMILE: results outside clinical trial
SMILE in 87 cases of NK/T-cell lymphomas Overall survival: newly-diagnosed Kwong et al, Blood 2012
Survivals of NK/T-cell lymphomas SMILE (all stages) CHOP (stage I/II)
Non MDR related chemotherapy Promace-CytaBOM (III) DHAP (I) SMILE (II)
Non MDR related chemotherapy Promace-CytaBOM (III) + RT SMILE (II)
Second generation non-mdr dependent regimens Kwong & Tse, Blood 2013
Second generation non-mdr dependent regimens Kwong & Tse, Blood 2013
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
Circulating EBV DNA 1. Plasma EBV DNA 2. Whole blood EBV DNA Cellular EBV DNA + plasma EBV DNA
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
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
Plasma versus PBMNC for EBV DNA
Plasma versus PBMNC for EBV DNA
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)
Quantification of circulating EBV DNA for prognostication and assessment of minimal residual disease
Plasma EBV DNA
Plasma EBV DNA
Presentation EBV DNA for SMILE treated NK/T-cell lymphoma
Impact of negative EBV DNA after SMILE (I) on OS Kwong et al Leukemia 2014
Impact of dynamic EBV DNA changes on DFS Kwong et al Leukemia 2014
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
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
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.
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)
Role of interim PET/CT in SMILE therapy
Role of interim PET/CT in SMILE therapy Khong et al J Nucl Med 2014
Role of interim PET/CT in SMILE therapy Multivariate analysis OS Deauville 5-point score P < 0.001 Multivariate analysis PFS Deauville 5-point score P < 0.001
Impact of mid-treatment PET/CT on OS Khong et al J Nucl Med 2014
Impact of mid-treatment PET/CT on PFS Khong et al J Nucl Med 2014
Impact of end-of-treatment PET/CT on OS Khong et al J Nucl Med 2014
Impact of end-of-treatment PET/CT and EBV DNA
Combined EBV DNA and PET/CT at end of treatment Prognostic impact Kim et al Lancet Haematol 2015
Combined EBV DNA and PET/CT at end of treatment Prognostic impact Kim et al Lancet Haematol 2015
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
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
Prognostic factors for ENKT EBV DNA PET/CT KIPI PINK PINK-E
Prognostic factors for ENKT EBV DNA PET/CT KIPI PINK PINK-E
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
PINK : prognostication OS DFS Kim et al Lancet Oncol 2016
PINK : prognostication OS DFS Kim et al Lancet Oncol 2016
PINK - E : prognostication OS DFS Kim et al Lancet Oncol 2016
PINK - E : prognostication OS DFS Kim et al Lancet Oncol 2016
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
Concurrent chemotherapy and radiotherapy
Survival of patients induced by concomitant chemotherapy and radiotherapy, and consolidated by L-asparaginse containing regimens
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
The outcome of concomitant or sequential chemotherapy and radiotherapy is comparable Concomitant Chemotherapy & Radiotherapy Sequential Chemotherapy & Radiotherapy
The outcome of concomitant or sequential chemotherapy and radiotherapy is comparable Concomitant Chemotherapy & Radiotherapy Sequential Chemotherapy & Radiotherapy
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
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
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%
CT, RT or CCRT for stage I / II Kwong et al Ann Oncol 2018
CT, RT or CCRT Kwong et al Ann Oncol 2018
CT, RT or CCRT Kwong et al Ann Oncol 2018
CT, RT or CCRT for stage I / II Kwong et al Ann Oncol 2018
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
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
Immunotherapy for NK/T-cell lymphoma CD56 CD30 CD56 Batlevi et al, Nat Rev Clin Oncol 2016
Immunotherapy for NK/T-cell lymphoma CD56 CD30 Batlevi et al, Nat Rev Clin Oncol 2016
Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016
Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016
Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016
Brentuximab vedotin in NK/T-cell lymphoma Poon & Kwong Ann Hematol 2016
Immunotherapy for NK/T-cell lymphoma Batlevi et al Nat Rev Clin Oncol 2016
Case presentation: refractory NKTCL M / 37 Nasal NK/T-cell lymphoma 2007: regional hospital ProMACE-CytaBOM + RT 2013: relapse PIGLETS x 6 2015: relapse SMILE x 3
M / 37 2016: Massive epistaxis Hemorrhagic shock Aspiration pneumonia Activated factor VII to stop bleeding Tracheostomy to protect airway
Case presentation: refractory NKTCL
EBV DNA response Pembrolizumab Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas CD3 Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas CD4 Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas CD8 Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas EBER Kwong et al, Blood 2017
Pseudo-progression during PD1 blockade in NK/T-cell lymphoma Kwong et al, Blood 2017
Targeting of PD1 in NK/T-cell lymphomas CASE 2
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
Targeting of PD1 in NK/T-cell lymphomas
Targeting of PD1 in NK/T-cell lymphomas
Targeting of PD1 in NK/T-cell lymphomas
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)
Targeting of PD1 in NK/T-cell lymphomas
Targeting of PD1 in NK/T-cell lymphomas All skin lesions disappeared after the tumor lysis syndrome Skin biopsy: complete pathologic remission
Targeting of PD1 in NK/T-cell lymphomas Before
Targeting of PD1 in NK/T-cell lymphomas Before After
Targeting of PD1 in NK/T-cell lymphomas Before
Targeting of PD1 in NK/T-cell lymphomas Before After
Targeting of PD1 in NK/T-cell lymphomas Before
Targeting of PD1 in NK/T-cell lymphomas Before After
Targeting of PD1 in NK/T-cell lymphomas H&E CD3 CD4 CD8 EBER pre
Targeting of PD1 in NK/T-cell lymphomas H&E CD3 CD4 CD8 EBER pre post
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
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
Acknowledgment NKTSG K. Oshimi, M. Yamaguchi, R. Suzuki ALSG W.S. Kim, S.T. Lim Haematology Team, Queen Mary Hospital
Acknowledgement
Hematology, Medical Oncology and Hematopoietic stem cell transplantation Queen Mary Hospital, Hong Kong