Interesting case in lymphoma. Kitsada Wudhikarn, MD Division of Hematology, Department of Medicine Faculty of Medicine, Chulalongkorn University

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1 Interesting case in lymphoma Kitsada Wudhikarn, MD Division of Hematology, Department of Medicine Faculty of Medicine, Chulalongkorn University

2 Eosinophilia Benign reactive etiologies 1. Allergy 2. Infection 3. Secondary to medical condition 4. Medication Hematologic Malignancies with reactive or clonal eosinophilia 1. Hodgkin lymphoma 2. B-cell and T cell NHL 3. AML with inv(16) or t(16;16) 4. AML with t(8;21) 5. MPNs esp CML Myeloid neoplasms associated with PDGFRA, PDFGRB and FGFR1 rearrangement Miscellaneous etiologies 1. CEL NOS 2. Lymphocytic variant HES 3. Paraneoplastic syndromes 4. Idiopathic HES

3 Differential Diagnosis of waxing and waning LAD Non Malignant Reactive Process Chronic/intermittent infection or reactivation Autoimmune Lymphadenopathy Follicular hyperplasia Lymphoma mimicker Kikuchi-Fujimoto syndromes Malignant Lymphoma Low grade lymphoma esp follicular lymphoma Hodgkin lymphoma T cell lymphoma

4 Eosinophilia and Lymphoproliferative disorders Frequency of eosinophilia Clinical HES Mechanism of HE Serum Biomarkers Impact on prognosis Malignant T cell LPD Mycoses Fungoides Sezary Syndromes AITL calcl PTCL-NOS EATL 20-25% (>700/µL) 6.5% (>1500/µL) 32-50% Uncommon Uncommon 2% Rare Advanced disease Rare Rare Rare Rare IL-5, IL-4, IL-13 CCR4 IL-5 CCL11, CCR3, IL-4 IL-5, GATA-3 IL-5 CCL17, CCL22 CCL11, CCL26 N/A CCL17 N/A N/A Negative N/A None Negative N/A N/A Indolent T cell LPD L-HES LyP 100% Rare Majority of cases Rare (FIP1L1+) IL-5, GM-CSF FIP1L1 CCL17 N/A Negative Malignant B cell LPD chl B-ALL/Eo 15% (>500/µL) <1% Rare Frequent (heart) IL-5, GATA-3 t(5;14) w IL-3 CCL17, CCL22 IL-3 Positive (blood) Negative (tumor) Bad if HES Roufosse F et al. Semin Hematol Apr;49(2):138-48

5 Exaggerated mosquito bite reaction EBV associated hypersensitivity Well s Syndromes Hematologic malignancy MSG-specific T cells NK cell help MSG-specific T cells Eosinophil help MSG-specific T cells MSG-reactive B cells Exaggerated reaction to mosquito bites Tatsuno et al. J Dermatol Sci Jun;82(3):145-52

6 Angioimmunoblastic T cell Lymphoma

7 Distribution of T-cell lymphoma Vose J et al. J Clin Oncol Sep 1;26(25):

8 Intlekofer AM and Younes A. Int J Hematol Mar;99(3): Intragumtornchai T et al. Hematol Oncol Feb;36(1):28-36 AITL in Asia Subtype Frequency (%) Worldwide North America Europe Asia Thailand PTCL-NOS AITL ALCL NKTCL ATLL EITL PCALCL HSTCL SPTCL Unclassified

9 Peripheral T cell Lymphoma Cutaneous Extranodal Nodal Leukemic Mycoses fungoides Sezary Syndromes Primary cutaneous CD30+ T cell disorders Primary cutaneous ALCL Primary cutaneous G/D TCL Primary cutaneous CD8+ aggressive epidermotropic Primary cutaneous CD4+ small/medium NK/TCL nasal type Enteropathy associated TCL Hepatosplenic G/D TCL Subcutaneous panniculitis like TCL Systemic EBV+ T-cell childhood LPD Hydroa vacciniforme-like Peripheral T cell Lymphoma-NOS Angioimmunoblastic TCL Anaplastic Large Cell Lymphoma Adult T cell Leukemia T-cell prolymphocytic Leukemia T-cell LGL Leukemia Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press, 2008

10 Clinical Presentation Median age 65 years (60-70) Most pts presented with generalized lymphadenopathy, hepatosplenomegaly & constitutional symptoms Mostly advanced stage at diagnosis but bulk of lymph node usually small Clinical course: Moderate to highly aggressive with some spontaneous regression More than 1/3 with autoimmune presentation Immune cytopenia Rashes Neuropathy Polyarthritis Vasculitis Diagnosis often follows an immune event, such as exposure to a medication, an infection, or an allergic reaction Some patients developed edema, effusion or ascites 60% with bone marrow involvement at the time of diagnosis

11 Clinical and laboratory features of AITL 1975 to 1999 (n=77) 2007 to 2016 (n=556) Thailand (n=55) Gender (Males,%) Median age range Clinical presentation (%) B-symptoms ECOG PS > 1 LDH elevation Advanced stage Low risk IPI (0-1) Areas of involvement (%) Multiple nodal stations Bone marrow Skin rash Laboratory tests (%) Hypereosinophilia Anemia Positive DAT (Coomb s test) Thrombocytopenia Hypergammaglobulinemia NA (Low & Low-Intermediate) Intragumtornchai T et al. Hematol Oncol Feb;36(1):28-36; Lunning MA et al. Blood Mar 2;129(9): NA NA NA NA NA NA NA NA

12 From angioimmunoblastic lymphadenopathy to AITL WHO Classification(s) KIEL Updated REAL : Angioimmunoblastic T cell lymphoma - Clonal cytogenetic abnormalities - Clonal T-cell receptor (TCR) gene rearrangement 1979: Atypical T cells immunoblastic T cell lymphoma 2012: Specific mutational landscape (TET2, IDH2, DNMT3, RHOA : Cell of origin of AITL: T FH Cell 1974: Description of angioimmunoblastic lymphadenopathy with dysproteinemia

13 T FH cells in Human health and diseases Immune deficiencies (Primary, HIV) Autoimmune diseases (SLE, Sjogren s, RA) Lymphoid neoplasms Hodgkin lymphoma Lymphoma derived from T FH cells Tangye SG et al. Nat Rev Immunol Jun;13(6):412-26

14 Nodal T cell lymphoma with follicular helper (TFH) phenotype THF phenotype At least 2 of: PD1, CD10, BCL6, CXCL13, ICOS, SAP and CCR5 Follicular T cell Lymphoma Nodal PTCL with TFH phenotype Angioimmunoblastic T cell Lymphoma

15 Pathologic features of AITL H&E CD3 CD20 CD10 Sensitivity ICOS C-MAF CD21 CXCL13 ICOS PD1 EBER CD23 PD-1 BCL-6 CXCL13 CD10 Specificity CD4+ αβt cells (TFH)

16 Genetic Signature of Mature T cell Lymphoma Morphological diagnosis AITL ALK+ ALCL ALK- ALCL ATLL ENKTL PTCL-NOS Diagnosis of PTCL-NOS (Waste basket) will become less as insight in molecular/genetic signatures continues to improve Iqbal J et al. Blood May 8;123(19):

17 Integrative clinicopathological & molecular analyses of nodal PTCL with TFH phenotype Dobay MP et al. Haematologica Apr;102(4):e148-e151

18 Integrative clinicopathological & molecular analyses of nodal PTCL with TFH phenotype Mutation AITL Nodal lymphomas of TFH cell origin TFH-like PTCL Other TFH-PTCL PTCL-NOS P-value across 4 entities TET2 48% 64% 75% 17% <0.01 DNMT3A 30% 10% 25% 4% 0.02 IDH2 33% 10% 0% 0% <0.001 RHOA (G17V) 58% 57% 60% 0% <1x10-6 F-PTCL TET2 DNMT3A IDH2 RHOA CD28/CTLA4- CD28 ITK-SYK PLCG1 TNFRSF21 Enhanced self-renewal Hematopoietic stem cells T-cell Lineage commitment Malignant transformation T lymphoma Dobay MP et al. Haematologica Apr;102(4):e148-e151

19 Nodal T cell lymphoma with follicular helper (TFH) phenotype Gene fusion ITK-SYK CTLA4-CD28 THF phenotype At least 2 of: PD1, CD10, BCL6, CXCL13, ICOS, SAP and CCR5 Mutations TET2 IDH2 DNMT3A RHOA CD28 Follicular T cell Lymphoma Nodal PTCL with TFH phenotype Angioimmunoblastic T cell Lymphoma

20 Spectrum of B- cell proliferations is broad in AITL From scattered to increased immunoblasts to DLBCL like HRS- like cells may be seen, should not be misdiagnosed as chl or composite EBV positive (more often) or EBV negative Plasma cell proliferation (monotypic or not) Up to one third of AITL show clonal B- cell population: clonality analysis may be misleading CD20/EBER LMP1 Attygalle AD et al. Histopathology Jan;64(2):171-99

21 Spectrum of B- cell proliferations is broad in AITL From scattered to increased immunoblasts to DLBCL like HRS- like cells may be seen, should not be misdiagnosed as chl or composite EBV positive (more often) or EBV negative Plasma cell proliferation (monotypic or not) Up to one third of AITL show clonal B- cell population: clonality analysis may be misleading Attygalle AD et al. Histopathology Jan;64(2):171-99

22 Treatment of AITL Front line therapy Should AILT be treated like PTCL-NOS? Is there an optimal front line regimen? Relapsed disease Is there an optimal agent?

23 Treatment of AITL (or most nodal peripheral T-NHL) Transplant candidate ASCT vs Allo-HSCT Palliative treatment Induction treatment CR/PR Consolidation treatment Relapse Non- Transplant candidate Relapse R/R treatment PD

24 Percent Survival Natural History of peripheral T cell NHL Event Free Survival AITL Others ALK+ ALCL PTCL-NOS ALK- ALCL Months Long term survival approximately 30% Fare worse than aggressive B cell lymphoma except ALK+ ALCL Anthracycline based regimens are still considered the standard of care CHOP most common CR in 17-70% of cases but high risk of relapse 5 yr OS of 38-58% meta-analysis Consolidate remission with high dose therapy and ASCT (phase 2 data) Schmitz N et al. Blood Nov 4;116(18):

25 Probability of survival Probability of survival Survival Outcomes of AITL Overall 0.6 Survival N= N=1207 Disease Specific Survival Time from Dx (years) Time from Dx (years) 2 year OS (%) 5 year DSS (%) ( ) 41.7 ( ) ( ) 46.7 ( ) ( ) 41.6 ( ) ( ) 48.5 ( ) Adverse prognostic factors: Older age, Advanced Stage and Male sex Xu B and Liu P. PLoS One Mar 20;9(3):e92585

26 EFS% EFS% CHOEP in peripheral T cell lymphoma CHOP All patients CHOEP P= Months Months Pts 60 years with normal LDH, etoposide improved improved 3-year EFS IPI > 1 have a poor prognosis and should be considered candidates for clinical trials Exclude ALK+ ALCL CHOP P=0.057 CHOEP Schmitz N et al. Blood Nov 4;116(18):

27 Progression Free Survival Overall Survival Survival Survival Dose adjusted EPOCH for PTCL PFS OS PFS OS 20 0 All patients Years on study 20 0 ( 60 years old) Years on study AITL PTCL-NOS P= Years on study PTCL-NOS AITL P= Years on study Maeda Y et al. Haematologica Dec;102(12):

28 R-CHOP in Peripheral T cell NHL: GELA Interim CT Newly diagnosed PTCL R-CHOP + IT MTX q 3 weeks x 4 cycles R-CHOP q 3 weeks x 4 cycles 4 wk Follow up CT #1 3 mo Follow up CT #2 Hypothesis: Disruption of putative B-T interactions and/or depletion of the EBV reservoir could improve the clinical outcome produced by conventional chemotherapy Delfau-Larue MH et al. Haematologica Oct;97(10):

29 Probability of survival Probability of survival R-CHOP in Peripheral T cell NHL: GELA PFS (months) OS (months) Not enough evidence that rituximab improved outcome of PTCL EBV viral load was associated with survival outcome Delfau-Larue MH et al. Haematologica Oct;97(10):

30 Probability of survival R-CHOP in Peripheral T cell NHL: GELA EBV < 100/µg EBV > 100/µg P= PFS (months) Not enough evidence that rituximab improved outcome of PTCL EBV viral load was associated with survival outcome 42 Delfau-Larue MH et al. Haematologica Oct;97(10):

31 PET in PTCL PET-CT improves accuracy of staging of PTCL as per Lugano Classification Change of stage/treatment infrequent End of treatment PET variably prognostic because of poor outcome Interim PET-CT scan results variable depending upon parameter Deauville score Total metabolic tumor volume No data to support altering treatment on basis of interim scan Better techniques in development to improve PET prediction

32 Novel targets for AITL Molecular defined AITL: Oncogenic pathways NFKB, TGFB and IL-6 signaling identified Iqbal J et al. Blood Rev Mar;30(2):89-100

33 Novel targets for AITL Iqbal J et al. Blood Rev Mar;30(2):89-100

34 Upfront treatment clinical trial in PTCL Regimen Phase N CR/PR (%) Survival outcomes Grade 3-4 toxicities CHOP-based combinations Bevacizumab+CHOP II 39 49/41 1-yr PFS/OS 44/NR Bortezomib+CHOP II 46 65/9 2-yr PFS/OS 37/52% ANC 41%, Everolimus+CHOP II 30 57/33 2-yr PFS/OS 33/70% ANC 80%, Plt 60% Romidepsin+CHOP Ib/II 37 51/17 30-mo PFS/OS 41/71% ANC 89%, Plt 78% Belinostat+CHOP Ib 23 72/17 NR ANC 26%, Hb 22% CEOP alternate with pralatrexade Non-anthracycline combinations II 33 52/18 2-yr PFS/OS 39/60% GVPM II 26 23/15 2-yr PFS/OS 14/36% ANC 45%, Hb 24% GPM II 44 43/NA 2-yr PFS/OS 39/65% GPP+Thalidomide II 52 52/15 2-yr PFS/OS 57/71% Myelosuppression 44% Yi JH et al. F1000Res Dec 12;6:2123

35 Overall Survival Progression Free Survival ASCT in AITL: EBMT Experience yr OS 67% 5-yr OS 59% yr PFS 55% 5-yr PFS 38% Time after ASCT (mo) Time after ASCT (mo) N=146 (101 Front-line); 33% CR, 36% PR at time of ASCT. Median age 53 years Median FU 31 months TBI containing regimens with less relapse after ASCT Kyriakou et al. J Clin Onc 2008

36 Progression Free Survival Overall Survival ASCT in AITL: EBMT Experience CR: 3-yr 80% 0.6 CR (n=70): 3-yr 58% Chemosens (n=56) 0.4 Chemosens 0.2 Chemoref (n=20) 0.2 Chemoref Time after ASCT (months) Time after ASCT (months) Most important predictive factor for good outcome: CR at transplantation Kyriakou et al. J Clin Onc 2008

37 Probability (%) Upfront ASCT consolidation in PTCL: LYSA group P= P= ASCT ASCT No ASCT 0.2 No ASCT Progression Free Survival (Years) Overall Survival (Years) Fossard G et al. Ann Oncol Mar 1;29(3):

38 AITL Summary of OS Older Studies (Before 2000) % OS Meta-analysis 5-years = 30 Internation T cell Project 5-years = 33 Recent Studies (After 2000) % OS SEER (mainly CHOP) 3 year 33 RCHOP (GELA) 3 year 33 CHOEP 3 year 67.5 CHOEP + ASCT 3 year 55 Bortezomib + CHOP 3 year 60 Bevacizumab + CHOP 2 year 55 ASCT in CR 4 year 60 AlloHSCT with chemosensitive disease 3 year 81

39 Cumulative probability Outcome of AITL after failing first line treatment AITL NKTCL ALCL+ PTCL-NOS Follow up (months) ALCL- Bellei M et al. Haematologica Jul;103(7):

40 Novel drugs in R/R peripheral T cell Lymphoma PTCL -NOS Overall Response Rate by common subtypes Pralatrexate Romidepsin Belinostat Brentuximab vedotin Lenalidomide Alisertib Mogamulizumab 31% 29% 23% 33% AITL 8% 30% 46% 54% ALCL 29% 24% 15% 86% Horwitz S et al. Blood 2014 Lunning WA and Vose JM. Blood Mar 2;129(9): Bachy E and Coiffier B. Blood May 15;123(20):

41 Cyclosporine Experience in AITL Level not monitored Responder CSA maintenance AITL (n=12) CSA induction mg PO bid for 6-12 months 3-5 mg/kg PO bid x 6-8 wks gradually taper by mg q 1-3 wks Non- Responder High or High Intermediate IPI, age years old ORR (8/12): 66% Duration of response months (9 mo) most response by 4-6 weeks Advani R et al. Leuk Lymphoma Mar;48(3):521-5

42 Treatment of AITL or most nodal T cell NHL PTCL-NOS or AITL Clinical trials CHO(E)P 4-6 cycles Younger, fit patients Transplant ineligible ASCT Relapse or progressive diseases Intensive chemotherapy Single agent therapy Allogeneic HSCT Clinical trials vs Palliative care

43 Conclusion Clinical trial should always be the first choice if available Outcomes of AITL with novel agents in combination with chemo in front line awaited Future challenges: Identifying subsets who may benefit from maintenance strategy Are there subsets where chemotherapy not required? Combinations of targeted agents BV/HDAI/Len Need a trial of ASCT vs no ASCT

44 Thank you for your attention