T-cell Lymphomas: Diagnosis and New Agents. Mary Jo Lechowicz Thursday, July 27 Debates and Didactics in Hematology and Oncology

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1 T-cell Lymphomas: Diagnosis and New Agents Mary Jo Lechowicz Thursday, July 27 Debates and Didactics in Hematology and Oncology 1

2 Mature T and NK-cell neoplasms in the WHO Classification 2016 revision T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK cells Aggressive Nk-cell leukemia Systemic EBV+ T-cell lymphoma of childhood Hydroa vacciniforme-like lymphoproliferative disorder Adult T-cell leukemia/lymphoma Extranodal NK-/T-cell lymphoma, nasal type Enteropathy--associated T-cell lymphoma Monomorphic epitheliotropic intestinal T-cell lymphoma Indolent T-cell lymphoproliferative disorder of the GI tract Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneious CD30+ T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous γδ T-cell lymphoma Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous acral CD8+ T-cell lymphoma Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Follicular T-cell lymphoma Nodal T-cell lymphoma with T-follicular helper phenotype Anaplastic large-cell lymphoma, ALK+ Anaplastic large-cell lymphoma, ALK- Breast implant-associated anaplastic large-cell lymphoma Swerdlow SH, et al. Blood. 2016;127(20):

3 Highlights of WHO 2016 revision for T cell lymphomas T-cell large granular lymphocytic leukemia New subtype Stat3 and Stat5B in the subset Stat 5b associated with more aggressive disease Systemic EBV+ T-cell lymphoma of childhood Changed to a lymphoma due to clinical course As to ensure distinction from chronic active EBV Enteropathy--associated T-cell lymphoma (EATL) Previously EATL type 1 Associated with celiac disease Monomorphic epitheliotropic intestinal T-cell lymphoma Formerly EATL type II Specific nature and no association with celiac disease Hydroa vacciniforme-like lymphoproliferative disorder Now a lymphoproliferative disorder because of relationship to EBV infection and wide range of clinical course Indolent T-cell lymphoproliferative disorder of the GI tract New entity Indolent with superficial monoclonal intestinal T cell infiltrate Swerdlow SH, et al. Blood. 2016;127(20):

4 Highlights of WHO Classification 2016 revision for T cell Lymphoma Lymphamotoid papulosis New subtypes similiar clinical behavior Different path features Primary cutaneous γδ T-cell lymphoma Important to exclude other entities Primary cutaneous acral CD8+ T-cell lymphoma New provisional entity Originating in the ear Primary cutaneous CD4+ small/medium T- cell lymphoproliferative disorder Provisional No longer a lymphoma Limited clinical risk Peripheral T-cell lymphoma, NOS Starting to recognize subtypes based on molecular Not routine yet Nodal T-cell lymphoma with T-follicular helper phenotype Umbrella term for TFH phenotype AITL, Follicular T cell lymphoma, and other Overlapping molecular abnormal may impact treatment Anaplastic large-cell lymphoma, ALK- Definitive entity Prognostic implications 6p25 rearrangements at IRF4/DUSP22 locus Breast implant-associated anaplastic largecell lymphoma Provisional entity distinguish from other Alk- Usually non invasive with excellent outcome Swerdlow SH, et al. Blood. 2016;127(20):

5 Comparison of Referral and Expert Diagnoses Among the Major Categories of Noncutaneous Disorders (N=31,910) Jan 2010 through Dec 2013 Lymphopath Network reviewed 42,145 samples 36,920 newly diagnosed mature lymphomas Diagnostic change between referral and expert occurred in19.7% of patients Estimated impact on patient care 17.4% Significantly higher with provisional diagnosis for second opinion 37.8% compared to sent with formal diagnosis 3.7% Laurent C, et al. J Clin Oncol. 2017;35(18):

6 Comparison of Referral and Expert Diagnoses Among the Major Categories of Noncutaneous Disorders (N=31,910) Major Changes with potential impact in patient care in 5,553 which is 88.3% of changes and 17.4% of samples Category A: Misclassification of lymphoma subtype 2,592 specimens and 41.3% of changes in 8.12% of samples Category B: Malignant to benign and vice versa 466 specimens and 7.4% changes and 1.46% of all samples Category C: Lymphoma to other malignancy and vice versa 192 specimens and 3% changes and 0.6% of all samples Category D: Unclassified lymphoma to classified lymphoma 2303 of samples and 36.6% of changes and 7.22% of samples Minor Changes 732 without impact in pt care in 732 samples (11.7% changes) and 2.3% samples overall Laurent C, et al. J Clin Oncol. 2017;35(18):

7 Comparison of Referral and Expert Diagnoses Among the Major Categories of Noncutaneous Disorders (N=31,910) Main Categories PTCLs Overall Concordance Number % AITL 429/ PTCL-NOS 309/ ALK+ ALCL 130/ ALK- ALCL 69/ Extranodal NKTCL 71/ EATL 49/ ATLL 23/49 47 T-LGL 29/34 85 HSTL 14/17 82 The 4,289 patients sent without diagnosis have been excluded. The concordance rate (number and %) was established as the number of patients of each lymphoma subtype with the same diagnosis from both the referral and expert pathologists among the total number of that subtype according to expert review. AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; EATL, enteropathy-associated T- cell lymphoma; HSTL, hepatosplenic T-cell lymphoma; NKTCL, natural killer T-cell lymphoma; NOS, not otherwise specified; PTCL, peripheral T-cell lymphoma; T-LGL, T-0cell large granular lymphocytic leukemia Laurent C, et al. J Clin Oncol. 2017;35(18):

8 Genetic Alterations of Diagnostic Use and/or Therapeutic or Prognostic Value in Routine Clinical Practice in Select Natural Killer- and T-cell Neoplasms Disease Subtype Genes** Frequency (%) Normal function Technology used to detect Prognostic marker*** Genotype-directed therapies ALCL ALK rearrangement DUSP22/IRF4 rearrangement TP63 rearrangement 100% of ALK+ ALCL Kinase FISH Favorable ALK inhibitors 30% of ALK-ALCL Phosphatase FISH Favorable 8% of ALK-ALCL Tumor suppressor FISH Adverse STAT3 38% of ALK-ALCL JAK=STAT signaling intermediate Sequencing JAK/STAT inhibitors AITL/PTCL RHOA 67/18 GTPase Sequencing IDH2 ~13/0 Α-KG hydroxylase in TCA cycle Sequencing Trials of mutant IDH2 inhibitors TET2 ~70/30 DNA hydroxymethylation Sequencing Trials of hypomethylating agents DNMT2A ~23/12 DNA methyltransferase Sequencing Other T/NK lymphoma STAT3 Up to 70% in LGL, 10% in GD-TCL JAK-STAT signaling intermediate Sequencing JAK/STAT inhibitors STAT5B Up to 35% in GD-TCL JAK-STAT signaling intermediate Sequencing Adverse in LGL JAK/STAT inhibitors SETD2 UP to 90% in MEITL and 25% in GD-TCL H3K36 tri-methyltransferase Sequencing PLCγ 15% in PTCL NOS Component of TCR pathway Sequencing PLCγ inhibitors **Mutations in gene names in bold are of diagnostic value. ***Those genes left blank do not have clear prognostic relevance currently. Taylor J, et al. Blood Jun 9 [Epub ahead of print]. 8

9 Proportion The Aggressive Peripheral T-Cell Lymphoma: 2015 Test P< Time Censor Fail Total Median PTCL-NOS Anaplastic large cell lymphoma, ALK Anaplastic large cell lymphoma, ALK Angioimmunoblastic T-cell lymphoma Nasal NK/T-cell lymphoma NK/T-cell lymphoma, nasal type Hepatosplenic T-cell lymphoma Enteropathy-type T-cell lymphoma Survival of the major subtypes of PTCL [Color figure can be viewed on wileyonlinelibrary.com] Armitage JO. Am J Hematol. 2017;92(7):

10 Novel therapies approved for relapsed/refractory peripheral T-cell lymphomas Approved Single- Agent Therapies Indications Mechanism of Action Outcomes (ORR, CR, DOR) Belinostat PTCL HDAC inhibitor 26%, 11%, 13.6 months Chidamine (approved only in China) Brentuximab vedotin PTCL HDAC inhibitor 28%, 14%, 9.9 months ALCL Α-CD30 linked to auristatin (antitubulin agent) Pralatrexate PTCL DHFR/thymidylate synthase inhibitor 86%, 57%, 13.2 months 29%, 11%, 10.1 months Pivotal Trials O Connor et al, 2015 Shi et al, 2015 Pro et al, 2012 O Conner et al, 2011 Romidepsin PTCL HDAC inhibitor 25%, 15%, 28 months 38%, 18%, 8.9 months Coiffier et al, 2014 Peikarz et al, 2011 Marchi E, et al. Hematol Oncol Clin North Am. 2017;31(2):

11 Treatments on the Horizon 11

12 Fenretinide Activity of synthetic retinoid, N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) Cytotoxicity from p53-and caspase-independent apoptosis and/or nonapoptotic mechanisms independent of classic retinoid receptors (Pozoni 1995, Clifford 1999) Tried in PO form now in Phase 1 IV form Mohrbacher AM, et al. Clin Cancer Res.2017 Apr 18 [Epub ahead of print]. 12

13 Fenretinide Phase 1 IV formulation Fentretinide delivered by continuous infusion days 1-5 of 21 day cycle 29 pts previously treated 3 leukemias, 11 B cell and 14 T cell lymphomas, or 1 MM enrolled and received drug Median 2 cycles per pt Toxicity Grade 3-4 thrombocytopenia, neutropenia, anemia, Grade 3-4 hypertriglyceridemia Grade 2 pancreatitis Mohrbacher AM, et al. Clin Cancer Res.2017 Apr 18 [Epub ahead of print]. 13

14 Fenretinide Phase 1 IV formulation 11 patients responded PTCL (9pts) 2 CRs PFS 68+ months 2 uprs PFS 5 months 5 SD 2-12 cycles Conclusion: Higher levels with IV Acceptable toxicity Go on to phase II for relapsed refractory PTCL Mohrbacher AM, et al. Clin Cancer Res.2017 Apr 18 [Epub ahead of print]. 14

15 Fenretinide Mohrbacher AM, et al. Clin Cancer Res Apr 18 [Epub ahead of print]. 15

16 Mogamulizumab Defucosylated humanized Anti-CCR4 antibody Makita S, et al. Expert Opin Biol Ther Jun 24 [Epub ahead of print]. 16

17 Mogamulizumab Phase 2 Mogamulizumab (1.0 mg/kg) IV once per week x 8 weeks Relapsed CCR4-positive PTCL or CTCL The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Ogura M, et al. J Clin Oncol. 2014;32(11):

18 Phase 2 Results 38 pts enrolled, 37 pts received mogamulizumab. Responses: ORR 13 of 37 patients (35%; 95% CI, 20% to 53%) 5/37 (14%) CR Median PFS was 3.0 months (95% CI, 1.6 to 4.9 months) Median OS was not reached for entire population, 14.2 months for PTCL Most common AEs were hematologic events, infusion reactions, pyrexia, and skin disorders Ogura M, et al. J Clin Oncol. 2014;32(11):

19 Dual PI3K δ/γ Inhibitor RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency for both isotypes Dose escalation study of RP6530 in 11 pts with mature T-cell neoplasms 3+3 design two expansion cohorts: 20 pts with PTCL 20 pts with CTCL Oki Y, et al. Blood. 2016;128: Abstract

20 Dual PI3K δ/γ Inhibitor 11 pts (6 PTCL and 5 CTCL) Enrolled at three dose levels: 200 mg BID, 400 mg BID and 800 mg BID ECOG performance status score was 0/1/2 in 10/1/0 pts Mean age 68 yrs (range 52-76) Median of 3 (range: 3-6) prior treatment regimens 5 pts had refractory disease 6 relapsed on prior treatments Oki Y, et al. Blood. 2016;128: Abstract

21 Dual PI3K δ/γ Inhibitor 52 non-serious adverse events: 41 Grade 1/2 and 11 Grade 3/4. Most common AEs: mild vomiting (18%), diarrhea (18%), fatigue (18%), and rash (18%). No Grade 3/4 adverse events were deemed related to RP6530 except for ALT/AST elevation in one pt No pt stopped treatment due to a safety issue Oki Y, et al. Blood. 2016;128: Abstract

22 Dual PI3K δ/γ Inhibitor Results Five pts evaluated for responses at Cycle 3, Day1 Two pts (1 PTCL and 1 CTCL) with PR (40%) that were ongoing >5 months Three pts SD lasting for >3 months (60%) Three pts rapid PD during first cycle, and discontinued treatment prematurely Oki Y, et al. Blood. 2016;128: Abstract

23 Treatments on the Horizon Alisertib Oral aurora kinase inhibitor Bendamustine Alkylating Agent Crizotinib and Sorifenib Alk inhibitors Plitidepsin Ibrutinib Avelumab Anti-PDL-1 antibody Sorafenib Bortezomib and Azacitidine Nivolumab Lenalidomide 23

24 Studies Open at Emory 24

25 Acknowledgements Patients Organizers Lymphoma Research team Lymphoma Clinical team Division of BMT 25