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Diagnosis and Evidence-Based Management of T-Cell Lymphoma

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Diagnosis and Evidence-Based Management of
T-Cell Lymphoma
Aaron Goodman, MD
Hematologist/Oncologist
Associate Professor o...

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Provided by i3 Health
ACCREDITATION
i3 Health is accredited by the ACCME to provide continuing medical education for physi...

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Disclosures
Aaron Goodman, MD
Advisory board or panel: Seagen, EUSA Pharma
Speaker’s bureau: Seagen, EUSA Pharma
Consultan...

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Diagnosis and Evidence-Based Management of T-Cell Lymphoma

  1. 1. Diagnosis and Evidence-Based Management of T-Cell Lymphoma Aaron Goodman, MD Hematologist/Oncologist Associate Professor of Medicine UC San Diego Health
  2. 2. Provided by i3 Health ACCREDITATION i3 Health is accredited by the ACCME to provide continuing medical education for physicians. i3 Health designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. i3 Health is accredited with distinction as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation. A maximum of 1.0 contact hour may be earned by learners who successfully complete this nursing continuing professional development activity. INSTRUCTIONS TO RECEIVE CREDIT An activity evaluation link will be available at the conclusion of this activity. To claim credit, you must submit a completed evaluation form at the conclusion of the program. Your certificate of attendance will be emailed to you in approximately 2 weeks for physicians and nurses. UNAPPROVED USE DISCLOSURE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. DISCLAIMER The information provided at this CME/NCPD activity is for continuing education purposes only and is not meant to substitute for the independent medical/clinical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. COMMERCIAL SUPPORT This activity is supported by an independent educational grant from Seagen.
  3. 3. Disclosures Aaron Goodman, MD Advisory board or panel: Seagen, EUSA Pharma Speaker’s bureau: Seagen, EUSA Pharma Consultant: Seagen, EUSA Pharma i3 Health has mitigated all relevant financial relationships
  4. 4. Learning Objectives TCL = T-cell lymphoma. Assess guideline recommendations for the diagnostic workup of TCL Evaluate emerging efficacy and safety data on novel therapies for newly diagnosed and relapsed/refractory TCL Apply strategies for optimizing the safety and tolerability of novel and established TCL therapies
  5. 5. Case Study 1: Mr. JM Image courtesy of Aaron Goodman, MD. LAD = lymphadenopathy; PTCL, NOS = peripheral TCL, not otherwise specified; CD30 = cluster of differentiation 30; PET/CT = positron emission tomography/computed tomography; CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone. 78-year-old male presents with fevers and LAD above and below the diaphragm A nodular rash on his extremities is also noted Biopsy of a nodule reveals PTCL, NOS CD30 labels 20% of the atypical cells PET/CT with LAD above and below the diaphragm, cutaneous disease, marrow involvement, spleen, and lungs How would you treat? A. CHOP B. Brentuximab vedotin + CHP C. Pralatrexate D. Alemtuzumab
  6. 6. Case Study 1: Mr. JM Image courtesy of Aaron Goodman, MD. LAD = lymphadenopathy; PTCL, NOS = peripheral TCL, not otherwise specified; CD30 = cluster of differentiation 30; PET/CT = positron emission tomography/computed tomography; CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone. 78-year-old male presents with fevers and LAD above and below the diaphragm A nodular rash on his extremities is also noted Biopsy of a nodule reveals PTCL, NOS CD30 labels 20% of the atypical cells PET/CT with LAD above and below the diaphragm, cutaneous disease, marrow involvement, spleen, and lungs How would you treat? A. CHOP B. Brentuximab vedotin + CHP C. Pralatrexate D. Alemtuzumab
  7. 7. Peripheral TCL
  8. 8. Peripheral T-Cell Lymphoma (PTCL): Introduction NK = natural killer cell; PS = performance status; LDH = lactate dehydrogenase; ALK = anaplastic lymphoma kinase; ALCL = anaplastic large cell lymphoma; OS = overall survival. Vose et al, 2008; International Non-Hodgkin’s Lymphoma Prognostic Factors Project, 1993; Gallamini et al, 2004. PTCL is a heterogeneous group of mature, post-thymic, T-cell, and NK- cell lymphoproliferative disorders 15%-20% of aggressive lymphomas and 5%-10% of NHLs Risk factors for poor outcome include advanced age, stage III-IV disease, >1 extranodal site, PS ≥2, and elevated serum LDH With the exception of ALK-positive ALCL, all PTCL subtypes have poor OS with standard therapies Molecular characterization has led to identification of subtypes with different prognoses and has contributed to discovery of novel pathway- directed therapies
  9. 9. T-Cell Differentiation and Function FDC = follicular dendritic cell; TFH = follicular helper T cell; AG = antigen. Jaffe et al, 2008.
  10. 10. Population Subsets of the Cells TH = T helper; IFN = interferon; HTLV1 = human T-lymphotropic virus type 1; TGF = tumor growth factor; CXCL = chemokine (C-X-C motif) ligand; IL = interleukin. de Leval & Gaulard et al, 2014. Cells and Corresponding T-Cell Lymphomas TBX 21 T-bet GATA3 BCL6 FOXP3 TH1 TH2 THF Treg IFN-g IL4 IL5 IL13 IL21 CXCL13 TGF-β IL10 Subset of PTCL, NOS Subset of PTCL, NOS Poor overall survival Angioimmunoblastic T-cell lymphoma AdultT-cell lymphoma/leukemia (HTLV1)
  11. 11. WHO Classification 2016 Swerdlow, et al, 2016; Swerdlow et al, 2017. Gene expression profiling (GEP) Led to molecularly defined groups of PTCL Copy number variation (CNV) Next-generation sequencing (NGS) Integration of data Mature T-Cell and NK/T-Cell Lymphomas T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK cells Aggressive NK-cell leukemia Epstein-Barr virus (EBV)–positive T-cell lymphoproliferative diseases of childhood Chronic active EBV infection, cutaneous Chronic active EBV infection, systemic Hydroa vacciniforme-like lymphoma Severe mosquito bite hypersensitivity Systemic EBV-positive T-cell lymphoma of childhood 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 gastrointestinal tract Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like-T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD-30-positive T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous acral CD8-positive T-cell lymphoma Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Follicular T-cell lymphoma Anaplastic large cell lymphoma, ALK-positive Anaplastic large cell lymphoma, ALK-negative Breast implant-associated anaplastic large cell lymphoma
  12. 12. TCL Entities: WHO 2017 PLL = prolymphocytic leukemia; LGL = large granular lymphocytic; LPD = lymphoproliferative disorder; MEITL = monomorphic epitheliotropic intestinal TCL; GI = gastrointestinal; SC = subcutaneous; AITL = angioimmunoblastic TCL; MF = mycosis fungoides; SS = Sézary syndrome. Jiang et al, 2017; Swerdlow et al, 2016; Siaghani & Song, 2018. Leukemic  T-cell PLL  T-cell LGL leukemia  Chronic LPDs of NK cells  Aggressive NK-cell leukemia  ATLL  Systemic EBV- positive TCL of childhood  Hydroa vacciniforme-like lymphoproliferative disorder Nodal  PTCL-NOS  AITL  Follicular TCL  Nodal PTCL with TFH phenotype  ALCL, ALK-positive  ALCL, ALK-negative  Breast implant– associated ALCL Extranodal  Extranodal NK/TCL, nasal type  Enteropathy- associated TCL  MEITL  Indolent T-cell proliferative disorder of the GI tract  SC panniculitis-like TCL  Hepatosplenic TCL Cutaneous  MF and SS  Primary cutaneous CD30-positive T-cell LPD  Primary cutaneous γδ TCL  Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic TCL  Primary cutaneous acral CD8-positive TCL  Primary cutaneous CD4-positive small/medium Most common in US and Europe Rare/provisional
  13. 13. Nodal PTCLs Jiang et al, 2017; Swerdlow et al, 2016. 3 main group of diseases, but in some cases with overlapping features Differential diagnosis with other lymphomas and reactive conditions Expert pathology review is critical Increasing role of genetic testing and molecular profiling Identification of distinct subgroups “Nodal” subtypes Exclusion diagnosis ALCL AITL PTCL -NOS
  14. 14. PTCL Not Otherwise Specified (PTCL-NOS) Image courtesy of Aaron Goodman, MD. TCR = T-cell receptor; DD = differential diagnosis. Maura et al, 2016. Variable cytological features Most cases TCR αβ, CD3- positive, CD4-positive CD30-positive in >50% cases DD ALCL, ALK-positive Subsets: CD8-positive with cytotoxic markers CD4-positive/CD8-positive, CD4- negative/CD8-negative
  15. 15. GATA 3 group (TH2) (mTOR, MYC, PI3K) TBX21 group (TH1) (IFN, CD8, NFkb signatures) Yr Median OS n (years) GATA3 37 0.9 Unclassifiable 20 1.41 TBX21 49 2.08 AITL ALK-negative ALK-positive ATTL NK 𝜸δT PTCL-NOS GATA3 TBX21 1.0 Proportion (OS) 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 Unclassifiable PTCL Subgroups: Molecular Diagnostic Signatures mTOR = mammalian target of rapamycin; MYC = oncogene c-MYC; PI3K = phosphatidylinositol-3-kinase. Iqbal et al, 2014. GATA3
  16. 16. PTCL-GATA3 PTCL-GATA3 PTCL-TBX21 PTCL-TBX21 Distinct Morphological Features in PTCL-NOS Amador et al, 2019. Classified by IHC Algorithm Pattern 1: monotonous pattern, intermediate size, clear (A) Pattern 2: large cells, clusters of cells (B) Pattern 3: small lymphocytes, mixed infiltrate (C) Pattern 4: small tumor cells with cluster of epithelioid histocytes (D) GATA 3 group (TH2) (mTOR, MYC, PI3K) TBX21 group (TH1) (IFN, CD8, NFkb signatures)
  17. 17. Spectrum of Nodal Lymphomas With TFH Phenotype fPTCL = follicular PTCL. Nguyen et al, 2017; Couronné et al, 2012; Lemonnier et al, 2012; Cairns et al, 2012; Odejide et al, 2014; Wang et al, 2015. Shared immunophenotypic features by IHC Similar gene expression profile signatures Unique genetic landscape TET2 (50%-80%) IDH2 (25%-45% AITL) DNMT3 (20%-30%) Therapeutic implications? TFH AITL fPTCL TFH PTCL
  18. 18. Angioimmunoblastic T-Cell Lymphoma (AITL) Image courtesy of Aaron Goodman, MD. Xie et al, 2021. Polymorphous infiltrate Proliferation of high endothelial venules and follicular dendritic cells Frequent expansion of EBV- positive B-cells Several TFH markers Older, disseminated disease Skin rash, effusions Cytopenias Anemia (Coombs-positive) Hypereosinophilia Hypergammaglobulinemia
  19. 19. Anaplastic large-cell lymphoma ALK- positive ALK- negative Systemic Cutaneous Breast implant–associated Children, young adults Cells usually large, horseshoe-shaped nuclei Most common translocation t(2;5) NPM-ALK CD30 Older patients Recurrent translocations: DUSP22, ROS1,TYK,TP63 rearranged Anaplastic Large-Cell Lymphoma (ALCL) Image courtesy of Aaron Goodman, MD. Tsuyama et al, 2017; Pina-Oviedo et al, 2021.
  20. 20. ALK-Positive and ALK-Negative ALCL: OS by IPI IPI = International Prognostic Index. Savage et al, 2008; Hapgood & Savage, 2015. ALK-positive ALCL 5-Yr OS by IPI 0/1: 90% 2: 68% 3: 23% 4/5: 33% ALK-negative ALCL 5-Yr OS by IPI 0/1: 74% 2: 62% 3: 31% 4/5: 13% Yr IPI 0, 1 IPI 2 IPI 3 IPI 4, 5 Yr ALK- positive 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 OS (%) P<0.001 ALK- negative 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 OS (%) P<0.001 15
  21. 21. DUSP22 and TP63 Rearrangements: Prognostic Significance Feldman et al, 2011; Pedersen et al, 2017; Aggarwal et al, 2017; ZytoVision, 2021. Chromosomal rearrangements involving DUSP22-IRF4 locus on 6p25.3 (DUSP22 rearrangement) Result in decreased expression of dual-specificity phosphatase-22 that regulates MAP kinase signaling TP63 rearrangements encode p63 fusion protein ALK-Negative ALCL
  22. 22. ALCL Outcome Differences Between Subtypes Parrilla Castellar et al, 2014.
  23. 23. Breast Implant–Association ALCL (BIA-ALCL) Images courtesy of Aaron Goodman, MD, and Dr. Joseph Mele, San Francisco Plastic Surgery Blog, 2018. Clemens et al, 2019; Lajevardi et al, 2022. Pathogenesis Malignant cells derived from Th1/Th17 cells Mutations in JAK/STAT signaling SOCS1 TP53 and DNMT3 Chronic inflammation is thought to play a role (bacterial biofilm gram–negative bacteria leading to T-cell stimulation via toll-like receptors, preponderance of Ralstonia found in BIA-ALCL samples) Associated with breast implants Median time to presentation: 8 years Arise in the seroma associated with the implant Can be aggressive and have invasive features ALK-negative Remove the seroma and the implant Radiation or chemotherapy based on extent of disease
  24. 24. Intestinal T-Cell Lymphomas Jaffe, 2020; Chander et al, 2018; Perry et al, 2013. EATL: associated with celiac disease and gluten sensitivity; αβ subtype, invasion of intestinal mucosa and surrounding villous; derives from small intestinal intraepithelial lymphocytes (innate lymphocytes) MEITL: formerly EATL type II; no association with Celiac disease; ɣȢ origin, CD8- and CD56-positive; surrounding mucosa intact Indolent T-cell LPD of GIT: small mature lymphoid cells that are mostly CD8-positive; indolent clinical course but symptomatic Intestinal involvement of PTCL Common sites Phenotype Genotype Clinical • Jejunum • Ileum • Jejunum • Ileum • Duodenum • Jejunum • Ileum • Colon • Stomach • Duodenum • SB, colon • ß > 𝛾δ • CD3+/CD5- • CD103+ • CD4-/CD8- • JAK-STAT • JAK1/STAT3 • RAS pathway • JAK-STAT • STAT5B/JAK3 • SETD2 • RAS pathway JAK-STAT RAS Epigenetic modifiers IL2 R/D • JAK-STAT • JAK3 • Celiac disease • Aggressive • No predisposing factors • All ethnic groups • Aggressive • Indolent • Slight risk of transformation • CD4 > CD8 • Indolent • No transformation reported • 𝛾δ > ß • CD3+/CD5- • CD8-/CD56+ • MATK • ß • CD3+/CD5+ • CD4 or CD8 • Neg 𝛾δ - ß • CD3+/CD5- • CD7+ • CD56+ EATL MEITL IT-LPD NK-ENT
  25. 25. Pathogenesis of EATL HLA = human leukocyte antigen; EATL = enteropathy-associated TCL; IEL = small intestinal intraepithelial lymphocyte; JAK = Janus kinase; STAT = signal transducer and activator of transcription. Image credit: Canva. Licensed under Free Media License. Chander et al, 2018. Presence of high-risk HLA alleles associated with celiac disease, serologic evidence of gluten sensitivity and decreased risk of lymphoma in patients on a gluten-free diet Refractory celiac disease (RCD): precursor to EATL RCD1: IEL normal phenotype and polyclonal RCD2: IEL is aberrant, and clonal, IL15 Mutations associated with deranged Microenvironment TCR pathway (EATL-1) Activation by gluten Reduced immunogenicity (loss of HLA class II) JAK/STAT pathway Mutations STAT-5b Epigenetics TET2, SETD2
  26. 26. Hepatosplenic TCL: a Rare but Challenging Entity Pro et al, 2020. Cytopenia Constitutional symptoms Hepatosplenomegaly Hemophagocytic syndrome Morphology Sinusoidal pattern Atypical cells, usually small but can resemble blasts Erythrophagocytosis can be seen Phenotype 80% 𝛾δ T cell; 20% ß T cells CD3-positive, CD2-positive, CD5- negative, CD7-positive/negative, CD4-negative/CD8-negative, CD56- positive, CD57-negative, TIA- positive, perforin-negative Chromosomal abnormalities Isochromosome 7q [i(7q)] Trisomy 8 Gene Mutations JAK/STAT pathway: STAT3 and STAT5 Chromatin modifying genes: SETD2, INO80, TET3, and SMARCA2 Clinical Presentation Induction therapy Transplantation in first remission with consideration for allogeneic stem cell transplant Treatment Morphology and Immunophenotype Genomic Findings
  27. 27. Principles of Therapy for PTCL CAR = chimeric antigen receptor. NCCN, 2022b. Appropriate staging Upfront therapy Role of high-dose therapy and autologous stem cell transplant (auto SCT) Relapsed disease: therapeutic options Allogeneic stem cell transplant (allo SCT) CAR T-cell therapy?
  28. 28. Appropriate Staging to Diagnose PTCL HIV = human immunodeficiency virus. NCCN, 2022b. Basic labs including the following: Complete blood count, comprehensive metabolic panel Lactate dehydrogenase Hepatitis B/C HIV serology HTLV1/2 serology Lymph node biopsy Excisional or incisional biopsy preferred over core needle biopsy PET/CT scan Expert review by hematopathologist is critically important
  29. 29. Treatment
  30. 30. NCCN Guidelines for PTCL FTCL = follicular TCL. NCCN, 2022b. Clinical trial ALCL Preferred regimen Brentuximab vedotin + CHP (cyclophosphamide/doxorubicin/ prednisone) (Category 1) Other recommended regimens CHOP (cyclophosphamide/ doxorubicin/vincristine/prednisone) CHOEP (cyclophosphamide/ doxorubicin/vincristine/etoposide/ prednisone) Dose-adjusted EPOCH (etoposide/ prednisone/vincristine/ cyclophosphamide/doxorubicin) Other histologies (PTCL, NOS; AITL; EATL; MEITL; nodal PTCL; TFH; and FTCL) Preferred regimens Brentuximab vedotin + CHP for CD30-positive histologies CHOEP CHOP Dose-adjusted EPOCH Other recommended regimens CHOP followed by IVE (ifosfamide/ etoposide/epirubicin) alternating with intermediate- dose methotrexate HyperCVAD (cyclophosphamide/vincristine/ doxorubicin/dexamethasone) alternating with high- dose methotrexate and cytarabine (Category 3) Suggested First-Line Treatment Regimens First-line consolidation Consider consolidation with high-dose therapy and autologous stem cell rescue
  31. 31. PTCL: Frontline Treatment CR = complete response; PR = partial response; U = unspecified. Ellin et al, 2014. PTCL-NOS AITL ALK-negative ALCL ALK-positive ALCL CHOP/CHOP-like CR or PR auto SCT auto SCT Non-auto SCT CHOEP CHOP (n=128) (n=124) (n=107) (n=145) 5-yr OS 48% 26% 47% 30% 5-yr PFS 41% 20% 40% 23% Low-risk ALK-positive ALCL → observe Yr ALK-positive ALCL ALK-negative ALCL ALK-U ALCL AITL PTCL-NOS PTCL-U PFS by Subtype in Nodal Types Swedish Registry (N=755) 0 20 40 60 80 100 0 2 4 6 8 10 12 14
  32. 32. Addition of Etoposide to CHOP NHL = non-Hodgkin lymphoma. Schmitz et al, 2010. Results from 7 trials of the German High-Grade NHL Study Group: TCL subset analysis (N=320) Positive effect of etoposide on event-free survival was confirmed in a subset analysis of ALK-positive ALCL This trend continued when the remaining PTCL subtypes were analyzed together High-Grade T-Cell Lymphomas
  33. 33. What We Know So Far BV = brentuximab vedotin; ORR = overall response rate; len = lenalidomide. Deng et al, 2019; Horwitz et al, 2022; Schmitz et al, 2010; Dupuis et al, 2012; Shustov et al, 2017; Johnston et al, 2021; Lunning et al, 2018; Herrera et al, 2019. CHOP-based therapies remain the backbone of upfront therapy (CR 31%-69%) For CD30-positive lymphomas and ALCL: BV + CHP (based on randomized data and shown to impact survival) has the best effect seen in ALCL; other subtypes, not so much Role of etoposide as the upfront regimen continues to be debated. Best data is by Schmitz et al: <60, normal LDH, improved OS. CHOEP followed by-high dose auto SCT has been used by several groups. Metanalysis by Deng et al did not show a difference between CHOP and CHOEP Ro-CHOP (CHOP/romidepsin) initial results: ORR 78%, including 66% CR. Randomized phase 3 is negative CHOP/pralatrexate: ORR 89%, CR 67% CHOP/belinostat: ORR 71%, CR 67%, PR 14% CHOEP/lenalidomide: ORR 69% and CR 48% CHEP/BV: ongoing. Possible EPCH + BV?
  34. 34. Romidepsin + CHOP (RO-CHOP Study) in PTCL TEAE = treatment-emergent adverse event. Bachy et al, 2020; Bachy et al, 2022. High rates of TEAEs with the addition of romidepsin hampered the ability to adequately administer 6 cycles of CHOP PFS Ro-CHOP (n=211) CHOP (n=210) Median PFS, mos (95% CI) 12.0 (9.0-25.8) 10.2 (7.4-13.2) HR 0.81 (95% CI 0.63-1.04), P=0.096 Grade 3/4TEAEs ≥30%: Thrombocytopenia 50% 10% Neutropenia 49% 33% Anemia 47% 17% Leukopenia 32% 20% Histology PTCL_NOS 41/59 42/68 AITL 53/101 57/94 ALK-negative sALCL 13/21 9/21 Other 15/30 21/27 3.7
  35. 35. DSHNHL2006-1B/ACT-2 Trial aSome patients without documentation of blood values within the nadir. Wulf et al, 2021. Alemtuzumab/CHOP Versus CHOP in Elderly Patients With PTCL Non-hematological adverse events grades 3-5 and hematologic toxicity grade 3-4 according to A-CHOP versus CHOP Patients treated with A-CHOP (n=58) Patients treated with CHOP (n=58) Non-hematological adverse events grade 3-5 Nausea 2 (3%) 3 (5%) Vomiting 1 (2%) 2 (3%) Diarrhea 5 (9%) 2 (3%) Constipation 2 (3%) 0 (0%) Mucositis/stomatitis 3 (5%) 0 (0%) Cardiac arrhythmia 1 (2%) 0 (0%) Cardiac general 4 (7%) 1 (2%) Hemorrhage/bleeding 1 (2%) 1 (2%) Renal/genitourinary 3 (5%) 5 (9%) Neuropathy sensory 5 (9%) 4 (7%) Mood alteration 1 (2%) 0 (0%) Allergic reaction/ hypersensitivity 1 (2%) 0 (0%) Infections 23 (40%) 12 (21%) Hematological adverse events Leukocytopenia grade 4a 35/50 (70%) 22/41 (54%) Thrombocytopenia grade 3/4a 8/42 (19%) 4/30 (13%) Anemia grade 3/4 17/58 (29%) 11/57 (19%) A-CHOP CHOP
  36. 36. ECHELON-2: Brentuximab Vedotin/CHP Versus CHOP aCyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 (CHOP only), prednisone 100 mg on Days 1-5. G-CSF primary prophylaxis, consolidative RT, SCT per investigator discretion. BICR = blind independent central review; HSTCL = hepatosplenic TCL; RT = radiation therapy; sALCL = systematic ALCL; Q3W = every 3 weeks. Horwitz, O’Connor et al, 2019. Multicenter, randomized, double-blind, double-dummy, active-comparator phase 3 trial Previously Untreated CD30-Positive PTCL 452 adult patients • Previously untreated CD30-positive (≥10% of cells) PTCL • sALCL (including ALK-positive with IPI ≥2 and ALK-negative), PTCL-NOS, AITL, ATLL, EATL, HSTCL • Stratification factors • IPI score (0-1 vs 2-3 vs 4-5) • Histologic subtype (ALK-positive sALCL vs other subtypes) Primary end point: PFS per BICR (SCT or RT consolidation not considered events) Secondary end points: OS, PFS per BICR in sALCL patients, CR, ORR, safety Brentuximab vedotin + CHP (n=226) BV 1.8 mg/kg + CHPa Q3W for 6-8 cycles Placebo for vincristine CHOP (n=226) Q3W for 6-8 cycles Placebo for brentuximab vedotin End-of treatment PET
  37. 37. ECHELON-2: Brentuximab Vedotin Horwitz, O’Connor et al, 2019. Baseline Characteristics Characteristic BV + CHP (n=226) CHOP (n=226) Male, n (%) 133 (59%) 151 (67%) Median age, years (IQR) 58 (45-67) 58 (44-67) Disease stage III/IV, n (%) 184 (81%) 180 (80%) IPI score, n (%) • 0-1 • 2-3 • 4-5 53 (23%) 140 (62%) 33 (15%) 48 (21%) 144 (64%) 34 (15%) Disease diagnosis, n (%) • sALCL • ALK-positive sALCL • ALK-negative sALCL • AITL • PTCL-NOS • ATLL • EATL 162 (72%) 49 (22%) 113 (50%) 30 (13%) 29 (13%) 4 (2%) 1 (0%) 154 (68%) 49 (22%) 105 (46%) 24 (11%) 43 (19%) 3 (1%) 2 (1%)
  38. 38. ECHELON-2: Brentuximab Vedotin (cont.) Horwitz et al, 2022. BV + CHP reduced risk of progression, death, or subsequent anticancer therapy by 30% versus CHOP (investigator assessment) Exploratory Analysis: PFS at 5 Years Patients at Risk (Events) BV + 226 (0) 179 (36) 150 (62) 138 (72) 123 (78) 104 (81) 85 (85) 67 (88) 44 (89) 32 (91) 21 (92) 10 (94) 4 (94) 2 (94) 0 (94) CHOP 226 (0) 159 (63) 128 (94) 116 (103) 101 (112) 94 (115) 79 (117) 70 (118) 55 (119) 39 (119) 24 (121) 6 (125) 0 (125 0 (125) 0 (125) 0 20 40 60 80 100 Patients Alive and Progression Free (%) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Median PFS: BV + CHP 62.3 mos versus CHOP 23.8 mos Median follow-up: 47.6 mos N Events Median (mos) HR (95% CI) P value BV + CHP 226 94 62.26 0.700 .0077 CHOP 226 125 23.75 (0.53‒0.91) Mos
  39. 39. ECHELON-2: Brentuximab Vedotin (cont.) Horwitz et al, 2022. The PFS analyses for key subgroups were consistent with overall study results and generally favored BV + CHP over CHOP Exploratory Analysis: PFS by Subset Events (N) HR (95% CI) ITT subgroups BV + CHP CHOP PFS per INV, all patients 94/226 125/226 0.70 (0.53‒0.91) IPI score 0‒1 14/52 27/48 0.42 (0.22‒0.81) 2‒3 59/141 79/145 0.72 (0.51‒1.01) 4‒5 21/33 19/33 1.14 (0.61‒2.15) Age, years <65 51/157 74/156 0.64 (0.45‒0.92) ≥65 43/69 51/70 0.68 (0.45‒1.04) Sex Male 60/133 79/151 0.84 (0.60‒1.17) Female 34/93 46/75 0.44 (0.28‒0.69) Baseline ECOG PS 0 36/84 56/93 0.63 (0.41‒0.96) 1 38/90 50/86 0.61 (0.40‒0.94) 2 20/51 19/47 0.99 (0.52‒1.88) Disease stage I 3/12 2/9 2.15 (0.22‒20.88) II 12/30 18/37 0.93 (0.43‒1.99) III 26/57 36/67 0.63 (0.37‒1.05) IV 53/127 69/113 0.66 (0.46‒0.95) Disease indication ALK-positive sALCL 7/49 16/49 0.40 (0.17‒0.98) ALK-negative cALCL 46/113 61/105 0.58 (0.40‒0.85) ATLL 2/4 2/3 0.69 (0.10‒4.94) AITL 19/30 12/24 1.41 (0.64‒3.11) EATL 1/1 2/2 Not estimable PTCL-NOS 19/29 32/43 0.79 (0.43‒1.43) sALCL 53/162 77/154 0.55 (0.39‒0.78) Non-sALCL 41/64 48/72 0.96 (0.63‒1.47) 0.1 0.5 1 10 Favors BV + CHP Favors CHOP
  40. 40. BV + CHP (n=223) CHOP (n=226) Treatment-emergent PN, n 117 124  Resolution, n (%)a 71 (61%) 82 (66%)  Improvement, n (%)b 13 (11%) 15 (12%) Patients with ongoing PN at last visit, n 47 42  Grade 1, n (%) 33 (70%) 30 (71%)  Grade 2, n (%) 13 (28%) 11 (26%)  Grade 3, n (%) 1 (2%) 1 (2%) ECHELON-2: Brentuximab Vedotin (cont.) Complete resolution or improvement of symptoms was observed in 72% and 78% of patients in the BV + CHP and CHOP arms, respectively aResolution: resolved/recovered with or without sequelae or returned to baseline or lower severity as of the latest assessment for preexisting events. bImprovement: decrease by ≥1 grade from the worst grade with no higher grade thereafter. Patients with improvement in any event at last follow-up had ≥1 improved event and the date of improvement was before last follow-up date. Subjects with all events resolved were excluded. Horwitz et al, 2022. Exploratory Analysis: Treatment-Emergent Peripheral Neuropathy
  41. 41. Role of Autologous Stem Cell Transplant ASTCT = American Society for Transplantation and Cellular Therapy; NCCN = National Comprehensive Cancer Network. NCCN, 2022; Kharfan-Dabaja et al, 2017. PTCLs have a poor outcome with upfront therapies alone 5-year survival remains at around 30% for most histologies, with the exception of ALK-positive ALCL with low IPI High-dose therapy and auto SCT are recommended Consolidation in CR1 in eligible patients: recommended by NCCN Relapsed disease in chemosensitive relapse if the patient has not had a prior transplant: ASTCT strongly recommends considering an allo SCT in this setting
  42. 42. n % proceeded to auto SCT CR % PR % OS % PFS % d’Amore et al 166 72% 51% 30% 51% at 5 years (ALK-negative ALCL: best) 44% (5 years) Corradini et al 62 74% 66% 16% 30% (12 years) DFS: 55% (12 years) Reimer et al 83 66% 39% 40% 48% (3 years) N/A Wilheim et al 111 68% 62% 20% 44% (5 years) 39% (5 years) Rodriguez et al 26 73% 65% 8% 73% (3 years) 53% (3 years) Mercadal et al 41 41% 49% 10% 39% (4 years) 30% (4 years) Autologous Stem Cell Transplant as Consolidation Therapy DFS = disease-free survival. Abeyakoon et al, 2020. Intent to Treat
  43. 43. PTCL: How Can We Improve Induction Therapy? Role of etoposide in young patients Phase 2 trial of BV + CHEP in newly diagnosed CD30-positive PTCL: ORR 100%, myelosuppression common Identification of low-risk patients Maintenance therapy for patients at high risk of relapse Many ongoing studies Alternative therapies for AITL/TFH-PTCL, CD30-negative cases? Herrera et al, 2019.
  44. 44. Azacitidine + CHOP as Initial Therapy for PTCL Primary objective: CR rate Secondary objective: ORR, safety, survival Exploratory: genomic, transcriptomic, and methylomic biomarkers HSCT = hematopoietic SCT. Ruan et al, 2020. Patients with untreated PTCL Nodal TCL with TFH phenotype (per WHO 2016) AITL Follicular TCL PTCL-NOS, TFH variant PTCL-NOS ALCL, ALK-negative ALCL, ALK pos w/IPI ≥2 Adult TCL/leukemia C1 C2-C5 C6 -6 1 8 15 21 1 8 15 21 1 8 15 21 CHO P CHO P CHO P Azacitidine Azacitidine Azacitidine Azacitidine: Cycle 1, Days -6 to 0; 1-5 days, Days 8-21 Cyclophosphamide/doxorubicin/vincristine: Day 1 Prednisone: Days 1-5 Growth factor (eg, pegfilgrastim) Treatment Azacitidine dosing: 300 mg/day, Days -6 to 0, then Days 8-21 in Cycles 1-5 Patients in CR/PR after 6 cycles can receive consolidative HSCT Phase 2 Trial
  45. 45. Azacitidine + CHOP in PTCL: Efficacy EOT = end of treatment; FU = follow-up; SD = stable disease; PD = progressive disease. Ruan et al, 2020. Response Interim EOT n Evaluable (n=20) PTCL-TFH (n=17) n Evaluable (n=20) PTCL-TFH% (n=17) ORR 17 85% 94% 15 75% 88% CR 11 55% 59% 15 75% 88% PR 6 30% 35% 0 0% 0% SD 2 10% 0% 1 5% 0% PD 1 5% 6% 2 10% 6% Discontinued 0 0% 0% 2 10% 6% Median FU, mos 15 (range: 9-23) Grade 3/4 Toxicities Neutropenia 71.4% Anemia Febrile neutropenia Fatigue Hyponatremia 14.3% Thrombocytopenia 9.5% Diarrhea Vomiting Rash Elevated ALT 4.8%
  46. 46. Non-CHOP Approaches for PTCL: Romidepsin + Azacitidine AE = adverse event. Falchi et al, 2021. Patients, both untreated and R/R (n=25) Treatment-naive: n=11 TFH/AITL: n=8 ORR: 70% CR: 50% (n=10 evaluable) Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation Most common grade 3/4 AEs Thrombocytopenia: 48% Neutropenia: 40% Febrile neutropenia: 12% Phase 2 study Patients CR SD SD SD PD SD CR PR CR CR CR PR CR PR PR CR CR CR CR PD PD PD SD - 100% Change in Sum of Product of Tumor Diameter -50% 0% 50% 100% Relapsed/refractory Treatment-naive
  47. 47. Azacitidine + CHO(E)P Versus Duvelisib + CHO(E)P AZA = azacitidine; DOR = duration of response; EFS = event-free survival; PRO = patient-reported outcome; BID = twice a day. Clinicaltrials.gov, 2021b. Patients with untreated, non- ALCL PTCL and <10% CD30 expression (N=170) AZA QD, Days -6 to 0, then Days 8-21 in Cycles 1-5 + CHO(E)P CHOP or CHOEP Duvelisib BID, Days 1-21 + CHO(E)P 6 cycles Primary end point: CR rate per PET/CT (goal: 25% difference) Secondary end points: safety/tolerability, ORR, DOR, PFS, EFS, OS, PROs Versus CHOP or CHOEP in CD30-Negative Untreated PTCL: A051902 (Phase 2)
  48. 48. Combination Therapies in the Upfront Setting Lunning et al, 2018; Shustov et al 2017; Advani et al, 2016; Kim et al, 2016; Dupuis et al, 2014; Dupuis et al, 2015; Shi et al, 2019. Combination N Results Adverse events Lenalidomide + CHOEP (2018) 40 ORR 68% CR 48% Hematologic toxicity Pralatrexate + CHOP, FOL-CHOP 12 ORR 89%, CR 67% No added toxicities noted COEP alternating with pralatrexate (2016) 33 ORR- 70%, CR 52%, 2-year PFS 39%, 2-yr OS 60% - Everolimus + CHOP (2016) 30 ORR 90%, 2-year OS 70%, 2-year PFS 33% Mucositis, hematologic Romidepsin + CHOP (2014) Randomization against CHOP is (2015) 19 ORR 68%, PFS 57% (18 months), OS 76.5% Neutropenia, thrombocytopenia, anemia Chidamide + CHOP (2019) 30 CR 46% PFS at 12 months: 54% OS 100% -
  49. 49. Relapsed/Refractory PTCL
  50. 50. Approaches and Outcomes in R/R PTCL R/R = relapsed/refractory. NCCN, 2022b. No clear optimal strategy at relapse Intensive combination chemotherapy is not clearly better (and in some cases may be worse) than single-agent/maintenance approaches In selected patients, allogeneic SCT can lead to long-term remissions and potentially cure CR is best pretransplant predictor of success with allogeneic SCT Determine transplant eligibility immediately Transplant-eligible patients need to immediately be referred for transplant
  51. 51. How to Choose the Next Line of Therapy: NCCN Clinical trial preferred Preferred regimens Belinostat Brentuximab vedotin for CD30-positive PTCL Pralatrexate Romidepsin Other recommended regimens Alemtuzumab Bendamustine Bortezomib Cyclophosphamide and/or etoposide (IV or PO) Duvelisib Gemcitabine Lenalidomide Radiation therapy IV = intravenous; PO = orally. NCCN, 2022b. Clinical trial preferred Preferred regimens Single agents Belinostat Brentuximab vedotin for CD30-positive PTCL Pralatrexate Romidepsin Combination regimens DHAP (dexamethasone/cisplatin/cytarabine) DHAX (dexamethasone/cytarabine/oxaliplatin) ESHAP (etoposide/methylprednisolone/cytarabine/cisplatin) GDP (gemcitabine/ dexamethasone/cisplatin) GemOx (gemcitabine/oxaliplatin) ICE (ifosfamide/carboplatin/etoposide) Other recommended regimens Single agents Bendamustine Duvelisib Gemcitabine Lenalidomide Combination regimen GVD (gemcitabine/vinorelbine/liposomal doxorubicin) Second-line therapy (with intention to proceed to transplant) and subsequent therapy Second-line or initial palliative intent therapy (no intention to transplant) and subsequent therapy
  52. 52. Dosing of FDA-Approved Agents for PTCL MOA = mechanism of action; IM = intramuscular; HDAC = histone deacetylase; QD = every day; QW = every week; GFR = glomerular filtration rate; DHFR = dihydrofolate reductase. Beleodaq® prescribing information, 2022; FolotynTM prescribing information, 2020. Agent PTCL MOA Dosing Belinostat Patients with PTCL HDAC • Recommended dose: 1,000 mg/m2 over 30 min by IV infusion QD on Days 21-day cycle • Repeat cycles until PD or unacceptable toxicity • Discontinue, interrupt, or reduce dose by 25% to manage toxicity Pralatrexate Patients with PTCL DHFR Pretreatment:  Vitamin B12 1,000 mcg IM every 8-10 weeks starting 10 weeks before dose  Folic acid 1.0-1.25 mg PO QD starting 10 days before first dose Recommended dose: • PTCL: 30 mg/m2 IV over 3-5 min QW for 6 weeks in 7-week cycles • In patients with severe renal impairment (GFR 15-29 mL/min/ 1.73 m2), reduce dose to 15 mg/m2
  53. 53. Agent Toxicity management Belinostat Monitoring:  CBC at baseline and weekly  Serum chemistry tests prior to first dose of each cycle Requirements at start of cycle and after interruption for toxicity:  ANC ≥1.0x109/L  Platelets ≥50x109/L  Grade ≤3 AEs Consult package insert for guidance on dosing following recovery from toxicity Discontinue treatment in patients with recurrent ANC nadirs <0.5x109/L and/or recurrent platelet count <25x109/L after 2 dose reductions AE Management for FDA-Approved Agents for TCL CBC = complete blood count; ANC = absolute neutrophil count. Beleodaq® prescribing information, 2022.
  54. 54. AE Management for FDA-Approved Agents for TCL (cont.) BL = baseline. FolotynTM prescribing information, 2020; Istodax® prescribing information, 2021. Agent Toxicity management Pralatrexate  Monitoring: - CBC and severity of mucositis at BL and weekly - Serum chemistry tests prior to first and fourth dose of each cycle  Do not use in patients with - Grade ≥2 mucositis - Platelets ≤100,000/mcL at first dose and ≤50,000/mcL at subsequent doses - ANC ≤1,000/mcL  Other AEs: - Interrupt therapy if grade 3 - Stop therapy if grade 4  Consult prescribing information for guidance on dosing following mucositis recovery to grade ≤1, myelosuppression recovery of other AEs to grade ≤2 Romidepsin  Nonhematologic toxicities (except alopecia): - Grade 2/3: delay therapy until recovery or BL, then restart at 14 mg/m2 - Recurrent grade 3: delay therapy until recovery or BL, then permanently reduce to 10 mg/m2 - Grade 4: delay therapy until recovery or BL, then permanently reduce to 10 mg/m2 - Discontinue if recurrent grade 3/4 toxicity after dose reduction  Hematologic toxicities: - Grade 3/4 neutropenia or thrombocytopenia: delay therapy until ANC ≥1.5 x 109/L and/or platelets ≥75 x109/L or restart at 14 mg/m2 - Grade 4 febrile (≥38.5C) neutropenia or thrombocytopenia requiring platelet transfusion: delay therapy-specific returns to grade ≤1 or BL, then permanently reduce to 10 mg/m2
  55. 55. Single Versus Combination Therapy for R/R PTCL Stuver et al, 2019. 57 patients retreated 26 combination chemotherapy, 31 single-agent Median follow-up 2 years Increased CR with single versus combination (41% vs 19%) Median OS, single versus combination: 38.9 versus 17.2 months Median PFS, single versus combination: 11.2 versus 6.7 months Stem cell transplants, single versus combination: 26% versus 8% Adverse events grade 3/4 more common with combination chemotherapy Results from COMPLETE Registry
  56. 56. Response N Median PFS, mos (95% CI) Median OS, mos (95% CI) CR 239 44.6 (17.9-201.5) 154.2 (72.8-201.5) PR 164 8.5 (6.1-16.6) 31.3 (16.8-64.2) 5-yr OS: 50.8% 5-yr PFS: 39.4% Single agent/novel Combo/traditional COMPLETE Registry: OS Outcomes: Post–Allogeneic SCT for TCL Approaches and Outcomes in R/R PTCL Stuver et al, 2019; Mehta-Shah et al, 2020. + N=57 100 80 60 40 20 0 Survival (%) Mos 66 0 6 12 18 24 30 36 42 48 54 60 Log-rank P value = 0.0170 26 31 22 29 16 26 11 22 6 16 2 9 2 8 1 6 1 5 1 5 3 10 1 + + + + + + + + + + + + + + + + 100 80 60 40 20 0 Mos from HSCT N=508 0 50 100 150 200 250 Survival (%) Patients at risk, n
  57. 57. Clinical Activity of FDA-Approved Treatments: R/R PTCL aIn ALK-negative. Coiffier et al, 2012; O’Connor et al, 2011; O’Connor et al, 2015; Horwitz et al, 2014; Pro et al, 2012. Response, % ORR CR ORR PTCL-NOS ORR AITL ORR ALCL HDAC inhibitor  Romidepsin  Belinostat 25% 26% 15% 11% 29% 23% 30% 46% 24%a 15%a Antifolate  Pralatrexate 29% 11% 32% 8% 35% Anti─CD30-targeted  Brentuximab vedotin 41% 24% 33% 54% 86%
  58. 58. Studies in R/R PTCL: Lymphoma or Leukemia BM = bone marrow; LN = lymph node; CNS = central nervous system; T-PLL = T-cell prolymphocytic leukemia; ILD = interstitial lung disease; QTc = QT corrected for heart rate. Bossi et al, 2020; Xalkori® prescribing information, 2021; Dearden et al, 2001. ORR: 83.3% (10/12) with CR 58.3% (7/12) FDA approval January 2021 For pediatric patients 1 year of age or older and young adults with R/R systemic ALCL that is ALK-positive Study ADVL0912: 26 patients; ORR 88% (95% CI: 71%-96%; CR: 81%) Crizotinib in R/R ALK‐ALCL PFS in ALK-positive ALCL OS in ALK-positive ALCL OS Probability (%) 100 80 60 40 20 0 0 1 2 3 4 5 6 PFS Probability (%) 100 80 60 40 20 0 0 1 2 3 4 5 6 Yr Yr Remission Rate in T-PLL With CAMPATH-1H (Alemtuzumab) Site of Disease Proportion Responding (%) Bloo d BM Spleen Skin LN Liver CNS 70 0 60 50 40 30 20 10 N=38 OS in T-PLL Patients 100 80 60 40 20 0 Proportion Surviving (%) Yr 0 1 2 3 4 5 + + + + + +
  59. 59. CR PR ORR, n/N (%) PTCL 0 1 1/7 (15%) AITL 6 3 9/12 (75%) Azacitidine in T-Cell Lymphoma Delarue et al, 2016; Lemonnier et al, 2018; Falchi et al, 2021. Treatment with azacitidine induces a sustained response in patients with AITL Responders had higher average number of mutations in genes involved in DNA methylation and histone deacetylation N CR % ORR % PTCL 23 43% 61% PTCL-TFH 15 60% 80% PFS Mos C 100 80 60 40 20 0 72 0 12 24 36 48 60 OS Mos B 100 80 60 40 20 0 72 0 12 24 36 48 60 Mos A 1 10 11 12 60 0 12 24 36 48 2 3 4 5 6 7 8 9 * * * * * * * Patient ID Treatment stop Treatment ongoing death CR PR SD PD * Oral azacitidine and romidepsin in PTCL CR Relapsed/Refractory Treatment-Naïve Change in Sum of Product of Tumor Diameter (%) Patients 100 50 0 -50 -100 PD PD PD SD SD SD SD SD PD SD CR PR CR CR CR PR CR PR PR CR CR CR Patients Mo Complete response Partial response Auto SCT Allo SCT Patient preference Progression 10 8 4 2 0 6 12 14 10 20 5 0 15 25 Responders Nonresponders Number of epigenetic mutations All epigenetic operations DNA methylation or histone deacetylation 0 2 4 6 8 10 12
  60. 60. Phase 2 Biomarker-Driven Study of Ruxolitinib aExcept for T-PLL, where untreated patients may be allowed after discussion with principal investigator. CTCL = cutaneous TCL; T-LGL = T-cell large granular lymphocytic leukemia. Moskowitz et al, 2021. Ruxolitinib demonstrates effectiveness of JAK/STAT targeting in TCL, with clinical benefit rate ranging from 18%-48% Study Design Results: clinical benefit rate, % Until PD, toxicity, recommended termination by the treating physician, or study termination This Analysis Patients ages 18 or older with relapsed/refractory peripheralTCL (T or NK lymphoma); CTCL with stage IB or greater; relapsed/refractory after 1 previous systemic therapya; ECOG PS (N=53) GroupA: activating JAK or STAT mutations Group C: neither or unknown Group B: functional evidence of JAK/STAT activation Primary end point: Clinical benefit rate defined as the combination of CR, PR, and SD lasting at least 6 months Ruxolitinib 20 mg PO BID 28-day cycles x6 cycles Rare subtype expansion cohort: T-PLL andT-LGL and non-MF CTCL and JAK fusion–mutant 48% 18% 36% PTCL (n=19) MF (n=2) PTCL (n=15) MF (n=2) PTCL (n=12) MF (n=3)
  61. 61. PRIMO: Duvelisib in R/R PTCL aWith potential scalation to 50, then 75. PJP = Pneumocystis jirovecii pneumonia; HSV = herpes simplex virus; VZV = varicella zoster virus; ALT = alanine aminotransferase; AST = aspartate aminotransferase. Brammer et al, 2021. Phase 2 Expansion Histologically confirmed PTCL after >1 cycle of prior standard regimen; CD4 lymphocyte count of ≥50/mm3; PJP prophylaxis required; HSV/VZV prophylaxis strongly recommended (N=125) Duvelisib 75 mg BID x2 cycles then 25 mg BID Until progression or unacceptable toxicity Primary end point: ORR Secondary end points: DOR, DCR, PDS, OS, and safety By IRC assessment: ORR: 50% CR: 32% ORR by subtype • PTCL NOS (n=42): 53% • ALCL (n=1): 9% • AITL (n=21): 67% • Other (n=4): 50% Interim Results (n=78) Select adverse events grade ≥3 • Neutropenia: 39% • ALT/AST increased: 24%/22% • Rash: 8% • Lymphocyte count decreased: 8% • Sepsis: 6%
  62. 62. Novel Single Agents for PTCL: Recent Updates Laribi et al, 2018; Barr et al, 2015; Brammer et al, 2021; Huen et al, 2020; Moskowitz et al, 2019; Horwitz, Feldman et al, 2019. Agent Mechanism of action RR N ORR CR PFS/OS Alisertib Aurora A inhibitor PTCL 37 30% 7% 3 months/ 8 months Crizotinib ALK inhibitor ALK-positive 9 100% 100% Duvelisib PI3K δ inhibitor PTCL 78 50% 32% 107 days Tenalisib PI3K δ/γ Inhibitor PTCL/CTCL 58 46% 9%, 20% for PTCL Median DOR 4.91 months (6.53 months PTCL, 3.8 months CTCL) Ruxolitinib JAK1/2 inhibitor PTCL 48 23% 6% Median DOR 7.3 months Cerdulatinib JAK and SYK inhibitor PTCL/CTCL 60 55% 35% for CTCL 41% Median DOR pending
  63. 63. Immunotherapies
  64. 64. Immune Checkpoint Inhibitors for TCL Barta et al, 2019; Bennani et al, 2019. Nivolumab Pembrolizumab Hyper-progression seen in 4 patients ORR: 33% Median PFS: 1.9 months N=18 ORR 33% 4/13 CR Median PFS 3.2 months Median OS 10.6 months Not a Big Hit as Single Agents
  65. 65. Major Turning Point in NK/T-Cell Lymphomas Kwong et al, 2017; Chan et al, 2018.
  66. 66. Nivolumab: Rapid Progression of TCL PD-1 = programmed cell death protein 1; PD-L1 = programmed death ligand 1. Ratner et al, 2018.
  67. 67. Nivolumab: Rapid Progression of TCL (cont.) Ratner et al, 2018. Laboratory Values of Patients Lab Baseline value Peak value after nivolumab treatment All patients Patient 1, chronic ATLL Patient 2, smoldering ATLL Patient 3, acute ATLL PD-L1 expression on ATLL cells (%) <1% <1% 5% Creatinine (mg/dl) <1.1 1.4 2.5 1.7 Calcium (mg/dl) <10.0 12.2 13.3 11.8 Lactate dehydrogenase (U/liter) <320 1335 351 3520 White-cell count (per mm3) <12.0 40.6 17.0 41.2 Factor increase in absolute lymphocyte count 11.7 1.5 10.6 Atypical lymphocytes (%) ≤5% 24% NA 30% Bilirubin (mg/dl) <1.0 2.5 0.6 21.7 Factor increase in HTLV-1 DNA 63.0 NA 2.4
  68. 68. Immune Checkpoint Inhibitor Combinations POD = progression of disease. Iyer et al, 2019; Marchi et al, 2020; Clinicaltrials.gov, 2021a; Clinicaltrials.gov, 2022a; Clinicaltrials.gov, 2022b; Clinicaltrials.gov, 2020; Clinicaltrials.gov, 2019. Pembrolizumab + romidepsin: ongoing ORR 44% in 15 evaluable patients 2 patients had hyper-progression Pembrolizumab + pralatrexate/decitabine: phase 1 4 patients in triple combination: 1 CR, 1 PR, no POD Nivolumab + EPOCH upfront therapy: just started Pembrolizumab + copanlisib Ongoing trials for NK TCL with single-agent PD-1 inhibitors With Chemotherapy or Other Agents for PTCL
  69. 69. Cutaneous TCL
  70. 70. Case Study 2: Mr. CB 2017: 67-year-old man developed itching of his groin without overlying rash, spread to generalized itching without rash; severe tingling, burning sensation. He is diagnosed with atopic dermatitis and small fiber neuropathy. He tried many different treatments including steroid cream, duloxetine, gabapentin, lorazepam, and oxycodone. He was evaluated by numerous doctors without any improvement 2020: he was treated with dupilumab (anti-IL4 and -IL13), then he broke out with a rash 2021: intense, unrelieved itching; plaques involve 85% of BSA; no fever, chills, night sweats, weight loss, or lymphadenopathy 4/13/21: skin biopsy of right lower back is consistent with mycosis fungoides Image courtesy of Aaron Goodman, MD. BSA = body surface area.
  71. 71. Epidemiology of Mycosis Fungoides (MF) Chihara et al, 2015; Dobos et al, 2020; Benavides-Huerto et al, 2019; Ai et al, 2014. MF is an indolent non- Hodgkin lymphoma Most common cutaneous TCL (approximately 50%) 6 cases per million per year (4% of NHLs) Median age: 50-60 Male to female: 2 to 1 More common among African Americans
  72. 72. Which of the Following Rashes Is MF? Nashan et al, 2007; Girardi et al, 2004; Jawed et al, 2014; Hodak et al, 2019. B D All of the above! A E C
  73. 73. Clinical Manifestation of MF Rash with predilection for non–sun-exposed areas (buttock, groin, breasts) “Premycotic period”: long history of rash that waxes and wanes over months to years with non-diagnostic biopsies Scaly patches or plaques, often misdiagnosed as chronic contact dermatitis, atopic dermatitis, or psoriasis Papules Erythroderma Intense pruritis Hypopigmented/hyperpigmented lesions Alopecia Tumor Cleveland Clinic, 2022; Chaudhary et al, 2013; Kreutzer & Effendy, 2020; Jawed et al, 2014. Many Different Presentations!
  74. 74. Pathophysiology of MF Girardi et al, 2004. Cause is unknown Malignant cells interact with the dermal capillary endothelial cells → bind to endothelial cells and leak into the dermis → migrate to epidermis (epidermotropism) and cluster around Langerhans' cells, forming Pautrier's microabscesses Malignant cells cluster at the dermal-epidermal junction and upper dermis CCR4 – CCL17, CCL22
  75. 75. Histology of MF Image courtesy of Paulo Henrique Orlandi Mourao under a CC-BY-SA 3.0 license. Jawed et al, 2014. Skin biopsy Atypical cell infiltration of dermal-epidermal junction Pautrier's microabscesses (pathognomonic for MF) Peripheral smear/flow cytometry Sézary cells Cerebriform nuclear convolution
  76. 76. Workup for MF Skin assessment: determine T stage Estimate BSA Patch Plaque Tumor Erythrodermic T = tumor. Images courtesy of the American Burn Association and Aaron Goodman, MD. Jawed et al, 2014; Scarisbrick, 2017.
  77. 77. TNMB TNMB Classification and Staging of Mycosis Fungoides and Sézary Syndromea: Clinical Staging Skin Node Visceral Blood T1 Limited patchesb, papules, and/or plaquesc covering <10% of the skin surface N0 No abnormal lymph nodes; biopsy not required M0 No visceral organ involvement B0 Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes or <250/mcL are atypical (Sézary) cells or <15% CD4-positive/CD26-negative or CD4- positive/CD7-negative cell of total lymphocytes T2 Patches, papulesb, and/or plaquesb covering ≥10% of the skin surface N1 Abnormal lymph nodes; histopathology Dutch 1 or NCI LN 0-2 T2a Patch only N2 Abnormal lymph nodes; histopathology Dutch 2 or NCI LN 3 M1 Visceral involvement (must have pathology confirmation and organ involved should be specified) B1 Low blood tumor burden: ≥5% of peripheral blood lymphocytes are atypical (Sézary) cells or >15% CD4-positive/CD26-negative or CD4-positiveCD7-negative of total lymphocytes but do not meet the criteria of B0 or B2 T2b Plaque ± patch N3 Abnormal lymph nodes; histopathology Dutch 3-4 or NCI LN 4 T3 ≥1 tumorsd (≥1 cm in diameter) NX Abnormal lymph nodes; histologic confirmation MX Abnormal visceral site; no histologic confirmation B2 High blood tumor burden: ≥1,000/mcL Sézary cellsa determined by cytopathology ≥1,000 CD4-positive/CD26-negative or CD4-positive/CD7-negative cell/μL or other abnormal subset of T lymphocytes by flow cytometry with clone in blood same as in skin. Other criteria for documenting high blood tumor burden in CD4-positive include CD4-positive/CD7-negative cells ≥40% and CD4-positive/CD26-negative ≥30% T4 Confluence of erythema ≥80% body surface area Staging of MF/SS aSézary syndrome is defined by B2 blood involvement and a clonal rearrangement of TCR in the blood (clones should be relevant to clone in the skin). bPatch = any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted. cPlaque = any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as folliculotropism or LCT (≥25% large cells), CD30-positive/-negative, and clinical features such as ulceration are important to document. dTumor = at least 1 >1 cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histologic evidence of LCT has occurred. Phenotyping for CD30 is encouraged. Olsen et al, 2011; NCCN, 2022a.
  78. 78. Staging of MF/SS (cont.) aSézary syndrome is defined by B2 blood involvement and a clonal rearrangement of TCR in the blood (clones should be relevant to clone in the skin). bPatch = any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted. cPlaque = any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as folliculotropism or LCT (≥25% large cells), CD30-positive or CD30-negative, and clinical features such as ulceration are important to document. dTumor = at least 1 >1 cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histologic evidence of LCT has occurred. Phenotyping for CD30 is encouraged. Olsen et al, 2011; NCCN, 2022a. TNMB TNMB Classification and Staging of Mycosis Fungoides and Sézary Syndromea: Clinical Staging Skin Node Visceral Blood T1 Limited patchesb, and/or plaquesc covering <10% of the skin surface N0 No abnormal lymph biopsy not required M0 No visceral organ involvement B0 Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes <250/mcL are atypical (Sézary) cells or <15% CD4-positive/CD26-negative or positive/CD7-negative cell of total lymphocytes T2 Patches, papulesb, plaquesb covering ≥10% the skin surface N1 Abnormal lymph nodes; histopathology Dutch 1 or NCI LN 0-2 T2a Patch only N2 Abnormal lymph nodes; histopathology Dutch 2 or NCI LN 3 M1 Visceral involvement (must have pathology confirmation and organ involved should be specified) B1 Low blood tumor burden: ≥5% of peripheral blood lymphocytes are atypical cells or >15% CD4-positive/CD26-negative or CD4-positiveCD7-negative of total lymphocytes but do not meet the criteria of B0 or B2 T2b Plaque ± patch N3 Abnormal lymph nodes; histopathology Dutch 3-4 or NCI LN 4 T3 One or more tumorsd (≥1 cm in diameter) NX Abnormal lymph nodes; histologic confirmation MX Abnormal visceral site; histologic confirmation B2 High blood tumor burden: ≥1,000/mcL Sézary cellsa determined by ≥1000 CD4-positive/CD26-negative or CD4-positive/CD7-negative cell/μL or abnormal subset of T lymphocytes by flow cytometry with clone in blood same in skin. Other criteria for documenting high blood tumor burden in CD4-positive include CD4-positive/CD7-negative cells ≥40% and CD4-positive/CD26-negative ≥30% T4 Confluence of erythema ≥80% body surface area
  79. 79. MF Subtypes and Variants Gu et al, 2022; Benner et al, 2012; Pulitzer et al, 2014; NCCN, 2022a. Folliculotropic MF Histologic variant of MF that lacks epidermotropism Atypical CD4-positive cells surround and permeate hair follicles Subset of folliculotropic MF; behaves indolently but is associated with worse prognosis Large cell transformation (LCT) 20%-55% of patients with MF have LCT >25% of lymphoid infiltrate is composed of large cells Often (but not always) corresponds to more aggressive growth of MF Can occur irrespective of stage but more frequent in advanced stage (1% early-stage disease vs 27% stage IIB disease vs 56%-67% stage IV disease)
  80. 80. Mycosis Fungoides Versus Sézary Syndrome Jawed et al, 2014; NCCN, 2022a. Mycosis Fungoides Skin tropic effector memory CD4-positive T cells MF lesions can coalesce to form erythrodermic MF Sézary Syndrome Thymic memory T cells Diffuse erythema (erythroderma) Sézary cells in the blood CD4-positive, CD7-negative, CD26-negative
  81. 81. Staging of MF/SS (cont.) NCCN, 2022a; Olsen et al, 2011. Early stage Late stage Clinical stage T (skin) N (node) M (visceral) B (blood involvement) Guidelines page IA (limited skin involvement) T1 (patches, papules, and/or plaques <10% body surface [BSA]) N0 M0 B0 or B1 MFSS-6 IB (skin only disease) T2 (patches, papules, and/or plaques ≥10% BSA) N0 M0 B0 or B1 MFSS-7 IIA T1-T2 N1-2 M0 B0 or B1 MFSS-7 IIB (tumor stage disease) T3 (1 or more tumors [≥1 in diameter]) N0-2 M0 B0 or B1 MFSS-8 IIIA (erythrodermic T4 (confluence of ≥80% BSA) N0-2 M0 B0 MFSS-10 IIIB (erythrodermic T4 (confluence of ≥80% BSA) N0-2 M0 B1 MFSS-10 IVA (Sézary syndrome) T1-4 N0-2 M0 B2 MFSS-11 IVA (Sézary syndrome or non-Sézary) T1-4 N3 M0 B0 or B1 or B2 MFSS-11 IVB (visceral disease) T1-4 N0-3 M0 B0 or B1 or B2 MFSS-11 Large-cell transformation (LCT) MFSS-12
  82. 82. Prognosis CLIPI = Cutaneous Lymphoma International Prognostic Index; LCT = large-cell transformation. Benton et al, 2013; NCCN, 2022a. CLIPI score: Low: 0-1 Intermediate: 2 High: 3-5 Other markers: LCT LDH Early stage Late stage OS PFS
  83. 83. Case Study 2: Mr. CB (cont.) Skin biopsy Psoriasiform and lichenoid CD4-positive lymphocytic infiltrate with loss of CD7 and clonal restriction consistent with mycosis fungoides (c84.00) CD3-positive immunostaining labels the entirety of the infiltrate, which is perijunctional with expansive thin sheets. CD4-positive, CD5-positive, CD7-negative, CD30-positive TCRg gene rearrangement–positive Involvement of 85% of BSA with plaques, intense itching, no tumors Labs, flow cytometry, PET/CT were normal Staging
  84. 84. Case Study 2: Mr. CB (cont.) What stage is this patient? A. IIA B. IIB C. IIIA D. IIIB E. IV (Sézary syndrome) Staging
  85. 85. Staging of MF/SS (cont.) NCCN, 2022a; Olsen et al, 2011. Early stage Late stage Clinical stage T (skin) N (node) M (visceral) B (blood involvement) Guidelines page IA (limited skin involvement) T1 (patches, papules, and/or plaques <10% body surface [BSA]) N0 M0 B0 or B1 MFSS-6 IB (skin only disease) T2 (patches, papules, and/or plaques ≥10% BSA) N0 M0 B0 or B1 MFSS-7 IIA T1-T2 N1-2 M0 B0 or B1 MFSS-7 IIB (tumor stage disease) T3 (1 or more tumors [≥1 in diameter]) N0-2 M0 B0 or B1 MFSS-8 IIIA (erythrodermic T4 (confluence of ≥80% BSA) N0-2 M0 B0 MFSS-10 IIIB (erythrodermic T4 (confluence of ≥80% BSA) N0-2 M0 B1 MFSS-10 IVA (Sézary syndrome) T1-4 N0-2 M0 B2 MFSS-11 IVA (Sézary syndrome or non-Sézary) T1-4 N3 M0 B0 or B1 or B2 MFSS-11 IVB (visceral disease) T1-4 N0-3 M1 B0 or B1 or B2 MFSS-11 Large-cell transformation (LCT) MFSS-12
  86. 86. Treatment
  87. 87. Case Study 2: Mr. CB (cont.) Stage IIIA MF How would you treat this patient? A. Enjoy photopheresis B. Betamethasone ointment all over the body C. Vitamin A derivative pills (as used in treatment of acne) D. Radiate the whole skin E. CHOP! Treatment of MF Image courtesy of Aaron Goodman, MD.
  88. 88. Case Study 2: Mr. CB (cont.) Treatment of MF Image courtesy of Aaron Goodman, MD. Stage IIIA MF How would you treat this patient? A. Enjoy photopheresis B. Betamethasone ointment all over the body C. Vitamin A derivative pills (as used in treatment of acne) D. Radiate the whole skin E. CHOP!
  89. 89. General Principals of Treatment of MF Kaye et al, 1989; Whittaker et al, 2016; NCCN, 2022a. MF is often an indolent disease and is incurable Allogeneic SCT is the only curative option Treatment does not seem to influence the natural course of disease Symptom-directed treatment Patients will eventually relapse off-therapy Choose agent with least side effects; most durable first If systemic therapy is needed, typically use 1 agent at a time Responses can differ by compartment (skin, blood, LN/viscera) Relapsed disease can respond to retreatment with previous therapy
  90. 90. Types of Therapy for MF NCCN, 2022a. Skin-directed therapy Topical steroids Topical imiquimod Topical nitrogen mustard Topical bexarotene Phototherapy Total skin electron beam therapy (TSEBT) Local radiation Systemic therapy for hematologist Methotrexate, pralatrexate Mogamulizumab Brentuximab vedotin Romidepsin, vorinostat Gemcitabine Liposomal doxorubicin Multiagent chemotherapy Allogeneic SCT Systemic therapy for dermatologist Oral bexarotene ECP
  91. 91. Topical Steroid aCR indicates complete remission; T1, <10% of skin involved; T2, ≤10% of skin involved. bMedian follow-up: 9 months. Zackheim et al, 1998; Wood Heickman et al, 2018. Can be used as monotherapy in stage IA or as an adjunct in more advanced stages Use class I-III steroids Apply generously ORR of 80%-90% Potency Class Topical corticosteroid Formulation Ultrahigh 1 Clobetasol propionate Cream, 0.05% High 2 Betamethasone dipropionate Ointment, 0.05% Fluocinonide Cream, ointment, or gel, 0.05% 3 Betamethasone dipropionate Cream, 0.05% Betamethasone valerate Ointment, 0.1% Triamcinolone acetonide Ointment, 0.1% Mycosis Fungoides Response to Topical Corticosteroidsa Maximum response, N (%) Last status, N (%)b Stage N CR PR SD PD TR CR PR SD PD TR T1 51 32 (63%) 16 (31%) 3 (6%) 0 (0%) 48 (94%) 19 (37%) 22 (43%) 8 (16%) 2 (4%) 41 (80%) T2 28 7 (25%) 16 (57%) 5 (18%) 0 (0%) 23 (82%) 5 (18%) 14 (50%) 6 (21%) 3 (11%) 19 (68%)
  92. 92. Topical Steroid: Side Effects If possible, avoid high-potency steroid to the face Steroid atrophy Striae formation Systemic absorption could be an issue, leading to Cushing’s syndrome NCCN, 2022a; Dhar et al, 2014.
  93. 93. Phototherapy: NB-UVB or PUVA PUVA = psoralen ultraviolet light A; NB-UVB = narrowband-ultraviolet light B. Image courtesy of Aaron Goodman, MD. Trarabadkar & Shinohara, 2019; Phan et al, 2019; NCCN, 2022a. 3-times-a-week schedule Taper after achieving best response Need 20-40 treatments before response is seen Unclear if maintenance therapy is beneficial Some data suggest that PUVA may be more effective than NB-UVB for CR Side effects: cutaneous carcinogenesis for PUVA (but not NB-UVB) and skin aging NOT Photopheresis
  94. 94. Total Skin Electron Beam Therapy (TSEBT) Jones et al, 2002; Hoppe et al, 2015. Electron beam penetrates the epidermis and superficial dermis Malignant cells are very sensitive to radiation therapy It is challenging to deliver a homogeneous dose to the whole body, especially areas that are “shadowed” Use low dose (12 Gy) Treatment can be repeated >80% response rates CR rate of 27%-75% depending on dose Responses can be durable Median 71 weeks in pooled analysis of phase 2 clinical trials
  95. 95. TSEBT (cont.) Elsayad et al, 2014.
  96. 96. TSEBT (cont.) Jones et al, 2002; Hoppe et al, 2015. Electron beam penetrates the epidermis and superficial dermis Malignant cells are very sensitive to radiation therapy It is challenging to deliver a homogeneous dose to the whole body, especially areas that are “shadowed” Use low dose (12Gy) Treatment can be repeated >80% response rates CR rate of 30%-90% depending on dose Responses can be durable Median 70.7 weeks in pooled analysis of phase 2 clinical trials Side effects: desquamation, temporary alopecia (long duration of therapy)
  97. 97. Thoughts to Ponder Who do you consider good candidates for TSEBT? What are your thoughts on TSEBT as frontline therapy in early-stage MF? Up to how many times can you re-treat? How often?
  98. 98. Bexarotene Duvic et al, 2001; NCCN, 2022a; Targretin® prescribing information, 2015. Synthetic retinoid (vitamin A derivative) Starting dose: 300 mg/m2 daily (can be adjusted to 200 mg/m2, then 100 mg/m2) Phase 2/3 trial of bexarotene 94 patients with stage IIB-IVB CTCL treated with bexarotene 45% response rate Projected duration of response: 299 days
  99. 99. Case Study 2: Mr. CB (cont.) 2 weeks after starting bexarotene, you get labs: TSH: 0.006 What do you do now? A. Stop bexarotene; TSH will normalize on its own B. Stop bexarotene and give methimazole; bexarotene causes hyperthyroidism C. Continue bexarotene; it’s a lab error that can happen with bexarotene D. Continue bexarotene and give levothyroxine; you should have given levothyroxine 2 weeks ago TSH = thyroid-stimulating hormone. On Bexarotene
  100. 100. 2 weeks after starting bexarotene, you get labs: TSH: 0.006 What do you do now? A. Stop bexarotene; TSH will normalize on its own B. Stop bexarotene and give methimazole; bexarotene causes hyperthyroidism C. Continue bexarotene; it’s a lab error that can happen with bexarotene D. Continue bexarotene and give levothyroxine; you should have given levothyroxine 2 weeks ago Case Study 2: Mr. CB (cont.)
  101. 101. Bexarotene (cont.) TRH = thyrotropin-releasing hormone. Sherman, 2003; Targretin® prescribing information, 2015. Central hypothyroidism Suppress pituitary TSH-β promotor When starting bexarotene, start levothyroxine and monitor free T4 Usually recovers when bexarotene is stopped Hyperlipidemia, hypertriglyceridemia Monitor lipid panel and treat with statin/fenofibrate Leukopenia Monitor CBC, nothing to do Side Effects
  102. 102. Extracorporeal Photopheresis (ECP) Images courtesy of Therakos and Aaron Goodman, MD. Cho et al, 2018. Peripheral blood is exposed to methoxsalen (photosensitizing agent) and UVA radiation in extracorporeal circuit Induces apoptosis of the malignant lymphocytes Converts circulating monocytes to immature dendritic cells (DCs), presents tumor-loaded DCs to cytotoxic T cells
  103. 103. ALCANZA: Brentuximab Vedotin Horwitz et al, 2021. 131 adult patients • CD30 expression ≥10% • MF (n=97) • C-ALCL (n=31) • Patients with SS were excluded • Early stage: 31% • Late stage: 67% • ≥1 prior therapy • ECOG PS 0-2 Physician’s choice (n=62) Methotrexate 5-50 mg QW orally or Bexarotene 300 mg/m2 QD orally Max 16 x21-day cycles or until progressive disease or unacceptable toxicity End points • ORR4: 54.7% versus 12.5% (P<0.001) • TTNT: 14.2 versus 5.6 mos (P<0.001) • Resolution or improvement of PN: 86% versus 50% • 3-year OS: 64.4% versus 61.9% Brentuximab vedotin (n=66) 1.8 mg/kg IV Q3W 1:1
  104. 104. MAVORIC: Mogamulizumab (Anti-CCR4 Ab) Kim et al, 2018. 372 patients • Relapsed/refractory • Stage IB-IVB MF or SS • ≥1 prior therapy Vorinostat 400 mg QD Until progression or unacceptable toxicity Primary end point • PFS 7.7 versus 3.1 months Subgroup analysis • More benefit in stage III/IV and in SS Mogamulizumab 1 mg/kg IV QW x4 then Q2W 1:1
  105. 105. Hematopoietic Stem Cell Transplantation (HSCT) TLI = trypsin-like immunoreactivity; ATG = antithymocyte globulin. Weng et al, 2020. Only potentially curative option reserved for relapsed/refractory disease Phase 2 study of novel non- myeloablative allogeneic SCT (TSEBT + TLI + ATG conditioning) for advanced MF (n=13) and SS (n=22) 5-year OS of 56% OS PFS EFS
  106. 106. Types of Therapy ECP = extracorporeal photopheresis. NCCN, 2022a. Skin-directed therapy Topical steroids Topical imiquimod Topical nitrogen mustard Topical bexarotene Phototherapy Total skin electron beam therapy (TSEBT) Local radiation Systemic therapy for hematologist Methotrexate, pralatrexate Mogamulizumab Brentuximab vedotin Romidepsin, vorinostat Gemcitabine Liposomal doxorubicin Multiagent chemotherapy Allogeneic SCT Systemic therapy for dermatologist Oral bexarotene ECP
  107. 107. Questions to Ponder How does the histology or type of MF influence your treatment decisions? Localized tumor stage Classic MF, pagetoid reticularis, granulomatous slack skin, hypopigmented MF B D E C Images courtesy of Aaron Goodman, MD. Jawed et al, 2014; NCCN, 2022a.
  108. 108. Special Considerations: Co-Infection With S. Aureus S = Staphylococcus. Talpur et al, 2008; Willerslev-Olsen et al, 2016. S. aureus enterotoxins stimulate malignant T cells to activate STAT3/IL-10 axis and could cause a flare MF and SS lesions are frequently colonized with S. aureus If suspicious for infection, treatment of S. aureus can improve lesions
  109. 109. Special Considerations: Sézary Syndrome NCCN, 2022a. ECP would be a favorable option given blood involvement Mogamulizumab is studied in SS, but BV is not studied in SS Consider TSEBT
  110. 110. Special Considerations: Dupilumab Kolkowski et al, 2021. Dupilumab is a monoclonal antibody against IL-4Ra, which modulate IL-4 and IL-13 pathways Advanced treatment of moderate/severe atopic dermatitis Several case reports of dupilumab unmasking and accelerating MF or SS The mechanism is unclear CTCL Exposed to Dupilumab
  111. 111. Dosing of FDA-Approved Agents for CTCL MAb = monoclonal antibody; ULN = upper limit of normal. Poteligeo® prescribing information, 2022; Zolina® prescribing information, 2020. Agent CTCL indications MOA Dosing Mogamulizumab Adults with R/R mycosis fungoides or Sézary syndrome and ≥1 prior systemic therapies CCR4- directed MAb • Recommended dose: 1 mg/kg IV over ≥60 min on Days 1, 8, 15, and 22 28-day cycle and on Days 1 and 15 of subsequent cycles; continue until disease progression or unacceptable toxicity Vorinostat Treatment of cutaneous manifestations in patients with cutaneous TCL with progressive, persistent, or recurrent disease on/after 2 systemic therapies HDAC inhibitor  Recommended dose: 400 mg PO QD with food  Reduce dose to 300 mg PO QD with food for intolerance – If needed, may further reduce dose to 300 mg QD with food consecutive days each week if needed Hepatic impairment: • Mild-to-moderate (total bilirubin 1-3x ULN or AST >ULN): initial, 300 once daily • Severe impairment (bilirubin >3x ULN): insufficient evidence to recommend a starting dose; doses of 100-200 mg once daily have studied in limited number of patients with severe impairment
  112. 112. Dosing of Agents for CTCL (cont.) . Istodax® prescribing information, 2021; FolotynTM prescribing information, 2020; NCCN, 2022a. Agent CTCL indications MOA Dosing Romidepsin Adults with TCL and ≥1 prior systemic therapy HDAC inhibitor • Recommended dose: 14 mg/m2 IV over 4 hours on Days 1, 8, and 15 of a 28-day – Repeat cycles every 28 days in patients who benefit • Discontinue, interrupt, or reduce dose to 10 mg/m2 to manage toxicity Hepatic impairment: • Moderate impairment (bilirubin >1.5-3x ULN): reduce initial dose to 7 mg/m2 • Severe impairment (bilirubin >3x ULN): reduce initial dose to 5 mg/m2 Pralatrexate NOT FDA approved CTCL but recommended by NCCN for patients generalized tumor disease, Sézary syndrome, or visceral organ disease DHFR inhibitor Pretreatment: • Vitamin B12 1,000 mcg IM every 8-10 weeks starting 10 weeks before first dose • Folic acid 1-1.25 mg PO QD starting 10 days before first dose Recommended dose: • Cutaneous TCL: 15 mg/m2 IV over 3-5 min once weekly for 3 weeks of a 4- treatment cycle • In patients with severe renal impairment (GFR 15-29 mL/min/ 1.73 m2), reduce dose to 15 mg/m2
  113. 113. Non-CHOP Approaches for Previously Untreated PTCL Ruan et al, 2020. Response, n (%) Evaluable patients (n=20) AITL (n=13) PTCL-NOS (n=6) ORR 15 (75%) 11 (84.6%) 3 (50.0%) CR 6 (30%) 5 (38.5%) 1 (16.7%) PR 9 (45%) 6 (46.2%) 2 (33.3%) SD 2 (10%) 1 (7.7%) 1 (16.7%) PD 3 (15%) 1 (7.7% 2 (33.3%) Median f/u, mos 8 Wk 1 Cycle 2 Lenalidomide, D1-21 Romidepsin Romidepsin Romidepsin D1 D8 D15 D22 Wk 1 Wk 2 Wk 3 Wk 4 Cycle 1 Romidepsin (10 or 14 mg/m2) D1, 8, 15 Lenalidomide 25 mg D1-21 Cycle length: 28 days Treatment: up to 1 year Most common grade 3/4 AEs Neutropenia: 45% Thrombocytopenia: 34% Anemia: 28% Fatigue: 17% Lung infections: 10% Phase 2 Study of Romidepsin + Lenalidomide
  114. 114. Case Study 2: Mr. CB (cont.) Patient had minimal improvement on bexarotene He had minimal improvement on romidepsin Referred for TSEBT
  115. 115. Key Takeaways PTCL is a heterogenous disease with many subtypes Accurate diagnosis is essential BV+CHP is the new standard of care for frontline treatment of ALCL Treatment of non-ALCL PTCL depends on CD30 status MF is an indolent CTCL that can present like almost any other rash MF could have a long prodromic period of months to years MF is incurable (except with allogeneic SCT). Do not overtreat with chemotherapy Mogamulizumab (CCR4 inhibitor) can be used for Sézary syndrome
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