Lymphoma Basics Case Studies Parameswaran Hari MD Feb

Lymphoma Basics & Case Studies Parameswaran Hari MD Feb 19, 2020 There are no conflicts of interest to disclose. The CIBMTR® (Center for International Blood and Marrow Transplant Research®) is a research collaboration between the National Marrow Donor Program® (NMDP)/Be The Match® and the Medical College of Wisconsin (MCW). CRP/DM CONFERENCE 2020 |.

Lymphoma Basics • Biology and Treatment Basics • Reporting and CIBMTR forms CRP/DM CONFERENCE 2020 | 2.

What is lymphoma? • A type of blood cancer which arises from lymphocytes – Can be of B-cell origin or of T-cell origin and rarely of NK cell origin – These cells normally fight infections • Lymphocytes normally reside primarily within lymph nodes, blood, bone marrow, and spleen. • Lymphoma therefore most commonly involves lymph nodes, bone marrow and spleen, but can involve any part of the body. Normal lymphocytes in peripheral blood 3 CRP/DM CONFERENCE 2020 | 3.

How common is lymphoma? • ~72, 000 new cases of NHL, and ~8, 000 new cases of Hodgkin lymphoma in USA in 2017 • An estimated 661, 996 people living with NHL and 204, 065 with Hodgkin lymphoma in the United States. • Male & Caucasian predominance • Median age at diagnosis is 67 years (NHL) & 39 years (Hodgkin) CRP/DM CONFERENCE 2020 | 4.

The Lymphatic System: where the cells of the immune system work and travel • We have a lot of “lymphoid tissue” in our bodies • Lymph nodes are normal • Lymph nodes normally enlarge and become painful with infection Lymphoma often grows in lymphoid tissues • “nodal”= growing in a lymph node • “extranodal”=growing outside of a lymph node CRP/DM CONFERENCE 2020 | 5.

Sites of Disease Nodal vs. Extra Nodal CRP/DM CONFERENCE 2020 | 6.

Some Clinical Situations CRP/DM CONFERENCE 2020 | 7.

Clinical Presentation • Non-tender lymph node enlargement • Unexplained fevers, night sweats, weight loss • Symptoms because of low-blood counts can be present • Can involvement any organ • Aggressive NHL can involve CNS CRP/DM CONFERENCE 2020 | 8.

Clinical Presentation - Systemic • Pruritus in ~10 -15% • Severe pruritus is a poor prognostic sign • Alcohol induced pain <10% (usually nodular sclerosis) CRP/DM CONFERENCE 2020 | 9.

There are more than 60 types of lymphoma Burkitt (2. 5%) Other subtypes (9%) T and NK cell (12%) Diffuse large B cell (DLBCL) (30%) Mantle cell (6%) Follicular (25%) Small lymphocytic (7%) MALT-type marginal-zone B cell (7. 5%) Nodal-type marginal -zone B cell (<2%) Lymphoplasmacytic (<2%) CRP/DM CONFERENCE 2020 | 10.

There are many ways to slice the “lymphoma pie” Hodgkin lymphoma Non. Hodgkin lymphoma CRP/DM CONFERENCE 2020 | 11.

Lymphomagenesis and Cell of origin CRP/DM CONFERENCE 2020 | 12.

Ideal tissue for diagnosis Lymph node biopsy Core needle biopsy Reactive LN CD 20 FNA Bcl 2 Abnormal node CD 3 Bcl 2 CRP/DM CONFERENCE 2020 | 13.

Making a diagnosis There are only 3 certain things in life: death / taxes and lymphoma classification will change CRP/DM CONFERENCE 2020 | 14.

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Immunohistochemical Stains / FISH / Karyotype FISH Probes for gene fusions/ deletions CRP/DM CONFERENCE 2020 | 16.

CIBMTR Forms – Qn 1 1. Specify the lymphoma histology: (at diagnosis) Hodgkin Lymphoma Codes Hodgkin lymphoma, not otherwise specified (150) Lymphocyte depleted (154) Lymphocyte-rich (151) Mixed cellularity (153) Nodular lymphocyte predomin • Special Situations: – Post Transplant Lymphoproliferative disease – DLBCL Subtype - CRP/DM CONFERENCE 2020 | 17.

Pathology report is your best friend FISH DLBCL with MYC and BCL 2 CRP/DM CONFERENCE 2020 | 18.

NHL- unclassifiable • B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma & DLBCL Ø Used to classify cases not meeting criteria for Burkitt lymphoma or DLBCL Ø Example of this category includes “double hit” NHLs. They are Bcell lymphomas characterized by a recurrent chromosomal translocation in combination with a 8 q 24/MYC translocation. CRP/DM CONFERENCE 2020 | 19.

NHL- unclassifiable • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL & classical Hodgkin lymphoma Ø Synonyms – Grey zone lymphoma – Large B-cell lymphoma with Hodgkin features Ø Most common in men ages 20 -40 Ø Usually presents with a large anterior mediastinal mass with or without supraclavicular node involvement CRP/DM CONFERENCE 2020 | 20.

NHL- Concurrent NHLs • Which lymphoma sub-type to report where when two NHLs are diagnosed at the same time? Ø Always report the more aggressive lymphoma as the primary disease for HCT. Ø For example- If mantel cell & DLBCL are diagnosed concurrently, DLBCL would be reported as the primary disease for HCT. CRP/DM CONFERENCE 2020 | 21.

NHL- Concurrent NHLs • Low grade or indolent NHLs (survival in years) Ø Small lymphocytic lymphoma (SLL) Ø Follicular NHL Ø Mantel cell NHL • Aggressive (survival in weeks to months) Ø Burkitt NHL (weeks) Ø DLBCL (months) Ø Lymphoblastic NHL/T lymphoblastic leukemia (weeks) CRP/DM CONFERENCE 2020 | 22.

NHL- Concurrent NHLs • Pre-TED Questions • Q 585 would be answered “no” • Q 586 would be answered “yes” CRP/DM CONFERENCE 2020 | 23.

NHL- Richter’s transformation • Richter’s transformation (or syndrome) Ø Occurs in about 5 -10% of B-cell CLL cases Ø The CLL transforms to a fast growing DLBCL • Report the primary diagnosis for HCT as DLBCL CRP/DM CONFERENCE 2020 | 24.

NHL- Richter’s transformation • Reporting DLBCL from a Richter’s transformation on the Pre. TED (F 2400)…. • Q 585 would be answered “yes” • Q 573 – 576 would also need to be completed for CLL CRP/DM CONFERENCE 2020 | 25.

Double-Hit DLBCL (DHL) • DLBCL with rearrangement of c-MYC plus BCL 2 and/or BCL 6 – 5 -10% of newly diagnosed DLBCL – Dismal prognosis with standard R-CHOP (Johnson et al. Blood 2009; Green et al. JCO 2012; Petrich et al. Blood 2014) MYC BCL 6 BCL 2 FISH with dual color break-apart probes for MYC, BCL 2, BCL 6. CRP/DM CONFERENCE 2020 | Photos courtesy of V. Bedell, 63 x Bioview imaging system. 26.

Common Staging Tests • History and physical examination. • CBC and differential • CMP with LDH • Hepatitis B & C testing/HIV • Bone marrow aspiration and biopsy* • CAT or PET scan chest/abdomen/pelvis • ±MUGA or Echocardiogram • Lung function testing • Fertility preservation Bone Marrow Aspiration/Biopsy CAT or CAT/PET Scanning CRP/DM CONFERENCE 2020 | 27.

Ann Arbor Staging CRP/DM CONFERENCE 2020 | 28.

How is lymphoma treated? • There is a wide range of treatments • Depends on: – The type of lymphoma – The goal of treatment – The age and condition of the patient • In general, surgery is NOT part of the treatment • Treatments are usually – – – Chemotherapy Immunotherapies (rituximab) Radiation Novel agents Blood / marrow transplantation 29 CRP/DM CONFERENCE 2020 | 29.

Conventional chemotherapy First patient ever treated with chemotherapy was a NHL patient in 1942 (nitrogen mustard) Goodman LS et al, JAMA 1946 Madagascar rosy periwinkle (vincristine) CRP/DM CONFERENCE 2020 | 30.

Rituximab as a Targeted Therapy in FL First m. Ab approved for treatment of cancer (Nov 26, 1997) • • Murine/human Ig. G 1 kappa m. Ab Binds to CD 20 antigen Half-life (at 375 mg/m 2) ~76. 3 hours after 1 st infusion and 205. 8 hours after the 4 th infusion Mechanism of action – CDC, ADCC, apoptosis, and ionizing radiation– induced cell death Murine variable regions bind specifically to CD 20 on B cells Human constant regions Human Ig. G 1 Fc domain works in synergy with human effector mechanisms CDC = complement-mediated cell death; ADCC = antibody-dependent cell cytotoxicity. CRP/DM CONFERENCE 2020 | 31.

Outcomes in DEL and DHL after R-CHOP Neither DEL DHL Johnson N. JCO. 2012; 30: 3452 -9 CRP/DM CONFERENCE 2020 | 32.

DHL & Upfront Autologous HCT EPOCH-like induction R-CHOP induction Landsburg D. ASH abs. 2016 CRP/DM CONFERENCE 2020 | 33.

Aggressive lymphoma & Hodgkin • Generally cured with chemotherapy alone (e. g. Rituximab plus CHOP or ABVD) • Sometimes cured with chemotherapy plus radiation • Some may need bone marrow transplant for cure CRP/DM CONFERENCE 2020 | 34.

“Newer” Targeted Therapies Ibrutinib Acalabrutinib Idelalisib copanlisib TGR 1202 Venetoclax Awan F, et al, CCR 2014 CRP/DM CONFERENCE 2020 | 35.

Autologous Transplantation – Basic Process SC Mobilizing Drugs “Thawing” Stem Cells “Freezing” Stem Cells Stem Cell Collection CRP/DM CONFERENCE 2020 | 36.

Selected Disease Trends for Autologous HCT in the US Number of Transplants Myeloma NHL/HL 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 001 002 003 004 005 006 007 008 009 010 011 012 013 014 015 016 017 018 0 2 2 2 2 2 37 CRP/DM CONFERENCE 2020 | 37.

Immunotherapy: T-cells Receptors have components inside of cell that send signals to T-cell to divide and secrete cytokines. CRP/DM CONFERENCE 2020 | 38. Newick, et al, Molecular Therapy – Oncolytics, 2016.

Creation of CAR T-cells from Patient’s Own (Autologous) T-cells CRP/DM CONFERENCE 2020 | 39.

Treatment Screening “Lymphodepleting ” Chemotherapy 1 st Tumor Assessment Cell Infusion Leukapheresis Day - 5 Day 0 Day 7 Day 30 Manufacturing Hospitalization Period Follow-up CRP/DM CONFERENCE 2020 | 40. 40

Significant Clinical Activity Before treatment 9 months after treatment CRP/DM et CONFERENCE Kochenderfer al, JCO 2015 2020 | 41.

PET/CT response at 1 month post CAR-T Still in CR at 2 years Pre CAR-T cells Day +28 PET/CT Slide courtesy of Nirav Shah CRP/DM CONFERENCE 2020 | 42.

Toxicities of CAR T-cells • Cytokine Release Syndrome • Neurotoxicity • Low blood counts CRP/DM CONFERENCE 2020 | 43.

4 4 Cytokine Release Syndrome (CRS) • A newly defined, potentially lethal complication of CAR-T cell infusion • CRS is a non-antigen specific toxicity that occurs as a result of high-level immune activation and can lead to hypotension, renal failure, shock, and death. • Syndrome with similarities to HLH (elevated ferritin>100 K, high grade fevers) Lee, D. W. , et al. , Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 2014. 124(2): p. 188 -95. CRP/DM CONFERENCE 2020 | 44.

DLBCL Trends for Autologous HCT in the US 1600 Number of Transplants 1400 1200 1000 800 600 400 200 0 08 009 010 011 012 013 014 015 016 017 018 0 2 2 2 45 CRP/DM CONFERENCE 2020 | 45.

Measuring Disease Burden CRP/DM CONFERENCE 2020 | 46.

Response Assessment Basics CRP/DM CONFERENCE 2020 | 47.

Measurement : CT scan vs. PET activity CRP/DM CONFERENCE 2020 | 48.

Nuances of Response - Metabolic • Complete metabolic remission requires all of the following: • A score of 1, 2, or 3 with or without a residual mass on a PET 5 point scale; and • Disappearance of any previously non-measured lesions; and • No new lesions PLUS No evidence of FDG-avid (PET) disease in the marrow. • Partial metabolic remission requires all of the following: • Score 4 or 5 on a PET 5 point scale with reduced uptake compared with baseline; and • No new lesions. CRP/DM CONFERENCE 2020 | 49.

Nuances of Response • Stable Disease • Does not meet metabolic criteria for complete remission, partial remission, or progressive disease. • Progressive Disease (after Partial Remission, Stable Disease), Relapsed Disease (after Complete Remission) • Metabolic progression or relapse requires at least one of the following: • Score 4 or 5 on a PET 5 point scale with increased uptake compared with baseline; or • Any new FDG-avid foci consistent with lymphoma; or • New or recurrent FDG avid foci in the bone marrow. CRP/DM CONFERENCE 2020 | 50.

Nuances of Response - Radiology • • LDi: longest transverse diameter of a lesion SDi: shortest axis perpendicular to the LDi SPD: sum of the product of the perpendicular diameters for multiple lesions PPD: cross product of the LDi and perpendicular diameter • Complete Remission (CR) requires all of the following: • All target nodes / nodal masses must have regressed as measured by CT to ≤ 1. 5 cm in longest diameter; and • Disappearance of any previously non-measured lesions; and • No extralymphatic sites of disease; PLUS No organomegally. CRP/DM CONFERENCE 2020 | 51.

Fournier et al Diagnostic and Interventional Imaging (2014) 95, 689 CRP/DM CONFERENCE 2020 | 52.

Nuances of Response • Partial Remission (needs all) • ≥ 50% decrease in the SPD of up to 6 target measurable nodes and extranodal sites 1; and • No increase in the size of previously non-measurable lesions; and • No new lesions. • If splenomegaly is present, a > 50% decrease in spleen length • Stable – not fitting CR/ PR or Relapse/PD CRP/DM CONFERENCE 2020 | 53.

Nuances of Response – PD or Relapse • An individual node must be abnormal with: – – LDi >1. 5 cm; and ≥ 50% increase from nadir in the PPD; or An increase in LDi or SDi from nadir ≥ 0. 5 cm increase in LDi or SDi from nadir for any lesion ≤ 2 cm; or ≥ 1. 0 cm increase in LDi or SDi from nadir for any lesion > 2 cm; or • • • A 50% increase in spleen length from baseline New or recurrent splenomegaly; or Clear progression of pre-existing non-measured lesions; or Regrowth of any previously resolved lesions; or A new node > 1. 5 cm in any axis; or A new extranodal site > 1. 0 cm in any axis or if < 1. 0 cm in any axis, its presence must be unequivocally attributable to lymphoma; or • Assessable disease of any size unequivocally attributable to lymphoma; or • New or recurrent involvement of the bone marrow. CRP/DM CONFERENCE 2020 | 54.

Questions CRP/DM CONFERENCE 2020 | 55.