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Home , Cervical lymph nodes, Inguinal lymphadenopathy, Night sweats

4/16/2021

Case 1 • 43 year old woman with no significant prior medical history presents for evaluation of enlarged cervical, axillary, and , notes generalized night sweats and intermittent with 10 lbs weight loss. • On physical exam noted to have palpable bilateral cervical, axillary, Approach to and inguinal lymphadenopathy, largest 2.5 cm in diameter • Labs significant for hemoglobin 10.5, mcv 90, wbc‐ 5.2, platelets David Bond, MD 188 Assistant Professor - Clinical • Department of Internal Referred to for further evaluation Division of Hematology The Ohio State University Wexner Medical Center

Approach to Lymphadenopathy Approach to Lymphadenopathy

• Broadly differential diagnosis includes: • Localized versus generalized? • Reactive process related to , trauma, auto‐immune disorder, Rx • Size? • Malignancy • Rare non‐malignant systemic disorders • Associated constitutional symptoms (or pruritis)?

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Generalized Lymphadenopathy – Initial Work‐up – Generalized Lymphadenopathy Differential Diagnosis • Minimum initial work‐up: complete blood count, • HIV infection, EBV, CMV, or other HIV testing, chemistry, Chest x‐ray

mycobacterial infection, rheumatologic • Consider serology for EBV, CMV, ANA if other relevant supporting symptoms (including SLE), , rare systemic disorders • biopsy if evaluation non‐diagnostic

Case 1 ‐ Continued Case 2 • 32 year old woman with a history of seasonal who notes • 43 year old woman with no significant prior medical history painless firm mildly enlarged lymph node for the past eight years. presents for evaluation of enlarged cervical, axillary, and inguinal She recently has relocated to the area. A palpable left anterior lymph nodes. cervical lymph node measuring approximately ≤ 1 cm is noted on routine physical exam. • On evaluation by hematology testing for HIV 1 returned positive • HIV RNA Viral load 841, 028 • She denies constitutional symptoms and ROS is otherwise negative. • EBV Viral capsid antigen IgG positive, negative monospot and IgM Physical exam is significant for no other areas of lymphadenopathy. • EBV Viral load by PCR 10,478 No hepato‐splenomegaly is appreciated. Labs are significant for negative HIV 1/2 serology and normal CBC, CMP, LDH. • Right axillary excisional lymph node biopsy performed with EBV positive cells, no evidence of malignancy • Referred to hematology for evaluation

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Approach to Localized Lymphadenopathy Case 2 –continued

• Anatomic location and size important considerations • 32 year old woman with a history of seasonal allergies • Lymph nodes ≤ 1 cm very unlikely to be malignant1 who notes painless firm palpable lymph node. • Lymph node size ≥ 3.4 cm associated with 6‐fold higher likelihood of • Given the size (1 cm) and stability over time reassurance malignancy in recent series2 provided with routine annual primary care follow‐up • Younger age, non smoker, and known rheumatologic condition recommended associated with lower likelihood of malignancy2

1Ferrer R. Am Fam . 1998;58(6):1313 2Nixon S. et al. JCO Oncol Pract. 2020 16(1):e29‐e36

Localized Lymphadenopathy Approach Localized Lymphadenopathy Differential Diagnosis • Thorough history, including travel and sexual history, and physical exam crucial to guide work‐up • Inguinal adenopathy: • Empiric antibiotics not recommended, empiric corticosteroids • Lower extremity trauma, infection • STI should be avoided (compromise diagnostic yield if lymphoma • Malignancy – lymphoma, skin of lower extremities (melanoma), present) cervical, vulvar, rectal, ovarian, penile most common • Location also important to guide work‐up malignancies • Supra‐clavicular location associated with high risk for • Axillary lymphadenopathy: malignancy • Infection or trauma in , breast, or chest wall • Cat scratch disease • Observation for 3‐4 weeks reasonable in absence of red flags • Malignancy –breast, lymphoma most common malignancies

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Localized Lymphadenopathy Uncommon Systemic Associated Differential Diagnosis with Lymphadenopathy • Castleman’s disease – localized or multi‐centric • Epitrochlear: • Kikuchi’s disease – typically cervical localization with constitutional • of hand or , infections including syphilis or symptoms tularemia, lymphoma most common malignancy • Kawasaki disease • Sub‐occipital, posterior auricular: • Most frequently related to scalp infection • Kimura disease • Cervical: • Progressive transformation of germinal centers • Head or infections, EBV or CMV infection, toxoplasmosis • Rasai‐Dorfman disease • Most common malignancy in older patients head and neck • IgG4 related disease , lymphoma most common malignancy • in younger patients Multinucleated giant cell containing an asteroid, microscopy. | Wellcome Collection https://wellcomecollection.org/works/daadvcez/images?id=tx3t62wk

Medications associated with risk for Case 3 lymphadenopathy (less common) • 23 year old male with no significant prior medical history • Quinidine who presents with gradual enlargement of a mass of the • Imatinib neck for the past three months with associated pruritus and • Allopurinol • Antibiotics including recent night sweats. penicillin, cephalosporines, • On physical exam 4 x 3 cm left supraclavicular lymph node sulphonomides palpable, 2 x 2 cm bilateral cervical lymph nodes palpable • Antihypertensives including hydralazine, atenolol, • Labs significant for normal hemoglobin (14.5), wbc 15.7 (left captopril shift), mild thrombocytosis (397), elevated ESR (59) • Anti‐epileptics including lamotrigine, carbamazepine Painting, ca. 1900. Attribution 4.0 International (CC BY 4.0) https://wellcomecollection.org/works/tebjpwj7/images?id=nhyp8u6g

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Case 3 ‐ continued James Diagnostic Clinic

• CT Chest with 4.3 x 4.2 x 6.0 • Nurse practioner lead multi‐modality clinic offering supraclavicular lymph node, 11.5 x 9.1 x 11.8 cm anterior evaluation to coordinate diagnostic evaluation mediastinal mass including biopsy in patients with suspected but • Core needle biopsy of unconfirmed malignancy supraclavicular lymph node consistent with classical Hodgkin’s lymphoma

Considerations for Lymph Node Biopsy Hodgkin’s Lymphoma Pearls • FNA useful for initial evaluation in cases of carcinoma, rarely • Pruritis can be presenting symptoms (similar to other B diagnostic in cases of lymphoma symptoms such as fever, night sweats, weight loss) • For lymphoma excisional lymph node biopsy remains gold standard • Histologic findings may be confounded by corticosteroids, • Core needle biopsy is alternative option for diagnosis and granulomatous reaction may be seen without clear Reed‐ has become increasing common for logistical reasons • Core needle biopsy may miss representative region and in Sternberg cells, important to maintain suspicion in some cases excisional biopsy is still necessary to establish appropriate context the diagnosis

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Summary Points • HIV testing essential in initial evaluation generalized lymphadenopathy • FNA useful in diagnosis of carcinoma but not sufficient in evaluation for lymphoma, core needle or ideally excisional lymph node biopsy necessary • Avoid empiric corticosteroids for undifferentiated

lymphadenopathy Digital ID: (digital file from original item) ppss 01106 http://hdl.loc.gov/loc.pnp/ppss.01106. Repository: Library of Congress Prints and Photographs Division Washington, D.C. 20540 USA http://hdl.loc.gov/loc.pnp/pp.print

Outline . Brief overview of lymphoma subtypes . Treatment approach for diffuse large B cell lymphoma . Treatment with CAR T cells and Bispecific T-cell Novel Treatments in Lymphoma: engagers (BiTEs) CAR T-cells and Bispecific T-cell Engagers . Mechanism of action . Efficacy Yazeed Sawalha, MD . Toxicities Assistant Professor Department of . Future Directions Division of Hematology The Ohio State University Wexner Medical Center 24

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Lymphoma Classification (Simplified) Lymphoma Classification (Simplified)

Lymphoma Lymphoma

Non- Non- ~8,500 Hodgkin ~87,000 new cases/year ~8,500 Hodgkin ~87,000 Hodgkin Hodgkin

Nodular lymphocyte Nodular Classical NK/T-cell ~ 7,000 B-cell ~ 80,000 Classical lymphocyte NK/T-cell ~ 7,000 B-cell ~ 80,000 predominant predominant HL HL

Aggressi Aggressi Indolent Indolent ~ 30,000 Indolent Aggressive Indolent Aggressive ~ 30,000 ve ve ~ 4,000 ~ 50,000 ~ 4,000 ~ 50,000

Diffuse Large B Cell lymphoma (DLBCL) DLBCL - Treatment

. Most common type of lymphoma, ~ 28,000 new cases . Potentially curable regardless of stage . Frontline treatment has been mostly the same for the last annually in the USA ~ 20 years: R-CHOP . Typical presentation: rapidly progressing lymphadenopathy, . Rituximab (anti-CD20 monoclonal antibody) extranodal involvement is common, B symptoms (30%) . Cyclophosphamide . Diagnosis based on review (excisional biopsy > . Doxorubicin (hydroxydaunomycin) . Vincristine (oncovin) core-needle, not FNA) . Prednisone (100 mg x 5 days) . Staging work-up: LDH, HIV & remote hepatitis panel, PET/CT, echo, +/- bone marrow biopsy . ~ 60% of patients with DLBCL are cured with R-CHOP

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Treatment of Relapsed or Refractory DLBCL “New” Treatment Options for

“Salvage” or second- Relapsed/Refractory DLBCL line chemotherapy Only a minority of patients . CAR T-cells. Three products FDA-approved ~50% ~50% Eligible Proceed Cured with relapsed or refractory for ASCT to ASCT . Bispecific T cell engagers (BiTEs). Not approved Relapsed ~50% DLBCL get cured or (yet) Refractor y DLBCL Ineligible ~40% of all for ASCT . Bendamustine, rituximab + polatuzumab: FDA- DLBCL approved June 2019 ASCT = autologous stem cell transplantation . Tafasitamab + lenalidomide: FDA-approved July 2020 . Selinexor: FDA-approved June 2020 Adapted from Maddocks, K. American Society of Hematology. Education Program, 2020, 101–106. 29 30

Chimeric Antigen Receptor (CAR) T cells Chimeric Antigen Receptor (CAR) T cells . T cells transfected by a viral vector to introduce a construct coding for a CAR into the T cell’s DNA

. The CAR mediates binding to the target tumor antigen, independent of MHC, and subsequently activates the T cell and induces target cell killing

31 Casucci M & Bondanza A, J Cancer 2011; 2:378-382 Jacobson32 C & Ritz J, Blood (2011) 118 (18): 4761–4762

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CAR T Cells Efficacy in Relapsed/Refractory DLBCL . Three CAR T cell products are currently approved in Tisa-cel Axi-cel Liso-cel relapsed/refractory DLBCL: No of patients infused 93 101 269 . Axicabtagene ciloleucel (axi-cel) (October 2017) Age, median (range) 56 (22-76) 58 (23-76) 63 (54–70) . Tisagenlecleucel (tisa-cel) (May 2018) ≥3 prior 52% 69% 51% . Lisocabtagene maraleucel (liso-cel) (March 2021) Prior ASCT 49% 21% 33% . All three are autologous anti-CD19 CAR T cells Overall response rate 52% 83% 73% Complete response (CR) rate 40% 58% 53% . Other approvals (all anti-CD19) Progression-free survival . Tisa-cel in pediatric and young adult patients with relapsed - All patients - 2- year 39% 1-year 44% acute lymphoblastic -InCR 1-year 83% 2- year 72% 1-year 65% . Brexucabtagene autoleucel in relapsed (July 2020) . Axi-cel in relapsed (March 2021) Schuster SJ et al, NEJM 2018. Neelapu et al, NEJM 2017. Locke et al, Lancet Oncol 2019. Abramson et al, Lancet 2020. 33 34

CAR T-cell Toxicities Cytokine Release Syndrome . Caused by the release of proinflammatory cytokines from 1. Cytokine release syndrome (CRS) T-cells and other immune cells . Typically occurs in the first few days after CAR T-cell 2. Immune effector cell-associated neurotoxicity infusion . Manifests with fever, tachycardia, hypoxia and hypotension syndrome (ICANS) . Hemodynamic instability and end-organ dysfunction occur in severe cases (in up to 22% of patients) 3. B-cell aplasia and hypogammaglobinemia . Management: . Intensive monitoring and supportive care 4. Prolonged myelosuppression and pancytopenia . High-dose corticosteroids . Tocilizumab (anti-IL-6 receptor antibody) 35 36

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Immune Effector Cell-associated Future Directions Neurotoxicity Syndrome (ICANS) . “Third-generation” CAR-T: Dual costimulatory domains with . Pathophysiology is less-well understood, likely caused by a enhanced proliferation and persistence capabilities supraphysiologic immune-activation state. . Combination therapies to reduce immune evasion and CAR T-cell . Commonly follows CRS exhaustion . Variable clinical presentations ranging from mild confusion . Dual antigen targeting to reduce CD19-antigen loss (e.g. and tremors to aphasia, obtundation, seizures, cerebral CD19/CD22 and CD19/CD20) edema, and coma. . “Armored” CAR T-cells: secrete proinflammatory cytokines or . Severe cases occur in up to 31% of patients. express ligands that stimulate not only CART but also other immune cells. . Management: . Supportive care . Allogenic CAR T-cells and natural-killer (NK) CAR cells . Corticosteroids . CAR T-cells in other hematologic malignancies (MM) and ? solid . Antiepileptics tumors. 37 38

Case Presentation Case Presentation #2 . A 57 year old female presented with rapidly progressing . Insurance denied coverage for CAR T-cells inguinal lymphadenopathy in 2018. . Enrolled on a phase I clinical trial of a CD20 x CD3 bispecific antibody . Biopsy confirmed DLBCL, transformed from lymphoplasmacytic lymphoma . PET/CT with diffuse lymphadenopathy above and below the diaphragm as well as bone marrow involvement (stage IV). . Received R-CHOP x 6 cycles (achieved complete response) . Underwent consolidative ASCT 2019 . Developed in 2020. Biopsy confirmed DLBCL 39 40 Baseline (at relapse) Two months later

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Bispecific T cell engagers (BiTEs) Common Features of BiTEs . Small linker peptides connecting two . Toxicity: Cytokine release syndrome (CRS) different single-chain variable fragments with one fragment . Require inpatient stay initially designed to bind to CD3 on T cells . Mitigation strategies: Split and step-up dosing; Premedications: steroids; and the other to a tumor associated SQ formulation antigen . Generally predictable and manageable; grade ≥3 CRS less common than with CAR-T . The simultaneous binding of CD3 on T cells and the tumor associated . “Off-the-Shelf” therapies antigen triggers T-cell mediated . Duration of treatment is still unclear cytotoxicity of the malignant cell.

https://commons.wikimedia.org/wiki/File:BiTE_antibody_01.svg . Limited data on response durability 41 42

Summary of Efficacy and Safety of Bispecific Antibodies in r/r NHL Future Directions Bispecific ORR (n CRS (Grade Population CR rate Antibody evaluable) ≥3) . ? Approval in B-cell NHLs - r/r FL 90% (30) 70% - r/r DLBCL, no prior Odronextamab1 55% (11) 55% 61% (7%) CAR-T . In combination with chemotherapy and other - r/r DLBCL, post CAR-T 33% (24) 21% - r/r indolent NHL 63% (67) 43% novel agents Mosunetuzumab2 29% (1%) - r/r aggressive NHL 37% (124) 19% - r/r FL 90% (10) 50% Epcoritamab3 59% (0%) . In earlier lines of treatment (e.g. in elderly/frail - r/r DLBCL 68% (22) 46% Glofitamab4 - r/r indolent NHL 67% (18) 54% 64% (4%) patients with previously untreated DLBCL) - r/r aggressive NHL 61% (23) 54%

1. Bannerji et al. ASH 2020. 2. Schuster et al. ASH 2019 3. Hutchings el al. ASH 2020. 4. Hutchings el al. ASH 2020 44

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