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EHA-TSH Hematology Tutorial on Lymphoma
Tutored Clinical Case 1
Speaker: Massimo Federico
University of Modena and Reggio Emilia
Modena
İzmir, Turkey
April 6-7, 2019
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Clinical history
‒ Patient T., 56 y.o., male;
‒ ECOG PS = 0
‒ Lymphnode enlargement in bilaterale laterocervical, supraclavear and axillary regions. Some of them with size exceeding 3 cm in maximum diameter
‒ Normal Blood cell count, LDH and beta2Microglobulin levels
‒ No fever;
‒ No night sweat;
‒ No weight loss more that 10% in 6 months;
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Lymph node biopsy was performed
More than 6 and less than 15 centroblasts per HPF
Immunohistochemical study
• CD 10 Positive
CD 19, CD20, CD22 Positive
CD 5, CD 23 Negative
CD 3 (Pan- T) Negative
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Diagnosis
Follicular non-Hodgkin lymphoma, Grade 2.
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Staging
‒ CT Scan: lymph node enlargement of mediastinal (< 5 cm) aortic (<5 cm) and iliac (3 cm) regions
‒ Bone marrow involvement
‒ BCL2 positivity in both Bone marrow and peripheral blood
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Final Diagnosis
Follicular non-Hodgkin lymphoma, Grade 2.
Stage 4 A
FLIPI 2 : Score 1
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FLIPI2– results from the multivariate analysisof PFS
HR pB2M 1.47 0.004
Hb 1.55 0.003
Age 1.43 0.005
BM 1.56 0.001
LoDLIN(*) 1.43 0.007
(*) LoDLIN: longest diameter of largest Lymphnode (≥ 6cm)
Federico et al J Clin Oncol. 2009 Sep 20;27(27):4555-62
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Kaplan-Meier Analysis of Probability of (A) Time to Treatment Failure and (B) Progression-Free Survival according to
Intention-To-Treat Principle
Federico M, et al. J Clin Oncol 2013;31:1506-1513©2013 by American Society of Clinical Oncology
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Treatment decisions and response
‒ 6 x R-CHOP + 2 x rituximab
‒ Achieved complete remission (CR)
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➢ Eighteen months later, at the age of 58 years, disease recurrence, classified as FL relapse, on clinical grounds
➢ 2nd line treatment: 2xR-GDP + 2xR-MAD
➢ HDC (Z-BEAM) + autologous stem cell transplantation (auto-SCT)
➢ Achieved 2nd CR
➢ Two years later, appearance of two subcutaneous nodules on the left anterior chest wall
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Diagnostic work-up
Re-biopsy first, with the suspicious of transformation
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➢New Biopsy: FL, Grade 3A, Ki-67 – 40%, Stage IE
➢ 3rd line treatment: RT 36 Gy + Rituximab maintenance (every 2 months for 2 years)
➢CR
➢One year later, at age of 60, during rituximab maintenance: lymph node enlargement in the right supraclavicular region
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Diagnostic work-up
Re-biopsy first, with the suspicious of transformation
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➢Biopsy: Mixed cellularity classical Hodgkin lymphoma (persistence of follicular lymphoma could not be excluded)
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Previous therapies6 R CHOP every 21 days (total anthracycline dose 300 mg/m2)
2 R GDP (rituximab 375 mg/m2 on day 1, gemcitabine 1000 mg/m2, on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 75 mg/m(2) on day 1), every 21 days
2 R MAD (rituximab 375 mg/m2 on day 1 or 4, plus cytarabine 2000 mg/m2 and dexamethasone 4 mg/m2 every 12 h on days 1-3 plus mitoxantrone 8 mg/m2 on days 1-3) every 28 days
Z-BEAM (Zevalin (ibritumomab tiuxetan) given at the fixed dose of 0.4 mCi/Kg on day -14 followed by carmustine 300 mg/m2 on day -7, cytarabine 200 mg/m2 twice a day on days -6 to -3, etoposide 100 mg/m2 twice a day on days -6 to -3, melphalan 140 mg/m2 on day -2) auto-SCT (day 0), and R on days +1 and +8 after auto-SCT.
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Treatment and Outcome➢ Bendamustine 90 mg/m2 days 1 and 2 every 28 days x 4
cycles
➢ PET negativity after 4 cycles
➢ 2 additional cycles of bendamustine
➢ 30 Gy radiotherapy (right supraclavicular region)
➢ CR achieved
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➢ Bronchoscopy with transbronchial needle aspiration: granulomatous lymphadenopathy without necrosis
➢ Infection? sarcoidosis?
➢ Response to corticosteroid therapy
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Mediastinal lymph node biopsy
Mixed cellularity classical Hodgkin lymphoma (PAX5+, CD20+, CD30+, CD15-,
ALK-).
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Treatment
➢Brentuximab vedotin (BD) as single agent, 1.8 mg/Kg, every 21 days
➢Following the 4th cycle, grade 4 neutropenia, complicated by culture-negative severe sepsis.
➢ Response assessment ……
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PET/CT after 4 BV cycles (Dauville Score 5, with new bone lesions)
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What is next?Check point inhibitor
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HL and PD-1 Pathway
Nivolumab and pembrolizumab are monoclonal antibodies targeting the programmed death-1 (PD-1) immune checkpoint pathway
These antibodies bind PD-1 receptors on T cells and disrupt negative signalling triggered by PD-1 ligands, PD-L1/PD-L2, to restore T-cell antitumour function1,2
MHC
PD-L1
PD-1 PD-1
PD-1 PD-1
T-cellreceptorT-cell
receptor
PD-L1PD-L2
PD-L2
MHC
CD28 B7
T cell
NFκBOther
PI3KDendriticcell
Tumor cell
IFNγ
IFNγR
Shp-2Shp-2
Nivolumab: PD-1 receptor-blocking antibody
1. Brahmer JR et al. J Clin Oncol 2010;28:3167–75; 2. Wang C et al. Cancer Immunol Res 2014;2:846–56
CheckMate 205B
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Hodgkin Lymphoma - Response to NivolumabPR (70%) CR (17%)SD
(13%)
Ansell et al. N Engl J Med. 2015;372(4):311-9.
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Nivolumab therapy➢ 3 mg/kg IV over 1 hour every
second week
➢ An excellent response
➢ Recently, the patient completed the 26th cycle of nivolumab. So far, treatment has been well tolerated
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Biopsies, biopsies, and biopsies ….
11/2017 CT scan (24th nivolumab): axillary lymph node (LN) 26 x 21 mm, iliac LN 16 x 10mm
Tru-cut biopsy of axillary LN 1/2018 and 2/2018: no evidenceof HL
Proceed with nivolumab
3/2018 Excisional biopsy of axillary LN: no evidence of HL: grade 1-2 follicular lymphoma
3/2018 PET scan (33rd nivolumab): increased FDG uptake in cervical and axillary region (SUV 6.7), paraortic, iliac external and inguinal regions and pharynx (SUV 7.9)
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Proceed with nivolmab
8/2018 FDG PET scan (42nd cycle): metabolic progression of nodal disease
9/2018 Excisional biopsy of cervical node: follicular lymphoma grade 1-2
STOP Nivolumab (44th infusion)
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11/2018: start idelalisib 150 mg BID
2/2019 Partial response after 3 courses, assessed by FDGPET
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References
Eichenauer‒ DA, Aleman BMP, Andre ́M, Federico M, et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 29 (Supplement 4): iv19–iv29, 2018 Publishedonline 23 May 2018
Kuppers‒ R et al.: Pathogenesis, diagnosis, and treatment of composite lymphomas. Lancet Oncol. 10: e435-46, 2014.
Younes A et al.: Results ‒ of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 30:2183-9, 2012
Ansell SM et al.: ‒ PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372:311-9, 2015.
Gopal AK et al‒ . PI3Kδ Inhibition by Idelalisib in Patients withRelapsed Indolent Lymphoma. N Engl J Med 370:1008-18, 2014
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Discussion
‒ Whenever possible, each lymphoma recurrence shouldbe biopsy proven
‒ Transformation into aggressive lymphoma does not always occur in follicular lymphoma
‒ In rare instances, two distinct lymphomas occur concurrently in a patient. Such composite lymphomas can be combinations of two non-Hodgkin lymphomas or a combination of a non-Hodgkin lymphoma and a Hodgkin lymphoma.
‒ Disease progression following an initial response should alert the haematologist to the possibility of a switch from one lymphoma to another.