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

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;

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

Diagnosis

Follicular non-Hodgkin lymphoma, Grade 2.

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

Final Diagnosis

Follicular non-Hodgkin lymphoma, Grade 2.

Stage 4 A

FLIPI 2 : Score 1

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

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

Treatment decisions and response

‒ 6 x R-CHOP + 2 x rituximab

‒ Achieved complete remission (CR)

➢ 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

Diagnostic work-up

Re-biopsy first, with the suspicious of transformation

➢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

Diagnostic work-up

Re-biopsy first, with the suspicious of transformation

➢Biopsy: Mixed cellularity classical Hodgkin lymphoma (persistence of follicular lymphoma could not be excluded)

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.

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

➢ Bronchoscopy with transbronchial needle aspiration: granulomatous lymphadenopathy without necrosis

➢ Infection? sarcoidosis?

➢ Response to corticosteroid therapy

Mediastinal lymph node biopsy

Mixed cellularity classical Hodgkin lymphoma (PAX5+, CD20+, CD30+, CD15-,

ALK-).

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 ……

PET/CT after 4 BV cycles (Dauville Score 5, with new bone lesions)

What is next?Check point inhibitor

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

Hodgkin Lymphoma - Response to NivolumabPR (70%) CR (17%)SD

(13%)

Ansell et al. N Engl J Med. 2015;372(4):311-9.

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

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)

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)

11/2018: start idelalisib 150 mg BID

2/2019 Partial response after 3 courses, assessed by FDGPET

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

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.