Self-assessment Case

DLBCL and Double Hit Lymphoma: Diagnosis and Treatment (First Line and Relapsed Disease)

Speaker: Burhan Ferhanoğlu, MD

İzmir, Turkey

April 6-7, 2019

EHA-TSH Hematology Tutorial on Lymphoma

Introduction

‒ A 69-year-old woman presented in March 2015with fatigue, decreased urine output and leftinguinal pain

‒ PET/CT revealed generalised involvement of supra-and infra-diaphragmatic lymph nodes andincreased FDG in mesentery, retroperitoneum andendopelvic fascia.

‒ Bilateral urinary stent was placed to manageureteric obstruction

‒ Biopsy of the retro-peritoneal mass performed.

- Immunohstochemical analysis showed DLBCL with a Kİ67 score of 80%

- The tumour cells were CD20,PAX5(+) bcl6, bcl2( 70%+), CD10 and, c-myc (>70%+)positive

IHC

CD5 negativeTdT negative

Bone marrow

Q1) According to immunohistochemical data, our DLBCL case is of:

1. Germinal center B-cell origin

2. Non-germinal center B-cell origin

Hans et al. Blood 2004

The initial PET/CT scanMach 2015

- Although our 69 year-old patient presented withfatigue, she was managing her daily activitieswithout difficulty.

- Involvement of the urinary bladder was biopsyproven

- The serum LDH level was above the upper limit of normal

Q2) What is the correct IPI score?

1. IPI 1

2. IPI 2

3. IPI 3

4. IPI 4

5. IPI 5

Bachy and Salles. Seminars in Hematology, 2015

IPI R-IPI NCCN-IPI

Age

>40 to ≤60

>60 to ≤75

>75

1 1

1

2

3

LDH

>1 to ≤3

>3

1 1 1

2

Ann Arbor Stage III-IV 1 1 1

Extranodal disease

>1 site

Any if BM, CNS, liver, GI tract or lung

1 1

1

Performance status ≥2 1 1 1

Score

Low

Low-intermediate

High-intermediate

High

0-1

2

3

4-5

0

1-2

≥3

0-1

2-3

4-5

≥6

Q3) Which additional genetic test(s) would you recommend according to immunohistochemical results?

1. MYC rearrangement

2. BCL2 rearrangement

3. BCL6 rearrangment

4. p53

5. MYC rearrangment first, and if it positive, BCL-2and BCL-6 rearrangement

All cases of DLBCL should be tested forMYC rearrangment

by FISH

further testing forBCL2 and BCL6

rearrangements

If the system has enough sources, evaluation of all three rearrangements is

recommended

Valera A. Mod Pathol.2016

Kluk MJ et al. Am J Surg Path 2016

Q4) What is your diagnosis according to WHO 2016 classification?

1. DLBCL

2. Plasmablastic lymphoma

3. Intravascular lymphoma

4. EBV+ DLBCL

5. High grade B cell lymphoma with MYC, BCL2 and BCL6 re-arrangement

Friedburg J.Blood 2017

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)Germinal-centre B-cell-like (GCB)Activated B-cell-like (ABC)

DLBCL subtypesT-cell/histiocyte-rich large B-cell lymphomaPrimary DLBCL of the CNSPrimary cutaneous DLBCL, leg typeEpstein-Barr virus–positive DLBCL, NOS of the elderly

EBV+ mucocutaneous ulcer

Primary mediastinal (thymic) large B-cell lymphomaIntravascular large B-cell lymphomaDLBCL associated with chronic inflammationLymphomatoid granulomatosisALK-positive DLBCLPlasmablastic lymphomaPrimary effusion lymphoma

HHV8-positive, DLBCL, NOS

B-cell lymphoma, with features intermediate between DLBCL and classical Hodgkin Lym.B-cell lymphoma, with features intermediate between DLBCL and Burkitt lymphoma

H i g h g r a d e B - c e l l l y m p h o m a , w i t h M Y C a n d B C L 2 a n d / o r B C L 6 r e a r r a n g e m e n t s , N O S

DLBCL WHO Classification Update 2016

Q5) Which regimen would you prefer to treat our patient?

1. R-CHOP

2. R-mini-CHOP

3. R-CHEOP

4. DA-EPOCH

5. Hyper CVAD

Oki et al. BJH 2014

Median ageR-CHOP: 62DA-EPOCH-R: 65 RHCVAD/MA: 55

R-CHOP: 57 (%44)R-EPOCH: 28 (%22)R-HCVAD/MA: 34 (%26)Other 10 (%7)

P=0.004 P=0.057

Q6) Regarding CNS involvement risk in this condition:

1. CNS prophylaxis should be offered for every DHL case

2. I would decide according to CNS-IPI

3. I would not offer intrathecal prophylaxis due to age

4. I would offer Hyper-CVAD which would provide required protection for CNS

5. I would offer intrathecal prophylaxis only

Oki et al. BJH 2014

13%

IT prophylaxis; 3 year CNS involvementdecreased from 15% to 5% (p=0.017)

Bone marrow involvementECOG ≥2

- After 2 courses of R-CHOP+ IT MTX, wereceived FISH analysis results, so then weswitched to DA-EPOCH

- Grade 4 neutropenia and related febrileepisode occured

- She had grade 4 mucositis and severe nutritional impairement

-Interim PET after2 R-CHOP and

2 cycles of DA-EPOCH

-still there wasDeauville5

changes in areasinvolved in July

2015

- She had severe pain and fatigue

- The PET scan before 6th cycles revealedprogressive disease

InitialInterim

Before 6th cycle

Q7) What is your next approach for this patient?

1. Refer for a clinical trial

2. Salvage regimen with stem cell support

3. R-Bendamustine

4. Venetoclax

5. Ibrutinib

- We planned to administer 3 cycles of ICE; to collectperipheral stem cells following the first cycle and toevaluate the disease status after the second cycle andperform ASCT

- Before the ICE treatment, atypical cells were seen in thecerebrospinal fluid and CNS involvement wasdemonstrated

- The bone marrow was also infiltrated

Bone Marrow

CSF

- After 2 courses of R-ICE chemotherapy, weadministered 1.5 g/m2 methotrexate due to CNS involvement in addition to IT MTX which was given 4 times in the beginning.

- -The disease progressed and she died on November2015, 8 months after diagnosis.

Self-assessment Case

DLBCL and Double Hit Lymphoma: Diagnosis and Treatment (First Line and Relapsed Disease)

Speaker: Burhan Ferhanoğlu, MD

İzmir, Turkey

April 6-7, 2019

EHA-TSH Hematology Tutorial on Lymphoma