ASH Hematology Review Series

Aggressive B-cell Lymphomas

Jennifer Amengual, MD
Disclosures
• Appia Pharmaceuticals
• Daiichi Sankyo
• SeaGen
What is Lymphoma?
• Lymphoma is a clonal disease of
blood cells and lymph nodes.

• Lymphocytes originate in the

bone marrow, travel peripherally,
through the blood and lymphatic
system to the lymph nodes.

• Lymphoma and leukemia are

overlapping diseases
– Leukemia is defined by the Lymphoblastic lymphoma: Disease of immature lymphocytes
presence of malignant Management per Acute Leukemia practices
lymphocytes in circulation
– Lymphoma a proliferation that Chronic lymphocytic leukemia: Disease of mature lymphocytes
arises in a discrete tissue Management per CLL/Indolent lymphoma practices
Revision of the WHO Lymphoma Classification
More than 85 Sub-types and counting…

Armitage JCO 1998; Swerdlow Blood 2016

Stages of B-cell Development: Cell of Origin

ASH SAP Version 7

Aggressive B-cell Lymphomas
• Making the Diagnosis
• Diffuse Large B-cell Lymphoma (DLBCL)
– Biology: Cell of Origin: Germinal Center (GCB) vs Activated B-cell (ABC)
– Treatment Strategies
– Early Stage/Favorable Prognosis DLBCL
– Primary Mediastinal B-cell Lymphoma
– High Grade: Double Hit and Double Expresser
– Immunodeficiency-Related DLBCL
• HIV-associated, Primary Effusion Lymphoma, Post-Transplant Lymphoproliferative Disorder (PTLD)
– Testicular
– Primary CNS Lymphoma
– Relapsed Disease
• Burkitt’s Lymphoma
• Mantle Cell Lymphoma
• Long Term Follow-up/Survivorship
 Clinical Presentation • B-symptoms: Cytokine secretion
• Fever
• Days → weeks • Weight loss
• Pruritus
• Expansion of lymphocytes • Drenching night sweats
– Enlargement of lymph nodes, spleen
• Invasion into extranodal sites • Paraneoplastic Syndromes
• Plethora: Superior Vena Cava (SVC) – Nephrotic syndrome
syndrome
– Hemolytic anemia and ITP
• Neurological deficits: CSF involvement

– Cytopenias
• Infections: Neutropenia
• Fatigue: Anemia
• Bleeding, Petechiae: Thrombocytopenia
 Approach to the Patient
• History • Laboratory Evaluation /
– Duration of symptoms Procedures
– (Host) Environmental factors
• Chronic Infections: HIV, HCV, H pylori – LDH
• Auto-immune diseases – SPEP
• Immunosupression
• Chemicals and radiation – Beta-2 macroglobulin
– Family History and # of siblings – Sed Rate
– Ethnicity and place of birth – HIV, HBV, HCV, EBV, CMV,
HTLV-1
• Exam
– Consider Lumbar Puncture
– Lymphadenopathy
– Hepatosplenomegaly – Consider ECHO
– Rash
Making the Diagnosis
Excisional or Core Biopsy
– Morphologic examination
• Chromatin structure
• Architecture
– Immunophenotype
• Flow cytometry
• Immunohistochemistry
– Molecular and Genetics:
• Cytogenetics
• FISH (Fluorescence in situ hybridization)
• PCR (polymerase chain reaction)
• Gene expression panels (NGS)

Bone Marrow Biopsy

-Consider for staging purposes
Staging
CT Scans give PET Scans give details on
details on SIZE METABOLIC ACTIVITY
SUV
Activity
More
indolent
Deauville Description
Score
2-6
1 No FDG uptake
2 FDG uptake ≤ mediastinum

7-13 3 FDG uptake > mediastinum ≤ liver

4 FDG uptake > liver
5 FDG uptake markedly > liver

>15
More
Aggressive
Stage and Prognosis
IPI (International Prognostic Index)
Age >60
Serum lactate dehydrogenase concentration above normal
ECOG performance status ≥2
Ann Arbor stage III or IV
ECOG Performance Status
Number of extranodal disease sites >1

Score Risk group 3-yr OS, percent

0 to 1 Low risk 91

2 Low-intermediate risk 81

3 High-intermediate risk 65
4 to 5 High risk 59
A: Age
P: Performance
E: Extranodal Site
L: LDH
S: Stage III/IV

NEJM 1993, Sehn Blood 2007, Cheson JCO 2014, Barrington JCO 2014
Case 1
A 33 year-old man receives a diagnosis
of DLBCL and chemotherapy is advised. Which of the following should you
He has a history of hepatitis B without advise at this time?
complications. On examination, the A. Hepatitis B vaccine
patient has cervical adenopathy and
B. Surveillance for hepatocellular
no stigmata of chronic liver disease.
carcinoma
Laboratory test results are as follows:
alanine aminotransferase 17 U/L, total C. Entecavir
bilirubin 0.6 mg/dL, hepatitis B surface D. Pegylated interferon
antigen positive, hepatitis B surface E. Nothing further a this time
antibody negative, hepatitis B core except chemotherapy
antigen positive, and hepatitis B virus
(HBV) DNA undetectable.
Diffuse Large B-Cell Lymphoma
• Most common Lymphoma:
– Incidence 30,000/yr

– Accounts for 30% of all NHL

– Approximately 2/3 of patients are cured

– Can arise anywhere in the body

Hans Criteria
• Morphology CD10+ CD10-
GC Subtype
– Large cell size (4-5x a normal lymphocyte)
BCL6 -
– Diffuse growth pattern BCL6 +
ABC Subtype

• Immunohistochemistry MUM1- MUM1+

– (+)CD19 CD20 GC Subtype ABC Subtype
DLBCL Cell of Origin
Level of gene Germinal-center Activated
B-cell–like Type 3 B-cell–like
expression
High

Genes
Low

In Germinal Center-type, mutations of BCL6, Histone Acetyltransferases

and EZH2 lead to a repressed transcriptional state.

In ABC-type, mutations in the B-cell Recepter Pathway lead to

unchecked activation of NFkB.

Rosenwald NEJM 2002

DLBCL Cell of Origin

Wright Cancer Cell 2020; Chapuy Nat Med 2018

DLBCL Cell of Origin
LymphGen Classification
Characteristics OS
MYD88 L265P mutations and CD79B mutations
CDKN2A deletions 40%

NOTCH1 mutations. BCOR, IkB kinase β mutations 27%

TP53 mutations/deletions
63%
Aneuploidy
NOTCH2 mutations, BCL6 translocation,
67%
TNFAIP3 (A20), BCL10, PRKCB mutations

SGK1 and TET2 mutated 84%

EZH2, CREBBP, KMT2D, EP300 mutations and

48%
BCL2, MYC, TP53, GNA13, FOXO1 alterations

EZH2, CREBBP, KMT2D, EP300 mutations and

BCL2 translocations 82%
CARD11, TNFAIP3 (A2) alterations

Schmitz NEJM 2018; Wright Cancer Cell 2020

DLBCL Treatment Strategies:
National High Priority Lymphoma Study
• 1st Generation CHOP CR 45-55%, OS 30-35%
• 2nd and 3rd Generation Regimens added MTX:
– m-BACOD, ProMACE-CytaBOM, MACOP-B
– Initial reports of OS- 55-65%

• 1986 – 1991 SWOG Phase III compared these 4

regimens in Int/High Grade Stage II-IV NHL
– 899 patients
– Median f/up 35 m

• Fatal toxicities: 1% CHOP, 3%ProMace-

CytaBOM, 5% mBACOD, 6% MACOP-B

• No significant difference in Overall Survival

Fisher NEJM 1993
DLBCL Treatment Strategies:
R-CHOP Chemotherapy
• Rituximab 375mg/m2
• Cytoxan 750 mg/m2
– Alkylating Agent/Hemorrhagic Cystitis
• Doxorubicin 50 mg/m2
– Topoisomerase II Inhibitor
– Risk of cardiomyopathy -> check ECHO
• Vincristine 1.4 mg/m2
– Antimicrotubular
– Neuropathy, constipation
• Prednisone 100 mg PO days 1-5

– Usually every 3 weeks x 6 cycles

– Consider growth factor support
– Antibiotic prophylaxis in the elderly
– Highly emetogenic

Coiffier NEJM 2002

DLBCL Treatment Strategies:
Rituximab
• Monoclonal Antibody to CD20
• Mechanism of Action:
– Activation of the complement cascade, which generates the
membrane attack complex that can directly lyse B cells by
complement-mediated cytotoxicity.
– Phagocytosis and antibody-dependent cell-mediated
cytotoxicity.
– Interaction with natural killer cells via FcRIII and complement
receptor 3, which leads to antibody-dependent cell-mediated
cytotoxicity.

• Human-Mouse Chimera
– Allergic reactions can occur especially with first dose
• Pretreatment: Acetaminophen/Diphenhydramine, also have in
hand hydrocortisone
• Also useful: Dexamethasone, loratadine and famotidine
• Pearls:
• Reactivation of HBV – ALWAYS CHECK PRIOR, give
prophylaxis if evidence of exposure
• TLS w Leukocytosis: Malignant Lymphocytes >25,000
• PML from JC virus
• Hypogammaglobulinemia

Taylor Nat Reviews 2007

Risk of CNS Relapse
CNS IPI Score
>60 years old
ECOG ≥ 2
Elevated LDH
Stage III/IV
Extranodal sites ≥ 2
Kidney and/or Adrenal Involvement

• Other Risks to Recognize

– Bone marrow
– Gonads/Breast
– Boney/spinal lesions
– Liver
– Orbits
– Double Hit, Dual Expressers • Prophylaxis Strategies:
– HIV – Intrathecal Chemotherapy (Methotrexate) 4-6 cycles
– Leg-Type – High Dose Methotrexate (3-3.5 grams) or Cytarabine 2-4 cycles

Schmitz JCO 2016; Puckrin ASH 2020 Abs#477; Orellana-Noia ASH 2020 Abs#478
DLBCL Treatment Strategies:
Attempts to Improve Upon R-CHOP
• ECOG-ACRIN 1412: Lenalidomide+R-CHOP, Nowakowski NCT01856192
– Positive study: 2 yr OS 87% vs 80% (Len 25 mg days 1-10)
• ROBUST: Lenalidomide+RCHOP, Nowakowski NCT02285062
– Len 15 mg days 1-14
• POLARIX: Polatuzumab+R-CHP, Tilly, NCT03274492
• PHOENIX: Ibrutinib+R-CHOP, Younes NCT01855750
• GOYA: Obinutuzumab-CHOP vs R-CHOP, Sehn NCT01287741
• CAVALLI: GOYA +/- Venetoclax, Morschhauser NCT02055820
• ALLIANCE/CALGB 50303: R-CHOP vs R-EPOCH, Bartlett NCT00118209
DLBCL Early Stage Disease:
Intergroup NCTN Study S1001
• Stage I/II, non-bulky ( <10cm)
• IPI: 0-3 (majority 0-2)
• R-CHOP x 3
• C3D15-18: PET/CT
– Deauville 1-3 (iPET-neg): additional R-CHOP
– Deauville 4-5 (iPET-pos): IRFT followed by
ibritumomab tiuxetan

• iPET-pos and iPET-neg have similar outcomes

– 5-yr PFS 86% vs. 88%
– 5-yr OS 93% vs. 91%

Persky JCO 2020

 DLBCL Favorable Disease:
FLYER Study: Short Course R-CHOP
• Phase III, non-inferiority
• Stage I/II, non-bulky (<7.5cm)
• IPI=0
• Age 18-60
• R-CHOP x 4 followed by rituxan
x 2 vs. R-CHOP x 6
• PET/CT after 3 and 6 cycles
• CR: 92% with 6 cycles vs. 91% with 4 cycles
• PFS: 94% vs. 96%
• EFS: 89% vs. 89%
• OS: 98% vs. 99%

Poeschel Lancet 2019

Primary Mediastinal Large
B-Cell Lymphoma
• Large mediastinal mass
– SVC syndrome, thrombosis common
• COO closer to HL than DLBCL
– CD30+, CD20+, c-rel, TRAF-1, PD-L1, CIITA
• Female > Male
• Med age 35

• DA-EPOCH-R
• Continuous infusion of chemotherapy
prevents resistance to treatment
• Dose is adjusted based on nadir of ANC
• Vincristine does not escalate

Rosenwald JEM 2003, Dunleavy NEJM 2013

Primary Mediastinal Large B-Cell Lymphoma
N=51

No patients required XRT

Of all cycles administered,

13% of these were associated
with admission for neutropenic
fever.

Only 6% of patients had ANC

Nadir <500

40% patients were escalated

to dose level 4

Dunleavy NEJM 2013

High-Grade B-cell Lymphoma

(A) HGBCL MYC/BCL6 + (B)Burkitts

(C) HGBCL MYC/BCL6/BCL2 + (D) DLBCL MYC/BCL2 +

Swerdlow Blood 2016

High Grade B-cell Lymphoma
MYC, BCL2, BCL6
• Double Hit Lymphoma
– DLBCL harboring translocations involving MYC and BCL2
or BCL6 oncogenes
– Represents 5-10% DLBCL
– Cumulative CNS disease 13%
– Disease of the elderly with average age approaching
71%

• Double Expresser Lymphoma

– Account for 20-25% of new DLBCL
– MYC protein expression (>50% cutoff)
– Associated with concomitant BCL2 expression (>70%
staining cutoff)
– Most do not carry translocations
– Generally have worse prognosis than DLBCL but not as
bad as DHL

Landsburg JCO 2017

HIV Associated DLBCL

Myc+ Myc +/-

CD138/CD38+

Dunleavy Blood 2012

HIV Associated DLBCL
• AIDS Malignancy Consortium- tested concurrent vs sequential rituximab in
110 patients

• R-EPOCH
– Doses adjusted based on counts
– Rituximab dosed when CD4>50
– Cytoxan: C1 187mg/m2 if CD4<100; 375mg/m2 if CD4>100
• C2-6: increase by 187mg/m2 if ANC nadir >1000 or plt nadir > 25,000
• C2-6: reduce by 187mg/m2 if ANC nadir <500 or plt nadir < 25,000
– Prophylatic Abx Support: Bactrim, Fluconazole, Quinilone days 8-15
– Patients who were on ART remained on ART * Consult with pharmacist regarding
interactions especially between protease inhibitors and vincristine*
– High risk for CNS relapse – recommend prophylaxis

• Concurrent Arm: ORR 88% (CR 73%), 2 yr OS= 70%, 2-yr PFS=66%

Sparano Blood 2010

Immunodeficiency Associated DLBCL
EBV(+)
• Setting of T-cell Primary Effusion Lymphoma
immunodeficiency – KSHV/HHV-8 associated
– Congenital immunodeficiency – HIV-associated or elderly
– Chronic immunosuppression
post-transplant
– Autoimmune phenomena
• Elderly
• Often have extranodal
disease
• Poor prognosis
Post-Transplant Lymphoproliferative
Disease (PTLD) • Early (<1 year post transplant)
– Acute EBV infection /
Often EBV (+) CD30 (+) reactivation in the setting of a
reduction in anti-EBV
Early Lesions Polymorphic cytotoxic T cell lymphocyte
Reflect EBV Infections Architectural effacement precursors
doesn’t meet criteria for
monomorphic
• Late (>1 year post transplant)
– Presumed to be the
Monomorphic Hodgkin-Like manifestation of lymphocyte
DLBCL deregulation in a chronically
Burkitt’s immunosuppressed state
PTCL
Plasma cell disorders • No treatment consensus:
– Reduce Immunossuppression
– Rituximab
– ?Brentuximab
– RCHOP vs R-EPOCH

Kojima Path Res and Pract 1998; Dharnidharka Nature Rev 2016
Primary Testicular DLBCL

• Most present with localized

disease
• Despite this high risk for relapse
– Treat with R-CHOP x 6 cycles
– Contralateral Testes
• XRT to tests
– CNS
• CNS Prophylaxis
• MYD88 and PD-L1 expression

Zucca JCO 2003

Primary CNS DLBCL • CNS Penetrant Therapies:
• High Dose Methotrexate 3-8
• Most ABC subtype grams
– CD79B, PIM1, MYD88, PD-L1 • Rituximab
• Can involve parenchyma, • Cytarabine
cranial nerves, eye, spinal • Thiotepa
cord, meninges • Temozolomide
• Work-up includes biopsy, • Whole Brain XRT
LP, BMBx, slit lamp exam, • ASCT
whole body PET/CT, • Potential Novel Agents:
lenalidomide, ibrutinib, PD1
testicular ultrasound
inhibitors
Relapsed DLBCL

Relapses occur in ~20-40% Evaluation for Transplant

– Fitness
Confirm with biopsy – Other medical problems
– Amount of residual lymphoma
Relapsed or Refractory DLBCL
Transplant Eligible
Second-line Chemotherapy ~ 60% Response Rate
• Rituximab +
• DHAP: Dexamethasone, cisplatin, cytarabine
• DHAX: Dexamethasone, cytarabine, oxaliplatin
• GDP: Gemcitabine, dexamethasone, cisplatin/carboplatin
• ICE: Ifosfamide, carboplatin, etoposide
• ESHAP: Etoposide, methylprednisolone, cytarabine, cisplatin
• GemOX: Gemcitabine, oxaliplatin
• MINE: Mesna, ifosfamide, mitoxantrone, etoposide

Alphabet Soup Basic Recipe

• Steroid: dexamethasone or methylprednisolone
• Platinum: Cisplatin, carboplatin, oxaliplatin
• Antimetabolite: Cytarabine, gemcitabine
• Alkylating agent: Ifosfamide
• Topoisomerase Inhibitor: Etoposide
Relapsed or Refractory DLBCL
ASCT
• CORAL STUDY:
• R-DHAP vs. R-ICE x 3 cycles followed by ASCT
• 62% of the patients s/p CHOP-like regimen
• ORR: 63% vs 63.5%, respectively with no difference in PFS or OS
• GC-DLBCL had improved outcome to R-DHAP compared to R-ICE as assessed by Gene
Expression profiling (3-year PFS 100 % vs 27%)

Gisselbrecht JCO 2010

ASCTs are Declining in the U.S.

First CAR-T Approval

Shah Blood 2021

Relapsed Refractory DLBCL
CAR-T Therapy
• Living Drug
• General Toxicities
– Fever
– Cytopenias
– Neurotoxicity
– Cytokine Release
Syndrome (CRS)
• Fever
• Low blood pressure
• Low oxygen
• Usually occurs within 2
days of treatment

Cancer.gov
Relapsed Refractory DLBCL
CAR-T Therapy Tisagenlecleucel
(Kymriah)
ORR 53%
CR 40%

Lisocabtagene
maraleucel
(Liso-cel/Breyanzi)
Axicabtagene ORR 73%
ciloleucil CR 54%
(Axi-cel/Yescarta)
ORR 82%
CR 54%

Neelapu NEJM 2017; Schuster NEJM 2019; Abramson Lancet 2020

New Treatment Strategies for R/R DLBCL
Polatuzumab
• Polatuzumab targets CD79b
with MMAE warhead
• 80 patients randomized with
Rituxan-Bendamustine in
R/R DLBCL in phase 2

Sehn JCO 2020

New Treatment Strategies for R/R DLBCL
Polatuzumab

Sehn JCO 2020

New Treatment Strategies for R/R DLBCL
Selective Nuclear Export Inhibitors
Selective Nuclear Export
Inhibitors (SINE) or Exportin
Inhibitors block the exit of
proteins from the nucleus

Forces retention of Tumor

Suppressors: p53, p21 in the
nucleus

Reduces the entry Oncogenes:

Myc, Bcl2, Bcl6 into the nucleus
New Treatment Strategies for R/R DLBCL
Selective Nuclear Export Inhibitors
Selinexor given 60 mg PO days 1 and 3 each week
Responses seen regardless of subtype
Median Duration of Response 9.3 months

Kalakonda Lancet Hem 2020

New Treatment Strategies for R/R DLBCL
Tafasitamab + Lenalidomide

Salles Lancet Onc 2020

New Treatment Strategies for R/R DLBCL
Tafasitamab + Lenalidomide

Salles Lancet Onc 2020

New Treatment Strategies for R/R DLBCL
Loncastuximab Tesirine
• Patients with R/R DLBCL have a poor prognosis and unmet
need for new treatment options
• Lonca had substantial antitumor activity and an
acceptable
safety profile in this single-arm open-label Phase 2 study
(NCT03589469) in adult patients with R/R DLBCL, who had
failed ≥2 established therapies

30-minute infusion of Lonca Q3W for up to 1 year Q12W for up to 3 years

150 µg/kg 75 µg/kg Follow-up

First 2 cycles After 2 cycles

Treatment-related TEAEs leading to treatment

Most common (≥10%) grade ≥3 TEAEs were:
discontinuation occurred in 26 (17.9%) patients, most
• Neutropenia (38 patients; 26.2%)
commonly (≥2%):
• Thrombocytopenia (26 patients; 17.9%)
• GGT increased (16 patients; 11.0%)
• GGT increased (25 patients; 17.2%)
• Peripheral edema (4 patients; 2.8%)
• Anemia (15 patients; 10.3%)
• Localized edema (3 patients; 2.1%)

Caimi Lancet Onc 2021

New Treatment Strategies for R/R DLBCL
Loncastuximab Tesirine
100 Complete response Lonca ORR:
90 Partial response
80
All patients
48.3%
Response (%)
70 (95% CI: 39.9, 56.7)
60 (N=145)
50
40
24.8
30 Lonca CRR:
20
10 23.4 24.8%
0 (95% CI: 18.0, 32.7)

Most responders had a response after 2 cycles; median time to first response was 41.0 days (range: 35–247)
Mean Lonca cycles: 4.5 (Std: ± 3.89) (Min, max: 1, 18)*

• 15 patients received CD19-directed CAR-T therapy with an

investigator-assessed ORR of 46.7% (6 CR; 1 PR)
• 9 patients proceeded to SCT as consolidation after Lonca
response

Caimi Lancet Onc 2021

DLBCL:
Themes to Remember
• Most common B-cell NHL
• 60-75% patients are cured
• R-CHOP therapy is used for most
• EPOCH-R is used for select cases
• PMBCL, HIV-Associated, DHL
• In relapsed setting first biopsy
• Assess if transplant eligible or not
• Salvage therapies lead to 60% ORR
• If not in complete remission
• Consider CAR-T
• New targeted options now
approved
 Case 2
A 18 year-old female presents with Which cytogenetic abnormality is
rapidly enlarging jaw mass, early present:
satiety and fevers. A. t(8;14)
Biopsy reveals high mitotic index B. t(14;11)
and apoptotic remnants, CD20+,
C. t(14; 18)
Bcl2(-), myc (+), Ki67 100%.
D. t(2:5)
Burkitt Lymphoma
Three Variants
Sporadic
HIV Associated -15-20% EBV infected
-25% latent -IgH locus translocations
EBV infection t(8;14)
African Endemic
- Most common
-All EBV infected
Lymphoma in children
- Mostly in children
- Ileocecum and peritoneum
- Mass involving mandible,
Abdominal viscera, kidneys,
ovaries, adrenals
Burkitt Lymphoma • Molecular
– Translocation c-MYC gene
• t(8;14) IgH
• Morphology
• t(8;22) Lambda
– Effaced by diffuse infiltrate • t(2;8) IgKappa
– Intermediate size round or oval – p53, TCF3, ID3 mutations
nuclei
– High mitotic index and numerous
apoptotic cells
– Nuclear remnants are phagocytosed
by benign macrophages

• Immunophenotype
– (+)CD19, 20, 10, Bcl6; (-)TdT
– Ki67 100% (Proliferative index)
– Almost never expresses Bcl2
Burkitt MD Anderson
2006 Cancer (updated 07)
PETHEMA Group
2008 Cancer
NCI
2008 ESMO meeting
NCI
JCO 1996

Treatment HyperCVAD+R
compared to historical control
-- 8 cycles of treatment and 8
GMALL NHL2002
protocol
DA-EPOCH-R
--3-6 cycles with one cycle
beyond CR
MAGRATH
-- CODOX-M-IVAC
--4 cycles in high risk patients
(German Multicenter Study
doses of Rituxan Group) -- 3 cycles CODOX-M for low risk
--6 cycles of treatment with 8 patients
doses of Rituxan

28 patients 36 patients 23 patients 26 patients

- median age 46 - median age - median age = 31 - median age = 25
- 29% > age 60 HIV(-)=36, HIV(+)=39 - 34 % HIV (+) - no HIV + patients
- 77% male - 53% HIV (+) - 78% male 14 patients
- no HIV pts - 80% male
- median age 47
CR=86% (vs 85%) CR=88% HIV- (vs 71- CR/CRu= 100% CR = 100%
ORR=96% 74% in NHL86, 90) ORR in older group =
CR=84% HIV+ 86%
3 yrs OS=89% (vs 53%) 2 yr OS (vs 4yr OS At 27 month f/up: 2 yr EFS = 100%
3 yrs DFS=88% 51%) OS = 100% 47 month DFS = 85%
HIV(+) = 82% PFS = 100%
HIV(-) = 95% EFS = 95% In older group: 21
2yr DFS HIV(+)=93% month DFS= 72%
HIV(-)=95%
Toxicities→dose reductions in Toxicities→ Toxicities→ Toxicities→
57% - neutropenia resulting in one - TLS in 1 pt -Neutropenia 100%
-4 pts w thrombocytopenia early discontinuation at 4 - Neutropenic fever 16% -- Mucositis 61%
-1 general poor condition cycles -- Sepsis 22%
-1 death -17% grade 3-4 mucositis
-17% septic episodes
Burkitt Lymphoma
Teaching Points Starry Starry Night
• Fastest growing lymphoma
– Ki67 nearly 100%
• Most common lymphoma in
children
• C-MYC Translocations
– Chromosome 8
• Often EBV associated
• Highly curable with
intensive chemotherapy
 Case 3
A 78 year-old male presents with You discuss which treatment with
fatigue and weight loss. CT scan the patient:
reveals lymphadenopathy above A. HyperCVAD
and below the diaphragm, as well
B. Maxi-RCHOP alternating with
as splenomegaly.
high dose cytarabine
Immunohistochemistry from biopsy followed by ASCT
reveals CD20bright, CD5(+),
C. R-Bendamustine
CD23(-) round cells. Ki67 is 25%.
Cytogenetics notable for t(11;14). D. CAR-T Therapy
Mantle Cell Lymphoma
• 6% of all NHLs • 3 Main Variants:
• Male predominance
– Blastoid: Ki67 >90%
• Advanced disease
• Extranodal sites: GI tract
– Aggressive: Ki67 >25%

– Indolent/Leukemia: Ki67 ~10%,

behaves like CLL, presents with
splenomegaly and peripheral
blood involvement
Mantle Cell Lymphoma
• Morphology
– Nodular to diffuse
– Small lymphocytes

• Immunohistochemistry
– Cyclin D1 (+)
– (+) CD5, CD19, CD20, FMC7,
IgM/IgD
– (-) CD23, CD10
– +/- SOX11, p53

• Molecular: t(11;14)(q13;q32)
Mantle Cell Lymphoma
Prognosis
M-IPI Prognostic Score

Points Age ECOG PS LDH/ ULN WBC

0 < 50 0-1 < 0.67 < 6700

Low IPI Ki67<30
Low IPI Ki67>30/Int IPI <30
1 50-59 0.67- 6700- Int IPI Ki67 >30/Hi <30
0.99 9999 Hi IPI Ki67 >30

2 60-69 2-4 1.0- 10k- Ki67

1.49 15k

3 >/= 70 > 1.5 >15k

Hoster Blood 2008; Hoster JCO 2016

MCL Confirm the diagnosis:
t(11;14) Cyclin D1 +

Front Line CD5+, CD23-

SOX11+

Treatment Strategy Risk Stratify:

MIPI, Ki67, p53,
Blastoid Variant

High Risk:
Ki67 >30%
High Risk MIPI
Diffuse Disease
Low Risk:
Ki67 <10%
Low Risk MIPI
Limited Disease
Physiologically “Young” Physiologically “Old”

Limited Therapy
Rituximab monotherapy
Dose-intensified Lenalidomide
R-Maxi-CHOP-HiDAC or Conventional
BTK Inhibitor
Hyper CVAD R-Bendamustine
Watch and Wait
Auto-Stem Cell Transplant BTK Inhibitor
Frontline MCL:
Intensive Immunochemotherapy + ASCT
• Median Obs. 11.4 years
• 10 yr OS 12.7y PFS 8.5yrs
Nordic Lymphoma Group Experience (MCL-2) • A subset of patients with molecular relapse received
rituximab maintenance
• Late toxicity – 11/160 with secondary malignancies

Geisler BJH 2012; Eskelund BJH 2016

 Frontline MCL:
R-Bendamustine
BRIGHT Study
R-CHOP/R- P P
BR CVP CR Value Value
Evaluable: IRC (n = 213) (n = 206) Ratio (NI) (Sup)
1.26
CR 31 25 (0.93- 0.022
(95% CI) (25.3-38.2) (19.5-31.7) 1.73) 5 0.1269

PR 65 66

OR of CR + PR 97 91
(95% CI) (93.3-98.7) (86.0-94.4)

Similar results across studies of iNHL and MCL

Flinn Blood 2014; Rummel Lancet 2013

 Recommended Bendamustine Dosing
• BR was associated with a higher • Initial therapy:
incidence of nausea and vomiting, • 90 mg/m2 d 1-2, q 4 wk
pyrexia, chills, drug hypersensitivity, • Prior cytotoxic therapy:
decreased appetite, rash, and pruritus • 60-70 mg/m2 d 1-2, q 4 wk
• Dosing in renal or hepatic dysfunction not
• R-CHOP and R-CVP were associated
fully defined
with a higher incidence of
constipation, paresthesia, peripheral • Precautions:
neuropathy, and alopecia – Myelosuppression, infections
– Infusion reactions, tumor lysis syndrome
• R-CHOP was associated with a higher – Rash, esp. with concomitant allopurinol
incidence of febrile neutropenia and
mucosal inflammation
Relapsed MCL:
Targeted Therapies
FDA
Target Drug
Approval • Other considerations:
Ibrutinib • Can use bendamustine if hadn’t
BTK Acalabrutinib
✔️ received in frontline
Zanubrutinib
• Allo an option
Idelalisib (δ)
Copanlisib (α, δ) • CAR-T an option
PI3K
Duvelisib (γ,δ) • Weigh toxicities and treatment
Umbralisib (δ)
goals
Lenalidomide
IMID ✔️

BCL2 Venetoclax
Proteosome Inhibitor Bortezomib ✔️
mTOR Inhibitor Everolimus ✔️ EU

62
 Relapsed MCL:
Bortezomib
• Multicenter, international trial Relapsed/
refractory Bortezomib
• All pts had rec’d prior anthracycline; 1.3mg/m2 IV bolus d1, 4, 8, 11 q3w →
MCL
• 1/3 with prior SCT (N=154) 4 cycles beyond CR, up to 1 year

• 90% of expected doses delivered

• 59% with >/= 4 cycles
• ORR 33%
• CR/CRu 8%
• Median DR 9.2 months, Median OS not reached
• DR 13.5 months for CR/CRu
• Rapid onset of response
• No difference in response if:
• Refractory to prior therapy
• Prior HDT or HyperCVAD

Fisher JCO 2006

Lenalidomide: Proposed Mechanism of Action

Expansion of T-cells: NK-cell Effects:

IL2 ↑ Immune Synapse
↑ Immune Synapse
↑T cell Activation CD20 ↑ADCC
actin
↑ Proliferation ↑ Direct NK-mediated
IFN
↑ CD8+ T-cell Effector killing
activity

Binding of Cereblon: CXCR4

IgG
binds to the E3 ubiquitin Microenvironment Effects:
FGF2 ↓ FGF2
ligase complex co-receptor,
Cereblon Altered Cytokine Levels
-this leads to down-reg of IRF4 ↑ IgG production
Inhibiting BCR dep NF-kB
Witzig JCO 2009; Zhang Am J. Hematol 2009; Ferrajoli Blood 2009
Relapsed MCL:
Lenalidomide + Rituximab

• Lenalidomide 20 mg
days 1-21/28
• Rituximab weekly x 4,
then maintenance
• Tox: cytopenias, febrile
neutropenia

Wang Lancet Onc 2012

Relapsed MCL:
BTK Inhibition
• Ibrutinib
• First in class Bruton's tyrosine
kinase (BTK) inhibitor
• Highly effective in lymphomas with
tonic BCR signaling
• Blocks mantle cell migration and
adhesion
• Blocks pERK, pJNK, and NF-kB
pathways in mantle cell lymphoma
lines.
Relapsed MCL:
Ibrutinib
Hematogenous AE:
Neutropenia Gr 3/4Hemorrhage 4%
Thrombocytopenia
Anemia
Any bleeding/bruising 39%
Nonhematogenous AE:
Cardiac Arrhythmias 4%
Diarrhea
Fatigue
Nausea
Upper respiratory tract infection
Dyspnea
Edema Peripheral
Rash
Constipation
Vomiting Grade
Decreased appetite 1
Contusion Grade
Abdominal pain 2
Cough Grade
Dizziness 3
Myalgia Grade
Pyrexia 4
Hyperuricemia Grade
Mucosal inflammation 5
Sinusitis
Urinary tract infection
0% 10% 20% 30% 40% 50% 60 % 70 % 80 % 90 % 100
%

Wang Blood 2012

Treatment for Relapsed MCL
Ibrutinib
Ibrutinib 560 mg daily, N= 111

Wang NEJM 2013

Relapsed MCL:
Acalabrutinib
• Acalabrutinib is a highly selective, potent BTK inhibitor developed to minimize off
target activity which may be responsible for Afib, infection and bleeding seen with
Ibrutinib
• Multicenter phase 2 study –
– excluded pts with prior
BTK, SYK, PI3K and BCL2 inhibitors
• 124 patients
• 100 mg PO BID
• Well tolerated without the off-
target side effects

Wang Lancet 2018

Relapsed MCL:
Acalabrutinib

Wang Lancet 2018

Relapsed MCL:
Zanubrutinib

Song CCR 2020

71
Relapsed MCL:
KTE-X19 CAR-T

Wang NEJM 2020

72
Mantle Cell Lymphoma
High Yield Facts
• CD5(+), Cyclin D1(+), t(11;14)
• CD23 (-) and CD20(+)Bright
differentiates from CLL
• Can range from indolent to aggressive
• Ki67!
• Treatment according to risk
• Intense Chemo→ASCT
• R-Benda
• Many Targeted options
• BTK inhibitors
• Lenalidomide
• CAR-T
 Aggressive B-cell Lymphoma
Follow Up and Survivorship
• Restage after cycle 4 with CT or PET/CT (PET can lead to false +)
• Restage at completion of treatment, then q 6 m x 2 years
– If (+) scan – re-biopsy to confirm relapse
• Exam and labs every 3-6 months x 5 y
• Evaluate for late side effects:
– Early bone loss – bone density test, dental care
– Sexual dysfunction, infertility, early menopause
– Thyroid dysfunction (XRT)
– CAD (XRT) and cardiomyopathy (anthracycline)
– Lung disease (bleo)
– Early cancer screening: mammo, colonoscopy
Aggressive B-cell Lymphomas
• Making the Diagnosis
• Diffuse Large B-cell Lymphoma (DLBCL)
– Biology: Cell of Origin: Germinal Center (GCB) vs Activated B-cell (ABC)
– Treatment Strategies
– Early Stage/Favorable Prognosis DLBCL
– Primary Mediastinal B-cell Lymphoma
– High Grade: Double Hit and Double Expresser
– Immunodeficiency-Related DLBCL
• HIV-associated, Primary Effusion Lymphoma, Post-Transplant Lymphoproliferative Disorder (PTLD)
– Testicular
– Primary CNS Lymphoma
– Relapsed Disease
Thank you for listening!
• Burkitt’s Lymphoma
• Mantle Cell Lymphoma Look forward to your questions.
• Long Term Follow-up/Survivorship
ASH Hematology Review Series
Aggressive B-cell Lymphomas
Updates
Jennifer Amengual, MD
 POLARIX Study: Polatuzumab Vedotin + RCHP
vs RCHOP as Frontline DLBCL Therapy
• International Phase 3 placebo-controlled study
• Primary Endpoint PFS, Secondary Endpoint OS
• N=879
• Median F/up 28.2 m
• mPFS 76.7% vs 70.2%, HR 0.73
• Improved outcome most pronounced in:
– patients > 60 yr old; High IPI; ABC subtype
• No change in OS; HR 0.94; or CR rate
• Safety similar between both arms
– Higher neutropenic fever, but not infection in P-RCHP arm

Tilly NEJM 2022

 CAR-T v ASCT for 2nd-Line
LBCL Therapy
Zuma-7

Locke NEJM 2022

CAR-T v ASCT

Locke NEJM 2022; Bishop NEJM 2022; Kamdar ASH 2021

Westin and Sehn Blood 2022

CAR-T Therapy Instead of ASCT for LBCL?
Zuma-7/Yescarta
• TRANSFORM
• Lisocabtagene (Liso-cel) vs SOC-ASCT in 2nd
Line.
• Results favor CART
• EFS 2.3 v 10.1 m; PFS 5.7 v 14.8 m

• BELINDA Study:Tisagenlecleucel (Kymriah)

• Not superior to SOC

• Retrospective study of axicabtagene vs ASCT

following PR to salvage therapy
• ASCT superior OS and lower POD
Locke NEJM 2022, Kamdar ASH 2021; Bishop NEJM 2022; Shadman Blood 2022