The Biology & Treatment

of Plasmablastic
Lymphoma
MONA SHAFEY, MD, FRCPC
HEMATOLOGY NOON ROUNDS OCTOBER 15, 2015

Objectives

To describe the pathological features of this disease and discuss the

challenges associated with making this diagnosis

To review the outcomes with current therapies for HIV and non-HIV
associated plasmablastic lymphoma (PBL)

Tale of Two Cases

Case 1

Case 2

47F, HIV positive x10 years, presents

with vaginal mass biopsy proven to be
plasmablastic lymphoma

42M, HIV negative, presents with

nasopharyngeal polyp biopsy proven
to be plasmablastic lymphoma

Non-bulky vaginal mass with local

extension into anal area, no LN or
disease elsewhere. BM negative.

Disease localized to nasal polyp, no

LN, BM negative.

C-MYC not reported. EBER+. LDH

normal. ECOG 0.

C-MYC negative. EBER+. LDH 291.

ECOG 0.

Questions to Consider:
HIV vs. non-HIV PBL

Is HIV-associated PBL pathologically distinct from non-HIV PBL?

Is the clinical presentation different?

Are the expected outcomes different?

Should the treatment be different?

History of PBL

Distinct subtype of DLBCL, described initially in 1997 in a report of 16 cases1

15/16 were HIV+

All patients had involvement of oral cavity

WHO 2008 description

Diffuse proliferation of large neoplastic cells which resemble B immunoblasts,

but in which all tumour cells have the immunophenotype of plasma cells

Over 600 articles published about PBL, half in the last 5 years, with largest
published series reviewing data from 590 patients2

1Delecluse

et al. Blood 1997 89(4):1413-20; 2Castillo et al. Blood 2015 125 (15):2323-30

Epidemiology

Rare, but incidence unknown

Strong association with HIV infection (63% of published cases)

But still only 2-3% of all HIV-related lymphomas

Also reported in other immunosuppressed states 6% of cases

Post solid organ transplantation (most commonly heart & kidney, 14% post alloSCT)

Autoimmune diseases

May arise from pre-existing lymphoproliferative disorder (i.e. transformation) 3% of cases

20 published cases, evolved from CLL (50%), follicular lymphoma (30%), other

HIV-negative PBL accounts for remaining cases (28%)

Reported in all ages (range 1-90), but infrequent in pediatrics (~3.5%, mostly HIV+)

Predominantly male (75%)

Cell of Origin The Plasmablast

A plasmablast is an activated B-cell that has

undergone somatic hypermutation and class
switching recombination, and is in the process
of becoming a plasma cell

Morphologically, centrocytes transform to

plasmablasts before becoming mature
plasma cells

Phenotypically express CD38, CD138, IRF4/MUM1

Lose CD20 expression

Pathogenesis of PBL incompletely understood,

but involves both EBV infection and MYC
dysregulation as important mechanisms

EBV Infection & PBL

The presence of plasmablasts is noted

in reactive processes associated with
viral infections such as EBV and HIV,
among others.

EBV infection is associated with

prevention of apoptosis in B cells by
several mechanisms

Induction of NF-B

Syk/Src mediation

Castillo et al. Blood 2015 125 (15):2323-30

MYC Dysregulation & PBL

MYC is a transcription factor that regulates

Cell proliferation

Cell growth

DNA replication

Cell metabolism

Cell survival

Also acts as an amplifier of the transcribed

genes associated with these processes

MYC dysregulation in PBL overcomes the

regulatory effects of BCL6 or BLIMP1

May also allow PBL cells to escape apoptosis

Castillo et al. Blood 2015 125 (15):2323-30

Match the picture with the diagnosis:

PBL, Multiple Myeloma, Primary Effusion Lymphoma

Pathological Features

Large cells with central oval nuclei,

prominent nucleoli, abundant
cytoplasm, perinuclear hof
CD79a+, IRF4/MUM1+, BLIMP1+,
CD38+, CD138+; negative for CD19,
CD20, PAX5

High Ki-67

EBER positivity 50% HIV-, 75% HIV+

MYC GR/amplification 44% HIV-, 78%

HIV+

Castillo et al. Am J Hem 2008 83:804-9

Differential Diagnosis
Castillo & Reagan Scientific
World J 2011 11:687-96

Clinical Features of PBL

HIV+ PBL

HIV- PBL

Median age 42, male 78%

Median age 55, male 66%

Extranodal disease >95%

Oral cavity involvement 40%

Oral cavity/jaw 48%

Advanced stage III/IV >65%

Advanced stage disease, BM positive,

B symptoms less common, 25%

BM positive, B symptoms in 40%

Immunosuppression major risk factor

Prognosis

Poor & dismal most commonly used to

describe outcome for this disease
Median OS of 8-15 months in
published series, OS rate 10-25% at 2-3
years.

Morscio et al. 2014

Am J Surg Path
38:875-86

Prognosis HIV association

HIV positive patients

Not clear if combined antiretroviral

therapy (cART) affects outcome

CD4+ count <200 not associated with

OS, but is associated with shorter PFS

HIV negative patients

Poorer outcomes reported in some

studies

Immunosuppression among HIVnegative patients associated with

poorer outcomes

Median OS 14 months
Median OS 9 months

Castillo et al. Leuk Lymph 2010 51:2047-53

Prognosis HIV+ PBL

Castillo et al. Oncologist 2010 15:293-99

Prognosis EBV Expression

EBV expression is not associated with

outcome in HIV-associated PBL in
some studies, better outcome in others

Better outcome in immunocompetent

patients with PBL

Morscio et al. 2014 Am J Surg Path 38:875-86

Prognosis MYC Aberrations

Presence of MYC associated with

shorter OS

Morscio et al. 2014 Am J Surg Path 38:875-86

Treatment

What we know about treatment

Dismal prognosis with current modalities thus no standard of care

CHOP is inadequate

CNS prophylaxis is highly recommended

Data generally comes from case reports & retrospective case series

NCCN Guidelines for PBL

Chemotherapy HIV+ PBL

Largest case series of HIV-positive PBL

(n=50) from 13 institutions over 10 year
period

Majority received CHOP, 37% received

intensive regimens

CR 66% but majority relapsed with

leading cause of death due to
progressive lymphoma

Castillo et al. Cancer

2012 118:5270-7

CHOP vs Intensive Regimens

Castillo et al. Cancer 2012 118:5270-7

HIV-negative PBL

Review of 70 patients with HIVnegative PBL treated mostly with

CHOP (60%)

Median OS 9 months

Age, extranodal disease, and

immunosuppression were adverse
prognostic factors

Liu et al. Leuk Res 2011 35:1571-7

DA-EPOCH for HIV-associated NHL

Barta et. al reported a pooled analysis

on 1546 patients with HIV-associated
NHL

Infusional EPOCH associated with

improved OS

PBL identified as other histology,

accounting for 6% of patients
DLBCL treated pre-rituximab

Barta et al. Blood 2013 122:3251-3263

HyperCVAD

MD Anderson group demonstrated

38% 5-year OS in PBL patients (n=25),
half of which received HyperCVAD

Patel et al. Blood 2013 122: abstract 4310

HDT-ASCT in HIV-associated
lymphomas

With the use of cART, intensive

chemotherapy and ASCT are feasible
treatment modalities with comparable
results to matched HIV-negative patients

TRM ranges from 5-10%

Higher rate of opportunistic infections in

HIV+, but did not impact TRM

Immune recovery is similar to HIVnegative patients

Effectiveness (DFS, OS) not significantly

different
Krishnan et al. Biol Blood Marrow
Transplant 201016:1302-8

HDT-ASCT for PBL

No trials have been reported or conducted in the setting of PBL, and none
are likely to be conducted because of the rarity of this disease and
heterogeneity of treatment

Most of the data have been extrapolated from larger phase II trials,
retrospective analysis of individual centers experience, or case reports of
subtype of DLBCL

ASCT for high-risk HIV+ NHL

Entire cohort (n=25)

Phase II multicenter trial of early consolidation with ASCT in

HIV+ aggressive NHL (n=25) with aa-IPI of 2 or 3 enrolled
between 2007-2014 (Re et al. 2014 ASH Abstract 2528)

Included 5 PBL patients

Induction therapy was CHOP+/-rituximab x6 cycles, followed

by PBSC collection with cyclophosphamide + GCSF when
chemosensitivity confirmed

All patients received cART throughout treatment

5-year OS 74.6%, PFS 70.9% for entire series

Successful ASCT in 14 patients

100% alive & disease-free at median F/U 38.5 months

TRM 0%

Includes at least 3 of the PBL patients

14 ASCT patients

ASCT for PBL

CIBMTR, unpublished data

20 patients received first ASCT for PBL in CR1 (n=11) or CR2 (n=9)between 2001 and
2012

Median age at transplantation 55 (range 32-76)

Outcomes

OS at 1 year 69%, at 3-years 45%. Relapse rate not reported.

64% for CR1 vs 44% for CR2

Based on available data, PBL patients with high-risk features should be

considered for consolidation with ASCT in first-line setting

aaIPI >2, HIV-negative, MYC gene rearrangement, or response less than CR with
induction
Al-Malki et al. Biol Blood Marrow Transplant 2014 20:1877-84

Bortezomib

Proteasome inhibitor bortezomib

highly active in myeloma

Some efficacy in lymphoma,

specifically in patients with activated
(post-germinal center) B-cell DLBCL

Case report of 3 patients (2 HIV+, 1

HIV-) who received bortezomib plus
DA-EPOCH as frontline therapy

Achieved CR

Acceptable short-term toxicity, no

long-term toxicity

Cases revisited
Case 1

Case 2

Stage IAE HIV+ PBL with IPI 1

Stage IAE HIV- PBL with IPI 0

Received CHOEP + HDMTX for CNS

prophylaxis, plus IFRT.

Offered HDT-ASCT but declined.

Received CHOP + HDMTX for CNS

prophylaxis, followed by HDT-ASCT
March 2015.

Resolution of mass on interim CT,

awaiting re-staging PET post RT.

Recent PET confirms CMR

Case 3

65M, HIV+, diagnosed with plasmablastic lymphoma presenting as cord

compression by T3 vertebral mass. Additional distal skeletal sites of
involvement (Stage IV). C-MYC positive, EBER negative. ECOG 3. LDH
normal. BM negative. IPI 3.

Received DA-EPOCH x3 cycles, followed by RT to spinal mass.

Achievement of CR (PET negative). Also received intrathecal
chemotherapy x2 treatments.

Relapsed 22 months later, neck & chest LN, and lung mass.

Treated with GDP (as per tumor board discussion), with achievement of at
least PR by CT. Referred for ASCT

Relapsed/Refractory PBL

Long-term survival in patients with relapsed/refractory disease is possible,

but rare

Treatment in this setting is generally considered palliative

Bortezomib, lenalidomide have both been used in this setting

Brentuximab for those with CD30+ disease (~30% of cases)

Some case reports of long-term outcomes with intensified salvage (i.e.

HDT-ASCT), with no difference in outcomes between HIV+ and HIVpatients.

Case 3 revisited

Case discussed at BMT meeting, decision made to not offer ASCT

New brain lesions 2 months after completing GDP.

Deceased 1 month later due to rapid progression of CNS involvement.

Key Points

Plasmablastic lymphoma is a rare, highly aggressive B-cell lymphoma,

commonly associated with HIV infection and other immunosuppressed
states

Both EBV infection and MYC dysregulation are important in the

pathogenesis of this disease, with the latter associated with poorer
prognosis

Current therapies, intensified or not, are inadequate

HDT-ASCT in first remission is recommended for high-risk disease