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44° CONGRESSO NAZIONALE SIE Società Italiana di Ematologia

Verona, 23 o+obre 2013

SIE, SIES, GITMO guidelines for the management of indolent, non follicular

B-‐cell lymphomas (marginal zone, lymphoplasmacy@c and small lymphocy@c lymphomas)

Terapia dei linfomi della zona marginale

Luca Arcaini Dip. di Ematologia Oncologia, Fond. IRCCS Policlinico San Ma+eo &

Dip. di Medicina Molecolare, Università di Pavia

SPLENIC B-‐CELL MARGINAL ZONE LYMPHOMA

Issue 1: DiagnosKc requirements

“A B-‐cell neoplasm comprising small lymphocytes which surround and replace the splenic white pulp germinal centres, efface the follicle mantle and merge with a peripheral (marginal) zone of larger cells including sca+ered transformed blasts; both small and larger cells infiltrate the red pulp. Splenic hilar lymph nodes and bone marrow are oWen involved; lymphoma cells may be found in the peripheral blood as villous lymphocytes”

Splenic marginal zone lymphoma (WHO 2008)

Ianni%o et al, Blood 2011

Peripheral blood morphology

SMZL: IgM+/IgD+, SIg +, CD20+, CD22+,CD24+, CD27+, FMC7+, CD79b+, CD103-‐, CD123-‐, CD10-‐, DBA44 + (75%), CD11c + (50%), CD23+ (30%), CD5 + (20%)

SMZL CLL MCL FL HCL HCL-‐v MALT Flow cytometry Strong SigM +++ +/-‐ +++ +++ +++ +++ +++ CD5 + +++ +++ -‐ -‐ -‐ -‐ CD23 + +++ -‐ + -‐ -‐ -‐ FMC7 +++ -‐ +++ +++ +++ +++ +++ CD11c ++ -‐ -‐ -‐ +++ +++ -‐ CD103 -‐ -‐ -‐ -‐ +++ ++ -‐ CD123 -‐ -‐ -‐ -‐ +++ -‐ -‐ CD25 + -‐ -‐ -‐ +++ -‐ -‐ CD27 ++ +++ +++ +++ -‐ ++ + Immunohistochemistry DBA44 ++ + -‐ -‐ +++ +++ -‐ IgM, IgD +++ +++ -‐ + +++ + + CD10 -‐ -‐ -‐ +++ -‐ -‐ -‐ BCL6 -‐ -‐ -‐ +++ -‐ -‐ -‐ CCND1 -‐ -‐ +++ -‐ + -‐ -‐ CD5 + +++ +++ -‐ -‐ -‐ -‐ CD43 + +++ +++ -‐ -‐ -‐ + CD23 -‐ +++ -‐ + -‐ -‐ -‐

CD27 ++ +++ +++ +++ -‐ ++ + Annexin A1 -‐ -‐ -‐ -‐ +++ -‐ -‐

Bone marrow histology

-‐ BM involvement in 100% of cases

-‐ Morphology not sufficient for dg

-‐ IHC: be+er dg if small infiltrate CD20+, bcl2+,

CD10-‐, bcl6-‐, cycline-‐D1-‐

-‐ Typical intrasinusal infiltrate

-‐ Not patognomonic Franco et al, Histopathology 1996

Costes et al, BJH 2002

Minimal diagnosKc criteria

1-‐ Splenic histology + CLL score ≤2

or in absence of spleen histology

2-‐ Typical morphology (PB and BM) + FC

+ CD20+ intrasinusal infiltrate

Matutes et al, Leukemia 2008

Issue 1: DiagnosKc requirements Recommenda@ons

-‐ According to WHO criteria, SMZL is most definiKvely diagnosed with splenectomy and examinaKon of splenic Kssue. However, the diagnosis of SMZL can be confidently achieved also by the combinaKon of BM biopsy with the i mm u n o c y t o c h e m i s t r y p r o fi l e (intrasinusoidal infiltraKon by CD20+ cells), PB and BM aspirate morphology and FC

Issue 2: Pre-‐treatment evaluaKon Recommenda@ons

-‐ In all cases, pre-‐treatment evaluaKons

for SMZL are: full blood and differenKal

counts, complete biochemistry including

r ena l and l i v e r f un cKon t e s t s ,

proKdogram, calcium level, LDH, β2-‐

mic rog lobu l in , se rum and ur ine

immunofixaKon

-‐ Serology for hepaKKs C virus (HCV), hepaKKs B virus (HBV) markers and human immunodeficiency virus (HIV) serology -‐ In HCV+ pts (serology), HCV-‐RNA, genotyping and cryoglobulins and cryocrit assessment should be performed


-‐ Helicobacter pylori by breath test should be tested if gastric symptoms are present -‐ Tests for hemolysis (reKculocyte count, DAT) should be performed in pts with anemia -‐ CT scan of neck, chest, abdomen and pelvis should be performed for the assessment of disease extension


-‐ US scan of the spleen should be done before therapy to have a monitoring tool of the spleen a]er therapy -‐ PET scan invesKgaKon may be considered in selected cases (i.e. when clinical and/or laboratory or instrumental data point to a possible shi] to high-‐grade histology in deep-‐sited lymph nodes)


Arcaini et al, Blood 2006

OS and CSS for SMZL

CSS according to prognosKc score

Arcaini et al, Blood 2006

5-‐y CSS 88 %

5-‐y CSS 73 %

5-‐y CSS 50 %

Issue 3: IndicaKon to start treatment Recommenda@ons

Criteria for iniKaKng convenKonal anK-‐lymphoma treatment in SMZL are the following: -‐  Progressive or symptomaKc splenomegaly -‐  Hemoglobin < 10 g/dL -‐  Neutrophils < 1,000/µL -‐  Progressive thrombocytopenia -‐  Systemic symptoms -‐  Progressive nodal disease -‐  AHA

9 pts with SLVL and HCV infecKon IFN-‐a 3 MU 3 gmes/week for 6 months 7 à HCV-‐RNA-‐ + CR 2 NR à Ribavirin à HCV-‐RNA-‐ 1 CR, 1 PR

AnKviral therapy in HCV+ SMZL

Hermine et al, NEJM 2002

18 pts with SLVL and HCV infecKon Symptomagc type II MC : 72%; genotype 1: 54% Hematological + virological response: 78% HCV genotype 1: 54% (4 / 7 responders)

Saadoun et al, Blood 2004

SMZL: therapeuKc algorithm

Indolent

ObservaKon

No Yes

Yes

HCV+ AnKviral therapy

-‐ Symptomagc splenomegaly -‐ Cytopenia -‐ Suspected transformagon into high grade -‐ No B symptoms -‐ No nodal involvement -‐ Limited BM involvement

Splenectomy if R-‐CHT

NR No

Issue 4: First-‐line treatment Recommenda@ons

-‐ Before deciding therapy for lymphoma,

SMZL pts should be categorized according to

the posiKvity for HCV infecKon. HCV+ pts and

no indicaKon to anK-‐lymphoma therapy,

should be treated against HCV infecKon

-‐ In pts in need of anK-‐lymphoma treatment,

the decision is among the following opKons:

splenectomy, CHT alone, rituximab or R-‐CHT

-‐ Splenectomy is the recommended therapy for SMZL when the disease presents with symptomaKc splenomegaly , and/or splenomegaly related cytopenias in the absence of high percentage of leukemic cells in PB, heavy BM infiltraKon, and diffuse nodal disease, provided that there are no contraindicaKons to surgery.

-‐ In HCV+ pts, splenectomy should be considered only a]er the exclusion of a severe chronic liver disease


-‐ R-‐CHT is indicated for fit paKents with disseminated disease. CombinaKons that proved effecKve in this sedng are rituximab associated with chlorambucil, CVP, fludarabine, or 2CDA -‐ Rituximab single agent is indicated in paKents with contraindicaKons to surgery or chemo-‐immunotherapy. Its use should be considered experimental and should be limited to registries or clinical trials


-‐ Pts without indicaKon for R-‐CHT or R

should be treated with CHT alone

-‐ So far there are no data supporKng the

role of maintenance with R or other drugs in

SMZL. For pts with PR a]er a 1st-‐line

treatment, there is no indicaKon to perform

addiKonal treatment unKl progression


Extranodal marginal zone lymphoma of mucosa associated lymphoid Kssue (MALT lymphoma) of gastric mucosa

(gastric MALToma)


-‐ Lympho-‐epitelial lesions CD5-‐, CD10-‐, CD 20+, CD 23+/-‐, CD 43-‐, cyclin D1-‐, CD 103-‐ -‐ Tesgng for Hp mandatory -‐ Histology less sensigve if:

-‐  limited number of gastric biopsies -‐  treatment within 2 weeks with PPI -‐  previous angbiogcs therapy

-‐  Hp serology only test not affected by recent PPI

Isaacson 2008 Hussel 1993 Zullo 2010 Christensen 1992 Andrew 1994 Dickey 1996 Eck 1999


-‐ t(11; 18) generagng a funcgonal AP12/

MALT1 fusion product able to acgvate the

NF-‐κB pathway

-‐ 25% of gastric MALT lymphoma

-‐ Correlated with both failure to response

to Hp eradicagon and to Hp negagvity Liu 2002 Nakamura 2007


-‐ In gastric MALT lymphoma, definiKve diagnosis requires excision biopsy of representaKve material from the primary disease site

-‐ A molecular geneKc analysis on lymphoma Kssue for detec@on of t (11;18) i s recommended for idenKfying disease that is unlikely to respond to anKbioKc therapy

-‐ The presence of acKve Helicobacter pylori infec@on must determined

-‐ The Panel recommended that the infecKon should be detected by the histological tesKng

-‐ In case of negaKvity, stool anKgen or urea breath test are recommended


Issue 2: Staging requirements and pre-‐treatment evaluaKon

-‐ Best staging system sgll controversial -‐ Modificagon of Blackledge staging system known as the “Lugano staging system” largely used -‐  No endoscopic US -‐  Not accurately described the depth of infiltragon of the gastric wall (predicgve for response to ang-‐Hp tx and risk for bleeding and perforagon) -‐ “Paris staging”: modified TNM staging (gastric wall and of the perigastric LN), proposed by the EGILS group -‐  Mulgfocal inv. of the GI tract inconsistently reported

RohaKner 1994 Ruskone-‐Fourmestraux 2003 Raderer 2000 Fishbach 2000 Koch 2002 Flieger 2005

Issue 2: Staging requirements and pre-‐treatment evaluaKon Recommenda@ons

-‐ In gastric MALT lymphoma, staging requirements include a detailed descripKon of the extension of the gastric lesion(s) and the assessment of the gastric wall infiltraKon along with the involvement of perigastric lymph nodes -‐ At present, these informaKon are opKmally obtained with US endoscopy that is recommended as the first local staging procedure

-‐ According with the lymphomas convenKona l s tag ing procedures , addiKonal invesKgaKons should include: laboratory tests, physical examinaKon, neck-‐chest-‐abdomen-‐pelvic CT scan, BM biopsy -‐ Staging classificaKon should be based on Ann Arbor staging system modified according to the Paris staging system

Issue 2: Staging requirements and pre-‐treatment evaluaKon Recommenda@ons

Issue 3: First-‐line therapy Is an@-‐helicobacter pilory an@bio@c therapy beOer than gastric surgery? -‐ The Panel agreed that the endpoint

crigcal for judgment of the issue should be CR and QoL -‐ Gastric surgery: long-‐term survival 75%-‐97% of the pagents -‐ Benefit of surgery has to be balanced with equivalent results provided by stomach-‐conservagve approaches

Vaillant 2000 Koch 2001, Kodera 1998 Kuo 2008 Vrieling 2008 Fishbach 2011

Issue 3: First-‐line therapy Is an@-‐helicobacter pilory an@bio@c therapy beOer than gastric surgery? -‐  Systemagc review of HP eradicagon (32

trials): in localised disease CR 77% -‐  Relapse 7.2% (yearly recurrence of 2.2%) -‐  Response higher in stage I compared to

stage II lymphoma (79% vs. 56%; p = 0.0003) and among pts without the API2-‐MALT1 translocagon than in those with this translocagon (78% vs. 22%; P = 0.0001)

Zullo 2010

Issue 3: First-‐line therapy Is an@-‐helicobacter pilory an@bio@c therapy beOer than gastric surgery? -‐  Standard regimen: a 14 d triple tx (PPI +

chlarytromycin + amoxicillin or metronidazole)

-‐  In pts who failed, indirect evidence of efficacy of a 2nd line with a bismuth-‐containing quadruple tx (uncontrolled clinical trials)

-‐  Levofloxacin-‐based triple tx suggested as an alternagve salvage therapy to bismuth-‐based tx

-‐ The Panel agreed that, despite the lack of RCT, the pooled data of systemagc review clearly in favour of the eradicagon strategy

Malfertheiner 2010

Issue 3: First-‐line therapy Is an@-‐helicobacter pilory an@bio@c therapy beOer than gastric surgery? Recommenda@ons

-‐ The 1st line treatment of Hp+ pts with gastric MALT lymphoma is Hp eradicaKon therapy, independently from the disease stage -‐ Surgery should be confined to pts complicated by perforaKon or bleeding not amenable with endoscopy (Quality of evidence high; strength of recommendaKons, strong)

Issue 3: First line therapy Is an@bio@c therapy recommended in Hp-‐ nega@ve pa@ents?

Recommenda@on -‐ In pts with localized Hp-‐ gastric MALT l ymphoma , Hp e rad i caKon i s no t recommended (Quality of evidence low, strength of recommendaKon, weak)

-‐ Angbiogc treatment for Hp-‐ gastric MALT lymphoma has been described in a limited number of pagents. -‐ Failure to Hp detecgon or infecgon by another strain of Hp, namely H. Heilmannii

Park 2010

Recommenda@ons -‐ A]er successful Hp eradicaKon, consolidaKon chemotherapy is not indicated (Quality of e v i d e n c e , m o d e r a t e , s t r e n g t h o f recommendaKons, strong)

-‐ Crigcal endpoint to assess: PFS -‐ 1 RCT chlorambucil vs WW in 110 stage I pts -‐ No stagsgcal difference in recurrence/progression rates and in OS

Issue 3: First line therapy Is chlorambucil beOer than observa@on in pa@ents reaching complete remission aRer an@bio@c therapy?

Hanckock 2009

Issue 4: Therapy for non-‐responding paKents or relapsed paKents

-‐  GELA grading system for post-‐tx: 2 consecugve gastroscopies with mulgple biopsies for histological CR -‐  CR usually occurs within 12 mo (some cases taking up to 72 mo) -‐  In the absence of RCTs, candidate approaches in pts unresponsive to Hp eradicagon are RT, CHT, R either alone or in combinagon

Copie-‐Bergman 2003 Fischbach 2004


-‐ Systemagc review -‐ RT vs CHT: RR 97.3 vs. 85.3%; P = 0.007 -‐ RT vs surgery: RR 97.3 vs. 92.5%; P = 0.2 -‐ No difference single vs combined tx (P = 0.6). -‐ RT 30-‐40 Gy: response rate nearly 100% -‐ Alkylagng agents as monotherapy (i.e chlorambucil or cyclophosphamide) ineffecgve in t(11;18)(q21;q21)-‐posigve lymphomas -‐ 2-‐CDA, bendamusgne, bortezomib, CHOP/CVP, rituximab, chlorambucil +/-‐ rituximab

Schechter 1998 Tsang 2003. Tomita 2009 Hammel 1995 Levy 2005 Streubel 2004 Vidal 2012 Conconi 2011 Aviles 2005 MarKnelli 2005


-‐  Recent large RCT on extranodal marginal lymphomas

-‐  94 pts with gastric MALToma/227

randomized MALT NHL pts

-‐  CLB + R vs CLB: 5-‐y EFS 68% vs 50% -‐  5-‐y OS idengcal in the two arms (88%)

Zucca 2013


-‐ Radia@on therapy is recommended in the IE-‐II1E paKents with gastric MLAT lymphoma relapsed/refractory to anKbioKc eradicaKon. -‐ CHT is recommended in other disease s tages . ParKcu lar ly , CVP reg imen, fl u d a r a b i n e -‐ c o n t a i n i n g r e g imen s , bortezomib, and bendamusKne have provided evidence of efficacy

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