DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse

$Page 1: DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse$
DLBCL: First line treatment

Dr Wendy OsborneNewcastle

Oxford management courseJune 2018

DLBCL is most common NHL 30-40% of cases

10-15% have primary refractory disease

20-30% relapse

Only 20 % of patients alive at 2 years if they relapse

Is DLBCL just one disease?

It’s just RCHOP isn’t it ?

Should we intensify treatment upfront?

What about the less fit patient?

Who should we give CNS prophylaxis to?

Is there a role for radiotherapy in DLBCL?







Is DLBCL just one disease?Diffuse large B-cell lymphoma (DLBCL), NOS

Germinal center B-cell type*

Activated B-cell type*

T-cell/histiocyte-rich large B-cell lymphoma

Primary DLBCL of the central nervous system (CNS)

Primary cutaneous DLBCL, leg type

EBV+ DLBCL, NOS*

EBV+ mucocutaneous ulcer*

DLBCL associated with chronic inflammation

Lymphomatoid granulomatosis

Primary mediastinal (thymic) large B-cell lymphoma

Intravascular large B-cell lymphoma

ALK+ large B-cell lymphoma

Plasmablastic lymphoma

Primary effusion lymphoma

HHV8+ DLBCL, NOS*

Burkitt lymphoma

Burkitt-like lymphoma with 11q aberration*

High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements*

High-grade B-cell lymphoma, NOS*

B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Swerdlow et al 2016 Blood ; 127(20):2375-2390

http://www.bloodjournal.org/content/127/20/2375?sso-checked=true#fn-2








WHO 2016 recognises molecular heterogeneity of DLBCL

Cell of origin:

IHC is insufficient to reliably distinguish GC from non-GC(Hans algorithm based on CD10, IRF4 and BCL6 expression (1))

Distinct gene expression dependent on COO classifies into ABC, GCB, and unclassifiable (10-15%)

Inferior outcome after RCHOP in non-GC phenotype DLBCL (2)

Rearrangements of MYC and BCL2/BCL6

Dual positivity for MYC and BCL2 protein expression:“Dual-expressers” which lack identifiable translocations: (not WHO distinct entity

1)Hans et al Blood 2004, 2) Lenz et al NEJM 2008







Before the chemotherapy…

Staging : PET scan/CT

Prognostic score:IPI (age >60, stage III,IV, PS>1, LDH, EN sites>2) (1)

The revised IPI (2) confirms the prognostic significance of IPI in the R-CHOP eraNCCN-IPI (3), superior at discriminating low and high risk groups.

Cardiac function

Bloods: Viral screen including hepatitis B/HIV and LDH

Fertility preservation

Specialist nurse and contact details

MDT discussion

1) NEJM 329, 987-994 (2) Sehn et al 2007 Blood 109, 1857-1861, (3) Zhou et l 2014 Blood 123,837-842

PET-CTStaging :

94% sensitivity for BM involvement, cf 24% with BMA T (1)

Extra-nodal disease and calculation of CNS IPIAssessment of bulk (>7.5cm)

Not for mid-point assessment : Interim PET(2),predictive, no benefit with escalation Mid-point CT should be performed

EOT scan:

Consider radiotherapy if PET positive

1)Berthet, L. et al. (2013) Journal of Nuclear Medicine; 2013 54: 1244–1250. 2) Duhrsen et al 2017 PETAL study 76.8093

RCHOP: How much? How often?

Combined modality therapy for non-bulky stage IA

No difference in PFS and OS between 6 and 8 cycles RCHOP 14 : RICOVER-60 (1)

RCHOP 14 vs RCHOP 21: No difference in outcome in 2 large phase III studies (2,3)

1) Pfreundschuh et al 2008, 2) Cunningham et al Lancet . 2013;381(9880):1817-1826, 3)Delarue et al Lancet Oncol.2013;14(6):525-533

Which antibody?

GOYA (1):

Is obinutuzumab (gycloengineered type II humanised anti-CD20) superior to rituximab

1400 patients

Randomisation of RCHOP vs OCHOP

1)Vitolo et al Blood 2016;21 (128);470

Which antibody? GOYA study

INV-assessed PFS G-CHOP (n=706) R-CHOP (n=712)

Patients with events, n (%) 201 (28.5) 215 (30.2)3-year PFS, % 69.6 66.9HR (95% CI), stratified p value* 0.92 (0.76 1.11), p=0.3868

Time (months)

Median follow-up: 29 months

R-CHOP (n=712)

G-CHOP (n=706)

6 12 18 24 30 36 42 48 54 60

Pro

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ity

1.0

0.8

0.6

0.4

0.2

0

0

Vitolo U, et al. J Clin Oncol 2017; Aug 10 doi: 10.1200/JCO.2017.73.3402;

3 yr PFS ABC 59%, GCB 75% unclassified 63%

Addition of targeted agent?

Bortezomib, maintain NF-kB in inactive state

Does addition of bortezomib improve PFS? (ABC COO has chronic active B-cell receptor signalling with constitutive activation of NF-kB pathway)

ReMoDL-B, randomised addition of bortezomib to RCHOP

Central real time GEP to determine COO

Study design

Amendment 2nd May 2014Bortezomib 1.6 mg/m2 day 1+8 sub cut

Powered to detect a 10%

improvement in 30 month PFS

(α=0.05; power 0.9). n=688 ABC and

GCB randomised. ABC 260

Davies et al 2017;Ann Onc 35:130-131

Progression-free survival according to

molecular classification

30monthPFSGCB:74.3%:HR=0.774,p=0.079Unc: 68.2%:HR=0.884,p=0.480ABC:68.1%:HR=1(Referencecategory)

Medianfollow-upofsurvivingpatients:28.4months NodifferenceinOSeither

Addition of targeted agent?

Ibrutinib : Not yetAwait PHOENIX study comparing RCHOP with RCHOP plus ibrutinib in non-GCB DLBCL (study completion expected June 2020)Central review of COO IHC before randomisation

Lenalidomide: Not YetR len CHOP compared with historical controls, improvement in PFS and OS in non-GCB group (1). Further evidence needed. GEP needed to identify true ABC patients which may cause selection bias

Lenalidomide maintenance: Maybe…REMARC study (2)

1) Nowakowski et al 2015; JCO 33(3): 251-257 2)Thieblemont et al JCO 2017;35(22):2473-2481

REMARC: Lenalidomide maintenance vs placebo in responding elderly patients treated with RCHOP

Thieblemont et al JCO 2017;35(22):2473-2481

PFS benefit irrespective of COO. No OS benefit, this was not due to toxicity.

Patients aged 60-80 yrs, 2yrs of lenalidomide 25mg/day for 21 days







Should we consolidate with autologous stem cell transplant?

SWOG (1) study, half of patients had RCHOP first line, PFS benefit if high or high/intermediate IPI but no OS benefit

Meta-analysis (2) shows that there is no clear value in up front auto

Cannot be recommended outside of a clinical trial

1) Stiff et al NEJM 2013;369(18):1681-1690, 2)Greb et al Cochrane Database Systemic Rev 2008: (1):CD004024

Is DA-R-EPOCH superior to RCHOP?

CALGB/Alliance Group ph III RCT

Only 6% with PMBCLFree Survival

Years from Study Entry

Pro

ba

bili

ty e

ve

nt

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0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

R-CHOPDA-EPOCH-R

Bartlett et al ASH 2016 abstract #469, Wilson et al Blood 2016;128(22);496

No difference in 3 yr EFS (80%) or OS (85%) and increased toxicity with DA-R-EPOCH

465 pts RCHOP vs DA-R EPOCH (6% PMBCL)

Are there subgroups which would benefit from intensification?

High IPI

Double Hit/Dual-expresser

Primary mediastinal lymphoma

High IPI patients IPI 3-5

German DSHNHL 2002-1 3 year EFS of 69.5% with RCHOEP-14

Large RCT phase III but not randomised with RCHOP but does suggest improvement in patients with high IPI (1)

UK NCRI phase II (2) intensification with RCODOX M/IVAC

(1)Dilhurdy et al 2010, BBMT 16, 672-677 (2)McMillan et al 2013 Blood 122,4348

High IPI: Phase 2 R-CODOX-M trial (1)

18-65 yrs stage II-IV untreated DLBCL/HGBL/BL IPI score ≥3 (1)

116 pts in the DLBCL/HGBL cohort. (2)

Median age was 50 years (range 18–65),IPI score was 3 (n=74; 64%), 4 (n=41; 35%) or 5 (n=1; 1%).11 pts (9.5%) had CNS involvement 62 (53%) had a performance status (PS) ≥2FISH available for 57 pts (7 patients were double/triple hit)

Median follow-up 53 months whole cohort: 3-year PFS 68% and OS 76 %

Good outcome in poor risk group of but further trials needed

1)McMillan et al, ICML 2015 2)Phillips et al S1548 EHA 23

Double Hit LymphomaCharacteristic %

Median age (range) 61 (19-87)

ECOG 0-1 71%

ECOG 2-4 29%

Stage 3-4 84% (69-100)

LDH elevated 78% (50-100)

CNS disease 17% (4-44)

BM disease 53% (26-89)

IPI ≥ 4 44% (26-87)

Ki67 median 80%

Cheah et al BJH 168, 2014. Sesques and Johnson, Blood 129, 2017. Petrich et al Blood 124, 2014. Howlett et al BJH 170, 2015

Intensification not possible in many

5-10 % of DLBCL

Dual-Expresser Lymphoma, similar but not to be confused with DHL

Swerdlow et al .Blood 2016

Defined only by protein expression

20-35% of DLBCL (do not have own WHO category)

Associated with a poorer prognosis but the data is difficult to interpret due to different cut offs and poor IHC reproducibility

What is the prognosis of DHL?

Johnson N A et al. JCO 2012;30:3452-3459

Improved PFS with intensification

Petrich et al Blood 2014;124(15):2354-2361

Retrospective data

But no OS benefit


ASCT in CR1: No OS difference

N=39


Double Hit Lymphoma

Current literature is retrospective

Petrich (multicentre) : Intensive induction had high rate of PFS but no OS benefit

Oki (single centre) : DA REPOCH had an improved EFS and OS cf RCHOP

Landsberg (multicentre): Analysis of pts who achieved CR, intensive induction associated with improved relapse free survival and OS cf RCHOP

Petrich et al Blood 2014;124(15):2354-2361, Oki et al BJHaem,. 2014;166(6):891-901,Landsburg et al JCO 2017;35(20)2260-2267

Primary mediastinal lymphoma

A subtype of DLBCL (7% of all DLBCL) : clinical, morphological biological characteristics overlap nodular sclerosing Hodgkin

Immunophenotypically distinct from DLBCL, >80% of cases expressing CD30

75% stage 1 or II (relapses usually stage IV)

50% have pleural or pericardial effusion

Frequent airway compromise and SVCO

Thrombotic complications in 28% of patients with PMBCL(1), consider LMWH

1) Roth ICML 2017

6 x CHOP-like (CHOP-21, CHOEP-21, MACOP-B and PMitCEBO) chemotherapy +/- rituximab

Of 824 pts enrolled, 87 pts had PMBCL (1)

IFRT (30–40 Gy) was given to sites of primary bulky disease; Also given to sites of primary extra nodal disease at the physician’s discretion

Definition of bulk varied 5-10cm

73% had radiotherapy, concern about secondary breast cancer/ IHD (2)

MInT subgroup analysis

1)Rieger et al Ann Oncol 2011;22(3):664-670 2) 2)Castellino et al Blood 2011;117,6

MInT subgroup analysis

3 Year EFS 78% PMBCL, R CHOP like chemo (73% of pts had radiotherapy)

Prospective, 51 pts, DA-R- EPOCH x 6-8, no radiotherapy

5 yr EFS 93% OS 97%

DA EPOCH-R Therapy in PMBCL.

Dunleavy et al NEJM 2013;368(15):1408-1416

6 weekly PET scans until negative or progression

36/51 had residual mediastinal masses

Half had Deauville 3 on first PET

Only 3 progressed

2 proceeded to radiotherapy

DA-R-EPOCH Therapy in PMBCL.

Dunleavy et al NEJM 2013;368(15):1408-1416

EOT PET

DA-EPOCH R in 156 pts including children

75% PET negative Deauville 1-3 post chemo

14% had radiotherapy

Roth et al ICML 2017

PMBCL EOT PET

No prospective RCT of front line therapy

Low threshold for biopsy

IELSG 37 randomisation to address role of radiotherapy consolidation

Deauville score , highest positivity for disease (1)

Deauville 4, monitor at a minimum

1)Martelli et al JCO 2014; 32(17):1769-1775







Less fit patients

How should we assess? CGA (1), Charlson Comorbidity Index (2), Cumulative Illness Rating Scale(CIRS) …

R-mini CHOP (3), 2 yr PFS 47%, OS 59% in >80yrs (TRM 21%)

RCVP/ RCGVP if cardiac compromise (4)

Steroid pre-phase if PS >2 (5)

Primary GCSF prophylaxis if >65 years (6)

INCA (Inotuzumab Ozogamicin with RCVP)

1) Olivieri et al 2012, the Onc 17, 663-672 2) Kobayashi et al 2011 J Ca Res Clin Onc 137, 1079-1084, 3) Peyrade et al 2011 Lancet Onc 12, 460-468 4)Fields et al 2014 JCO 32, 282-287 5) Pfreundschuh et al 2010 Blood 116, 5103-5110 6) Repetto et al 2003 Eur Journ Canc 39, 2264-2272







CNS IPI: >2000 patients analysed for CNS relapse DSHNHL and MINT studies(validated by BCCA)

Schmitz et al JCO 2016;34(26):3150-3156

CNS IPI: Risk of CNS relapse by number of risk factors

Risk Factors

Age>60yrsElevated LDHPS>1>1 EN siteStage III or IVRenal or adrenal

Schmitz et al JCO 2016;34(26):3150-3156

CNS prophylaxis: Newcastle guidelines

Offer prophylaxis to patients with renal, adrenal, breast , testicular disease and double hit lymphomas. (NICE guidance)

Offer prophylaxis to patients with 4 points or more on CNS IPI as below

CNS IPI Risk factors : 1 point scored for each risk factor (2 yr risk CNS disease 0.6% in low risk group, 3.4% in int med gp, 10.2 % in high risk)

LDHAge above 60Performance status >1>1 Extranodal siteStage III or IVRenal or adrenal

CNS IPI: Schmitz et al JCO 2016;34(26):3150-3156

The debate of optimal prophylaxis

First do no harm

Must not delay primary curative therapy

Intrathecal vs intravenous methotrexate

Methotrexate 3.5g/M square at day 10 cycles 2,4 and 6 of RCHOP

Delivery during induction as events often early (1)

1)Boehme et al Ann Onc 2007 ; 18(1):149-157







Radiotherapy : Newcastle approach

Bulk disease > 7.5cm (? Only if PET positive)

PET positive disease at end of treatment

Extra-nodal sites : BulkLimited stageBone (1-3 sites)Contralateral testisCritical sites e.g. presenting with SCC

Radiotherapy

30Gy as effective as higher doses (1)

Unfolder:Patients with bulk >7.5cm were randomised to 36Gy IFRT or no further treatment. Closed early due to benefit of radiotherapy

RICOVER-60: (pts 61-80 comparing 6 vs 8 RCHOP)

addition of 36Gy IFRT to bulk >7.5 cm and extra nodal disease resulted in EFS, PFS, and OS benefit (2)

OPTIMAL >60: Radiotherapy can be spared in elderly (aged 61 to 80) if negative PET after immunochemotherapy (3)

1) Lowry et al 2011 rad and onc 100,86-92 2) Held et al 2014 JCO 32, 1112-1118 3) Pfreundschuh et al abstract 120

PET guided approach to bulk, Canadian data

Freeman et al ASH 2017 Abstract 823

Freeman et al ASH 2017 Abstract 823

Conclusions

Is DLBCL just one disease? No

It’s just RCHOP isn’t it ? At the moment ….

Should we intensify treatment upfront? High IPI/DHL/PMBCL

What about the less fit patient? Co-morbidity assessment

Who should we give CNS prophylaxis to? CNS IPI

Is there a role for radiotherapy in DLBCL? PET may inform this

Conclusions

Any Questions?

Documents

DLBCL: First line treatmentDr Wendy Osborne Newcastle Oxford management course June 2018 DLBCL is most common NHL 30-40% of cases 10-15% have primary refractory disease 20-30% relapse