Treatment of Large Cell Lymphoma

Treatment of Large Cell Lymphoma

Andre Goy, MDChairman / Director John Theurer Cancer Center

Lymphoma Program HeadProfessor of Medicine UMDNJ

Early Stage DLBCL

Early Stage DLBCL (SWOG) 8 CHOP vs 3 CHOP + IFXRT

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8

CHOP plus radiotherapy

Year post randomization

% S

urvi

val

P = 0.02

CHOP alone

Miller, NEJM July 1998

200 pts per arm / stage I (2/3 pts) / stage II 1/3 pts

5y OS 72% vs 82% for CMT

Presenter

Presentation Notes

BackgroundPatients with clinically localized, intermediate- or high-grade non-Hodgkin’s lymphoma usually receive initial treatment with a doxorubicin- containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. MethodsWe compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly as- signed to receive CHOP plus radiotherapy, and 201 received CHOP alone. ResultsPatients treated with three cycles of CHOP plus radiotherapy had significantly better progression- free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was de- creased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). Conclusions Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin’s lymphoma. (N Engl J Med 1998;339:21-6.) ©1998, Massachusetts Medical Society.

CHOP alone vs CHOP + IFXRT in Stage I-II DLBCL > 60y (GELA)

Bonnet JCO, March 2007

290 pts per arm / Med flup 7y

5y NO difference / Prognostic factor: Stage II <

PFS OS

Presenter

Presentation Notes

BackgroundPatients with clinically localized, intermediate- or high-grade non-Hodgkin’s lymphoma usually receive initial treatment with a doxorubicin- containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. MethodsWe compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly as- signed to receive CHOP plus radiotherapy, and 201 received CHOP alone. ResultsPatients treated with three cycles of CHOP plus radiotherapy had significantly better progression- free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was de- creased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). Conclusions Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin’s lymphoma. (N Engl J Med 1998;339:21-6.) ©1998, Massachusetts Medical Society.

Localized DLBCL

Bindra & Yahalom, Expert Rev Anticancer Ther, 2011 Sep;11(9):1367-78.

Controversy on number of cyclesand need for radiation consolidation

Radiation improved local control and often > PFS Difference in OS debated

MINT Trial – R-CHOP / CHOP for Young Patients with good-prognosis DLBCL

Pfreundschuh, Lancet Oct 2011

18–60 y with 0 or 1 risk factor according to the aa-IPI,stage II–IV disease or stage I-bulky

420 pts each arm / Median follow-up of 6 years

Rituximab obviously improves all subgroups / Pts with IPI = 0, no bulk > 90%

- R-Chemo is also > in early stage DLBCL

- Impact of bulky disease is reduced by R-chemo but remains prognostic

- Do we still need XRT in R-chemo era?

Stage I/II, no B symp, mass ≤10 cm (Vancouver)

Can PET Scan Help?

Sehn L, ICML 2011, abst # 28

65 patients

Stage I/II, no B symp, mass ≤10 cm (Vancouver)

Can PET Scan Help?

Ongoing GELA study / PET to decide 6 vs 4 cycles

PET –ve excellent outcome / PET +ve high relapse rate of distant relapse NEED other approaches

Sehn L, ICML 2011, abst # 28

- Problem is series vary I, II and BULK or not

- Most relapses are distant relapses

Are late and distant relapses a reflection of inadequate systemic therapy?

Issues with Early Stage DLBCL

GELA – ACBVP vs CHOP + IFRT

Reyes, NEJM, March 2005

Previously untreated patients < 61 years old / Stage I or II aggressive lymphoma

320 pts each arm / No IPI risk factors / Median follow-up of 7.7 years

5y EFS 82% for chemo alone vs 74% for CMT / also > in PFS and OS

(similar In bulky or non-bulky)

DLBCL – Early Stage- Very limited disease (stage I / non bulky): R-CHOP x 3 w/wo XRT (3 +1 if PET –ve?) R-CHOP (6/6 vs 4/6) FLYER study Germany

- Stage I bulky / IE or II non bulky R-CHOP x 6 / limit nb cycles + XRT? 6 R-CHOP-21 vs 6 R-CHOP-14

(UNFOLDER) 6 v 4 R-CHOP if PET –ve (GELA)

- Stage II bulky = like advanced stage DLBCL

Advanced Stage DLBCL

Established Superiority of R-CHOP vs CHOP

1. Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391. 2. Sehn L, et al. ASH 2003.Abstract 88. 3. Habermann T, et al. J Clin Oncol. 2006;24:3121-3127. 4. Coiffier B, et al. ASCO 2007. Abstract 8009. 5. Pfreundschuh M, et al. Lancet Oncol. 2008;9:105-116.

Confirmed by multiple studies even in < 60y

0 1 2 3 4 5 6 80

0.2

0.4

0.6

0.8

1.0

Years

R-CHOP

7

P < .0001

109

CHOP

GELA

0 1 2 3 4

Years

Maintenance

Observation

0 1 2 3 4 50.0

0.2

0.4

0.6

0.8

1.0 ECOG 4494[3]

CHOPR-CHOP

Months

0Months

P = .000000007

R-Chemo

Chemo

1.0MInT[1]

0.8

0.6

0.4

0.2

05 10 15 20 25 30 35 40 45 50

British Columbia[2]

Years

Post-rituximab

Pre-rituximab

P=.00010

0.2

0.4

0.6

0.8

1.0

R-CHOP-14

P = .000025

RICOVER 60[5]

CHOP-14

0 5 10 15 20 25 30 35 40 45

R-CHOP-21

is The “Standard”

How can we improve?

DLBCL: Current Challenges w/R-CHOP

Coiffier et al, Blood June 2010

GELA 98-05 - median follow-up time of 10 years

½ failures occur in 1st 12 to 18ms

Poor outcome of early relapse (<1y) target for improvement +++

80%

of drop

1st 3 years 40% at 10 ystill NED in R-CHOP

Presenter

Presentation Notes

median follow-up time of 10 years

DLBCL: Strategies to improve / R-CHOPNb cycles / 6 vs 8 cyclesRICOVER trial (q2kws)

Dose-intensityR-CHOP-14 vs 21

Consolidation w/ DI / HDT-ASCT upfront

Continuous infusionR-EPOCH

“More“ chemo

New combinations / R-CHOP + X

Prediction response on PET

Revisit maintenance strategies

Pts stratification ++

Presenter

Presentation Notes


Schubert J, et al. ASH 2007. Abstract 788Pfreundshuh M. Lancet Oncol. 2008;9:105-116.

Adjust Number of cycles: 6 vs 8 Cycles (R)-CHOP-14 (RICOVER)

Regimen 6 cycles 8 cycles

CHOP 53% 58%R-CHOP 70% 70%

FFTF

CRu PR

0Months

1009080706050 4030 2010

0

%

CR

8 R-CHOP 146 R-CHOP 14



20 40 600Months

0 20 40 60Months

20 40 60

PFS according to mid-therapy restaging

NO benefit from 8 cyclesNo benefit from XRTBulk in CR-CRu

RICOVER Trial: 6 vs 8 CHOP-14 ± R in DLBCL > 60y (GHGLSG) / > 800 pts

Cunningham D et al, , ASCO 2011, abst # 8000.

R-CHOP-21 vs R-CHOP-14UK NCRI Phase III Trial

Newly diagnosed CD20+veDLBCL

R-CHOP-21 CHOP-21: 8 cycles

Rituximab x 8

R-CHOP-14 CHOP-14 x 6 Rituximab x 8

Lenograstim dasy 4-12

1080 pts, 540 / arm / 119 sites / May 2005 Nov 2008

Primary endpoints: OS

Stratified by age, IPI

R

Recruitment by age

0

50

100

150

200

250

300

350

400

450

<30 30-39 40-49 50-59 60-69 70-79 80+Age range

Pat

ient

s re

crui

ted

52%


No difference clinical parameters btw both arms 2/3 stage III-IV / 50% bulky



R-CHOP-21 (8) vs R-CHOP-14 (6)UK NCRI Phase III Trial

ORR 88% for RCHOP-21 vs 90% for RCHOP-14

No difference in ORR, CR rate, PFS or OS

DLBCL, age >18, Bulky IA (>10cm), IB, II, III, IV

Radiological CR 47% in both arms

PFS OS



Higher % neutropenia and F/N in R-CHOP21 reflects the primary prophylaxis with G-CSF in R-CHOP14

OS by phenotype

53 28963 271

EventsTotalsnon GC GC

Pro

babi

lity

0.00.10.20.30.40.50.60.70.80.91.0

0 1 2 3 4 5 6

p=0.2082


No difference in bulky, IPI, KI-67 (MIB-1), LDH, etc..


Delarue, ICML 2011 abst # 124

R-CHOP-21 vs R-CHOP-14 (8 cycles)GELA Trial

Interim analysis200 pts

Med flup 39 ms

Delarue et al, ASH 2009: abst # 406

Update ICML Lugano

R-CHOP14 R-CHOP21

CR + CRu 71% 73%

PR 16 % 12 %

ORR 87 % 85 %

• 60 to 80 y• Stage II to IV• AA IPI 1,2 or 3

Delarue, ICML 2011 abst # 124

R-CHOP-21 vs R-CHOP-14 (8 cycles)GELA Trial

Delarue et al, ASH 2009: abst # 406

EFS OS

3y-EFS : 57% vs 60% 3y-OS : 70% vs 73%

No benefit ORR, CR, EFS, PFS or OS

Continuous Infusion – R-EPOCH

Wilson WH, et al. J Clin Oncol. 2008;26:2717-2724.

Phase II Study of dose-adjusted R-EPOCH in DLBCL 72 pts stage II or more, med age 50, 40% had a high-intermediate or high IPI

Ongoing randomization R-CHOP-21 vs R-EPOCH (CALGB) w/ GEP

IPI score / PFS (P = .007)

Risk 5y PFSLow-risk 91%Low-interm 90%High-interm 67%High risk 47%

LNH98-5: R-CHOPhigh risk

5y EFS 47%

More Intensive Induction Regimens?

Recher Blood Nov 2010 abst # 109

LNH 03-2B Trial

*No radiotherapy in both arms

NO ASCT

R60 3 12 15 189 21

R-ACVBP 14

R-CHOP 21

Wks

MTX R-IFM-VP16 Ara-C

0 2 4 6 10 14 24 Wks

4 IT-MTX

380 pts / young pts IPI ≥ 1

More Intensive Induction Regimens?

LNH 03-2B Trial

3-y PFS 87% in R-ACVBP armvs 73% in R-CHOP arm

3-y OS was 92% R-ACVBPand 84% (R-CHOP arm

Recher Blood Nov 2010 abst # 109

R-ACVBP significantly improves EFS, PFS, DFS and overall survival

Consolidation w/ HDT – ASCT

Greb, Cancer Treatment Reviews (2007) 33, 338-346

Meta analysis 15 large randomized studies with chemo vs ASCT in DLBCL frontline

2728 pts

In pre rituximab era multiple studies conducted NOT conclusive

Presenter

Presentation Notes

ACVBP is a dose dense CHOP-Bleo (q 2 w) like therapy HDT MTX 3g/m2 x2 + Ifos, VP-16 and Cytarabine and Asparaginase + IT MTX x 4 cycles Responders only had BEAM ASCT / 10% collection failure Leuk Lymphoma. 2010 Sep;51(9):1668-77.Comparison of two high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone derived regimens in patients aged under 60 years with low-intermediate risk aggressive lymphoma: a final analysis of the multicenter LNH93-2 protocol.Morel P, Munck JN, Coiffier B, Gisselbrecht C, Ranta D, Bosly A, Tilly H, Quesnel B, Thyss A, Mounier N, Brière J, Molina T, Reyes F; Groupe d'Etude de Lymphomes des l'Adulte (GELA).Collaborators (96)Service d'Hématologie Clinique, Centre Hospitalier Schaffner, Lens, France. [email protected] of patients aged <or=60 years with aggressive lymphoma are at low-intermediate risk (LIR). Before the rituximab era, we prospectively compared ACVBP with ECVBP, a similar regimen including epirubicin instead of doxorubicin and increased dose intensity of cyclophosphamide, followed by conventional consolidation with an increased amount and dose intensity of cytosine-arabinoside, methotrexate, etoposide, and ifosfamide, in 652 patients with LIR aggressive lymphoma. The overall response rate, 5-year event-free survival (EFS), and survival were estimated to be 86%, 60%, and 74%, respectively, with no differences between the two arms. In patients with diffuse large B-cell lymphoma (DLBCL) who received ACVBP, the 5-year EFS and survival were estimated at 69% and 82%. These findings do not support the use of a chemotherapy regimen more intensive than ACVBP in patients aged <or=60 years with LIR aggressive lymphoma. The results in the control arm, without rituximab, have led to a randomized comparison of R-ACVBP and R-CHOP in this patient population.

Consolidation w/ HDT – ASCT UpfrontIn Rituximab Era

Vitolo, ICML 2011 abst # 72

R-CHOP-14 vs R-mega CHOP consolidation or not w/HDT-ASCT / High risk DLBCL pts AAIPI 2-3 /188 pts / arm

DLCL04 Trial

2y PFS no HDT-ASCT: 59% vs 72% for HDT-ASCT

2y OS: no difference

Presenter

Presentation Notes



LeGouill ASCO 2011 abst # 8003

R-CHOP-14 x 8 vs HDT (CCEP/MC/DHAP) inductionfollowed by BEAM ASCT / 340 pts

GOELAMS Trial 075

0 10 20 30 40 50 60 70Months

0,

0,2

0,4

0,6

0,8

1,0

Cum

ulat

ive

Surv

ival

3y EFS R-CHOP 56 % 3y EFS R-HDT 41 %

R-CHOP

R-HDTp= 0.03

3y PFS 81 % vs 79 % / No diff in OS or by IPI

Presenter

Presentation Notes



Schmitz, ICML 2011 abst # 73

DSHNHL Trial

R-MegaCHOEP not > (CR rate and PFS) and >> toxicity

8 CHOEP + 6 R vs 4 MegaCHOEP+ 6RMegaCHEOP increasing dose 3 ASCR / 130 pts /arm / young pts high risk

Presenter

Presentation Notes



Stiff, ASCO 2011 abst # 8001

S9704 Trial (SWOG + Canada)Bulky stage II, III, and IV H-Int / High IPI DLBCL

Hypothesis: is HDT-ASCT > after 5 CHOP+/- R?

Presenter

Presentation Notes



Stiff, ASCO 2011 abst # 8001

S9704 Trial (SWOG + Canada)Bulky stage II, III, and IV H-Int/High IPI diffuse

(except in AN UNPLANNED subset analysis > for high

risk pts)

HDT-ASCT improved PFS even for pts who received R-CHOP but no diff OS

Outcome%

ASCT arm Conventional arm

Hazard ration P-value

2-year PFS 69 56 1.72 .005

2-year OS 74 71 1.24 .16

Presenter

Presentation Notes


Consolidation w/ DI / HDT – ASCT Upfront??

• Rituximab is likely to decrease potential differencesbetween conventional and high-dose regimens

• Lack of impact on OS means it does not matter if ptsreceive HDT-ASCT

HDT should not be part of routine upfront consolidation

A subset of high risk pts might benefit from DI / HDT approaches upfront (difficult to identify)

Presenter

Presentation Notes


Can we identify high risk patients upfront

/ early on??

Presenter

Presentation Notes


Adjust Response Based on PET

Can we use functional imaging

to detect chemosensitivity

in-vivo?

Presenter

Presentation Notes


Early Interim PET in Lymphoma

Kostakoglu et al, Cancer 107: 2678, 2006

Interim-PET +

Haioun et al, Blood 106: 1376, 2005Mikhaeel et al, Ann Oncol 16: 1514, 2005

Spaepen et al, Ann Oncol 13: 1356, 2002

PET after 4th cycle PET after 1st cycle

PET after 2nd cyclePET after 3rd cycle

No event in PET-ve group

PET+ve

ΔSUV (drop ≥70%) might be better predictor?

Strong predictor if NEGATIVE

Issues: consistency / false +ve / NEED BIOPSY

Early Interim PET in Lymphoma

• Evidence that pts benefit from having their treatmentadapted based on early FDG-Pet is limited and conflicting (need better standardization interpretation)

• Most data so far „adjusting“ based on PET were preRituximab

• Ongoing risk-adapted studies / still pending

Haouin, ICML 2011 abst # 139Moskowitz, ICML 2011 abst # 140

Ongoing studies FDG-PET remains investigational

Djor, ICML 2011 abst # 132

Risk Adapted Therapy

Patientsstratification ++

Presenter

Presentation Notes


CLINICAL Prognostic Factors – IPI (APLES)

Shipp et al, NEJM 1993

Risk Group Risk Factors,

n

CR, %

5-Yr OS, %

Patients (all ages) Low 0-1 87 73

Low intermediate 2 67 51

High intermediate 3 55 43

High 4-5 44 26

Patients 60 yrs of age or younger Low 0 92 83

Low intermediate 1 78 69

High intermediate 2 57 46

High 3 46 32

Prognostic models CAN BE INFLUENCED by EVOLVING therapies

Revised IPI (R-IPI)

PFS Overall Survival

Sehn et al, Blood, 2007

R-IPI cannot predict population < 50% OS @ 5y!

365 pts DLBCL R-CHOP

Bari A et al, Ann Oncol 2010;21:1486-1491Ziepert et al, JCO May 2010

IPI still debated in the R-chemo era

Other factors: beta-2microglobulin, BM+, bulky NOT included!

Impact of biological

heterogeneity of DLBCL

Cellular Origin of B-cell Lymphomas

Kuppers et al, Nat Rev Cancer, 2005

Classification of lymphomas based on B-cell differentiation steps and molecular (oncogenic) features

DLBCL Subtypes Resemble Stages of B-cell Differentiation and Activation

Alizdeh et al, Nature 2000.

GC-DLBCL

ABC-DLBCL

Kuppers et al, Nat Rev Cancer, 2005

2 main molecular subtypes of DLBCL

correspond to different cell of origin

Presenter

Presentation Notes

Primary Mediastinal Large Cell lymphoma (PMBL) Have Distinct GEP

Rosenwald et al, J Ex Med, Sept 2003

A group of 46 genes allowed to separate PMBL from other DLBCL

PMBL signature overlaps w/ classical Hodgkin lymphoma

3 Main Subtypes of DLBCL w/ Different Outcome

Rosenwald et al, J Ex Med, Sept 2003

Rosenwald A, et al. N Engl J Med. 2002;346:1937-1947

Distinction ABC / GC remains after R-CHOP in DLBCL

Lenz et al, NEJM, Nov 2008

Non GC subtype still worse outcome

Definition of ABC and GC Subtypes by IHC

Hans, CP, et al. Blood. 2004;103:275-282.

CD 10+

GCB+

-Bcl-6

- Non-GCB

+ MUM-1

-GCB

+ Non-GCB

GCB Non-GCB76% 34%

Choi model addition of GCET-1 (GC) and FOXP-1 (ABC)

Hans algorithm

Choi et al, Clin CA Res, Nov 2009.

Stromal Signatures in DLBCL

Lenz G et al. N Engl J Med 2008;359:2313-2323

GEP on lymph node biopsies of 233 pts treated w/ R-CHOP

Stroma 1: extra-cellular

matrix, myeloid, macrophages

Stroma 2: endothelial,

angiogenesis signature

Also predictive for PFS

Presenter

Presentation Notes

The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. Methods We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression–based survival-predictor model derived from a training group was tested in a validation group. Results A multivariate model created from three gene-expression signatures — termed “germinal-center B-cell,” “stromal-1,” and “stromal-2” — predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. Conclusions Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Other Mutations

Genomic(MYC, double-

hit, CGH)

Epigenetic (Histones,

methylation)SNPs

MicroRNAs

Evolving COMPLEXITY Of Signatures in DLBCL

GROWING awareness of molecular Heterogeneity of

DLBCL

BUT

not yet ready for routine clinical decisions

Presenter

Presentation Notes

IWC, International workshop criteria; PET, positron emission tomography

What Happen After R-CHOP(Relapse / refractory setting)?

Presenter

Presentation Notes

IWC, International workshop criteria; PET, positron emission tomography

Guideline Recommendations for Treatment of Relapsed DLBCL

Second-line therapy in candidates for high-dose therapy + ASCT– DHAP ± rituximab

– ESHAP ± rituximab

– GDP ± rituximab

– GemOx ± rituximab

– ICE ± rituximab

– miniBEAM ± rituximab

– MINE ± rituximab

Second-line therapy for patients who are not candidates for high-dose therapy– Clinical trial

– Rituximab

– CEPP ± rituximab

– PEPC

– EPOCH ± rituximab

NCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. v.1.2011.

Presenter

Presentation Notes

ASCT, autologous stem cell transplantation; CEPP, cyclophosphamide, etoposide, procarbazine, prednisone; DHAP, dexamethasone, cisplatin, high-dose cytarabine; DLBCL, diffuse large B-cell lymphoma; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; ESHAP, etoposide, methylprednisolone, cytarabine, cisplatin; GDP, gemcitabine, cisplatinum, dexamethasone; GemOx, gemcitabine, oxaliplatin; ICE, ifosfamide, carboplatin, etoposide; MINE, mesna, ifosfamide, mitoxantrone, etoposide; miniBEAM, carmustine, etoposide, cytarabine, melphalan; PEPC, prednisone, etoposide, procarbazine, cyclophosphamide. More aggressive treatments, such as regimens containing cytarabine or gemcitabine, are appropriate for patients with relapsed DLBCL who are transplant candidates. Second‑line treatment for those not physically able to undergo high‑dose therapy and autologous stem cell transplantation (ie, the standard of care) include less toxic regimens such as cyclophosphamide, etoposide, procarbazine, and prednisone; and prednisone, etoposide, procarbazine, and cyclophosphamide. Clinical trials are also suggested for this patient population.

PARMA Study: Bone Marrow Transplantation vs Salvage Chemotherapy

Philip T, et al. N Engl J Med. 1995;333:1540-1545.

P = .0010

20

40

60

80

100

EFS

(%)

0 15 30 45 60 9075Mos After Randomization

P = .0380

20

40

60

80

100

OS

(%)

0 15 30 45 60 9075Mos After Randomization

TransplantationConventional treatment

All PRE rituximab

Presenter

Presentation Notes

EFS, event-free survival; OS, overall survival. The standard of care for patients with relapsed DLBCL who are transplant candidates is based on the PARMA study, which showed that patients receiving autologous stem cell transplantation had improved outcomes compared to patients receiving conventional dexamethasone, cisplatin, high-dose cytarabine (DHAP) chemotherapy.

CORAL – Relapse / Refractory DLBCL

C. Gisselbrecht et al. JCO Sept 2010

N =400 patients

Patients with relapsed/refract

oryCD20+ DLBCL,

< 65 years

R-ICE

R-DHAP

ASCT

Rituximab q2 m x 6

Observation

RANDOMIZE

R-ICE and R-DHAP : similar activity

OS PFS

2 questions: Salvage regimen and benefit of maintenance post ASCT

CORAL – Relapse / Refractory DLBCL

C. Gisselbrecht et al. JCO Sept 2010

Impact of prior Rituximab Impact of early relapse

Prior rituximab exposure and relapse within 12 ms of diagnosis 3y PFS 23% after HDT-ASCT

BIO- CORAL Study

Thieblemont et al. ASH 2010, abt # 993

Paired biopsies showed no diff in GC / non-GC over time and by GEP

p = NS

Non GCGCHans algorythm

R-DHAPR-ICE

p = 0.04p = NS

31%

27%

52%

32%3 years3 years

Difference in outcome confirmed when based on GEP +++

CORAL – Update on Maintenance post ASCT

Gisselbrecht ASC0 2011, abst # 8004

Outcome4- years %

R-maintenance

No further treatment

P-value

EFS 55 53 .7435PFS 55 57 .8314OS 64 67 .7547

At 45 months, mobilization-adjusted ORR comparable after induction therapy

• ORR 51.5% for R-ICE vs 56.5% for R-DHAP (NS)

• EFS 29% vs 33% (NS)

• OS 48% vs 51% (NS)

R-maintenance is not superior to observation after salvage ASCT(except in women > > PFS @2y and > OS for MR (p= 0.0066)

Effect of R-CHOP Induction Debated

Moore ICML 2011, abst # 76

Salvage after R-CHOP

• Primary failures to R-CHOP do VERY POORLY +++

• Early failures to R-CHOP do worse than late failures (>1y) but if chemosensitive should be transplanted

• Need for new strategies / (new combinations / allogenic TH2)

Special Considerations in the Treament of DLBCL

R-Mini-CHOP in > 80y

>80 y - Stage I-X to IV

R-mini-CHOP: cyclophosphamide: 400 mg/m2

doxorubicine: 25 mg/m2

vincristine: 1 mg total dose D1

6 cycles q21d / GCSF optional

Primary endpoint efficacy / OS

Schmitz N, et al. ASH 2010. Abstract 112.

Elderly w/ good PS can still do well with reduced dose R-CHOP

150 pts 51 males 99 females

38 GELA centers

108 pts completed 6 cycles

ORR 74% / CR-CRu 63%

2y OS 59% / PFS 48%

30 deaths: 1/3 tox / 1/3 NHL / 1/3 other

Life expectancy of an 80y person is 9 years!

Presenter

Presentation Notes

CHOEP, cyclophosphamide, doxorubicin, prednisone, etoposide, vincristine; CNS, central nervous system; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DSHNHL, German High-Grade Non-Hodgkin Lymphoma Study Group; DLBCL, diffuse large B-cell lymphoma; MInT, MabThera International Trial; PD, progressive disease; R, rituximab.

Location: Testes Lymphoma - IELSG-10 (CONSORT Trial)

Vitolo, JCO July 2011

> Outcome / historical controls

Fifty-three patients (22-79) with untreated stage I or II PTLR-CHOP-21 + IT MTX + XRT (controlateral testis)

Cumulative incidence of CNS relapse at 5 years was only 6%

(up to 35% in prior studies)

Is IT only sufficient? Common brain parenchymal relapses

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CNS Disease in DLBCL

CNS involvement in DLBCL poor prognosis ++

Few data available on impact of systemic therapy on CNS events in DLBCL

2797 patients ≥ 60 yrs DLBCL in the DSHNHL and MInT trials

– 2196 pts received CHO(E)P ±R for 6-8 courses or MegaCHOEP + R

Peyrade, et al. ASH 2010. Abstract 853

Current prophylaxis (IT MTX) – not needed in “low risk” / NOT “helpful” in high risk redefine risk factors? HD MTX?

CNS disease developed in 56 patients (2.5%) @ median: 7.0 mos; range, 0.2-85.0 mos

CNS disease reduced in patients with IPI 0 or 1 receiving rituximab

NOT for high risk pts

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Can we add to R-CHOP?

DLBCL: Add Mab (anti CD22) to R-CHOP

Micallef et al, Blood Oct 2011

R-CHOP-21 + Epratuzumab 360 mg/m2 on day 1 of each cycle

ER-CHOP feasible / appears to improve EFS comp to historical controls

107 pts

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DLBCL: Add Mab to R-CHOP

Therapy type Drug / Rationale / design

Anti CD20 GA-101 / Ofatumumab

RIT R-CHOP RIT

HDT RIT salvage

Anti-angiogenesis?? Bevacizumab

MAIN trial stopped

Anti VGEF (aflibercept)

Anti CD30 Brentuximab vedotin 64% CR rate

in CD30+ve lymphomas

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DLBCL – Novel Therapies New biologicals: small molecules

Therapy type Drug Rationale / design

CommentsEfficacy / Toxicity

Proteasomeinhibitors

Strong rationale for combinations

R-CHOP-Bz

R-EPOCH-BzmTOR inhibitors RAD-001 (Everolimus) ORR 30% / DOR ≈ 6ms

PILLAR 2 trial: rand maintenance in CR post R-CHOP

IMiDs Lenalidomide NHL-003 trial ORR 31%

Median of 3 prior RX (1-10)R2-CHOP Len 265 days 1-10 / 30 pts

ORR 100% / CR rate 83%++ MAINT post R-CHOP in > 60y (REMARC)

PKCβ inhibitor Enzastaurin Maintenance post R-CHOP / suggest > PFS

Other HDAC inhibitors Ongoing

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2002 started CORAL study R-ICE and R-DHAP Chemosensitivity ASCT Rand R x 6 vs obs (1 q 2 ms x 1 y) 11 countries 400 pts Both arms well balanced sIPI and 44% early relapse Same ORR: ORR 63% both arms CR rate 38% Pnc / ORR (p<.0001) were: refractory/relapse < 12 months:46 % vs 88 %, secondary IPI >1:52% vs 71% and prior exposure to rituximab:51% vs 83%. There was not significant difference between R-ICE and R-DHAP for 3 yr EFS (26% vs 35% / same Pnc factors 3 yrs EFS was affected by: prior treatment with rituximab, 21% vs none 47% (p<.0001); early relapse< 12 m 20% vs >12m 45% (p <.0001); secondary IPI 2-3: 18% vs 0-1: 40% (p=.0001). ½ ASCT No diff in OS and PFS 56% and 45% between 2 arms Pnc factors prior R, early rel (<12ms) and sIPI 2-3 (if all salvage <20%) ABC GC ongoing UNMET need

Validation of NFKB Target in ABC DLBCL

Dunleavey, Blood June 2009

Differential efficacy of Bortezomib + chemotherapy within molecular subtypes of DLBCL

Rationale for ongoing trial R-CHOP +- Bortezomib in ABC-DLBCL (PYRAMID Trial)

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2002 started CORAL study R-ICE and R-DHAP Chemosensitivity ASCT Rand R x 6 vs obs (1 q 2 ms x 1 y) 11 countries 400 pts Both arms well balanced sIPI and 44% early relapse Same ORR: ORR 63% both arms CR rate 38% Pnc / ORR (p<.0001) were: refractory/relapse < 12 months:46 % vs 88 %, secondary IPI >1:52% vs 71% and prior exposure to rituximab:51% vs 83%. There was not significant difference between R-ICE and R-DHAP for 3 yr EFS (26% vs 35% / same Pnc factors 3 yrs EFS was affected by: prior treatment with rituximab, 21% vs none 47% (p<.0001); early relapse< 12 m 20% vs >12m 45% (p <.0001); secondary IPI 2-3: 18% vs 0-1: 40% (p=.0001). ½ ASCT No diff in OS and PFS 56% and 45% between 2 arms Pnc factors prior R, early rel (<12ms) and sIPI 2-3 (if all salvage <20%) ABC GC ongoing UNMET need

Differences in responses to Lenalidomide monotherapy in relapsed/refractory

GCB vs. Non GCB DLBCL

% o

f res

pons

e

ORR 8.7% in GC vs. 53% in non-GCB DLBCL treatedwith lenalidomide-monotherapy (n=40) (p = 0.006)

No differences in the median number or treatments, IPI score, histology, stage or other demographic characteristics @ time lenalidomide Rx btw the two groups

P = 0.006

Hernandez-Ilizaliturri, et al, Cancer April 2011

P = 0.004

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*One patient in the Non-GCB group was censored as SD by standard protocol criteria, but had complete clearing of “leukemic phase” and extensive bone marrow disease, along with becoming PET negative in FDG-positive nodal sites and therefore was classified as CR for this analysis

Targeting BCR Pathway in Lymphoma

1 Quiroga MP, et al. Blood 114(5):1029-37, 07/20092 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009From: Nat Rev Immunol 2:945

BCR-associated kinases are targets of new drugs in preclinical and clinical development

Inhibitor Activity in DLBCL

Syk (spleen tyrosine kinase) Fostamatinib

5/23 responded ORR: 22%

Btk (Bruton’styrosine kinase) PCI-32765

ORR 29%? More CR in ABC

PI3K inhibitor CAL-101

Activity in CLL,MCL, FL

DLBCL: Strategies to improve / R-CHOP6 cycles enough!

R-CHOP-14 vs 21 no difference

? Subset benefit fromHDT-ASCT upfront

Continuous infusionR-EPOCH?

“More“ chemo

New combinationsR-CHOP + X

Prediction response on PET?

NEW maintenance strategies

Patients stratification ++

Patients stratification will help develop novel

strategies in DE-(RE)FINED subsets of pts

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DLBCL: Considerable Progress!

Induction Consolidation Maintenance Relapse

CHOP-21

BEFORE

ASCT Debated?

No maintenance HDT / ASCT

R-CHOP-21+++

NOW

No HDT/ASCTSubset of pts?

New agents ??

New MabDAC

LenalidomideBTZSYKBTKi

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Treatment of Large Cell Lymphoma

Economy & Finance

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