AGRESİF B HÜCRELİ LENFOMALARDA TEDAVİ -...

AGRESİF B HÜCRELİ LENFOMALARDA

TEDAVİ

Dr. Evren Özdemir

Hacettepe Üniversitesi Onkoloji Hastanesi

20.04.2013

Risk factors

>60 years

2-4

Elevated

>1 site

III-IV

2-4

Elevated

III-IV

Patients of all ages

Age

Performance status

Lactate dehydrogenase (LDH) level

Extranodal involvement

Stage (Ann Arbor)

Patients ≤60 years (age-adjusted)

Performance status

LDH

Stage

International Prognostic Index (IPI)

Shipp, et al. N Engl J Med. 1993;329:987

IPI: Overall Survival by Risk Categories Among Patients With “Aggressive” NHL Treated With Chemotherapy

75

50

25

0

0 2 4 6 8 10

High

High-intermediate

Low-intermediate

Low

Pati

en

ts (

%)

Year

100

Shipp, et al. N Engl J Med. 1993;329:987

RICOVER - 60 Study

• R-CHOP > CHOP

• R-CHOP x 6 + 2R = R-CHOP x 8

Pfreundschuh, et al. ASH 2005; Schubert, et al. ASH 2007

Diffuse Large B-Cell Cell Lymphoma: At Least Three Diseases

Germinal center

B cell-like

(GCB DLBCL)

Activated

B cell-like

(ABC DLBCL)

Cell of Origin

Oncogenic

Mechanisms

Clinical

Outcome

Germinal center

B cell

Post-germinal

center B cell

•BCL-2 translocation

• c-rel amplification

Constitutive activation

of NF-kB

Favorable

59% 5-yr survival

Poor

30% 5-yr survival

Thymic B cell

Chr. 9p24

amplification

PDL1, PDL2 …

Favorable

64% 5-yr survival

Primary Mediastinal

B Cell Lymphoma (PMBL)

Lossos IS, et al. JCO 2005; 23(26):6351-6357

R-CHOP ile GCB DLBCL >

ABC DLBCL

• R-CHOP ile GCB DLBCL’de PFS

ve OS ABC DLBCL’den daha iyi

• 3 Yıllık genel sağkalım (OS3)

– GCB DLBCL için %84

– ABC DLBCL için %56

Gisselbrecht & Meunier, ASCO 2011

Lenz G et al, NEJM 2008; 359: 2313

High-Risk DLBCL treated with

R-CHOP-like chemotherapy Subgroup Survival

aaIPI=2 (<61 years) 90% (3 years)

aaIPI=3 (<61 years) 70% (3 years)

Low-intermediate risk (ages 61-80) 71% (5 years)

Intermediate-high risk (ages 61-80) 55% (5 years)

High risk (ages 61-80) 52% (5 years)

Very old cases (>80) Median 2.2 years

ABC type 56% (3 years)

myc breakpoint 32% (5 years)

Double hit Median 0.21-1.5 years

CNS involvement (ages18-60) Median 6.5 months

CNS involvement (ages 61-80) Median 2.8 months

Pfreundschuh, et al. ASCO 2011

R-CHOP-21’den daha iyi bir tedavi var mı?

• Mevcut rejimlerin uygulama

sıklığının/doz yoğunluğunun artırılması

• Mevcut rejimlere yeni ajanlar eklenmesi

• Diğer rejimler

• Konsolidasyon/idame tedavileri

• Başlangıçta nakil (ilk remisyonda)


• Mevcut rejimlerin uygulama sıklığının/doz

yoğunluğunun artırılması

R-CHOP14 compared to R-CHOP21 in elderly

patients with DLBCL: Final analysis of the

LNH03-6B GELA study.

R-CHOP-14 (n=304) R-CHOP-21 (n=296)

LDH elevated 66% 71%

Beta-2 elevated 43% 47%

IPI 3-5 72% 78%

Febrile neutropenia 21% 19%

Grade III/IV anemia 22% 18%

EFS3 56% 60%

PFS3 60% 62%

OS3 69% 72%

Delarue et al. ASCO 2012 # 8021


• Mevcut rejimlere yeni ajanlar eklenmesi

Comparison of ER-CHOP intention-to-treat results with R-CHOP treated patients

Micallef, et al. Blood 2011;118:4053-4061

N = 107, 81 eligible

Median age 62

IPI 3-5 51%

No unexpected toxicity

Phase 2 in newly diagnosed

DLBCL

R-CHOP x 6 + day 1

epratuzumab 360 mg/m2

R-CHOP + Lenalidomide (R2CHOP) initial therapy

for aggressive B-cell lymphomas: phase I study

• R-CHOP-21 + lenalidomide days 1-10 (pegfilgrastim day 2)

• N = 24; Median age 65 (35-82)

• Lenalidomide 15 mg (N=3), 20 mg (N=3), or 25 mg (N=18)

• No DLT; no toxic death

• Grade IV neutropenia 67% (febrile neutropenia 4%)

• Grade IV thrombocytopenia 21%

• RR 100%, CR 77%

• Lenalidomide in DLBCL

• ABC > GCB (activity) Nowakowski GS, et al. Leukemia 2011


• Diğer rejimler

R-ACVBP > R-CHOP in Younger Patients with Non-GC

DLBCL in the GELA Trial LNH03-2B.

• GELA, NHL03-2B trial, cases with ages 18-59

• n=379 229 evaluable

– 107 cases on R-ACVBP

– 122 cases on R-CHOP

• For GCB population (n=101), EFS, PFS, OS = for R-

ACVBP and R-CHOP

• For non-GCB population (n=128), R-ACVBP better than

R-CHOP, EFS (p=0.02), PFS (p=0.007), OS (p=0.007)

Molina et al. ASH 2011 # 2632


• Konsolidasyon/idame tedavileri


• Başlangıçta nakil (ilk remisyonda)

CORAL: Collaborative trial in Relapsed

Aggressive Lymphoma

Relapsed/

refractory

DLBCL

n = 396

R

A

N

D

O

M

I

S

E

R-ICE

x 3

R-DHAP

x 3

ASCT

BEAM

SD, PD off study

PR, CR

R

A

N

D

O

M

I

S

E

Rituximab 375 mg/m2

q2mo x 6

Observation only

Gisselbrecht et al. J Clin Oncol 2010; 28:4184–4190

R-DHAP = rituximab, dexamethasone,

high-dose cytarabine, cisplatin

R-ICE = rituximab, ifosfamide, carboplatin, etoposide

Which salvage regimen is the best?

Place of immunotherapy

Post-transplantation?

CORAL Study – Final Report

Relapsed / Refractory DLBCL, n=477

R-ICE x 3 (n=191)

R-DHAP x 3 (n=197)

Rituximab (+),

Every 2 months for 1 year (n=122)

Rituximab (–)

(n=120)

BEAM

(n=242)

Gisselbrecht et al. ICML-11 Lugano # 75

CORAL Study – Final Report

• Rituximab maintenance post-ASCT is not effective

• Rituximab maintenance post-ASCT is more effective in

females than males: EFS4 63% in females, 37% in

males (p=0.01)

Gisselbrecht et al. ICML-11 Lugano # 75

Second

Randomization

Rituximab-

Maintenance

(n=122)

Observation

(n=120)

p value

EFS3 54% 54% NS

PFS3 54% 57% NS

OS3 66% 69% NS

A multicenter phase II study of bendamustine with

rituximab in patients with relapsed/refractory DLBCL

Group n CR PR Median PFS

All cases 59 22 (37.3%) 15 (25.4%) 6.7 months

Age ≥ 65 37 14 (37.8%) 9 (24.3%) 6.3 months

Age < 65 22 8 (36.4%) 6 (27.3%) 6.7 months

Ogura et al. ASCO 2012 # 8023

An update on gemcitabine, rituximab, and oxaliplatin

in combination for relapsed/refractory NHLs

• 58 Cases with relapsed / refractory NHL

• DLBCL = 45 cases

• Prior rituximab yes = 38 cases, no = 20 cases

• Prior lines of therapy – 1 Line = 33 cases

– 2 Lines = 12 cases



• CR = 15 (26%), PR = 18 (31%)

• Median PFS = 134 days

• Median OS = 296 days

Crescentini et al. ASCO 2012 # 8084

Everolimus in Combination with Rituximab Induces

CRs in Heavily Pretreated DLBCL

• Dana-Farber, R/R DLBCL, n=25

• Stage III/IV at relapse = 76%, elevated LDH = 64%

• Median number of prior therapies = 4

• Prior ASCT = 20%

• Everolimus 5mg (days 1-14) if tolerated everolimus

10mg (days 15-28); Rituximab (days 1,8,15,22 cycle 1)

(day 1 cycles 2-6), repeated every 28 days upto 6

cycles

• Best ORR = 36%

• CR = 12%, PR = 24%

• Median PFS = 3.4 months, median OS = 8.6 months

Barnes et al. ASH 2011 # 1635

Novel Targeted Agents for DLBCL Derived

from Gene Expression Profiling Studies*

Drug GEP Subgroup Target

Bortezomib ABC NF-κB

Enzastaurin ABC; Fatal/Refractory PKCβ

Bevacizumab Stromal-2 signature VEGF; angiogenesis

Lenalidomide Stromal-2 signature; ABC Angiogenesis, NF-κB, pleiotropic

Fostamatinib BCR-dependent; ABC Syk & BCR signaling; NF-κB via CARD 11

PCI-32765 BCR-dependent; ABC Syk & BCR signaling; NF-κB via CARD 11

CAL-101 Under investigation Associated with BCR signaling (PI3K-delta)

Everolimus

(RAD001)

ABC mTOR (downstream from PI3K/AKT pathway)

DCS4968q

(anti-CD796 ADC)

Phase 1 Trial (Genentech) BCR signaling

SMI of BCL61 BCR-dependent (pre-clinical) BCL6-dependnet DLBCL

Friedberg et al. Clin Cancer Res 2011; 17:6115

BURKİTT LENFOMA - TEDAVİ

-- En kısa sürede, kısa, sık ve yoğun, çoklu ajan

immünokemoterapi rejimlerine başlanmalı,

intratekal KT ile SSS profilaksisi verilmeli

-- CHOP veya CHOP benzeri tedaviler inferior

(OS %75 vs %22)

-- Bu prensiplere uyan 3 majör tedavi kategorisi

mevcut;

-- Doz-yoğun, ardışık kemoterapi

-- ALL-benzeri kemoterapi

-- Yüksek doz kemoterapi ve otolog KİT

konsolidasyonu ile biten kısa, doz-yoğun tedavi

-- Faz II çalışmalar, karşılaştırmalı çalışma yok

Erişkin Burkitt Lenfoma Faz II Çalışmaları N Median

Yaş

Rejim 2-yıllık

DFS

Kaynak

24 33 Kısa/doz yoğun/pediatrik NHL % 49 Hoelzer 1996

35 36 Kısa/doz yoğun/pediatrik NHL % 51 Hoelzer 1996

54 24 CODOX-M/IVAC % 89 Magrath 1996

(NCI)

48 58 Hyper-CVAD % 39 Thomas 1999

52 27 Modifiye CODOX-M/IVAC % 70 Mead 2002

92 47 Kısa/doz yoğun % 50 Rizzieri 2004

(CALGB)

14 47 Modifiye CODOX-M/IVAC

% 71 Lacasce 2004

27 36 Kısa/doz yoğun/ BEAM-Otolog KİT % 81 Van Imhoff 2005

(HOVON)

31 46 R-Hyper-CVAD % 89 Thomas 2006

10 51 Kısa/doz yoğun % 72 Kujawski 2007

The incorporation of rituximab and liposomal

doxorubicin into CODOX-m/IVAC for untreated Burkitt

lymphoma (BL): Final results of a prospective

multicenter phase II study

• After cycle 2 ORR 100%, CR 78%

• After cycle 3/4 ORR 100%, CR 100%

• Median follow-up was 24 months

• PFS2 was 86%

• OS2 was 86%

Evens, et al. ASCO 2012 # 8080

Hyper-CVAD and Rituximab for De Novo Burkitt

Lymphoma/Leukemia

• MDACC, newly diagnosed BL (n=30) or B-ALL (n=27),

non-HIV, median age 44

• Rituximab on days:

– 1 & 8 of Hyper-CVAD

– 1 & 8 of MTX/Ara-C

– Every 21 days

R-Hyper-

CVAD, n=57

Hyper-CVAD,

n=48

CR 43/47 (92%) 41 (85%)

OS5 74% 50%

R R R R R R R R Thomas et al, Cancer 2006;106:1659

H-CVAD M/A H-CVAD M/A H-CVAD M/A H-CVAD M/A

IT IT IT IT IT IT IT IT IT IT IT IT IT IT IT IT

Thomas et al. ASH 2011 # 2698

Burkitt Lenfoma ve myc Pozitif DLBCL İlk

Basamak Tedavisinde DA-EPOCH-R

• Tedavi edilmemiş, 12 yaşın üzerindeki 31 Burkitt

lenfoma olgusu

• HIV negatif = 20, HIV pozitif = 11

• Tüm olgular IT MTX profilaksisi almış

• CR=30, CRu=1, ORR=%100

• EFS5=%97, OS5=%100

Dunleavy, et al. ICML-11 Lugano # 71

Long-Term Outcome of Cases with Lymphoblastic

Lymphoma After Hyper-CVAD Variants

• MDACC

• 49 Cases

• Median follow-up was 80

months (~60%)

• Current scheme:

• Hyper-CVAD x 8

• Nelarabine 650mg/m2

daily for 5 days x 2

Cases in

each variant

5-Year CR

Duration

OS5

C – 21 69% 63%

AI – 11 70% 55%

No AI – 17 78% 79%

C: Classic Hyper-CVAD, AI: Modified

hyper-CVAD with anthracyclin

intensification, No AI: Modified hyper-

CVAD without anthracyclin intensification

Thomas et al. ASH 2010 # 2831

Other Aggressive B-Cell Lymphomas in the

WHO Classification

• Burkitt(BL)/DLBCL and MYC

– MYC: BL 100%

– MYC: double-hit 100%

– MYC: DLBCL 8-10%

– MYC: Plasmablastic 50%

• B-UNC/BL/DLBCL MYC/BCL-2/BCL-6(

)

– More CNS relapses

– Bone marrow involvement common

– MYC positives & negatives do the same with DA-EPOCH-R

regimen

Jaffe, et al. ASH 2011

R-CHOP and MYC rearranged DLBCL

Barrans et al. JCO 2010

EFS

OS

35 (14%) with MYC

rearrangements

19 also had t(14;18)

3 also had BCL6

7 “triple hit”

Therefore most

“MYC+” are “double”

or “triple” hit

Salaverria I, et al. J Clin Oncol 29:1835-1843

Aukema SM, et al. Blood 2011;117(8):2319-2331

Phase II study of dose adjusted R-EPOCH in

previously untreated BL and c-MYC + DLBCL

NCT01092182

• Inclusion criteria

– Burkitt lymphoma or B-cell lymphoma, unclassifiable, with features intermediate between Diffuse Large B-cell lymphoma and Burkitt Lymphoma

– c-MYC + DLBCL

– c-MYC+ plasmablastic lymphoma

Diffuse Large B-Cell Lymphoma (DLBCL)

• R-CHOP x 6-8

• R-CHOP x 3 + IFRT

• IPI High Risk: High dose chemotherapy followed by autologous stem cell transplantation in CR1

• Relapsed DLBCL: Salvage chemotherapy (if chemo. sensitive) followed by autologous stem cell transplantation

Mantle Cell Lymphoma (MCL)

• Front-line aggressive regimen: R-HyperCVAD, etc.

• Autologous stem cell transplantation in CR1

• Relapsed MCL: RIC

Burkitt/Lymphoblastic Lymphoma/Double hit/Gray zone

• High-dose sequential regimens: R-HyperCVAD, R-CODOX-M/IVAC, ALL-like regimens

• Autologous stem cell transplantation in CR1

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