agresİf b hÜcrelİ lenfomalarda tedavİ -...
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AGRESİF B HÜCRELİ LENFOMALARDA
TEDAVİ
Dr. Evren Özdemir
Hacettepe Üniversitesi Onkoloji Hastanesi
20.04.2013
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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
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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
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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
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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
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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
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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
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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)
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R-CHOP-21’den daha iyi bir tedavi var mı?
• Mevcut rejimlerin uygulama sıklığının/doz
yoğunluğunun artırılması
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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
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R-CHOP-21’den daha iyi bir tedavi var mı?
• Mevcut rejimlere yeni ajanlar eklenmesi
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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
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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
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R-CHOP-21’den daha iyi bir tedavi var mı?
• Diğer rejimler
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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
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R-CHOP-21’den daha iyi bir tedavi var mı?
• Konsolidasyon/idame tedavileri
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R-CHOP-21’den daha iyi bir tedavi var mı?
• Başlangıçta nakil (ilk remisyonda)
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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?
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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
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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
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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
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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
– 3 Lines = 8 cases
– 4 Lines = 5 cases
• CR = 15 (26%), PR = 18 (31%)
• Median PFS = 134 days
• Median OS = 296 days
Crescentini et al. ASCO 2012 # 8084
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Salaverria I, et al. J Clin Oncol 29:1835-1843
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Aukema SM, et al. Blood 2011;117(8):2319-2331
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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
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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