DLBCL Flashcards
What are the components of the IPI score? (APpLES)
Age (>60) Performance status (2-4) LDH (>1 ULN) Extra nodal NHL (>1 site) Stage (III and IV)
What is the aa IPI?
Meant for patients 60 years and below
Stage
LDH
PS
How does the IPI correlate with OS?
IPI Low - CR 80-90%; 5y OS 70% Low intermediate - CR 60-70%; 5yOS 50% High intermediate - CR 50-60%; ;5yOS 40% High - CR 40%; 5y OS 20-30%
Describe the LNH 03-2B study
Christian Recher et al, Lancet 2011
Aim = to identify if R-ACVBP is better than RCHOP n terms of survival
Incl criteria:
- 18-59yo
- untreated DLBCL
- aaIPI =1
2 arms:
- RACVBP vs RCHOP
- both arms no RT
Results:
- 3yr EFS: 80% (RACVBP) >70%
- 3 yr PFS : 87% > 73%
- OS 90% vs 80%
- SAE 40% vs 15%
- FN rate 40% vs 10%
- Overall RR 90% vs 90%
How is R-ACVBP given?
Induction phase of 11 weeks
Consolidation phase of 19 weeks
Induction phase:
- R-ACVBP for 4 cycles Q2weekly. + IT MTX
Consolidation phase:
- Starts with 2 doses of IV MTX as Cycle 5 and 6, separated by 2 weeks
- followed by Rituximab + Ifosfamide+ Etoposide Q2weekly for 4 cycles
- ends with Cytarabine 2 doses separated by 2 weeks
What is R-ACVBP
Rituximab Doxorubicin Cyclophosphamide Vin desire Bleomycin Prednisone
What is the treatment for young patients with good prognosis DLBCL?
What is the evidence?
RCHOP x6
MInT study by Pfreundschuh Lancet Oncoogy 2006
N=800
18-60yo
0-1 risk factors (aaIPI)
Stage II-IV disease or Stage I with bulk
2 arms:
A) RCHOP x6
B) CHOP-like therapy x 6
Bulky and extra nodal sites received RT
Results:
- 3 yr f/u
- EFS 80% vs 60%
- PFS 85% vs 70%
- OS 90% vs 80%
Describe the NHL-B1 trial
Pfreundschuh Blood 2004
Aim:
CHOP-21 was standard then
Wanted to know if CHOP-14 or CHOEP-21/CHOEP-14 can improve results in those 18-60yo with good prognosis
N=700 2x2 factorial study Those in Q14days, received GCSF \+ RT to bulky disease and Extranodal writes. A) CHOP-21 B) CHOP-14 C) CHOEP-21 D) CHOEP-14
Results: CR: CHOEP >CHOP - 88% vs 80% 5y EFS: CHOEP>CHOP - 70% vs 60% OS: - interval reduction improved OS - 75% (CHOP-21); 85% (CHOP-14) - 83%( CHOEP-21); 85% (CHOEP-14)
Why RCHOP-21 and not RCHOP-14?
Cunningham Lancet 2013
CHOP-14>CHOP-21
Aim is to find out if RCHOP-14>RCHOP-21
N=1100
2 arms:
A) 6RCHOP-14 + 2R
B) 8RCHOP-21
Results: (4yr f/u)
- 2yOS 83% (RCHOP14) vs 81%
- 2yPFS ~
- ORR ~
Conclusion:
RCHOP-14 is not superior to RCHOP-21
What are the reasonable options for High Risk DLBCL in young patients?
1) RCHOP-21
2) R-EPOCH
3) R-ACVBP for young patients with 1 risk factors
- LNH03-2B by Christian Recher Lancet 2011
- OS 90% vs 80%
- 3y EFS 80% vs 70%
- 3y PFS 87% vs 73%
4) Clinical trial is an option
5) High dose-transplant in selected patients
- aa IPI high risk
- double-hit lymphomas
6) CNS prophylaxis should be considered
- IT vs HD MTX
What are the upfront transplantation trials that suggest benefits?
1) Santini et al
- Italian trial 1998
- 2 arms:
» VOCP-B–>DHAP
» VOCP-B–>HDT
2) GELA study by Haioun et al 1997
3) MILAN study by GIanni et al 1997
2arms:
- MACOP-B
- Sequential HDT
4) Milpied et al GOELAMS study 2004
2 arms:
- CHOPx8
- CEEPx2–>MTX+Cytarabine –> BEAM
Describe the Milpied transplant study
GOELAMS study NEJM 2004
Aim - to find out what is the efficacy of 1st-line intensive chemo+transplantation of Autologous hematopoietic stem cells in adults with disseminated aggressive lymphoma
2arms:
A) HD therapy + ASCT
B) CHOP
N=200
80% completed treatment
Med f/u 4 years
Results:
- 5y EFS 55% vs 40% (CHOP)
- 5y survival rate in high-intermediate aaIPI group:
» 70% vs 40% (CHOP)
What are the trials that suggest no benefit from upfront transplantation?
1) Gisselbrecht et al 2002 2arms: - ACVBP - Shortened initial chemo+HDT Conclusion: 5y EFS and OS higher in conventional arm
2) EORTC study by Kluin et al 2001 2arms; - CHVmP/BV x6 - CHVmP/BVx3 --> HDT Conclusion: No differences in EFS/OS
3) Italian study by Martelli et al 2003 2 arms: - MACOP-B - Abbreviated MACOP-B --> HDT Conclusion: No differences in EFS and OS
4) German study by Kaiser et al 1999 2 arms: - CHEOP - CHEOP --> HDT Conclusion = no difference in EFS and OS
What is the PARMA study about?
Philip NEJM 1995
Aim: to evaluate efficacy of HD chemo–> ASCT in NHL with relapses
N=200 Relapses of NHL patients all s/p 2 cycles of conventional chemo. Those with response then randomized to: A) 4# chemo + RT B) RT+ intensive chemo + ASCT
Median f/u 5 years
RR 80% (after ASCT); 40% after chemo w/o transplant
5yEFS 46% in transplant vs 12%
OS 50% vs 30%
Conclusion:
HD Chemo+ ASCT improved EFS and OS
Describe SWOG 9704
Stiff et al NEJM 2013
Aim: to test the efficacy of ASCT during 1st remission in patients with NHL (with high-intermediate or high risk) in Rituximab era
N=400
Aa-IPI = high risk or high-intermediate risk
2 arms: A) 5CHOP - If response, assigned to: >> 3CHOP or (Control) >> 1CHOP+ASCT (transplant) B) 5RCHOP - if response, assigned to: >>3RCHOP (control) or >>1RCHOP+ASCT (Transplant)
Results:
2y PFS: 70% (Transplant group) vs 55%
2y OS: 74% vs 71%
Conclusion:
Early ASCT improved PFS in those with high-intermediate-risk or high risk disease who had a response to induction therapy
OS not improved, ?secondary to effectiveness of salvage therapy
What is the evidence to show that Rituximab improves outcomes of DLBCL in older patients?
Fisher NEJM 1993
Coiffier NEJM 2002
FIsher NEJM 1993: 4 arms comparable - CHOP - m-BACOD - ProMACE-CytaBOM - MACOP-B
Coiffier:
- RCHOP >CHOP
Describe the SWOG study by Fisher
Fisher NEJM 1993
50-60yo, n=900
4arms:
- CHOP
- m- BACOD
- ProMACE-CytaBOM
- MACOP-B
OS: ~50%
Fatal Toxic reaction : 1% with CHOP, 5% with m-BACOD, 3% with ProMACE-CytaBom, 6% with MACOP-B
Conclusion= CHOP remains best available to for advanced intermediate-grade or high-grade NHL
m-BACOD = low-dose MTX+Leucovorin, Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Dexamethasone
ProMACE-CytaBOM = Prednisone, Doxorubicin, Cyclophosphamide, Etoposide,–> Cytarabine, Bleomycin, Vincristine, MTX+Leucovorin
MACOP-B = MTX with Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin
Describe the Coiffier paper NEJM 2002
= LNH-98.5, by GELA group
Aim=to compare CHOP vs RCHOP in elderly patients
60-80yo, untreated DLBCL
2 arms:
A) 8CHOP-21
B) 8RCHOP-21
Results:
CR 75% vs 63%
2y EFS 60% vs 40%
2y OS 70% vs 60%
10y fu:
10y PFS:37% vs 20%
10y OS 44% vs 28%
Since we know CHOP is good, and CHOP-14 better in younger patients, how about in elderly?
How about the addition of Etoposide?
Pfreundschuh DSHNHL group, NHL-B2 trial
N=700
61-75yo
4 arms: A) 6CHOP-21 B) 6CHOP-14 C) 6CHOEP-21 D) 6CHOEP-14 2-weekly regimen patients received GCSF RT to bulky disease or extra nodal sites
Results: CHOP-21 did the worst. CHOP-14 did the best CHOEP-21>CHOP-21, 10% increase for CR rate, 5yEFS and 5yOS CHOEP-14 did not do better than CHOP-14
How about in the Rituximab era?
and how many cycles of ? 6 or 8
Pfreundschuh RICOVER-60 Lancet Onco 2008
Aim = assess if 6 or 8 cycles better, in Rituximab era
N=1200 61-80yo
4arms: A) 6CHOP-14 B) 8CHOP-14 C) 6RCHOP-14 D) 8RCHOP-14 RT to sites of initial bulky disease +/- sites of Extranodal disease
Results:
- 6RCHOP-14 did the best
- 8CHOP-14 did the worst
- Addition of R to CHOP-14 improved EFS by 20% from 47 to 67% and improved OS by 10% from 68% to 78%. Also improved CR rate by 10% from 68% to 78%
Then why do we use RCHOP-21 and not RCHOP-14? Esp in elderly patients?
Delarue LNH03-6B study
Aim = Ascertain if RCHOP-14 >RCHOP-21
N=600, 60-80yo
Untreated DLBCL, at least 1 adverse prognostic factor
2 arms:
A) RCHOP-14
B) RCHOP-21
Results:
RCHOP-14 did not improve efficacy
Toxic side-effects similar but R-CHOP14 a/w increased need for Red cell transfusion
3yEFS ~60%
5yOS ~60%
ORR 85%
G3/4 neutropenia rate 65% (RCHOP21) vs 74% (RCHOP14)
Since LNH03-6B showed that RCHOP-21 is preferred over RCHOP-14 in elderly, how about other age groups?
Cunningham Lancet 2013
Aim = to investigate if the survival benefit from dose intensification persists in the presence of Rituximab in all age groups
N=1000
4y f/u
Results:
- 2y OS 83% (RCHOP-14) vs 81% (RCHOP-21)
- 2yPFS similar 75%
Conclusion: RCHOP21 remains SOC
How about those >80yo with DLBCL?
R-mini-CHOP
Peyrade et al
N=150, median age 83 yo 70% PS0/1 75% Stage III/IV IPI 3-5 70% 50% with limitation in iADL
F/u 2 years
Med OS 29m, 2yOS 60%
Med PFS 21m, 2yPFS 50%
12 deaths attributed to toxicity of treatment
Any other options besides R-mini-CHOP in >80yo?
R-Bendamustine
Weidmann
Phase II study, n=14 median age 85yo Stage III/IV 40% 60% IPI 0/1 ECOG 1-2 80% 80% DLBCL, 40% with extra-nodal involvement
54% with CR, 15% PR, 31% PD
Med OS 8m, med PFS 8m
How about localized intermediate and high grade NHL?
Miller paper, NEJM 1998
Clinically localized, intermediate or high grade NHL
2 arms:
A) 8#CHOP
B) 3#CHOP+IFRT
Results:
5yPFS: 80% (CHOP+RT) vs 60% (CHOP)
5yOS: 80% (CHOP+RT) vs 70% (CHOP)
But no R!
What inhibits the BTK receptor?
Ibrutinib
Dasatinib
What are the 3 molecular subtypes for DLBCL?
ABC DLBCL
GCB DLBCL
Unclassified DLBCL
What are the different markers between GCB and non-GCB DLBCL?
Hans et al Blood 2004
GCB:
- CD 10+
- CD10-,BCL6+,MUM1-
Non-GCB:
- CD10-, BCL6-
- CD10-, BCL6+, MUM1+
Based on the aaIPI, what is the score like?
0 = low risk 1 = low Intermediate risk 2 = High intermediate risk 3 = high risk
What are the 3 studies that proved RCHOP-21 > CHOP-21?
GELA LNH 98.5
- Coiffier NEJM 2002, 10-yr update Blood 2010
- 60-80yo patients,
- 10y PFS 40% vs 30%
- CR rate 75% vs 63%
ECOG 4494
- Haberman JCO 2006
- 1st randomization to CHOP vs RCHOP, those who responded, got randomized again into maintenance R vs observation
- -> R as induction/maintenance with CHOP chemo prolonged FFS in older patients
- -> After RCHOP, no benefit was provided by MR.
MInT
- Pfreundschuh Lancet Oncol 2006
- 800 18-60yo , aaIPI 0 or 1
- 6CHOP vs 6RCHOP
- 3y EFS 80% vs 60%
- 3y OS 90% vs 80%
- 3y PFS 85% vs 70%
What are the studies supporting RCHOP-14>CHOP-14?
RICOVER-60
1200 patients, 61-80yo
2aims:
- 6# or 8#
- Whether R better or not
6CHOP-14
6RCHOP-14
8CHOP-14
8RCHOP-14
Pref: RCHOP-14
Results:
- 3y OS: 6RCHOP-14 78%, 8RCHOP14 73%; 6CHOP14 68% and 8RCHOP14 66%
- CR rate 6RCHOP14 78%
What is the evidence to say CHOP-14 > CHOP-21?
DSHNHL NHL-B2 study
- Pfreundschuh Blood 2004
- 2 aims: Whether added Etoposide better and if -14 better than -21.
- CHOEP-14 comparable to CHOP-14, lesser toxicities
» CR 76% (CHOP-14) vs 72%; 5y OS 50%~, 5y EFS 40% ~
- CHOEP-14 or CHOEP-21 > CR 76% vs 60%, 5y OS 50% vs 40%, 5y EFS 40% vs 30%
Why RCHOP-21 > R-CHOP-14?
GELA LNH 03-6B study
- Delarue study
- 600 patients 60-80, aa IPI 1 and above
- RCHOP-14 did not improve efficacy cf to RCHOP-21
- 3y EFS 56%(RCHOP-14) vs 60%
- G3/4 neutropenia rate and FN rates higher as well
UK NCRI trial - Cunningham Lancet 2013 - n=1000 - 60%>60yo - 2 arms: 8RCHOP-21 vs 6RCHOP14 +2R - 65% Stage III/IV , 40% bulky, 40% B symptoms - Results: >> No difference in RR, ORR both 90% >> No diff in PFS/OS
What is the diagnostic criteria for DLBCL?
CD20+ CD10 +/- CD5+/- BCL2 mostly + BCL6 mostly +
CD43-
Ki67>40%
Is scrotal RT needed?
Yes, in testicular lymphoma, after completion of chemo.
25-30Gy
How can CNS prophylaxis be given?
4-8 doses of IT MTX and/or Cytarabine Or Systemic MTX (3-3.5g/m2)
During course of treatment
Tell me about the NCCN-IPI score
Published in Blood, Zhou et al 2014.
4 risk groups:
- Low : 0-1
- Low-intermediate: 2-3
- High-intermediate: 4-5
- High 6 and above
Age - >40 up to 60 years: 1 - >60 to 1 up to 3 - 1 - >3 2 Stage III/IV disease EN disease
Do you know of any prognostic model to assess risk of CNS disease ?
Schmitz et al In hematol Oncol 2013
Savage et al in Blood 2014:
Prognostic model to assess risk of CNS disease
- .60yo
- LDH>normal
- PS>1
- Stage III/IV
- EN involvement >1 site
- Kidney or adrenal gland involvement
In CNS Disease in DLBCL, which is more common, leptomeningeal or parenchyma?
Parenchyma 60%
Leptomeningeal 40%
In CNS Disease in DLBCL, which is more common, leptomeningeal or parenchyma?
Parenchyma 60%
Leptomeningeal 40%
What are the possible strategies for CNS prophylaxis?
1) Intrathecal therapy
- MTX via LP
- MTX via Ommaya
- Liposomal Cytarabine
- ?Rituximab
2) Systemic CNS penetrating therapy
- High Dose IV MTX
3) RT
