1
New10_1.ppt
Lymphoma Reporting Basics
January 31, 2012
Disclosures
Janet Brunner, PA-CI have nothing to disclose
P. Hari, MD MSI have nothing to disclose
G. Laport, MDI have nothing to disclose
Objectives
1. Be able to report the correct NHL disease classification.
2. Be able to determine & report the disease status at time of HCT & at post-HCT follow-up intervals.
3. Be able to report the correct primary NHL disease & date of diagnosis for HCT when a transformation has occurred.
SPOTLIGHT ON LYMPHOMASDLBCL
FOLLICULAR NHLT-CELL NHL
GINNA LAPORT, MD
Indications for Hematopoietic Stem Cell Transplants in the United States, 2009
SUM-WW11_8.ppt
Num
ber
of T
rans
plan
ts
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
MultipleMyeloma
NHL AML HD ALL MDS/MPD AplasticAnemia
CML OtherLeuk
Non-Malig
Disease
OtherCancer
Allogeneic (Total N=7,012)Autologous (Total N=9,778)
Non-Hodgkin Lymphoma
DLCL 31%
Follicular 22%
Discordant 12%
Mantle cell 6%
Small lymphocytic 6%
Peripheral T-cell 6%
MALT 5%
Lymphoplasmacytic 1%
Anaplastic T-cell 2%
Mediastinal B-cell 2%Burkitt-like 2%
Lymphoblastic 2%
Burkitt < 1%
2
Diffuse Large Cell Lymphoma:Background
Diffuse Large Cell Lymphoma:Background
Most common subtype of NHL
Median age ~ 65-70 yr
Frontline chemotherapy (anthracycline-based + RTX)
Long term remission 50-60%
High-dose chemotherapy with autologous SCT
Relapsed/Refractory
• Chemosensitive 40-60%
• Chemo-refractory 10-20%
Relapse is most common cause of failure
DLBCL: International Prognostic IndexDLBCL: International Prognostic Index
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
Adverse risk factors correlated with response to chemotherapy and survival– Older than 60 yrs of age
– LDH > normal
– PS ≥ 2
– Ann Arbor stage III/IV
– Extranodal involvement > 1 site*
International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994.
*Prognostic for patients older than 60 yrs of age only.
CHOP vs R-CHOP Elderly Patients With Diffuse Large B-Cell NHL
CHOP vs R-CHOP Elderly Patients With Diffuse Large B-Cell NHL
Coiffier B, et al. N Engl J Med. 2002;346:235-242.
R-CHOP = rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone
R-CHOP
Ove
rall
Su
rviv
al
Years
CHOP
P < .007
For DLCL patients with relapsed or refractory disease Median survival is 6 months w/o further therapy
Standard of care Autologous SCT
Platinum-based regimens
R-ICE (ifosfamide/carboplatin/etoposide)
R-DHAP (dexameth, high dose araC, cisplatin)
R-ESHAP (etoposide, solumedrol, high dose araC, cisplatin)
Other regimens
R-bendamustine
Diffuse Large Cell Lymphoma:Autologous SCT for Relapsed/Refractory Disease
Diffuse Large Cell Lymphoma:Autologous SCT for Relapsed/Refractory Disease
Years
0 2 61 3 4 5
Survival after Autologous Transplants for Diffuse Large B-Cell Lymphoma, 2000-2009
- By Disease Status -
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Prob
abili
ty o
f Sur
viva
l, %
P < 0.0001
SUM-WW11_36.ppt
Slide 37
Sensitive (N=6,337)
Resistant (N=453)
Years
0 2 61 3 4 5
Survival after Allogeneic Transplants for Diffuse Large B-Cell Lymphoma, 2000-2009
- By Disease Status -
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Prob
abili
ty o
f Sur
viva
l, %
P < 0.0001
SUM-WW11_37.ppt
Slide 38
Sensitive (N=383)
Resistant (N=124)
3
Summary: Diffuse Large Cell LymphomaSummary: Diffuse Large Cell Lymphoma
• Diffuse large cell lymphoma is the most common NHL
• R-CHOP is the standard of care for first line therapy
• Autologous HSCT• Offered to patients with relapsed or primary refractory disease
(after platinum-based salvage therapy)
• May benefit patients in CR1 with high IPI at diagnosis
• Allogeneic HSCT Failed prior auto HSCT
BM involvement
Chemosensitive preferred
Characteristics• 24,000 cases/yr• Median age: 59 yr• 50% of patients present as stage IV disease• Most are asymptomatic at diagnosis
Histologic transformation• Occurs in 30%-40% of patients• New symptoms, rapid progression, elevated LDH,
increased activity on PET imaging• Generally poor prognosis
Follicular Lymphoma: Background
Follicular Lymphoma: Background
Waxing and waning course• Spontaneous regressions
Sensitive to chemotherapy and radiotherapy• Remission usually achieved• Continuous pattern of relapses shorter
remission durations• Very treatable…difficult to cure
Median survival ~ 8-12 yr
FL: Characteristics and Clinical Course FL: Characteristics and Clinical Course Follicular Lymphoma International Prognostic Index (FLIPI)
Follicular Lymphoma International Prognostic Index (FLIPI)
• Age > 60 yr• Ann Arbor stage III/IV
disease• LDH > ULN• Hemoglobin < 120 g/L• > 4 nodal sites
FLIPI Risk Group
Risk Factors, N 5-Yr OS 10-Yr OS
Low 0-1 91% 71%
Intermediate 2 78% 51%
High ≥ 3 53% 36%
Solal-Céligny P, et al. Blood. 2004;104:1258.
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72 84 96Time (mo)
108 120
P < .00001
Low
Int
High
0
20
40
60
80
100
0 2 4 6 8 10
n 4-yr PFS 4-yr OSCHOP + MoAb 179 61% 91%ProMACE + MOPP 425 48% 79%CHOP 356 46% 69%
OS
(%
)
Years After Registration
Fisher RI, et al. J Clin Oncol. 2005;23:8447-8452.
Changes in the Natural History of FL Overall Survival by Treatment (1974-2000)
Changes in the Natural History of FL Overall Survival by Treatment (1974-2000)
Treatment of Follicular NHL:Indications
Treatment of Follicular NHL:Indications
Disease-related symptoms • Cytopenias
• Fevers, sweats, weight loss, fatigue
Enlarging or bulky lymph nodes
Enlarging liver, spleen
Bone marrow or organ compromise
Autoimmune complications (AIHA, ITP)
Evidence of histologic transformation
Patient preference
4
Considerations Regarding InitialTherapy
Considerations Regarding InitialTherapy
Patients with low tumor burden
• Watchful waiting
• Single-agent antibody therapy
• R-CVP
• R-CHOP
• BR
• R-FND
Patients with high tumor burden
• R-CVP
• R-CHOP
• BR
• R-FND
NCCN Guidelines: Non-Hodgkin lymphomas. Version 4.2011.
Years
0 2 61 3 4 5
Probability of Survival after Autologous Transplants for Follicular Lymphoma,
2000-2009- By Disease Status -
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Prob
abili
ty o
f Sur
viva
l, %
P < 0.0001
SUM-WW11_34.ppt
Slide 35
Sensitive (N=2,030)
Resistant (N=172)
Overall Survival After HLA-Matched Sib Allogeneic SCT: FL 1998-2008
Overall Survival After HLA-Matched Sib Allogeneic SCT: FL 1998-2008
Years0 2 61 3 4 5
Chemosensitive, reduced intensity (n = 388)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
bab
ilit
y o
f S
urv
ival
(%
)
Chemosensitive, myeloablative (n = 351)
P = .011
Chemoresistant, reduced intensity (n = 64)
Chemoresistant, myeloablative (n = 85)
Pasquini MC, et al. CIBMTR summary slides, 2010. http://www.cibmtr.org Accessed December 19, 2011.
Summary: Follicular NHLSummary: Follicular NHL
• Treatment needs to be individualized– Age– Comorbidities
• Frontline – Watchful waiting– Involved field radiation– R + chemotherapy
• Relapsed/Refractory– Involved field radiation– R + chemotherapy + maintenance R– Novel agents– HSCT
Summary: Follicular NHL (cont)Summary: Follicular NHL (cont)
HSCT• Should be offered to patients who progress after
1-2 prior regimens
Autologous HSCT• No role as first-line therapy • May prolong OS in chemosensitive, less heavily treated
patients
Allogeneic HSCT• Less relapse compared with autologous HSCT• Myeloablative regimens have high treatment-related
mortality• Reduced intensity regimens are promising• Chemosensitivity is best predictor of survival
Peripheral T cell LymphomaBackground
Peripheral T cell LymphomaBackground
T-NHL accounts for 10-15% of all NHL
Geographic variation Nodal disease: Western hemisphere Extranodal: Asia
Clinical features Middle aged to elderly Systemic symptoms Generalized lymphadenopathy Marrow and blood Extranodal
Prognosis• Low response rates to chemotherapy• Most patients relapse within 2-3 years 5 year survival < 30%
5
Most Common PTCL SubtypesMost Common PTCL Subtypes
• PTCL-NOS is the most common subtype
• Anaplastic large cell lymphoma (ALCL) ALK+/- and angioimmunoblastic lymphoma are also common subtypes
1. Armitage J, et al. J Clin Oncol. 2008;26:4124–4130.
Poor Outcome For Most Subtypes With Standard Tx:International PTCL Project
Poor Outcome For Most Subtypes With Standard Tx:International PTCL Project
Vose et al. J Clin Oncol, 2008
PTCL PrognosisPTCL Prognosis
Most PTCL subtypes have a worse prognosis than aggressive B-cell NHL Median overall survival for most subtypes of PTCL is 1–3 years ALK+ ALCL is an exception, with a 5-year survival = 65–90%
1. Armitage JO, et al. Ann Oncol. 2004;15:14472. Savage KJ. Blood Rev. 2007;21:2013. Rüdiger T, et al. Ann Oncol. 2002;13:140
Initial Treatment of PTCLInitial Treatment of PTCL
• NCCN guidelines recommend clinical trials for initial treatment of PTCL1
• CHOP is the most commonly prescribed regimen in the first-line setting2,3
1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. 2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.
2. Rosenstein LJ, Link BK. Clin Lymphoma Myeloma. 2008;8:S180–S186. 3. Horwitz SM. Hematology Am Soc Hematol Educ Program. 2008;2008:289–296.
Suggested Treatment Regimens for PTCL (in alphabetical order)1
First-line therapy Clinical trial preferred
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)
HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine
First-line consolidation All patients except low-risk (aaIPI) should be consolidated with high-dose therapy and stem cell rescue (autologous)
ALK-1+ ALCL is a subtype with good prognosis and does not need consolidative transplant if in remission
n = 83Only CR1/PR1 pts autoSCT
3 yrs OS and PFS = 48% and 36%
Overall SurvivalOverall Survival
SCT
no SCT
Le Gouill, S. et al JCO 2008.
n=77
HLA identical = 60Myeloablative = 57Prior AutoSCT = 19 1 yr TRM = 32%
OS
EFS
AITL
PTCL
ALCL
Other
6
Summary: Peripheral T cell LymphomaSummary: Peripheral T cell Lymphoma
• PTCL are a heterogeneous group of rare entities
• Compared to B cell NHL, prognosis is poor (OS <30%)
• Best initial therapy is undefined
• Autologous HSCT more efficacious in early disease
• CR1 pts have better outcomes compared to >CR1 pts
• Moderately better PFS/OS than population based series with CHOP
• 30-50% pts do not reach transplant due to PD or toxicity
• Does auto HSCT as consolidation improve results or just selecting for healthier people with chemosensitive disease?
• Myeloablative allogeneic HSCT associated with high TRM
• Reduced intensity conditioning promising
Disease ClassificationQuestions
The surgical pathology reports the lymph node biopsy to be a follicular lymphoma grade I-II, how should the subtype be reported on the Pre-TED form (2400)?
Grade I
Grade II
Grade III
33% 33%33%
a) Grade Ib) Grade IIc) Grade III
Answer Now
Form 2400
Question 2 (please answer on next slide)
How should the disease be reported on the Pre-TED if it’s described as a ‘composite NHL’? The patient’s bone marrow biopsy reports 80% of the abnormal cells are follicular & 20% classic Hodgkin.
Answer Now …
NHL
Hodgkin
Other
33% 33%33%
a)Follicular NHL
b)Hodgkin lymphoma
c)Other disease, specify
Answer Now
7
Question 3 (please answer on next slide)
A patient is diagnosed with Hodgkin & NHL at the same time. Both are in remission at the time of HCT. Which disease should be reported as the primary on the Pre-TED for HCT?
Answer now…
NHL
Hodgkin
Other
33% 33%33%
Answer Now
a. NHLb.Hodgkin
lymphomac. Other
disease, specify
Reporting Disease Status for Lymphoma
P. Hari, MD MS
CR, PR ….
Cheson et al JCO- 2007 vol 25: 5; 579
PIF, REL , Sens, Res ???? Basic things
1. Make sure responses tally and make sense.
e.g. Person in CR has to have sensitive disease
2. In order to relapse, person should first have established CR
3. Induction failure – NEVER achieved a CR.
8
Rule 1. Response and Disease State should tally CASE STUDY
53 yr old woman with DLBCL Initial Therapy – RCHOP chemo After 6 cycles – Lymph Nodes all normal
sized. Spleen still enlarged and PET positive.Disease response: Sensitvity:Disease Status:
Case continued
Patient had a splenectomy which showed residual disease PET Scan – no evidence of disease Consideration of transplant at this
time Response SensitivityDisease Status
Case continued Patient declined transplant but
relapsed 4 mo later with abdominal LNReceived salvage chemotherapy with
full resolution of all imaging abnormalities. Transplant at this timeDisease Response SensitivityDisease Status
Case continued
What if she had residual PET abnormalities after the salvage chemotherapy prior to the transplant?Disease Response SensitivityDisease Status
Disease Status Questions
9
Question 1 (please answer on next slide)
A patient with NHL has undergone their pre-HCT evaluation and the only evidence of disease is a positive molecular study on bone marrow for t(11;19). Can the disease status be reported as CR at the time of HCT despite the positive molecular study?
Answer now …
Yes N
o
Unknown
33% 33%33%
a)Yesb)Noc)Unknown
Question 2(please answer on next slide)
A patient with NHL has no morphologic evidence of disease on the bone marrow biopsy, but flow results from the marrow indicate disease prior to the start of the prep regimen. What disease status should be reported at time of HCT?
Answer now …
CR
PR
Unknown
33% 33%33%
a)CRb)PRc)Unknown
Answer Now
Question 3
A 55 yo WM has PET positive & biopsy proven NHL in the inguinal nodes at diagnosis. He was treated & relapsed before achieving a 4th CR prior to HCT. Day 100 PET/CT scan revealed positivity in the inguinal area. The transplant physician decides not to biopsy an inguinal node, but would obtain a PET/CT scan a few weeks after tapering immunosuppression.
Is it acceptable to report a relapse based on the PET/CT
scan only?
Yes N
o
Unknown
33% 33%33%
a)Yesb)Noc)Unknown
10
Transformed Lymphoma Questions
Question 1.1(please answer on next slide)
A patient was diagnosed with follicular NHL in 2005. The NHL transformed to DLBCL in 2009 and the patient is now scheduled for an upcoming auto HCT. What is the correct NHL subtype to report on the Pre-TED (F2400) as the primary diagnosis for HCT?
Answer now…
NHL
DLBCL
Other
33% 33%33%
a)Follicular NHL
b)DLBCLc)Other B cell
lymphoma, specify
Answer Now
What is the correct date of diagnosis to report?
2005
2009
Neither
33% 33%33%
a)2005b)2009c)Neither
Answer Now
Question 2.1(please answer on next slide)
A 55 yo WM is diagnosed with CLL in 2007 & achieved a CR with fludarabine. They are monitored at regular intervals & three years later they are noted to have bilateral inguinal masses. A biopsy reveals DLBCL. This patient’s disease underwent a Richter’s transformation. What disease should be reported as the primary diagnosis for HCT?
Answer now …
CLL
DLBCL
Other
33% 33%33%
Answer Now
a)CLLb)DLBCLc)Other B cell
lymphoma, specify
11
What is the correct date of diagnosis to report?
2007
2010
Neither
33% 33%33%
a)2007b)2010c)Neither
Answer Now
Questions