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Lymphoma and CLL Forms
Parameswaran Hari, MD, MSCIBMTR , Milwaukee
WHAT IS LYMPHOMA?
Neoplasm of the lymphatic/immune system
Subtypes vary based on the cell oforigin (most NHL are B-cell)
Estimated 65,000 new cases in US
85% Non-Hodgkin lymphoma
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Normal lymph nodes
Cancer Mortality in the United States*
9%Prostate
31%
Lung and bronchus
24%
All other sites
3%Kidney and renal pelvis
3%Non-Hodgkin’s lymphoma
3%Urinary bladder
4%Esophagus
4%Liver and intrahepatic bile duct
4%Leukemia
6%Pancreas
9%Colon and rectum
Brain and other nervous system
2%
Leukemia4%
Pancreas6%
Lung and bronchus26%
All other sites
Liver and intrahepatic bile duct
Uterine corpus
Non-Hodgkin’s lymphoma
Ovary
Colon and rectum
Breast
23%
2%
3%
3%
6%
10%
15%
Women270,100
Men289,550
*Estimated for 2007.American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society; 2007.
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Indications for Hematopoietic Stem Cell Transplantation in North America
2003
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
Myeloma
NHL AMLHodgkin
ALL MDS/Other Leuk
CMLNeuroblastoma
CLL Other Cancer
Non-Malig Dis
Tra
nsp
lants
Allogeneic (Total N=7,300)
Autologous (Total N=9,600)
SUM05_16.pptSlide 6
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
AML ALL MDS/MPS Lymphoma CML OtherLeukemia
OtherCancer
AplasticAnemia
Other Non-malignantDisease
Tra
nsp
lants
Related donor (Total N=8,326)Unrelated donor (Total N=6,996)
Allogeneic Hematopoietic Stem Cell Transplantation CIBMTR 2005
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Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15.Adapted from Jemal et al. CA Cancer J Clin. 2006;56:106.
United States
0
15,000
30,000
45,000
60,000
1980 1985 1990 1995 2000 2005
Estim
ated
ann
uali
ncid
ence
Year
~4% compound annual increase in incidence
How common is NHL?
Hodgkin lymphoma
Thomas Hodgkin(1798-1866)
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Hodgkin Lymphoma - epidemiology
8000 cases yearly in U.S.Patients at high risk?
Bimodal age distribution
Peak in 20s, second peak in 60s-70sFamily history: 7x increase for sibs, 100x for identical twinsHIV EBV related (seen in about 30% of HL biopsies)
Pathology
Reed Sternberg cells:
large, bi- or multi-nucleated, abundant cytoplasm, two or more nucleoli. Surrounded by an inflammatory response.
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Reed-Sternberg cell
Hodgkin lymphomaHistologic subtypes
Classical Hodgkin lymphomanodular sclerosis (most common subtype)mixed cellularitylymphocyte-richlymphocyte depleted
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HL – clinical presentation
Asymptomatic Lymph Node enlargementMediastinal involvement can cause symptoms, but sometimes very bulky with minimal symptoms.Generalized pruritis is common, may precede Dx by months
B Symptoms : Fever / Night Sweats / Weight loss in 25% - rare in early stage diseaseCNS involvement – very rareMost common sites involved are cervical, supraclavicular, and mediastinal
2/3 will have mediastinal involvement at presentation
HL – Initial evaluation / staging
History: esp B symptomsGood exam with Lymph node measurementsCT Scan Neck /C/A/Pelvis – Lymph Node
MeasurementsPET scanEnsure accurate pathology: r/o NHL, reactive nodeMarrow Biopsy
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Stage I Stage II Stage III Stage IV
Staging of lymphoma
A: absence of B symptomsB: fever, night sweats, weight loss
Ann Arbor Staging
Staging
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7/7/06 9/7/06
PET – CT scans to follow disease
Active Disease by PET scan
How does NHL differ from HL?
HL NHL
Subtypes 2 >30
Peak age 20s over age 60
Cases / yr 8,000 60,000
Common sites Neck, mediastinum Various
S/Sx Usually mild Often severe
5 yr Survival 80+ % Varies
10
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
NHL
HD
~58,870 NHL cases/y~7800 HD cases/y
Age at Diagnosis for Hodgkin andNon-Hodgkin Lymphoma
Data for diagnoses from 1997 to 2001.Jemal et al. CA Cancer J Clin. 2006;56:106.At: http://seer.cancer.gov. Accessed March 23, 2005.
Age at diagnosis (y)
Cas
es/1
00,0
00
NHL Diagnosis
Physical examinationCT or PET scanBiopsy
Bone marrow biopsy may suffice in some cases.Specialized pathology tests may be key to determining the NHL subtype
Flow cytometryProtein stainsChromosome tests (“FISH”)Molecular tests
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B-cell development
stemcell
lymphoidprecursor
progenitor-B
pre-B
immatureB-cell
maturenaiveB-cell
germinalcenterB-cell
memoryB-cell
plasma cell
DLBCL,FL, BL, HL
LBL, ALL
CLLMCL
MM
MZLCLL
REAL/WHO Classification of NHL
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Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795; Harris NL et al. Ann Oncol. 1999;10:1419-1432; Hiddemann W et al. Blood.1996;88:4085-4089; Horning SJ. Blood. 1994;83:881-884; Liu Q et al. J Clin Oncol.
2006;24:1582-1589; Fisher RI et al. N Engl J Med. 1993;328:1002-1006; Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.
MAL
TLSL
L*/C
LL
FL*
DLB
CL*MCLPMLBCLALCL
PTCL
BLLLL
Other
22%
Indolent(low grade)
Aggressive(intermediate grade)
Very aggressive(high grade)
• Slowly progressive• 5-year OS ≤95%
• Rapid clinical course• 5-year OS ≤50%
• Grows rapidly• Survival 0.5-2 years
31%
6%
2%
2%
6%
2%
2%
6%5%
16%
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REAL/WHO Classificationsfor B-Cell Neoplasms
Precursor B-lymphoblastic lymphoma/leukemiaBurkitt’slymphoma/ Burkitt’s cell leukemia
Follicular lymphoma, grade III (IWF:D)*
PLLPlasmacytoma/plasma cell myelomaMCLDLBCL*
Mediastinal large B-cell lymphomaPrimary effusion lymphoma
CLL/SLL* (IWF:A)LymphoplasmacyticleukemiaHCLSplenic marginal zone lymphomaMarginal zone B-celllymphoma
ExtranodalNodal
Follicular lymphoma,grades I-II (IWF:B-C)*
Very Aggressive(High Risk)
Aggressive(Intermediate Risk)
Indolent(Low Risk)
Harris NL et al. Ann Oncol. 1999;10:1419-1432.Hiddemann W et al. Blood. 1996;88:4085-4089.Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.
Histology
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The challenge of lymphoma classification
Clinical
Diseases that have distinct
• clinical features• natural history• prognosis• treatment
Biologic relevance
Diseases that have distinct
• morphology• immunophenotype• genetic features• clinical features
How clinicians think about lymphoma?
Category Survival Cure
Non-Hodgkin lymphoma
Slow Growing
Years Generally not curable
Aggressive Months Curable in some
Very aggressive
Weeks Curable in some
Hodgkin lymphoma
All types Variable –months to years
Curable in most
Transplant
Curative Allograft
Auto >> Allo
Alloor Auto
Auto >> Allo
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Clinical Course of NHLIndolent (low grade)
Slowly progressiveLong natural history – “chronic disease”Median survival: 6-10 years
5-year OS: 53-91% (FLIPI)Up to 50% risk of transformationTreatable, but not curable
Aggressive (intermediate grade)Rapid clinical course
5-year OS: 26-73% (IPI)Potential long-term survival with treatment
Highly aggressive (high grade)Grows rapidlySurvival: 0.5-2 yearsPotential long-term survival with treatment
Horning SJ. Blood. 1994;83:881-884.Fisher RI et al. N Engl J Med. 1993;328:1002-1006.Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.Solal-Céligny P et al. Blood. 2004;104:1258-1265.The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N EnglJ Med. 1993;329:987-994
Transformed Lymphoma
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Follicular lymphoma
Diffuse large B-cell lymphomaReactive lymph node - Benign
Normal lymph node
47 yo male, with fatigue, night sweats, diffuse bone pains. Biopsy showed Diffuse large B-cell lymphoma
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Translocation in the Pathogenesis of FL
14 18 t(14;18)
Bcl-2 Apoptosis
Accumulation of mutations/
transformation and proliferation
Translocation
Chromosomal Translocations Commonly Associated With Activation in B-Cell
Malignancies
Zinc-finger transcription
factor
Transcription factor
NF-κB inhibitor
BCL-2 (antiapoptosis)
Cyclin D1
Protein DiseaseTranslocationOncogene
Burkitt’s NHLt(8;14)myc
DLBCL (some follicular NHL)
t(3;14)bcl-6
CLLt(11;19)bcl-3
FL, some DLBCL
t(14;18)bcl-2
MCLt(11;14)bcl-1
National Comprehensive Cancer Network. Practice Guidelines in Oncology. v1. 2006.
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Primary mediastinal DLBCL. 36 yo female, before and after R-CHOP. At diagnosis can see the mass penetrating through the anterior chest wall and bilateral (R>L) pleural effusion. Achieved CR with R-CHOP, went on to receive auto PBSC and consolidative XRT.
May 2005 August 2005
8/23/05 1/31/06 5/23/06
44 yo F, Dx with Stg IV mantle cell lymphoma in 8/05. WBC 40,000 (50% MCL). BMBx – 50% involved. Treated with Rituxan-HCVAD x8 (thru 1/06), followed by Auto PBSC on 2/15/06.
21cm14cm
12cm
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3/14/06 4/24/06
27 y/o F arthralgias, palpitations, SOB and chest pain.
CT scan - large sternal mass. Biopsy Burkitt’s lymphoma (with t(8;14) present).
6/15/06 8/1/06
25 y/o M
LE weakness and ataxia.
Multiple ring-enhancing parenchyma lesions with vasogenic edema.
Stereotactic biopsy of right parietal lobe lesion showed large B-cell lymphoma (primary CNS lymphoma)
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Follicular Lymphoma Histology
Numbers of centroblasts (large cells) increase with gradeCriteria for grading*
Grade 1: 0-5 centroblasts/hpf; centrocytespredominateGrade 2: 6-15 centroblasts/hpfGrade 3: >15 centroblasts/hpf; centroblastspredominate
Grade 1 Grade 2 Grade 3
Warnke RA et al. Tumors of the Lymph Node and Spleen. Washington, DC: Atlas of Tumor Pathology, Armed Forces Institute of Pathology; 1995.Harris NL et al. Ann Oncol. 1999;10:1419-1432.
THERAPY OF INDOLENT NHL
Paradoxical in that cure not obtained with conventional therapyWatchful waiting approach with therapy for symptomatic progressionRadiation in limited diseaseChemotherapyBiologic therapy (MoAb, IFN)Hematopoietic cell transplant (allo vsauto)
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Overview of DLBCL
Patients typically present with a rapidly enlarging mass
~1/3 present with B symptoms~1/3 present with stage IV diseaseMore than 2/3 have any extranodal site
~1/3 have >1 extranodal site~1/6 present with bone marrow involvement
DLBCL is rapidly progressive if not treated
It follows a rapid clinical course75%-80% of patients respond well to treatment
Armitage JO, Weisenburger DD. J Clin Oncol.1998;16:2780-2795.Fameli-Pavlaki M. Haema. 2005;8:201-214.
Morphology • Diffuse centroblastic, diffuse centroblastic/centrocytic,or immunoblastic
Clinical features • Aggressive behavior• Heterogeneous clinical response
Immune Phenotype • Pan B-cell antigens (CD19, CD20, CD22, CD79a), surface IgM
Genetic features • Most have somatic hypermutation of Ig variableregion genes
• t(14;18) (q32; q21) bcl-2 oncogene rearrangement• (3q27) bcl-6 oncogene rearrangement• t(1;14) (p22; q32) bcl-10 rearrangement• c-myc oncogene deregulation
Overview of DLBCL
Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.Fameli-Pavlaki M. Haema. 2005;8:201-214.
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International Prognostic Index (IPI) for Aggressive NHL
CriteriaAge (≤60 vs >60 years)Performance status (0 or 1 vs ≥2)LDH (≤ normal vs > normal)Extranodal sites (≤1 vs >1)Stage (I or II vs III or IV)
Age-adjusted criteria (patients ≤60 years)
Performance status (0 or 1 vs ≥2)LDH (≤ normal vs > normal)Stage (I or II vs III or IV)
The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.
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43
51
73
5-year OS (%)
34
54
66
84
2-year OS (%)
16
22
27
35
Patients (%)
4-5High
3High-intermediate
2Low-intermediate
0-1Low
FactorsRisk Group
32
46
69
83
5-year OS (%)
37
59
79
90
2-year OS (%)
14
32
32
22
Patients (%)
3High
2High-intermediate
1Low-intermediate
0Low
FactorsRisk Group
THERAPY OF AGGRESSIVE NHL
Aggressive therapy with curative intent
CHOP-based therapy for B-cell neoplasms
Adjunctive radiation to sites of bulk disease
Risk stratification for patients to be considered for BMT in 1st remission
Biologic therapy (anti-CD20 based therapy)
Hyper-CVAD for mantle cell / highly aggressive diseases
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Prior Therapy – Pre HSCT Treatment
Wide Variety of Drugs used
Antibody based strategies
Chemotherapy
RadioImmunotherapy in the Treatment of NHL
90Y Radionuclide
Chelator
Ibritumomab
Tiuxetan
Tositumomab
131I radioisotope
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Response
CRU???Status reserved for patients having response typical of CR, but with residual lesion of uncertain significance
Example: Large LN mass shrinks with each of first 4 cycles CHOP, no further shrinkage and small 2cm mass after therapy. Not amenable to biopsy. All other disease “gone”.
Response to Pre HSCT Therapy !!
Start and Stop DateResponseResponse dateRelapse ?
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PET SCAN
Pretransplant Disease Status
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Remission State Pre HSCT
Looks more complicated
than it actually is
Pre HSCT disease status - Terms
UnknownCRu – can be 1, 2, 3+
UntreatedREL– can be 1, 2, 3+
ResistantCR – can be 1, 2, 3+
SensitivePIF – never had a CR
Qn 2.How did it respond?
Qn 1.Where is disease at?
e.g.PIF Sens a PR to initial treatment then Tx = PR1Rel1 Sens CR , Relapse then PR to chemo pre transplant
CR – has to be sensitive!PIF – can be sens, res, unt/unkREL – can be sens/res/unt/unkCru –has to be sensitive
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Pre HSCT disease status -
22 combinations offeredShould cover all possible scenarios
Post Transplant - Response
CCRCR
CRuPR
NR/SDREL/PROG
NA
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Post Transplant Treatment Maintenance / Consolidative
NOT for RELAPSE or ProgressionUsually Per Protocol
Can be : ChemotherapyRadiationImmunotherapy – Rituximab/MabThera (antiCD20)
Campath / Alemtuzumab (antiCD52)IL2/Aldesleukin
Did the patient Relapse?
DateHow detected?Where – sites?
Molecular studiesFISHPET
Final Questions – Current Disease Status (time of reporting)
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CLL
Same Disease Specific ThemeHistology – define the diseaseStagePre transplant treatmentsPretransplant disease status
Post Transplant Responses
CLL
Most common leukemia8100-12,500 cases each year = 2.5/100,000Majority of patients have a cytogenetic abnormality
Del 13q present in 55%Del 11q23 present in 18%Trisomy 12 in 16%Mutation of p53 at 17p13.3 in 15%
3-15% will transform to a more aggressive form i.e. Richter syndrome
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CLL Immune effects
HEMOLYSIS20-30% have + Coombs test 10-25% have evidence of hemolysis
PLATELET COUNT2% develop ITP
1% develop red cell aplasia (aka PRCA)Also many other problems:
Membranoproliferativeglomerulonephritis/ angioedema/ pemphigus
Staging of CLL
5 LN areas:Cervical/AxillaInguinofemoralLiver/Spleen
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Dohner H et al. N Engl J Med 2000;343:1910-1916
SURVIVAL in the Five Genetic Categories of CLL
32 79 111 133
Cytogenetics is Important
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Cytogenetics is Important !
Where do I look for these?Addendum to marrow reportsPeripheral Blood FISHKaryotypeInitial Consult note at Transplant Center
Sensitive Tests Pre Transplant
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CLL Response Criteria
Lymph NodesOrganomegalyBlood lymphocyteMarrow lymphocytesNeutrophilsPlateletsHemglobinB Symptoms
CR – Nod PR -- PR – SD – Progr. disease
Criteria for Response - Definitions
50% reduction or increase (min 2cm to be significant)50% change in size of liver /spleenPB lymphocytes -50% change (min > 5x 109/L)CBC Thresholds
ANC 1.5, Platelets 100 x 109/LHemoglobin 11
50% CHANGE PRProgression – NOT based on CBC!For CR – Marrow has to be <30% lymphocytes
Lymph NodesOrganomegalyBlood lymphocyteMarrow lymphocytesNeutrophilsPlateletsHemglobinB Symptoms
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CLL Response Criteria
CLL Post TransplantResponse to Transplant – Same criteriaReporting the best Response to Transplant is importanti.e CR at day 120 but relapse at day 270 important that the CR be reported as the best response
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CLL Post transplant
Maintenance TherapyMolecular and Flow cytometryassesmentsRelapse/Progression ?Current Disease Status
