Follicular Lymphoma Flashcards
What are the common symptoms at presentation for FL?
B Symptoms
Fatigue
Local mass effect of LN
Cytopenias
Describe FL
Indolent Lymphoma
Follows a chronic, relapsing course
Median survival of 7-10 years
Minority little or no progressions
Spontaneous and prolonged remissions
20-30% transform to high grade
Incidence of 20-25% amongst B Cell lymphoma
Median age 60 yo
What are the main oncogenic events that occur in the development of FL?
Ectopic expression of B-cell lymphoma 2 (BCL2)
Changes in the epigenome
BCL2 - promotes an anti-apoptotic programme
- provides survival signals to the malignant cells
Changes in the epigenome due to:
- Genetic inactivation of the histo economy methyltransferase MLL2
- Genetic inactivation of the acetyltransferases CREB-binding protein (CREBBP)
- Genetic inactivation of the E1A-binding protein p300 (EP300)
- activation of his tone methyltransferase enhancer of zeste homologous (EZH2)
What is the immunophenotype of FL?
CD20+
CD10+
BCL2+
BCL6+
CD23+/-
CD5-
CD43-
CCND1+
Any characteristic chromosomal translocation of FL?
BCL2 t(14;18) in 90% of cases
What are the differential diagnosis for FL?
1) NLPHL
- small and scattered large cells
2) CLL
- CD5+, CD23+
- CD10-, BCL6-
3) MCL
- Cyclin D1 +, CD5+
4) MZL
- CD10-, BCL6-
Anything in particular about FL with 1p36 deletions?
- Predominant diffuse pattern in inguinal LN,
- large localized mass
- CD23+
- Typically G1 or G2
- good prognosis
Anything about IRF4 translocations?
Usually DLBCL, but occasionally pure FL Grade 3B;
And often could be DLBCL + FL Grade 3B
Typically present with Waldeyer’s ring involvement
Often children/young adults
Locally aggressive, but responds well to chemo +/- RT
BCL2-
Should NOT be treated as low-grade FL
What is the Waldeyer’s ring?
Ring of lymphoid tissue in the pharynx.
Formed by:
- Palatine tonsils ('tonsils)
- pharyngeal tonsils
- tubal tonsils
- lingual tonsil
- adenoidsWhat are the suggestions that a histologically transformation has occurred?
LDH rising
Single site growing disproportionately
Extranodal disease develops
New B symptoms
What are the indications for treatment in FL (Grades 1-2)?
Candidate for clinical trial Symptoms Threatened end-organ function Cytopenia secondary to lymphoma Bulky disease Steady progression
GELF Criteria:
1) LN
- 3 or more LN areas each 3 or more cm
- any nodal or Extranodal site 7cm or bigger
2) Blood
- Cytopenias (Plts, Leukocytes)
- Leukemia
3) Organ
- Splenomegaly
- Ascites/Pleural effusions
4) General
- B Symptoms
What is the GELF criteria?
1) Blood
- Cytopenias (Plt 5x10^9 malignant cells)
2) Organ
- Splenomegaly
- pleural effusions/ascites
3) LN
- 3 or more LN regions, each 3cm or bigger
- any LN or Extranodal site 7cm or bigger
4) General
- B symptoms
What is FLIPI-2 ?
Age >60 yo Long diameter of largest LN >6cm BM involvement (stage) Beta-2microglobulin increased (Serum marker) Hb
What are first-line treatments for fit FL patients?
R-Bendamustine RCHOP RCVP Rituximab (375mg/m2 weekly for 4 doses) R-Lenalidomide
Addition of R has shown to increase ORR, Response duration, PFS as well as possibly OS
What are first-line therapies for FL who are elderly or infirm ?
1) Rituximab (375mg/m2 weekly for 4 doses) - preferred
2) Single-agent alkylators +/- Rituximab
- Chlorambucil
- Cyclophosphamide
3) Radioimmunotherapy
What are 2nd-line and subsequent therapies approved for FL?
1) Chemoimmunotherapy
2) Rituximab
3) Lenalidomide +/- R
4) Idelalisib
5) Fludarabine + Rituximab
6) RFND
- Rituximab, Fludarabine, Mitoxantrone, Dexamethasone
How do we give Idelalisib?
Small molecule inhibitors
Recommended dose is 150mg PO BD
Possible s/e: - Fatal +/- serious hepatotoxicitis >> stop if ALT/AST >5xULN >> when transaminitis resolved, need to reduce dose to 100mg BD - severe diarrhea or colitis >> severe diarrhea/colitis can be managed with systemic or nonabsorbable steroids - pneumonitis - intestinal perforation
When used for CLL, upon initiation of Idelalisib, transient increase in absolute lymphocyte count is expected in most patients
- does not mean PD
- may persist for several weeks on treatment
What are the grades of FL?
Grading is performed according to the number of blasts per hpf
Grade 1: 5 or less than 5 blasts/hpf
Grade 2: 6-15 blasts/hpf
Grade 3A: >15 blasts/hpf, centroblasts with intermingled centrocytes
Grade 3B: >15 blasts/hpf, pure sheets of blasts
Tell me what you know about FL3B with cytogenetic abnormalities at BCL6 (3p27)
More similar to germinal center DLBCL than FL1-3A
A/w more aggressive clinical course
What are the other variants of FL?
1) Pediatric-type FL:
- Rare variant of FL
- lack of BCL2 rearrangement and t(14;18)
- better prognosis than adult FL
- often cured with minimal therapy
2) Primary intestinal FL:
- common in small intestine, usually duodenum
- similar to those of nodal FL
- clinically indolent, localized disease
- survival appears excellent even w/o tx.
3) Other Extranodal FL
- usually localized disease
- systemic relapses rare
4) FL-in-situ
- Preservation of LN architecture
- incidental finding of focal strongly positive staining for BCL2 restricted to germinal centers
- also has strong staining for CD10 in involved follicles
- detection of t(14;18) by FISH
- has been reported in patients with prior FL or concurrent FL at other sites
What is primary cutaneous follicle Centre lymphoma? (PC-FCL)
Defined as:
- tumor of neoplastic follicle center cells,
- includes centrocytes, variable number of centroblasts
- with a follicular and diffuse or a diffuse growth pattern
Most common B-cell lymphoma of the skin
Indolent, rarely disseminates to extra cutaneous sites
BCL6+, CD10+ likely
BCL2 often negative
Excellent prognosis, 5y OS 95%
What are the 3 trials that advocated for WW in advanced stage asymptomatic FL in the pre-Rituximab era?
1) Ardeshna 2003
- treatment arm: Chlorambucil
2) Brice 1997
- Arm 2: Prednimustine
- Arm 3: IFN
3) Young 1988
- ProMACE-MOPP + total nodal irradiation
Which 2 criteria can we use to assess if a FL patient is suitable for WW approach?
1) BNLI
2) GELF Criteria
What is the BNLI criteria?
Absence of any:
- pruritus or B symptoms
- rapid growth in 3 months
- life threatening organ involvement
- marrow infiltration causing Hb
Describe the Ardeshna paper that compared Rituximab vs WW in asymptomatic FL. What is the result?
Ardeshna in ASH 2010
Inclusion criteria:
- asymptomatic FL,
- Stage II, III, IV
- non-bulky
- n=380
Primary endpoints:
- time to start of new treatment
3 arms:
A) Rituximab (375) weekly x4 –> Rituximab q2monthly
B) Rituximab (375) weekly x4 –> regular clinic visits
C) WW
Results:
- 3y PFS: WW 30%, R–>O 60%, R–>MR 80%
- TTNT: 46% (WW) vs 88% (MR) vs 78% (Rituximab induction)
- improvements in mental adjustment to cancer scale score and illness coping style score
- MR group did not show improvements in QoL cf WW group.
- No difference in 5y OS, all ~60%
Conclusion: R mono therapy should be considered as a treatment option for patients with asymptomatic advanced stage low-tumor-burden FL.
Examples of small cells Lymphoma
CLL/SLL Mantle Cell Lymphoma Splenic MZL Hairy cell Leukemia Lymphoplasmacytic lymphoma Extranodal MZL (MALT) Nodal MZL FL
What is the usual immunophenotype of FL?
CD5- CD10+ BCL6+ BCDL2+ T(14;18)+
85% of FL will be BCL2+ or t(14;18)+
What is the median survival of FL
7-10years
What is the rate of transformation to HG from FL?
20-30%
What are the Germinal center neoplasm?
Burkitt’s Lymphoma
DLBCL - GC subtype
FL
What are the post-Germinal Centre neoplasms?
Marginal Zone Lymphomas
DLBCL - ABC subtype
Multiple myeloma
What are the pre-Germinal Center neoplasms?
CLL/SLL
Mantle Cell Lymphoma
What is the FLIPI-I Criteria?
AAHLN
Age 60years and above
Ann Arbor Stage III/IV
Hb ULN
No. Of nodal sites 5 or more
What is the risk group associated with FLIPI-I chart?
AAHLN
(Age, Ann Arbor Stage, Hb, LDH, No. Of nodal sites)
Low - 0-1 factor
Intermediate - 2 factors
High - 3 or more
What is FLIPI-1 used for?
This is designed in pre-Rituximab era
Identifies patient with higher risk of transformation
Not validated prospectively to guide treatment
Used to guide prognosis and treatment in clinical trials.
What is the evidence for R-chemotherapy ?
1) Hiddemann ASH 2005
N=400
Untreated, advanced stage FL
2 arms:
1) CHOP
2) CHOP
RESULTS:
RCHOP reduced the RR for treatment failure by 60%
TTTF: increased with R
ORR 96% vs 90%
Prolonged duration of remission increased as well
Superior OS with R chemo
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2) Marcus JCO 2008
Prev untreated FL
Stage III/IV
2 arms:
RCVP vs CVP
RESULTS:
All outcome measures show improvement
OS 83% vs 77%
What is the evidence for R-Benda?
Rummel ASH 2009
Advanced FL, MCL, Indolent NHL
2arms:
A) Bendamustine (90) D1, D2 + Rituximab D1 q28days
B) RCHOP
RESULTS: CR 40% (R-Benda) vs 30% PFS 50% vs 30% PFS (FL) not reached vs 47 TTNT not reached vs 40m R Benda with lesser risk of neutropenia/infections
Any evidence for maintenance Rituximab in FL?
1) PRIMA study Salles Lancet 2011
Prev untreated G1-III FL. N=1200
3 different chemo regimens with R. RCHOP, RCVP, R-FCM
Those who achieved CR/PR then underwent a 2nd randomization n=1000:
A) Maintenance Rituximab (375) X 2 years
B) Observation
RESULTS:
3y PFS 75% (maintenance) vs 60%
2y CR+uCR 70% vs 50%
No difference in OS
When to start maintenance Rituximab?
E4402 (RESORT) study
FL + Low tumor burden s/p frontline Rituximab (375) for 4 weeks
Those with CR/PR (n=300) randomized to:
A) Maintenance R every 3 months
B) Retreatment at Progression with R weekly for 4 months
RESULTS:
- TTTF 4y (RR) 4y (MR)
- 3y Freedom from cytotoxic: 80% (RR) vs 95% (MR)
What are the consolidation therapy trials in FL?
1) FIT trial
- Morschhauser JCO 2008
2) SWOG 0016
- ASH 2011
3) SWOG 9911
- Fisher JCO 2005
What do you know about radio-immunotherapy in FL?
1) FIT trial by Morschhauser. JCO 2008
CD20+Advanced FL with CR/CRu/PR to 1st one induction chemo
N=400
2 arms:
1) Rituximab (250) D0, 7 + Y-90-Ibritumomab 14.8MBq/kg D7
2) Observation
RESULTS: 8y PFS 40%(Y-90) vs 20% Med PFS 4y vs 1 y TTT 8 y vs 3 y Estimated 8y OS ~
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2) SWOG 0016 trial by Press ASH 2011
Untreated advanced FL
N=550
2 arms:
1) RCHOP
2) CHOP–> Tositumomab 2 weeks later
RESULTS:
2y PFS 76% vs 80%(RIT)
2y OS 97% vs 93% (RIT)
Conclusion –> not significant
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3) Tositumomab alone. NEJM 2005 Kaminski et al
Stage 3/4 FL
S/p Tositumomab single dose–> I-labeled Tositumomab 1 week later
RESULTS:
75% with CR
5y PFS 60%
Med PFS 6years
Under which conditions can Bendamustine not be used?
CrCl
Tell me about Bortezomib in NHL
Proteasome inhibitor
Active as single agent in indolent NHL (FL, MZL)
Optimal dosing not established
Preclinical data suggest Bortezomib may enhance Rituximab efficacy
