Flashcards in Follicular Lymphoma Deck (43)
What are the common symptoms at presentation for FL?
Local mass effect of LN
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?
Any characteristic chromosomal translocation of FL?
BCL2 t(14;18) in 90% of cases
What are the differential diagnosis for FL?
- small and scattered large cells
- CD5+, CD23+
- CD10-, BCL6-
- Cyclin D1 +, CD5+
- CD10-, BCL6-
Anything in particular about FL with 1p36 deletions?
- Predominant diffuse pattern in inguinal LN,
- large localized mass
- 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
Should NOT be treated as low-grade FL
What is the Waldeyer's ring?
Ring of lymphoid tissue in the pharynx.
- Palatine tonsils ('tonsils)
- pharyngeal tonsils
- tubal tonsils
- lingual tonsil
What are the suggestions that a histologically transformation has occurred?
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
Threatened end-organ function
Cytopenia secondary to lymphoma
- 3 or more LN areas each 3 or more cm
- any nodal or Extranodal site 7cm or bigger
- Cytopenias (Plts, Leukocytes)
- Ascites/Pleural effusions
- B Symptoms
What is the GELF criteria?
- Cytopenias (Plt 5x10^9 malignant cells)
- pleural effusions/ascites
- 3 or more LN regions, each 3cm or bigger
- any LN or Extranodal site 7cm or bigger
- B symptoms
What is FLIPI-2 ?
Age >60 yo
Long diameter of largest LN >6cm
BM involvement (stage)
Beta-2microglobulin increased (Serum marker)
What are first-line treatments for fit FL patients?
Rituximab (375mg/m2 weekly for 4 doses)
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
What are 2nd-line and subsequent therapies approved for FL?
3) Lenalidomide +/- R
5) Fludarabine + Rituximab
- Rituximab, Fludarabine, Mitoxantrone, Dexamethasone
How do we give Idelalisib?
Small molecule inhibitors
Recommended dose is 150mg PO BD
- 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
- 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
- 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)
- 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?
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
- asymptomatic FL,
- Stage II, III, IV
- time to start of new treatment
A) Rituximab (375) weekly x4 --> Rituximab q2monthly
B) Rituximab (375) weekly x4 --> regular clinic visits
- 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
Mantle Cell Lymphoma
Hairy cell Leukemia
Extranodal MZL (MALT)
What is the usual immunophenotype of FL?
85% of FL will be BCL2+ or t(14;18)+
What is the median survival of FL
What is the rate of transformation to HG from FL?
What are the Germinal center neoplasm?
DLBCL - GC subtype
What are the post-Germinal Centre neoplasms?
Marginal Zone Lymphomas
DLBCL - ABC subtype
What are the pre-Germinal Center neoplasms?
Mantle Cell Lymphoma
What is the FLIPI-I Criteria?
Age 60years and above
Ann Arbor Stage III/IV
No. Of nodal sites 5 or more
What is the risk group associated with FLIPI-I chart?
(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
Untreated, advanced stage FL
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
2) Marcus JCO 2008
Prev untreated FL
RCVP vs CVP
All outcome measures show improvement
OS 83% vs 77%
What is the evidence for R-Benda?
Rummel ASH 2009
Advanced FL, MCL, Indolent NHL
A) Bendamustine (90) D1, D2 + Rituximab D1 q28days
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
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
- 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
1) Rituximab (250) D0, 7 + Y-90-Ibritumomab 14.8MBq/kg D7
8y PFS 40%(Y-90) vs 20%
Med PFS 4y vs 1 y
TTT 8 y vs 3 y
Estimated 8y OS ~
2) SWOG 0016 trial by Press ASH 2011
Untreated advanced FL
2) CHOP--> Tositumomab 2 weeks later
2y PFS 76% vs 80%(RIT)
2y OS 97% vs 93% (RIT)
Conclusion --> not significant
3) Tositumomab alone. NEJM 2005 Kaminski et al
Stage 3/4 FL
S/p Tositumomab single dose--> I-labeled Tositumomab 1 week later
75% with CR
5y PFS 60%
Med PFS 6years
Under which conditions can Bendamustine not be used?