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Flashcards in Follicular Lymphoma Deck (43):
1

What are the common symptoms at presentation for FL?

B Symptoms
Fatigue
Local mass effect of LN
Cytopenias

2

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

3

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)

4

What is the immunophenotype of FL?

CD20+
CD10+
BCL2+
BCL6+

CD23+/-
CD5-
CD43-
CCND1+

5

Any characteristic chromosomal translocation of FL?

BCL2 t(14;18) in 90% of cases

6

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-

7

Anything in particular about FL with 1p36 deletions?

- Predominant diffuse pattern in inguinal LN,
- large localized mass
- CD23+
- Typically G1 or G2
- good prognosis

8

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

9

What is the Waldeyer's ring?

Ring of lymphoid tissue in the pharynx.
Formed by:
- Palatine tonsils ('tonsils)
- pharyngeal tonsils
- tubal tonsils
- lingual tonsil
- adenoids

10

What are the suggestions that a histologically transformation has occurred?

LDH rising
Single site growing disproportionately
Extranodal disease develops
New B symptoms

11

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

12

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

13

What is FLIPI-2 ?

Age >60 yo
Long diameter of largest LN >6cm
BM involvement (stage)
Beta-2microglobulin increased (Serum marker)
Hb

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

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%

22

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

23

Which 2 criteria can we use to assess if a FL patient is suitable for WW approach?

1) BNLI
2) GELF Criteria

24

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

25

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.

26

Examples of small cells Lymphoma

CLL/SLL
Mantle Cell Lymphoma
Splenic MZL
Hairy cell Leukemia
Lymphoplasmacytic lymphoma
Extranodal MZL (MALT)
Nodal MZL
FL

27

What is the usual immunophenotype of FL?

CD5-
CD10+
BCL6+
BCDL2+
T(14;18)+

85% of FL will be BCL2+ or t(14;18)+

27

What is the median survival of FL

7-10years

28

What is the rate of transformation to HG from FL?

20-30%

29

What are the Germinal center neoplasm?

Burkitt's Lymphoma
DLBCL - GC subtype
FL

30

What are the post-Germinal Centre neoplasms?

Marginal Zone Lymphomas
DLBCL - ABC subtype
Multiple myeloma

31

What are the pre-Germinal Center neoplasms?

CLL/SLL
Mantle Cell Lymphoma

32

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

33

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

34

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.

35

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

========
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%

36

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

37

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

38

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)

39

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

40

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 ~

============
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


==========
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

41

Under which conditions can Bendamustine not be used?

CrCl

42

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