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Chronic Lymphocytic Leukemia (CLL)- Chronic Relapsing Remitting
Most  common leukemia in adults
Incurable but treatable
*Remember Supportive Care*
Median age of 72
M > F
80% incidental
SLL: lymphocytes in lymph nodes and spleen instead of blood

 Presentation: 
1) Fatigue
2) B symptoms
3) High WC
4) Cytopenias (Marrow infiltrate, AIHA, ITP, Hyposplenism)

Rule out: Reactive (viral serology)- Hepatitis, HIV

Investigate: 
1) FBC + blood film (mature lymphocytes) w/ trend
2) Haemolysis screen + Coombs test
3) B2 Microglobulin (prognostic marker)
4) IGs + serum electrophoresis
5) Flow cytometry (immunophenotyping)
6) LN Bx (core) especially if lymphadenopathy (*SLL)
7) BMBx
8) Tp53 (17p del or mut)
9) CTNTAP if treatment indicated

 
Confirm : 
1) Lymphocyte morphology (blood film)- monomorphic mature small w/out nucleolous r/o aggressive pro-lymphocytes r/o prominent nucleoli in reactive lymphocytosis
2) 5x10^9 / L circulating clonal B cells for over 3 months on Flow…if below, need annual FBC monitoring 
3) Immunophenotype scoring out of 5 (1 point each): +ve CD5, +ve CD23, weak IG expression, absent/weak CD22, absence of FMC-7...need 4 or 5/5

 Staging : 
1) BINIT A/B/C
2) RAI 0-4


Prognosis: CLL International Prognostic Index
1) Age
2) B2 Microglobulin
3) TP53 status- continuous therapy better if TP53 mut
4) IGHV mutation- better if present
5) RAI or BINIT

The International Working Group for CLL (iwCLL) treatment- Risk vs. Benefit
    1) Cytopenias Hb <100, Plts <100
    2) Bulky disease >10cm LN length
    3) Constitutional sx disease related
    4) AIHA (10-20%) and ITP (2-5%)
    5) Symptomatic or fnxnal extranodal involvement
    6) Massive Splenomegaly >6cm from costal margin or progressive SM + Sx
    7) Lymphocyte doubling time < 6 months or  > 50 percent rise in 2 months 

 
WATCH and WAIT if not reaching criteria

Infection risk (bacterial):
   1)   Vaccination (NB: NO LIVE VACCINES)
   2)   IVIG in immune paresis
   3)   Prophylactic Abx (azithromycin)
   4)   PCP prophylaxis while on treatment

Need IRRAD blood products

Trials for Traditional treatments vs. BTK1 and BCL2
1) Alliance 
2) Mayo clinic study
3) FLARE
4) CLL14 (German) and Illuminate trials 

Treatment:
1) Traditional:  FCR
2) Targeted:
    a.    1st gen BTK1- Ibrutinib 420mg OD (continuous)
    b.    2nd gen BTK1- Acalabrutonib 100mg BD (continuous)
    c.    BCL-2 inhibitor- Venetoclax 400mg OD
            i.       Frontline : OVen.. Ven + Obinutuzumab (CD20 mAb) - 1 yr
            ii.       Relapse: VenR... Ven + Rituximab (CD20 mAb)- 2 yrs

    d.   PI3K inhibitor- Idelalisib - 3rd line as bridging for 2x refractory/2x exposed

*High Risk*: Doublet therapy (targeted combined)
i. Jain et al. – Phase 2 trial
ii. CAPTIVATE trial: Ibru + Ven <65,  TP53 mut/del OR unmutated IGHV 

TRIPLET Therapy trials

-ALLO SCT- early referrals in high risk with first progression

·   Primary Progression: <6m of response
·   Relapse: >6m respon

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