HANAN.A.ELTIB2 0 1 4

Chronic lymphocytic leukemia

OVERVIEW

The most prevalent type of adult leukemia in western countries

Median age of diagnosis of CLL is ~ 72 years, with only 10% of patients younger than 50 years of age

CLL morbidity rapidly increases with age

More common in men than women (2:1 ratio)

Pathophysiology

Historically CLL considered disease of accumulation due to defect in apoptosis

CLL more proliferative disease than previously thought

CLL cells up regulate gene signature consistent with BCR and NF-KB pathway activation

Diagnosis

CBC: at least 5000 monoclonal B-lymphocytes/cml in the peripheral blood

Morphologically :small mature lymphocytes

N.B :Fewer clonal B-Cells LNS less 1.5 cm no anemia or thromocytopenia +/_ the immunophenotybe of the CLL ALymphoproliferative disorders :monoclonal B-

lymphocytosis(MPL)

CLL/SLL

Different manifestation of the same disease managed in the same way

The major difference SLL: the abnormal lymphocytes are

predominantly found in the LNS-diagnosis mainly by LN biopsy-no more than 5000 clonal B-cells in the peripheral blood

CLL: significant number of the abnormal lymphocytes are also found in the BM and blood

Initial Work-up of CLL Patients

Flow cytometry of the peripheral blood Kappa/lambda CD5 + CD19 + CD23 + CD10 - CD20 dim Surface IG dim Cycline D1 –

Atypical CLL : t(11;14) by FISH :LN biopsy with IHC CD3 CD5

CD10 CD20 CD23 Cyclin D1

Anemic pt : RC count - direct combs‘ test

LN biopsy only if diagnosis not confirmed by flowcytometry

Bone marrow aspirate and biobsy not necessary in absence of cytopenias

No CT scan unless symptoms are present; PET scan can be helpful if Richter’s suspected

Informative for prognostic and/or therapy determination flowcytometry or IHC: CD38-CD70 cytogenetics analysis : +12, del(13q), del(17p)and del(11q) mollecular analysis : IGVH gene status assessment-TP53 serum level : β2-microglobulin

Initial Work-up of CLL Patients

Physical Exam LNs : size-symptoms liver-spleen size

B-symptoms

Performance

Useful under certain circumstaces haptoglobin Serum QIG level uric acid LDH HBV

Initial Work-up of CLL Patients

RAI’s CLINICAL STAGING SYSTEM

Stage Clinical Features at Diagnosis Median Survival (years)

0Low risk

Blood lymphocytosis>5000/mcl,Bone marrow lymphocytosis>30%

>12,5

IIntermediate risk

Stage 0and enlarged lymph node(s)

8

IIIntermediate risk

Stage 0-Iand enlarged spleen and/or liver

6

IIIHigh risk

Stage0-IIand anemia (Hb < 11g/dl)

1,5-2

IVHigh risk

Stage0-IIIand thrombocytopenia(< 100 000 /mcl)

1,5-2

When to Treat CLL Patient

No advantage to treating CLL until symptoms develop

Constitutional symptoms due to disease (fatigue, B symptoms)

Enlarging, symptomatic lymph nodes (> 10 cm)

Enlarging, symptomatic spleen (> 6 cm BCM)

Cytopenias due to CLL (hemoglobin < 11 g/dL, platelets < 100,000 cells/μL)

Poorly controlled AIHA or ITP

Absolute lymphocytic count alone is not indication for treatment unless above 200-300×109/L Or symptoms related to leukostasis

Treatment options

Alkylating agents

Purine anologue vs Alkylators Higher RR and PFS Better QOL Not OS

Purine/alkylator combo vs. purine: Higher RR and PFS Not OS

Treatment options

CLL8 study ;chemoimmunotherpy : FCR VS FC

• More neutropenia

• A better therapy for young –physically fit pt

• Significantly improves ORR and CR

• Significantly improves PFS

• Significantly improves OS 7% Most genetic groups benefit from FCR therapy

except for del(17p13)

Treatment options

CLL10 study; FCR VS BR

Bendamastin: An Alkylator agent with apurine like benzimidazole ring component Identical ORR Higher CR rates observed with FCRPFS significantly longer with FCRAcute (and long-term?) toxicity greater with BR

PCR Pentostatin: purine analog No advantage over FCR Cyclophoshamide is an important component

AlemtuzumabHuminazied Monoclonal Ab target CD52Not as afirst line treatment option except in the setting of del (17p)

In elderly: Treatment options

FCR not well tolerated –less effective by pts 70 ys

Fludrabine vs chloreambucil 65 ys Better ORR CR TTTF QOL analysis favoured fludrabine NO PFS OS difference SO Chloreambucil is avalid option

In elderly: Treatment options

Bendamastin vs chlorambucil Higher RR/PFS

Higher toxicity CLL11 study :Obinituzumab + chlorambucil is

an effective, well-tolerated therapy Most appropriate for elderly ? question of whether obinituzumab is superior to rituximab

in other clinical contexts

First line therapy

Fit patient Chemoimmunotherapy e.g FCR/FR/BR/PCR

Elderly pt-comorbidity Chlorambucil+/- R Fludarabine+/- R Cyclophosphamide , prednisolone+/-R Bendamastin+/-R Rituximab

First line therapy

Frail pt Chlorambucil Pulse steroides Rituximab

Molecular guided therapy

Pt with del(17p) Trial FCR HDM+R Alemtuzumab+/-R Ibrutinib for patients with

relapsed/refractory disease Pt with del(11q) Regimens containing an alkylator

Considerations for Relapsed CLL

Outcome of patients at time of relapse dependent on: – Interphase cytogenetics, β2-microglobulin, and stage – Previous therapy (ie, monotherapy or chemoimmunotherapy) – Time of remission with last treatment Treat relapsed patients when symptomatic only Interphase cytogenetics should be repeated prior to initiating salvage therapy All patients with cytopenias should have repeat bone marrow to assess for MDS if prior FCR given Transplant evaluation should be considered early in this population if any unfavorable features present

Salvage therapy

IbrutinibChemoimmunotherapyOfatumabLenalidomide+/- RAlemtuzumab+/- R

Supportive Care for pts with CLL

1-Recurrent infection Antimicrobials as appropriate IVIG, if <500mg/dl2-Antinfective prophylaxis PCP-Herpes virus CMV HBV3-vaccination Annual INFLUENZA vaccine Pneumococcal vaccine/5y

Supportive Care for pts with CLL

Blood product :irradiate all blood productTumor lysis syndromeTumor flare reaction :lenalidomideThromboprophylaxis :lenalidomideAutoimmune cytopenias - Steroides - IVIG - Cyclosporin A - Rituximab - Splenectomy

In clinical practice)) Follow up

Constitutional symptomsPhysical Examination Organomegally LNSBlood parameters blood counts+/_BM

Richter's syndrome))Histological Transformation

DLBCL or HL2-5 %Increase with NO. of prior regimensPoor prognosis Extra nodal involvement, Sharp rise in LDHChemoimmunotherapy e.g R-CHOP/ R-HYPERCYVAD Allogeneic HSCT, considered following initial therapy

Prolymphoctic leukemia. > 55% increase in prolymphocytes Progression of splenomegaly & cytopenias Refractoriness to treatment.