Chronic Leukaemias

Dr RA Bolarinwa MBChB;MSc;FMCPath
Senior Lecturer and Consultant Haematologist
 Objectives of the Lecture
• Students should be able to define and classify
chronic leukaemias (CL)
• Characterize different types of CL
• Identify motphology of CL and genetics defects
• Enumerate the diagnostic methods and useful
drugs in the management of CL
• Identify complications associated with CL and
its management
 Lecture Outline

• Introduction/Definition of chronic leukaemia

• Classifications of Chronic Leukaemias
-CML and case presentation
-CLL
• Diagnosis of CML/CLL
• Investigation of CML/CLL
• Treatment Modalities of CML/CLL
• Prognostic Factors of CML/CLL
• Questions???
The definition of chronic leukemia (CL):

Chronic leukemia arise from genetic defect in

a single cell in the BM and/or in the
peripheral tissue, giving rise to a clonal
population of blood cells which when
enlarged enough caused a serious disease
condition. CL runs a chronic course.

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Classification of CL.

• There are two types:

1- chronic myeloid leukemia (CML).

2- chronic lymphoid leukemia (CLL).

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Definition of CML:
CML is defined as a stem cell disorder
characterized by the presence of Philadelphia
(Ph) chromosome in all stem cells. There is
replacement of normal BM cells by cells with
an abnormal chromosome – Ph chromosome
t (9; 22)(q34; q11).

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Philadelphia chromosome

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 Pathogenesis
Genetic abnormality
• CML is the result of an acquired genetic abnormality
• A translocation between chromosome 9 and 22 [t(9;22)] –
the Philadelphia chromosome
• The oncogene BCR-ABL encodes an enzyme – tyrosine
phosphokinase (usually p210)
•The function of the normal abl gene product ( p145abl ) is not
well understood but it is known to have tyrosine kinase
activity and play a role in the regulation of several different
growth factor receptors, including those for epidermal
growth factor, platelet derived growth factor, and colony
stimulating factor receptors.
 Pathogenesis
• The chimeric bcr-abl fusion gene produces a
chimeric protein of molecular weight 210,000
daltons (p210bcr-abl ). This protein has a more
powerful tyrosine kinase activity than normal
abl gene
• (p210bcr-abl ) enhance and push the
proliferation and differentiation in a novel
manner particularly in chronic phase.
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Translocation t(9;22)(q34;q11)
Chronic Myeloid Leukaemia (CML)
• CML is a triphasic myeloproliferative disorder of
pluripotent stem cells
• Chronic, accelerated & blastic phases
↑proliferation, ↓apoptosis
• Ph chromosome → reciprocal translocation; with
transfer of “abl” oncogene on 9q to “bcr” on 22q
• There’s production of abnormal bcr-abl gene that
codes for synthesis of mutated tyrosine kinase protein
• A minority of CML cases are Ph-negative → (poorer
prognosis)
 Incidence
• CML comprises <20% of all leukaemia, its
rarer than CLL.
• The incidence rate is 1-2/100,000
population; with a peak of incidence in the
middle age people.
• The disease occur in either sex (M:F; 1.4 -
1.8:1), however, it may occur in children,
neonates and very old people.

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 Epidemiology of CML
• Unknown aetiology
-irradiation
-therapy with DNA topoisomerase inhibitors
• Uniform annual worldwide incidence 1-2/100,000; and
M:F ratio =1.8: 1 in Nigerians
• Incidence rate similar for Nigerian and American black
and white patients
• The median age of Ph+ CML in Nigeria = 38yrs,
compared to 67yrs in the Western World
• Disease very uncommon > 60yrs in Africans
 Chronic Phase of CML
• Leucocytosis 20-200 x 109/μl
-predominance of myelocytes, metamyelocytes,
polymorphs
-relative abundance of basophils and eosinophils
• Absolute lymphocytosis (mean 15 x 109/l) due mainly to
balanced increase in T4 and T8 cells; B cells are not
increased
• Subnormal leukocyte alkaline phosphatase (LAP)
• Normal to increased platelet count
• Mild to moderate anaemia (ie, HCT 25%-35%)
 Accelerated Phase of CML
• Blood & marrow blasts + promyelocytes of 10-19%
-Peripheral blood basophils at least 20%
-Persistent thrombocytopenia (< 100 x 109/l) or
thrombocytosis (>1,000 x 109/l) unresponsive to therapy
• Increasing splenomegaly & increasing WBC count;
unresponsive to therapy
• Cytogenetic evidence of clonal evolution
-i.e. appearance of new genetic abnormalities; that were not
present at diagnosis
• Megakaryocytic proliferation in sizeable sheets & clusters,
associated with marked reticulum or collagen fibrosis
 Blastic Transformation Phase

• Presence of one or more of the following:

-Blasts 20% or more in blood or bone marrow
-Extramedullary blast proliferation
-Large foci or clusters of blasts on bone
marrow biopsy
Clinical Presentation:
• Increasing splenomegally, which is associated
with discomfort, pain or indigestion.
• Refractory anaemia that include pallor, weakness
and tachychardia.
• Bruising, epistaxis due to abnormal platelet
functions.
• Gout or renal impairment due to hyperuricemia.
• Visual disturbances.
• Increase requirement for chemotherapy to
maintain remission.
• Massive increase of circulating granulocytes.
Blood film picture in CML
 Diagnosis
• Leucocytosis and characteristic blood film
picture
• Presence of Ph chromosome on karyotyping
or FISH
• Demonstration of bcr/abl 1 gene on RT-PCR
 Conventional Cytoreductive Therapy
• Hydroxyurea or Busulphan:
-Median survival = 3-5 yrs; Range = <1 yr - >10 yrs
-Median survival < 1 yr in accelerated phase & just a
few weeks in blastic phase
• Neither of the drugs is associated with cytogenetic
remission
 Potentially Curative Agents
• Tyrosine Kinase Inhibitors
• Prolonged use of alpha interferon (α-IFN)
• Early allogeneic haematopoietic stem
transplantation
 Imatinib Therapy for Ph+ CML
• Ability to specifically inhibit some tyrosine kinases:
Abl, Arg (abl-related gene), c-Kit, platelet-derived
growth factor receptor (PDGFR) & their oncogenic
forms, in particular bcr/abl
• Complete cytogenetic remission rate of 70-80% in
CML
• Estimated 5-year survival rate of 90-95% of CML
patients
• Also responsible for durable remissions in >50% of
patients with advanced GIST
 Tyrosine Kinase Inhibitors
• Imatinib Mesylate (Glivec):
-2-phenylaminopyrimidine compound
-The classical abl tyrosine kinase inhibitor
• Dasatinib:
- thiazolecarboxamide structurally unrelated to glivec
- Inhibits both the abl- & Src-related kinases
-effective against all imatinib-resistant mutants, except T315I
- 300-fold more potent than imatinib
• Nilotinib:
- an aminopyrimidine structurally derived from glivec
-20-50-fold more potent than imatinib
-active against most imatinib-resistant mutations, except T315I mutant clone
- Ineffective against Src-related kinases
• Bosutinib: effective against T315I mutant clone
 Currently Approved TKIs For All Phases of CML
(Sweet et al: Jr of Hematol & Oncol 2013 6:54)

DRUG YEAR APPROVED INDICATIONS FOR CML Potency

relative to
Imatinib 2001 CP, AP, or BC after failure of interferon therapy Imatinib
2003 Newly diagnosed CP

Dasatinib 2006 CP, AP, or BC after resistance to or intolerance of imatinib X 325

2010 Newly diagnosed CP

Nilotinib 2007 CP or AP after resistance to or intolerance of imatinib X 30

2010 Newly diagnosed CP

Bosutinib 2012 CP, AP, or BC after resistance to or intolerance X 30-50

of prior therapy

Ponatinib 2012 CP, AP, or BC after resistance to or intolerance

of prior TKI therapy

CP, chronic phase; AP, accelerated phase; BC, blastic phase

Management of Glivec Resistance
• Escalation of imatinib dosage in patients with
partial resistance (bcr/abl-dependent).
-Response may not be durable & many patients
may not tolerate the very high dose
• Use of other ABL kinase inhibitors:
Dasatinib or Nilotinib or Bosutinib
• Homoharringtonine (HHT), the plant alkaloid has
been effective in some imatinib-resistant patients
• Allogeneic stem cell transplantation
 Case Presentation
• 63yo trader with history of early satiety and
abdominal swelling of 9/12
• Hearing impairment of 3/52, and no other
complaints
• Referred from the GOPD when a result of FBC
in addition showed marked elevation pf WBC.
Blood chemistry was normal and abd USS
showed splenomegaly
 FBC report

• PCV-35%, WBC- 423 X 109/L, Platelet count- 384

X 109/L, N-83%, L-13%, E-2% and M-2%

• PBF showed white cells at different levels of

maturation. No blast seen

• BMA was done and showed blast count of 8%,

cellular marrow with no abnormality in the cell
lines
 Other tests and Treatment
• Bcr/abl was detected at 45% with e14a2
transcript
• Diagnosis of CML in chronic phase was made
and was counselled
• He was commenced on HU and glivec®
• He was also requested to take a lot of fluid
and allopurinol
Chronic Lymphocytic Leukaemia (CLL)
 Definition
• CLL is a clonal lymphoproliferative disorder of
mature long-lived functionally defective
lymphocytes
• Its the same disease as Small lymphocytic
leukaemia (SLL)
 CLL
• CLL is the most common of the chronic
lymphoid leukemias.

• Is characterised by the accumulation of non-

proliferation mature-appearing lymphocytes
(Lymphocytosis) in the blood, marrow, lymph
nodes, and spleen.

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 Epidemiology
• CLL incidence varies worldwide
-West: CLL is the commonest leukemia; ~30% of
all leukemias; 95% being B-cell
-Asia: CLL is ~5% of all leukemias; Tcells being
more common than B-cells
• More males affected than females; M:F ratio
~2:1
• Age: 60-65 years; CLL almost non-existent in
children
 Cytogenetics & Immunophenotype
• CLL cells express pan-B-cell antigens; CD19, 20
• CD5, a mature T-cell antigen, is expressed by ~95% of CLL cells
• CD23+ & FMC7-: differentiates CLL from Mantle Cell
Lymphoma
• Weak sIg+ in ~90% CLL
• CLL clonality defined by κ/λ restriction, clonal cytogenetics or
clonal rearrangement of IgH/IgL genes
• Recently, ZAP-70/CD38 has been identified as a poor
prognostic cytogenetic marker
• Other prognostic factors include: LDH, β2 Microglobulin, 13q-
abnormality
 Diagnosis
• ALC ≥ 10,000/μL or ≥ 5,000/μL clonal B-cells with ≥ 30% bone
marrow infiltration
• Film shows uniform mature lymphocytosis, smear/smudge
cells
• Differentials include;
-mature B/T-cell leukemia,
-NHL in leukemic phase,
-Hairy cell leukemia (HCL),
- Splenic lymphoma with villous lymphocytes (SLVL),
-Mantle cell lymphoma (MCL), and
- Waldenström’s macroglobulinemia.
Blood film picture
 Other lymphoproliferative disorders

B-cell disease T-cell disease

• B-PLL • T-PLL
• Hairy cell leukaemia (HCL) • T-large granular
• Hairy cell leukaemia variant lymphocytic leukaemia (T-
(HCL-variant) LGL)
• Sezary cell leukaemia
Staging :
• Staging is very important for prognosis and
treatment.

• There are two staging system (Rai and Binet).

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A-Rai Classification:

Stage definition

0 Absolute lymphocytosis >15x109/l.

1 Stage 0+enlarged lymph nodes.

11 Stage 0+liver or/and spleen   adenopathy.

111 Stage 0+anemia organomegally or adenopathy.

1V Stage 0+thrombocytopenia organomegally or adenopathy.

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B-Binet Classification:

Stage . Organomegally Hb Platelet.

.
A(50-60%) 0,1,or2areas

B(30%) 3,4,or 5areas 10 100

C(<20%) Not considered <10 and /or

<100

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 Immunological abnormalities
• Infections
• Auto-immune hemolytic anemias (AIHA)
• Auto-immune thrombocytopenia (AIT)
• Other auto-immune diseases
-Rheumatoid arthritis
-Hashimoto or Graves‘ disease
-SLE
Treatment :
• Since cure is rare, the treatment aim is only
symptoms control.
• Indication for treatment:
– Troublesome organomegaly.
– Hemolytic episodes.
– Increase doubling time
– Bone marrow suppression.

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 Treatment options: drugs
• Chemotherapy
-Chlorambucil ± Prednisolone
-Cyclophosphamide ± Prednisolone
-Cyclophosphamide, Vincristine &Prednisolone (CVP)
-Fludarabine alone or in various combinations eg cyclo +
fludarabine + rituximab is presently a frontline treatment for
patients with CLL
• Newer drugs: Cladribine, Pentostatin.
• Monoclonal antibodies (mAb) alone or combined with others
-Alemtuzumab (Campath-1H, anti-CD52)
-Rituximab (anti-CD20)
 Treatment options: transplant & others
• Haematopoietic stem cell transplantation (HSCT)
-Only a minority of CLL patients require HSCT
- usually those with rapidly progressing disease
• Most CLL patients are elderly (> 60 yrs), have co-morbidities & have
complex drug history; So, they are not eligible for conventional HSCT
programs
• Auto-HSCT; has limited role, but easily tolerated
• Allo-HSCT; more intense, less tolerated & results are best with a matched
related donor (MRD)
- Limited by patients‘ age, co-morbidities & toxicity of
myeloablative regimens
- Non-myeloablative (reduced intensity conditioning) regimens
are being examined
• Other therapies for resistant patients: IV Immunoglobulins, Splenectomy,
Danazol, Cyclosporine
 Prognosis
• 50% of the patients will receive partial
remission.
• < 30% of the patients will have complete
remission.
• 30% of the cases will transfer into PLL.
• 5% of the cases will have Richters syndrome in
which the blastic phase of CLL occur in lymph
nodes (immunoblastic transformation).
Thank you for your attention