By Mohammed Adem, Jigjiga University

1. Chronic leukemias
Mohammed Adem
Jimma university
Clinical pharmacy PGYI
mohzum@hotmail.com
31,Augest 2011
Mohammed A 1

2. Outline
• Definition
• Introduction
• Epidemiology
• Etiology & path physiology
• Clinical feature and diagnosis
• patient management
• Outcome Evaluation
CML then CLL
31,Augest 2011
Mohammed A
2

3. Chronic leukemias
• when the malignant clone is able to differentiate
accumulation of more mature cells of the affected
cell type.
• Differs from acute in that its clinical course is
indolent. Most are asymptomatic at presentation
• survive for several yrs after their initial Dx, even
without Rx.
• In certain CL evolution in to acute d/se may occur,
which may need d/t mgt approach.
Mohammed A 3
31,Augest 2011
3

4. Chronic leukemias…
Include:
hairy cell leukemia, and
prolymphocytic leukemia.
CML,CLL,
.
Mohammed A 4
31,Augest 2011

5. CML
 Is a hematologic cancer that results from an abnormal
proliferation of an early myeloid progenitor cell.
 Results in abnormal proliferation and accumulation of
progenic cell ,mature myeloid cells, erythroid compartment
and platelets in the bone marrow& peripheral blood
• The cytogenic hall mark Ph chromosome (9:22) in up to
95%
BCR gene on chrom 22q11-ABL gene on chrom9q34.
Mohammed A 5
31,Augest 2011

6. Mohammed A 6
31,Augest 2011
6

7. CML…
• The clinical course has 3 phases: chronic phase,
accelerated phase, and blast phase/crisis.
• The disease begins in the chronic phase in which
s/s can be controlled with chemotherapy.
• Then progresses to a transition phase, known as
accelerated phase, in w/c blast counts in the bone
marrow and peripheral blood increase despite
ongoing therapy.
Mohammed A 7
31,Augest 2011
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8. CML…
• Finally, there is blast crisis, a terminal phase that
is similar to acute leukemia that can lead to rapid
clinical deterioration and death.
• Why transition? poorly understood.
• 85 to 90% present in the chronic phase.
• Today this evolution into the accelerated& blastic
phases can be delayed if not prevented/cured
Mohammed A 8
31,Augest 2011
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9. Epidemiology
• The incidence of CML is 1.5 per 100,000 people/yr.
• 1/5th of all cases of leukemia in the US.
• The commonest leukemia in Africa& Ethiopia.
• uncommon in children and adolescents
• Median age at presentation is 70-80.
• Common male
Mohammed A 9

10. Etiology
• The cause is unclear
• No familial association of CML has been noted.
.
• Benzene exposure does not inc. the risk of CML but AML.
• Is not associated with any known oncogenic viruses
• smoking can accelerate the progression to blast crisis in
pre-imatinib era.
• CML is not a frequent 2dry leukemia after Rx of other
cancers with radiation or anti-CA agents or both.
• Ionizing radiation in high doses is the only known risk
factor for CML. Mohammed A 10

11. Pathogenesis
Genetic abnormality
The product of the fusion gene plays a central role in the
dev’t of CML.
The oncogene BCR-ABL encodes an enzyme tyrosine
phosphokinase (usually p210).
Through this chromosomal translocation, the ABL
protooncogene is able to escape the normal genetic controls
on its expression and is activated into a functional
oncogene p210BCR-ABL
Mohammed A 11

12. Pathogenesis…
• The attachment of the BCR sequences to ABL results in:
• p210BCR-ABL is constantly active, and this unregulated
activity results in cell proliferation, inhibition of apoptosis,
and accumulation of the malignant clone.
Mohammed A 12

13. Pathogenesis…
Hematopoietic abnormality
 Expansion of granulocytic progenitors and a decreased
sensitivity of the progenitors to regulation increased
white cell count
 Megakaryocytopoiesis /plt is often expanded
 Erythropoiesis is usually deficient
 Function of the neutrophils and platelet is nearly normal
Mohammed A 13

14. Clinical Presentations
approximately 70% of patients are asymptomatic at the time of Dx.
• Sx related to hyper metabolism:
weight loss, lassitude, anorexia or night sweats
• platelet dysfunction.
Bruising ,epistaxis, menorrhagia or hemorrhage from any site.
• Anemia.
• Organ infiltration:
Splenomegally early satiety , LUQ pain/mass
Other Sx
Urticaria,visual disturbance, Unexplained fever , bone and joint pain
,thrombosis such as vasoocclusive disease, CVA,MI .
Mohammed A 14

15. Physical Findings
• Splenomegaly :the most common physical finding (> 90%)
• Mild hepatomegaly ( occasionally).
• Persistent splenomegaly despite continued therapy is a
sign of disease acceleration.
• Lymphadenopathy and myeloid sarcomas are unusual
except late in the course of the disease; when present the
prognosis is poor.
• Bruising , Fever, Bleeding (gingivae most common)
Mohammed A 15

16. Laboratory and Radiographic Work-up:
• CBC with manual differential
• Leukocyte alkaline phosphatase
• Uric acid level
• Cytogenetic study: Ph chromosome
• Bone marrow biopsy
• organ functions
Mohammed A 16

17. Lab feature…
Lab feature in Stable/chronic phase CML
1. CBC
 RBC a mild degree of NCNC anemia
 Leukocytosis (WBC >100 103 /µL,
 or 100 109/L). Usually <5% circulating blasts
 +/- Basophilia, eosiophilia
 Thrombocytosis ( ~50% of patients in chronic phase)
2. Phagocytic functions of neutrophil are usually normal
Mohammed A 17

18. Lab feature…
3. Bone marrow or chromosomal findings
 Hypercellularity with presence of blasts
 Presence of Ph/ shortened chromsome
 increased myeloid to erythroid ratio
4. Other basic studies;
organ function, uric acid…
Mohammed A 18

19. Prognostic Factors
• The clinical outcome of patients with CML is variable
• Before imatinib era, expect death 10% of pts within 2 years
and in about 20% yrly thereafter, and the median survival
time was ~4 years
Sokal system
• percentage of circulating blasts,
• spleen size,
• platelet count,
• age, and
• cytogenetic clonal evolution
Mohammed A 19

20. Treatment of CML
Desired Outcome
complete hematologic remission. early goal.
complete Cytogenetic remission. Elimination of ph.
complete molecular remission. ????RT-PCR -tive
Mohammed A 20

21. Treatment…
Nonpharmacologic Therapy
 Allogeneic Stem Cell Transplantation
• Is the only curative treatment option for CML.
• It is an option for younger pts (younger than 50 yrs)
• Cure rates are superior when pts are transplanted in
chronic phase within the 1st yr of dx and may be as high as
70%.
• significant risks10% to 20% early mortality (100 days).
 Splenectomy
 Leukapheresis
Mohammed A 21

22. Nonpharmacologic...
Leukapheresis
 Useful in emergencies where leukostasis-related
complications such as pulmonary failure or cerebrovascular
accidents are likely.
 Possible role in the treatment of pregnant women in whom it
is important to avoid potentially teratogenic drugs
Splenectomy
 painful splenomegaly unresponsive to chemotherapy or
hypersplenism
 Does not influence survival but improves certain aspects of
management Mohammed A 22

23. Outcome of SCT depends on:
• the patient (e.g., age and phase of disease);
• the type of donor [e.g., syngeneic (monozygotic twins) or
HLA-compatible allogeneic, related or unrelated];
• the preparative regimen (myeloblative or reduced
intensity);
• posttransplantation treatment.
Mohammed A 23

24. Treatment…
Pharmacologic Therapy
 The success of therapy depends in part on the clinical
phase of the disease.
 I. tyrosine kinase inhibitors:
Imatinib mesylate (Gleevec). 1st line 400mg/d, 600-800mg/d
 induces CHR in more than 97%. 6wks
 CCR in about 76% of pts in chronic phase. 9-12months
 Most pts have traces of the d/se when measured by RT-
PCR &are not cured of their d/se. CMR 7%
 Progression to other phases is 3%. Then <1%
Mohammed A 24

25. Treatment…
II. an alternative therapy
for patients who do not respond to imatinib and
are not candidates for stem cell transplantation.
 Nilotinib (400mg bid) , Dasatinib (100mg/d)
.
 Interferon-α & Cytarabine.
 Conventional chemotherapy {hydroxyurea* or busulphan}
Mohammed A 25

26. Clinical data
 Allogeneic SCT can be considered for pts with
accelerated/blastic phases or who fails to respond to
imatinib.
 imatinib (400 mg/d) is more effective than IFN- and cytarabine.
 CHR and CCR rate, at 18 months with imatinib was 97%
and 76% compared to IFN and Cytarabine.(69% and 40%
respectively).
 Cyclophosphamide +total-body irradiation had more
complications(hospital admision and stay) compared to
Cyclophosphamide+ Busulfan.
 If no any CR following six months of imatinib are unlikely to
achieve major MR and other t/t approaches should be
offered .
Mohammed A 26

27. Clinical data...
IFN-α
1–3 mu SC 3 xwk, increasing to daily as tolerated
 Before imatinib, when allogeneic SCT was not feasible.
 Only longer follow-up of patients treated with imatinib will
prove whether IFN- consideration.
 With availability of TKIs, it is now offered only if all other
options have failed
Hydroxyurea
 induces rapid disease control
 1–4 g/d to be halved with each 50% reduction of the
WBC.
 cytogenetic remissions are uncommon
Mohammed A 27

28. Clinical data...
Busulphan
• acts on early progenitor cells, has a more prolonged
effect.
• not recommended due to its serious A/Es:
 Unexpected &occasionally fatal myelosuppression
in 5–10%
 Endocardial; Marrow and Pulmonary fibrosis
 Addison-like wasting syndrome;
 Obstructive bronchiolitis ,Alopecia
Mohammed A 28

29. Rx of accelerated phase
Is similar to stable/chronic phase of CML
Rx of Blast Crisis
• Rx is generally ineffective and depends on the
phenotype blast cells.
• AML/ALL treatment protocol.
imatinib poor response.(HR 21%). In 52% of patients
Mohammed A 29

30. STG of Ethiopia
General Rx
 Symptomatic anaemia, dehydration and electrolyte if present
 Allopurinol, 100 mg P.O. TID should be started before the
initiation of specific treatment
Chemotherapy
• Hydroxyurea p.o 2 to 4 g/day initially .depending on the cell
count. withheld if the WBC count < 10,000/ L
• Busulphan, 4 to 8mg/day .stopped when the WBC count
below 20,000/ L.
Mohammed A 31,Augest 2011 30
30

31. Outcome Evaluation
Monitor for complications of disease and treatment
& for relapse.
• HR at 3 months.
• CR at 9 to 12 months.
• MR/ bcr-abl transcripts is currently the best
available test to monitor d/se response. Q 3month
• ADR and manage accordingly
• ddI imatinibe (cyp3A4,fluid retention)
Mohammed A 31
31,Augest 2011
31

32. Take a Break !…
or
Chronic lymphocytic leukemia
Mohammed A 31,Augest 2011 32
32

33. Chronic lymphocytic leukemia
 A cancer of lymphoid cells with primary involvement of bone
marrow and blood. lymph nodes, and spleen.
 In most cases, the cells are monoclonal B lymphocytes
(95% ) that are CD5+
 T cell CLL can occur rarely.
 The main feature is a progressive accumulation of
functionally incompetent, long-lived lymphocytes
 considered to be due to decreased apoptosis rather than
increased proliferation.
Mohammed A 31,Augest 2011 33
33

34. Epidemiology
• is the most prevalent form of leukemia in western
countries.
• 1/3rd of all cases and is 2x as CML.
• most frequently in older adults and is exceedingly
rare in children. Age of presentation 70 years.
• More common in white persons than in African
Americans. M:F 2:1
Mohammed A 34
31,Augest 2011
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35. Etiology
• The specific aetiology of CLL is unknown.
• Genetic factors play a role in high incidence of CLL in some
families.
Chromosomal abnormalities deletion at 13q14 (50%).
• No established viral etiology.
• No definite leukemogenic role of environmental factors
chemicals, including benzene, exposure to Ionizing radiation
and virus.
• There is inc. incidence in farmers (???role of herbicides or
pesticides) rubber manufacturing workers, asbestos workers,
and tire repair workers
Mohammed A 35

36. Pathogenesis
Cell of Origin
The exact cell of origin is controversial but has been
described as an antigen-activated B lymphocyte.
• The normal T cell to B cell ratio is reversed in CLL where
nearly 90% of all lymphocytes are B cells.
• Monoclonal lymphocytes accumulate in the
peripheral blood, bone marrow, lymphoid tissues, and
sometimes other organs.
• Infiltration of the bone marrow may eventually result in
pancytopenia( too few cells)
Mohammed A 36

37. Pathologyimmunodeficiency
I. Deficiency of normal B cells often leads to bacterial
infection.
II. The absolute number of T cells may vary But the function
is invariably abnormal.
III. Defective regulation of T-cell immunity leads to chronic
inflammation.
IV. Regulatory mechanisms normally control and terminate T
cell activation.
V. however, these mechanisms fail leading to chronic T
cell activation and subsequently to inflammation
Hypogammagloblenimia.
• Dysfunctional antibody generation by the incompetent
malignant and normal B cells under the dysregulation of
aberrant T cells.
Mohammed A 37

38. Autoimmunity ..
PathologyAutoimmunity
• Frequent autoimmune complications in CLL and
due to antibodies restricted to hematopoietic/
blood cell
• Autoimmune hemolytic anemia occurs in 10% to
25% of cases at some time during the course.
• Autoimmune thrombocytopenia (2%)
• Pure red cell aplasia (dec cell growth). <1%
• Autoimmune neutropenia (< 1%)
Mohammed A 38

39. Clinical presentations
• Approximately 40% are asymptomatic at dx.
Often found incidentally when a CBC is done for another
reason.
• In symptomatic cases complaint is
 features of anemia,
 Easy bruising/Gingival bleeding, Thrombocytopenia.
 Organomegaly, bone pain ;Flank pain; generalized itching
 Lymphadenopathy when present as lymphoma.
 Frequent infections. CLL weakens B cell immunity
• B symptoms are not common at dx.
Mohammed A 39

40. Diagnosis
 Careful Hx and PE
 Diagnostic testings
• CBC
• Peripheral blood smear
• Bone marrow biopsy
• Cytogenetic studies/Immunophenotyping.
• Molecular testing/Cytometry
• Imaging studies of the chest and abdomen,pelvis
• major organ function test RFT,HFT, electrolytes
Mohammed A 40

41. The diagnostic criteria for CLL
A. A peripheral blood lymphocyte count of greater than >5 ×
109/L; usually >10 × 109/L.
B. presence of B cell-specific antigens CD5(+) .
C. A bone marrow aspirates showing greater >30%
lymphocytes
D. A patient presenting with an autoimmune hemolytic
anemia or autoimmune thrombocytopenia. B-cells CLL
E. Findings may include hypogammaglobulinemia,
hypergammaglobulinemia, or monoclonal gammopathy.
F.
Mohammed A 41

42. Mohammed A 42

43. Staging of Typical B Cell Lymphoid Leukaemia
Stage Clinical Features Median Survival, Years
RAI System
0. Low risk Lymphocytosis only in blood and marrow >10
I: Intermediate risk Lymphocytosis + lymphadenopathy 7
II Intermediate risk Lymphocytosis + splenomegaly /hepatomegaly
III: High risk Lymphocytosis + anemia 1.5
IV High risk Lymphocytosis + thrombocytopenia
Binet System
A  Fewer than 3 areas of clinical >10
lymphadenopathy.
 no anemia or thrombocytopenia
B Three or more involved node areas; 7
 no anemia or thrombocytopenia
C Hemoglobin 10 g/dL and/or 2
 platelets <100,000/L
Mohammed A 43

44. Poor prognostic factors
• Advanced Rai or Binet stage
• Lymphocytosis
• Splenomegaly/Hepatomegaly; Lymphadenopathy
• Anemia; Thrombocytopenia
• Diffuse marrow histology
• Poor response to chemotherapy
Mohammed A 44

45. Treatment
Desired Outcome
 provide palliation of symptoms and improve overall
survival.
 Reduction in tumor burden and improvement in d/se Sx
 Resolution of lymphadenopathy and organomegaly
 Normalization of peripheral blood counts,
 Elimination of lymphoblasts in the bone marrow.
Mohammed A 45

46. Treatment...
Nonpharmacologic Therapy
Stem cell transplantation.
 Offers longer d/s free remissions
 Early mortality after transplant is as high as 40% in
CLL.
 Mortality can be dec by reducing its intensity but
unclear whether it will produce long-term disease-free
survival.
Mohammed A 46

47. Treatment...
Treatment...
Pharmacologic Therapy
Single-Agent Chemotherapy
1. purine analog: fludarabine
2. an alkylating agent: chlorambucil (Leukeran®)
3. Monoclonal Antibodies: Rituximab
Mohammed A 47

48. Treatment...
Treatment...
Fludarabine
 fludarabine based chemotherapy is used as first-line
therapy for younger patients.
 is superior to chlorambucil in achieving higher
response rates and producing a longer duration of response.
 is effective in previously untreated pts, as well as in pts
who have chlorambucil-resistant d/se.
 The most commonly used dose is 20 mg/m2 iv daily for 5
consecutive days. every 4 weeks .
Mohammed A 48

49. Treatment...
Treatment...
Chlorambucil
• can be taken daily po tabs 4 -10 mg/day. to a
single dose of 40–80 mg every 3–4 weeks
• The ease of administration and limited S/Es
make it practical option for symptomatic elderly
pts who require palliative therapy.
Mohammed A 49

50. Treatment...
Treatment...
Rituximab
• directed against the CD20 molecule on B lymphocytes.
• Alone can induce partial responses in untreated and
previously treated CLL patients.
• 3 times weekly for 4 weeks rather than once weekly
• higher doses are required than those used in non-Hodgkin’s
lymphoma.
• however, the typical 375 mg/m2 dose is still used commonly
Mohammed A 50

51. Treatment...
Treatment...
Combination Therapy.
 The combination of fludarabine, cyclophosphamide, and
rituximab is supperior compared with fludarabine alone.
 Cyclophosphamide 250 mg/m2 + fludarabine)
complete responses in 69% of patients
molecular remissions in 50% of the cases
 Regimen used in other lymphomas CVP ;CHOP
but at the expense of increased infections.
Mohammed A 51

52. Treatment...
Treatment...
• Associated conditions should be managed independently of
specific antileukemia therapy.
• Steroids therapy for autoimmune cytopenias and
• Immunoglobulin replacement for patients with
hypogammaglobulinemia. in the setting of serious infection
• Antibiotics
• Blood products
• Radiotherapy, Splenectomy
Mohammed A 52

53. STG of Ethiopia
General
• Early stage and asymptomatic d/se should be observed w/o t
Rx.
• Infections, if present, should be treated aggressively
• symptomatic anemia should be transfused packed RBC.
• Allopurinol, 100mg P.O.TID is given before the initiation of
specific Rx.
First line
• Chlorambucil, 0.1 to 0.2mg/kg P.O. QD for 3 to 6 weeks. 15
-30mg/m2 P.O. may be given over 3 - 4 days every 14 -21
days. PLUS
• Prednisolone, 0.5-1mg/kg may be added. OR
• Cyclophosphamide, 2 -4 mg/kg P.O daily PLUS Prednisolone
Mohammed A 53

54. Outcome Evaluation
• Reduction of malignant lymphocytes.
• Stage of the disease
• Response to treatment and possible relapse
• Regular follow-up throughout treatment ;Since CLL is not a
curable d/se, palliation of Sx is a reasonable goal in older
pts, and
• Aggressive therapies are reserved for younger pts with
high-risk CLL.
• ADRs
Mohammed A 54

55. REFERENCES
Joseph T. Dipiro et.al; Pharmacotherapy,
pathophysiologic approach, 7th edition.
Pharmacotherapy principle and practice, 2007
Harrison’s Principle of Internal Medicine,17th
ed.2008.
Mohammed A 55

56. Thank you
Questions????
Mohammed A 56
31,Augest 2011
56