2. Leukemia: Cancer that starts in blood forming cells in B.M.
Classified based on the cell of origin
Types (classifications):
1. Acute lymphoblastic (lymphocytic) leukaemia (ALL)
2. Chronic lymphocytic leukaemia (CLL)
3. Acute myeloid (myelogenous) (Myeloblastic)leukaemia
(AML)
4. Chronic myeloid (myelogenous) leukaemia (CML)
3.
4. It is fatal within weeks to months if not treated.
Median age at diagnosis of pts. with AML is about 67
years
The peak age for ALL pts. is 2 to 3 years (8-10 Y).
ALL account 30% of all malignancies in children.
About 75-80% of children with leukemia have ALL and 10-
15% AML (The 2 most common type of childhood leukemia)
The prognosis of adult acute leukemia is generally worse
than that of childhood leukemia
When all ages are included, the 5-year relative survival
rate in USA (2008) for ALL was 66% and 25% for AML
Aetiology unknown (Ionizing radiation and benzene exposure are
the only environmental risk factors strongly associated with ALL or
AML).
5. Symptoms:
Feeling unwell
Fatigue/weakness
Dizziness
Easy bleeding (gum,
epistaxis) and bruising.
Patients may have bone
pain (in arms, legs, joints)
from a hyperactive bone
marrow. (ALL)
SOB
Frequent infection
Temperature is often
elevated and may be
caused by disease or
infection
Unexplained weight loss
6. Note :
Symptoms disease complications:
1. B.M failure:
↓WBC neutropenia infection
↓RBC anemia weakness, SOB, palpitation …..
↓Plt thrombocytopenia bleeding, bruising,
petechiae
2. Other organ involvement: CNS (In ALL)
3. Organ failure (kidney) TLS
Other symptoms:
Splenomegaly, hepatomegaly, and/or lymphadenopathy
are common in patients presenting with ALL
AML may present with gum hypertrophy & bleeding.
7. CBC
Anaemia (normochromic and normocytic).
Thrombocytopenia
Leukocytosis or leukopenia (blood cell (WBC) count
≥50,000 cells/mm3, WBC <10,000 cells/mm3)
Bone marrow aspirate and biopsy (Confirm diagnosis)
Lymphoblast in bone marrow (>20%)
Lymphoblast in peripheral blood (smear/film)
Pts. with ALL should have a screening lumbar puncture
performed to assess CNS involvement
8. Aetiology: Unknown; atom bomb, children exposed to
radiation in utero, pesticides, cigarette smoking, maternal
use of alcohol.
Symptoms (discussed in previous slides)
Fever (61%)
Bleeding (48%)
Bone pain (23%) usually severe
ALL non specific symptoms; may share other childhood
disease (Juvenile R.A).
Physical examination:
Lymphadenopathy (50%)
Splenomegaly (63%)
hepatosplenomegaly (68%).
9.
10. At diagnosis at least 59% of patients have a normal or low
WBC count; the remainder have elevated counts.
The WBC differential typically shows a low % of neutrophils
and bands, and a marked lymphocytosis.
Lymphoblasts may be present in the peripheral blood even
with a low WBC count (e.g., 2,000–4,000 cells/μL), but
they are more likely when the WBC count is elevated.
Anemia (a normochromic, normocytic ), along with
thrombocytopenia, is present in most patients.
No stages
11. Diagnosis:
A bone marrow aspirate & biopsy usually necessary to
confirm the diagnosis of ALL.
Patients with ↑ WBC counts, diagnosis can be confirmed by
studies of lymphoblasts in the peripheral blood.
The diagnosis of ALL is made when at least 20% of lymphoid
cells in the bone marrow are blasts.
Most ALL patients have far greater than 20% blasts, and
many have complete replacement of bone marrow with
lymphoblasts.
12. ALL poor prognosis:
Male sex
Age (<2 years or > 12 years)
WBC ≥ 50.000 (increase risk of relapse)
CNS involvement
Philadelphia chromosome (Ph+) very high risk to relapse
Treatment: (over all period is 2.5 years)
Induction (induction of remission) typically last 28 days.
Consolidation phase (post-induction phase)
CNS prophylaxis
Maintenance treatment/phase (2 years)
13.
14. 1. Induction phase
3-4 weeks (28 days)
Goal is complete remission (blasts < 5%, normal Hb and plt)
Corticosteroids, vincristine, and various asparaginase
products come closest to this ideal in terms of activity,
primarily against lymphocytic leukemia (these agents are
selectively toxic to the leukemia cells while sparing normal B.M
elements)
CVP other option
Plus
MTX 12 mg IT day 1,15, 29 (CNS therapy)
Supportive bld, plt, antibiotics
Vincristine reduce GI motility stool softener
Dexamethasone behaviour disturbance ; sleep
disturbance, depressed mood, listlessness
Promethazine (PO)
15.
16. Asparaginase S.E:
Acute pancreatitis
Hyper sensitivity reaction (20-35%), IgG mediated.
(Anaphylactoid rxn less common with IM
administration)
Thrombotic events
17.
18. Early response, (measured by either clearance of blasts
from the peripheral blood or morphologic bone marrow
remission e.g.,<5% bone marrow blasts) on day 7 or
14 of therapy, is predictive of long-term disease-free
survival.
The rapid of response; marker of treatment sensitivity.
Children who were slow responders were 2.7 times
more likely to have a relapse than those with more
rapid clearance of blasts.
19. CNS prophylaxis
IT chemotherapy
Prevent CNS relapse.
MTX alone
Triple IT (MTX, cytarabine, Hydrocortisone)
WARNING:
Administration of vincristine into IT space is fatal.
IT MTX acute arachnoiditis 12-24 hr after injection
(N,V, headache)
20. 2. Consolidation phase
Usually uses combination approaches that are somewhat
different than induction therapy
Designed to kill leukemia cells in the cell cycle that were
not destroyed by induction therapy.
Prevent relapse
Produce event-free survival (80% in low risk pt.)
2-6 week treatment cycle.
21. Eg. For consolidation regimen:
Methotrexate 1 g/m2 IV for 24 hours, every 3 weeks ×
6 doses
Vincristine 1.5 mg/m2 IV on weeks 8, 9, 17, and 18
Prednisone 40 mg/m2 PO daily × 7 days, weeks 8 & 17
Vincristine 1.5 mg/m2 IV on days 0, 10, 20, 30, and 40
Dexamethasone 10 mg/m2 PO daily, days 0–7, 14–20
Vincristine 1.5 mg/m2 IV on days 0, 7, and 14
PEG-asparaginase 2,500 units/m2 IM on day 3
Doxorubicin 25 mg/m2 IV on days 0, 7, and 14
22. 3. Maintenance treatment (2 years)
Less intensive than previous phases.
Longest phase
Goal: sustains the complete remission achieved from
induction chemotherapy
Consists mostly of continuous oral chemotherapy with
infrequent intravenous and CNS therapy.
Most effective drugs: MTX , Mercaptopurine
Methotrexate: Methotrexate is most effective and least
toxic when administered intermittently, in oral doses of
20 mg/ m2 /week
Mercaptopurine is effective and well tolerated orally
when dosed daily, usually at a dose of 50 to 75 mg/ m2
/day.
23. Appears suddenly and progresses rapidly.
Death as a result of infection or bleeding within weeks
to months if pt. is not effectively treated
Most common acute leukemia in adults (80% of cases).
< 10% of acute leukemias in children younger than 10
years of age.
The incidence increases with age ( 1.3 cases/ 100,000
for those <65 and 12.2 cases/100,000 > 65 years)
At age 40 years, there is only 1 case of AML per
100,000, but the annual incidence increases to 15% at
age > 75 years
Male to female ratio 5: 3
Prognosis is directly related to age.
24. Treatment:
Induction phase
Most commonly is ‘’7+3” regimen combine a 7-day
continuous (IV) infusion of cytarabine with a short
infusion or bolus of an anthracycline (daunorubicin) given
on days 1 through 3.
Eg: Daunorubicin 90 mg/m2/day on days 1 to 3 as an IV bolus
injection, plus cytarabine 100 mg/m2/day as a continuous IV
infusion on days 1 to 7.
Continuous infusions of cytarabine are preferred/higher
response rates.
60%-80% of adult pts. attain complete remission
Median duration of remission ONLY 12-18 months
25. 20-40% of pts has DFS exceeding 5-years
Complications of induction: TLS, Myelosuppression
Very high WBC bld hyperviscosity (ringing ears, stroke,
headache, …)
Give hydroxyurea 2-4 g PO/ leukapheresis
If plt < 10,000 cells/ml plt transfusion every 2-3 days
Hg < 8 mg/dl give packed RBC transfusion
26. Consolidation phase
High-dose cytarabine has been the consolidation
chemotherapy of choice for younger patients with good
intermediate risk disease.
HiDAC alone (>1g/ m2 /day) or in combination with
other agents such as an anthracycline or etoposide.
Patients (60 to 75 years of age):
most clinicians will base induction and consolidation
therapy recommendations on a patient’s performance
status, patient’s wishes, and prognostic factors.
S.E:
Cytarabine normal dose : myelosuppression, fever, skin
rash.
High dose cytarabine: cerebellar toxicity (ataxia), ocular
toxicity, Hand-foot syndrome = plantar-palmar
erythrodysesthesia (PPE).
27. Less than 50% of patients achieving a second remission
Median survival ranging from 3 to 12 months
If relapse salvage regimen
I. intermediate-dose cytarabine to HiDAC
II. combination regimens:
fludarabine, cytarabine, and G-CSF (FLAG)
cladribine, cytarabine, and G-CSF (CLAG)
followed by allogeneic HCT
28. The typical clinical presentation of the chronic leukemias is
an indolent course
Sing & symptoms:
40%-50% asymptomatic at presentation & are diagnosed
by routine CBC (lymphocytosis, anemia, or thrombocytopenia)
Fatigue
Weight loss
Fever
Anorexia
On physical examination: splenomegaly CML
Night sweats, painful lymphadenopathy CLL
Diagnosis: BM biopsy (hallmark Ph chromosome in CML)
translocation t(9;22) create new protein BCR-ABL
29. Characterized by unregulated stem cell proliferation in B.M
and an increase in mature granulocytes in the peripheral
blood.
Increase WBC, differential normal, splenomegaly.
50-70% pts. Present with WBC > 100,000 cells/μl
The median age of diagnosis is 50 to 60 years.
Seldom seen in paediatric.
CML accounts for 15% of adult leukemia cases.
The estimated 7- to 10-year survival rate is 80% to 85%
since the introduction of TK inhibitors (stop regulating BCR-
ABL)
Bone marrow biopsy reveals the cytogenetic hallmark of
CML (Philadelphia chromosome), >95% cases
30. The natural history of CML can be divided into 3
distinct phases:
I. Chronic phase (earliest phase)
II. Accelerated phase
III. Blast phase.
> 90% of patients are diagnosed in chronic phase
The terminal stage of CML is characterized by rapid
accumulation of blast cells in the BM(Blast crisis)
and suppression of normal hematopoiesis that
ultimately leads to death (6-months).
Most problem: Transformation into acute leukaemia
31. phases:
1. chronic phase: patients exhibit leukocytosis & associated
symptoms (described previously), <10% blasts in BM and
peripheral blood.
The duration of the chronic phase may range from a few
months to many years
2. Accelerated phase: increased blast & leukocytosis,
anemia, increased splenomegaly, fever, and bone pain.
If not treated, accelerated phase will generally progress to the
blast phase in less than 6 weeks if not treated.
3. Blast phase (blast crisis): characterized by predominance
of immature cells. Blast crisis is defined as more than
20% blasts in the peripheral blood or BM
In blast crisis, patients often experience bone pain,
fatigue, fever, infections, and bleeding complications.
This phase is often refractory to conventional induction
chemotherapy regimens for AML, (median survival is 6 months)
32. Treatment:
Allogeneic Hematopoietic cell transplantation (HCT)
remains the only curative therapy for CML to date high
risk of morbidity & mortality
TK inhibitors are 1st line therapy in most patients (not
curative)
Goals of the TK inhibitors are to prolong survival,
prevent progression of disease, & attain a complete
hematologic or cytogenetic remission.
1. Imatinib
2. Nilotinib, approved for patients with resistant Ph+
chromosome chronic- or accelerated phase CML
Patients in accelerated or blast phase at presentation or
those progressing during TK inhibitor are generally
referred for HCT (achieved a 40% and 10% 5-year,
Leukemia free survival, respectively).
33. Newly diagnosed patients who present with very high
leukocyte counts (>100,000 cells/μL), the initial goal of
therapy is to immediately reduce leukocytosis and its
related symptoms.
Hhydroxyurea is the most common agent used for
initial leukocyte reduction.
Dose is 2 g/day P, titrate the dose until leukocyte count
< 20,000 cells/ML
Use hydroxyurea 3 - 5 days before transitioning to a TK
inhibitor. (Imatinab 400mg PO daily with food)
Resistance can be seen at 6-months (rare, 15-25%), no
cytogenetic response.
In suboptimal response escalate imatinabe to 400mg
twice daily
If still no response, change to Nolitinib (400mg BID)
34. • The most common toxicities reported with imatinib
(Gleevec) are superficial edema (face, feet, hands),
nausea, muscle cramps, and rashes
• Nolotinib (Tasigna) demonstrate a higher incidence of
rash, headache, pruritus, and alopecia/hair loss and a
lower incidence of nausea, diarrhea, vomiting, edema,
and muscle spasm.
• Take Tasigna at least 1 hour before or 2 hours after
eating any food
35. IFN-α was the preferred agent in the treatment of CML.
(before TK-I)
IFN-α relegated to pts. who fail TK-I and are not
candidates for allogeneic HSCT.
Associated with both short-term toxicities and potentially
dose-limiting long-term toxicities (so limited use)
Early toxicity is a flu-like syndrome (fever, chills, myalgia,
headache, and anorexia)
Cardiovascular toxicities (tachycardia, hypotension)
15% of pts. in the first few weeks.
Long-term S.E:
weight loss, alopecia, neurologic effects (paresthesia,
cognitive impairment, depression)
immune-mediated complications (hemolysis,
thrombocytopenia, nephrotic syndrome, SLE, hypothyroidism) 5%
to 20% of patients
36. patients undergoing transplantation in the accelerated
and blast phases achieved a 40% and 10% 5-year,
leukemia-free survival, respectively.
For those who relapse after HCT, initiation of a TK
inhibitor has improved long-term outcome
37. Mature but not functional lymphocytes.
The most common type of leukemia in adults
Annually, 15,000 new cases and 4,400 deaths
CLL is a disease of the older population
90% of patients > age 50 at diagnosis (median age at
diagnosis is 65 years).
Characterized by overproduction of functionally
incompetent B-cell lymphocytes derived from a single stem
cell clone in B.M
These lymphocytes accumulate in the blood, B.M, lymph
nodes, and spleen.
Some patients experience an indolent course & maintain
good QoL , others experience more aggressive disease and
weakness.
38. 40% of patients are asymptomatic at presentation
Diagnosed by routine CBC (lymphocytosis, anemia, or
thrombocytopenia).
Usually, patient will seek medical check for infection, bleeding……
Symptomatic patients commonly experience:
Night sweats
Fatigue,
weight loss,
Fever
Painful lymphadenopathy
Survival is variable/ depends on the stage of disease at diagnosis.
CLL is staged based on peripheral lymphocyte counts;
enlargement of lymph nodes, liver, and spleen; and the presence
of anemia or thrombocytopenia.
39. Stages: (Binet classification)
Stage A: no need to treat (watch-wait).
Stage B: depends on symptoms.
Stage C: Needs to treat.
Stage Lymphocytosis
(>5000 cells/μl)
Thrombocyto
penia
(<100,000)
Anaemia
(<10g/dl)
L.Ns
involve
Medium
Survival
A + _ _ <3 12 years
B + _ _ ≥3 7 years
C + + + Any 2-4 years
40. Treatment (stage C):
1. Alkylating agent (oral chlorambucil or
cyclophosphamide) +/- prednisone
chlorambucil +/-prednisone is recommended for patients
older >= 70 years, or in younger patients if they have
significant comorbidities
2. Fludarabine is now considered the single most active
agent in the treatment of CLL.
Fludarabine monotherapy ( dose range of 25 to 30
mg/m2/dose IV × 5 days), or with cyclophosphamide
and rituximab to increase the response .
Fludarabine my have improved OS compared with
chlorambucil
Fludarabine S.E: Typically mild include fever and
immunosuppression. Increased incidence of infection
and autoimmune hemolytic anemia can occur.
41. 4. Rituximab:
Anti-CD 20
The CD20 surface antigen is expressed on a high
percentage of CLL cells.
Rituximab monotherapy is reserved for patients with
significant comorbidity. (375 mg/m2 weekly, for 4
doses)
Generally it is used in combination therapy with
cytotoxic agents
4. Combination therapy:
FC-R:
Fludarabine 25 mg/m2 IV on days 1 to 3,
cyclophosphamide 250 mg/m2 IV on days 1 to 3
rituximab 375 mg/m2 IV on day 1 of cycle.
FCR is recommended in patients younger than 70
years without significant comorbidities.
42. Indications for treatment initiation in CLL include:
significant anaemia or thrombocytopenia
progressive disease: demonstrated by
lymphadenopathy, hepatomegaly, splenomegaly, a
lymphocyte doubling time of less than 6 months
Persistent B symptoms (fever, night sweats, and weight
loss)
Threatened end-organ function
Recurrent infection.
43. Refractory/ Relapsed CLL
Classified as treatment-sensitive if the disease
relapses > 3 years after treatment, or refractory if the
disease relapses within 2 years of treatment
Treatment-sensitive: Same as treated before, unless
became >70 years or with significant comorbidities.
Treatment refractory: add at least one anti-cancer
agent did not used before.
Eg:
FCR + other agent
If > 70 with comorbidities : high dose
methylprednisolone + Rituximab OR chlorambucil+
prednisolone
44. Acute VS. Chronic leukaemia:
Acute Chronic
Age All ages Usually adults
Clinical onset Sudden Insidious
Grow grows & progress very
fast
More indolent/slow
Course (untreated) < 6-month 2-6 years
Leukemic cell Immature blast >20% More mature cells
Anaemia Prominent Mild
Thrombocytopenia Prominent Mild
Lymphadenopathy/
Splenomegaly
Mild Often prominent