2. Hematologic Malignancies
2
Cancers arising from hematopoietic cells and
lymphoid tissue are termed “hematologic
malignancies,” and include:
Leukemias
Lymphomas
Multiple Myeloma (Plasma cell disorders) and
Myeloproliferative disorders
3. Cont.……
3
Relative to solid tumors:
HMs are less prevalent.
Chemotherapy is the primary treatment for most
cases of HMs because they are usually
disseminated at the time of diagnosis.
The growth rate of most HMs is rapid and
aggressive
Combination chemotherapy regimens can provide
high response rates and cures.
Complex supportive care regimens are often
needed in conjunction with chemotherapy because
of multiple disease symptoms and toxicities with
4. LEUKEMIAS
4
Leukemias are heterogeneous hematologic malignancies
characterized by unregulated proliferation of blood-
forming cells in the bone marrow.
These immature leukemic cells (blasts):
o physically “crowd out” or inhibit normal cellular
maturation in BM, resulting in anemia, neutropenia, and
thrombocytopenia.
o Then after it Infiltrate a variety of tissues like lymph
5. ALL MM
CLL Lymphomas
Hematopoietic
stem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor
Myeloproliferative disorders
AML
Lymphoid
progenitor T-lymphocytes
Plasma
cells
B-lymphocytes
naïve
6. 6
Acute leukemia is characterized by the expansion
and differentiation arrest of immature hematopoietic
cells.
If the blasts have lymphoid features, the leukemia is
classified as acute lymphocytic leukemia (ALL).
If the blasts have myeloid features, the leukemia is
classified as acute myeloid leukemia (AML).
7. 7
Chronic leukemias follow a more insidious onset
and course than acute leukemias and are
associated with proliferation of more mature
hematopoietic cells.
Chronic lymphocytic leukemia (CLL) is xized by
overproduction of mature lymphocytes.
Chronic myeloid leukemia (CML) is associated
with overproduction of mature neutrophils or
8. 1. Acute leukemia
8
Acute leukemia differences from chronic leukemia in that:
Immature cell and large number of blast cells
Appears suddenly and progressive rapidly
Death due to infection or bleeding occurs within weeks to
months if the patient is not effectively treated.
AML accounts for most cases of acute leukemia in
adults, and occurs with increasing frequency in elderly
pts.
The average age of diagnosis for:
AML is about 65 yrs, and
9. Etiology
9
The exact cause is unknown.
Multifactorial factors: genetics, drugs & chemicals,
environmental and socioeconomic factors, toxins,
immunologic status, and viral exposures (EBV)
Drugs: Alkylating agents
Chemical: benzene, pesticides
Ionizing radiation: cigarette smoking, maternal marijuana
use or ethanol use.
10. Pathophysiology
10
AML probably arises from a defect in the
pluripotent stem cell or a more committed myeloid
precursor.
ALL is cxized by proliferation of immature
lymphoblasts.
Defect in lymphopoietic stem cell or very early
lymphoid precursor.
12. Clinical presentation
12
Clinical Presentation of AML and ALL
Pts may have vague symptoms for 1-3 mths prior to
presentation.
Pts generally are in no obvious distress.
Symptoms
Weakness, malaise, bleeding, and weight loss
Neutropenia (febrile and infection)
Anemia (fatigue, pallor, tiredness)
13. 13
* Gum hypertrophy is indicative of AML M4 and M5
subtypes.
*Disseminated intravascular coagulation (DIC) is common
in AML M3
Lymphadenopathy, massive hepatosplenomegaly
(infiltration of leukemic cells), and bone pain
common in ALL
CNS involvement is common at diagnosis for ALL
15. Case
15
MV is a 8-year-old boy who presents to the pediatric
emergency department with his father with a history of
aches, chills, and fevers for the past 4 to 5 days. He has
had
several colds over the past few weeks that do not seem
to be improving. He has also had bone pain in his legs
over the past couple of weeks. Physical examination
reveals pallor, cervical lymphadenopathy, and
16. 16
Electrolytes and uric acid are within normal limits. A CBC
shows a normochromic, normocytic anemia with a
hemoglobin of 7.0 g/dL hematocrit of 21% and WBC
count of 2.1 × 103/mm3, Platelet count 35,000. Flow
cytometry from the peripheral blood is consistent with
pre–B-cell ALL
What information is consistent with the diagnosis of
ALL?
17. 17
MV is admitted to the pediatric oncology service. A bone
marrow biopsy and aspirate is done, which shows 85%
replacement with precursor B-cell blasts. FISH analysis
performed on the peripheral blood is positive for the BCR/
ABL translocation (Ph+) in 5.5% of the cells examined. He is
started on intravenous hydration with sodium bicarbonate
and allopurinol. A diagnostic lumbar puncture (LP) is performed,
which is negative for CNS leukemia. During the LP, MV receives
interathecal cytarabine.
1.What is the role of CNS prophylaxis for MV?
2. What is the BCR/ABL translocation? How does the presence of
this chromosomal abnormality change MV’s risk status?
18. Diagnosis of AML and ALL
18
Laboratory Tests
CBC with differentials
Normochromic and normocytic anemia
Platelet count <50,000 (in > 50% of children)
WBC will be normal, decreased or increased
Uric acid is increased (secondary to rapid cellular
turnover)
Electrolyte: (K & P often are elevated, Ca usually low)
19. 19
Other Diagnostic Tests
Bone marrow aspirate and peripheral blood:
morphologic examination, immunophenotyping (flow
cytometry), and cytogenetic (chromosome) analysis
(FISH analysis).
At diagnosis, a lumbar puncture is performed to
determine if CNS leukemia is present.
21. Treatment
21
Goal of therapy of ALL and AML
To achieve complete and continuous remission (CCR).
Initially, the goal is to rapidly achieve a complete clinical
and hematologic remission (CR).
CR is defined as the disappearance of all clinical and
bone marrow evidence (with <5% blasts) of leukemia,
with restoration of normal hematopoiesis.
After a CR is achieved, the goal is to maintain the patient in
continuous CR.
22. Treatment of ALL
22
The treatment for ALL consists of three main
elements:
Remission induction
Intensification (consolidation), and
Continuation (maintenance) phases
Therapy to eradicate subclinical CNS leukemia
is also a mandatory component of therapy for
ALL.
23. 23
Primary objective of treatment is to eliminate all
morphologic evidence of dx and restore normal
hematopoiesis.
The CR rate is 98% for standard-risk
Induction consists of standard three-drug regimen:
Glucocorticoid (prednisone or dexamethasone)
Vincristine, and L-asparaginase (up to 30% of patients
develop a treatment-limiting hypersensitivity reaction) or
pegylated asparaginase ( to decrease immunogenicity).
For pts with high risk ALL, daunorubicin is added to the
Remission Induction
24. 24
Asparaginase
The rationale behind asparaginase is that it takes advantage
of the fact that ALL cells are unable to synthesize the non-
essential amino acid asparagine, whereas normal cells are
able to make their own asparagine; thus leukemic cells
require high amount of asparagine.
These leukemic cells depend on circulating asparagine
Asparaginase, however, catalyzes the conversion of L-
asparagine to aspartic acid and ammonia.
This deprives selectively leukemic cell of circulating
25. 25
Consolidation therapy in ALL is started after a CR has
been achieved
The goal of intensification is to further reduce the
burden of clinically undetectable (residual leukemic
cells)
Important for prevention of relapse in children with
ALL
Regimens usually incorporate:
Either non–cross-resistant drugs that are different
from the induction regimen, or
Intensification (Consolidation)
26. Cont.… Case
26
MV begins induction therapy with vincristine,
prednisone,
daunorubicin, and asparaginase. According to his
protocol,
he will begin Imatinib in the middle of his induction
treatment, on day 15. MV has a bone marrow on day 29
showing a morphologic remission, and on day 29
was less that 0.1% blasts. He is now ready to begin
consolidation.
What is the role of Imatinib for Ph+ ALL?
27. 27
Standard consolidation lasts 4 weeks and usually
consists of vincristine, mercaptopurine, and
intrathecal methotrexate.
Children with testicular disease usually receive
radiation during this phase of therapy if a complete
clinical response in the testes is not achieved by the
end of induction.
Imatinib has been incorporated into consolidation
28. Continuation (Maintenance)
28
The goal of maintenance therapy is to further
eradicate residual leukemic cells and prolong
remission duration.
The two most important agents in maintenance
chemotharpy are a combination of weekly oral
methotrexate and 6-mercaptopurine.
The optimal duration of maintenance therapy in both
children and adults is unknown, but most regimens
29. CNS Prophylaxis
29
The goal of CNS prophylaxis is to eradicate
undetectable leukemic cells from CNS while
minimizing neurotoxicity and late effects.
Leukemic meningitis is more easily prevented than
treated.
Once CNS relapse has occurred, patients are at
increased risk of BM relapse and death from
refractory leukemia.
30. 30
Hence, CNS prophylaxis is necessary in any treatment
regimen for ALL.
CNS prophylaxis relies on:
Intrathecal CT (methotrexate, cytarabine, and
corticosteroids)
Systemic CT with dexamethasone and high-dose
methotrexate, and
Craniospinal irradiation (XRT) in selected high-risk
31. Treatment of relapsed ALL
31
Approximately 20% of children with ALL will relapse.
The most common site for relapse is the bone marrow
(53%), although isolated relapses can occur in CNS
(19%) or testicles (5%), in addition to multiple sites of
disease.
Children who fail to achieve a CR by day 29 of
induction therapy at initial diagnosis receive an
additional 2 weeks of four-drug induction therapy.
32. Treatment of AML
32
As with ALL, the primary aim in treating pts with AML is
to induce remission and there after prevent relapse.
Treatment of AML, unlike that of ALL, usually only
consists of:
induction and
intensive post-remission therapy
CNS prophylaxis is not routinely given to patients with
AML.
33. Remission Induction
33
The goal is to “Empty” the BM of all hematopoietic precursors,
and allow repopulation with normal cells.
The combination of an anthracycline (e.g., daunorubicin,
doxorubicin, or idarubicin) and the antimetabolite cytarabine
forms the backbone of AML induction therapy.
The most common regimen (7+3) combines daunorubicin
administered as a short infusion of 45 to 60 mg/m2/day on
days 1 to 3, along with cytarabine administered as a
continuous 24-hour infusion of 100 to 200 mg/m2/day on
34. Post-remission Therapy
34
Once an initial remission is achieved, further intensive
therapy is imperative to prevent relapse.
Induction therapy fails to provide adequate cell kill, and
leukemia cells survive the initial treatment.
Three options available for pts:
High dose CT,
Allogeneic BM transplantation, and
Autologous BM transplantation
High-dose cytarabine is a key part of post-remission
35. 35
Monitor remission status following induction phase
Monitor side effect of the treatment
a patient is considered to be "cured" after being in
continuous CR for at least 5 years.
Current regimens induce clinical remission in 96% to
99% of children with ALL.
Outcome evaluation
36. Chronic myelogenous leukemia
(CML)
36
The clinical course of CML has three
phases:
Chronic phase (<10%) blasts in peripheral blood
or bone marrow)
Accelerated phase (transition) phase (10%-19%)
blasts in peripheral blood or bone marrow
Blast crisis phase (>20%) blasts in peripheral
blood or bone marrow)
- similar to acute leukemia
37. 37
Chronic phase:
Nearly 90% of patients present with chronic phase at
the time of diagnosis.
Bone marrow hyperplasia and accumulation of
differentiated myeloid cells in the peripheral blood
are the initial presenting features of the disease.
38. 38
Accelerated phase is characterized by progressive
myeloid maturation arrest and loss of efficacy of drug
therapy directed to attenuate the increase in WBC.
Clinical findings of AP include anemia, increasing
peripheral blood and bone marrow blasts and basophils,
extra-medullary disease sites (bone, breast, CNS, mucosal
tissue, lymph nodes, and skin), exacerbation of
splenomegaly, and either thrombocytosis or
thrombocytopenia.
39. 39
Blast crisis is the terminal stage of CML develops
over a period of years and is characterized by rapid
accumulation of blast cells in the bone marrow and
suppression of normal haematopoiesis that will
ultimately become fatal.
Clinically resembles acute leukemia
>20% blasts in the peripheral blood or bone marrow, extra-
medullary disease, or large clusters of blasts in the bone
40. 40
Risk factors CML
Ionizing radiation and
Heavy occupational exposure to benzene
Pathophysiology
Genetic and molecular abnormality in Philadelphia
chromosome (Ph) is specifically implicated in the
pathogenesis of CML.
The Philadelphia chromosome (Ph) codes for the
BCR-ABL oncogene. The Ph is the consequence of
breaks in chromosomes 9 and 22 resulting in a
transposition.
Risk factors
41. Clinical Presentation of CML
41
General
90% of pts are diagnosed in chronic phase
50% are asymptomatic in chronic phase and often
diagnosed following abnormal CBC
Signs and Symptoms
Fatigue
Left upper quadrant pain
Abdominal pain or distension
Weight loss
Night sweats
42. Diagnosis
42
Physical Examination
Hepatosplenomegaly
Laboratory Tests
Peripheral blood
Leukocytosis (most present with WBC count more than
100 × 103/mm3), , thrombocytosis, basophilia
Low or undetectable leukocyte alkaline phosphatase (ALP)
Elevated uric acid and lactate dehydrogenase (LDH)
Molecular testing
Presence of BCR-ABL by reverse-transcription PCR
43. 43
Bone marrow
• Hypercellular
• Fully mature myeloid cells
• Increased megakaryocytes
• <10% blasts in chronic phase
Cytogenetics
• Presence of the Ph chromosome
Diagnosis
44. Case on CML
44
KC is a 32-year-old man who presents to his ophthalmologist
with complaints of blurry vision when looking at a distance. KC’s
medical history consists of GERD treated with twice daily
famotidine and bipolar depression treated with ziprasidone. An
eye examination reveals retinal infiltrates. A CBC is drawn and
shows the following:
total WBC: 225 × 103/mm3, (4% [0.04] blasts, HgB: 8.3 g/dL (83
platelets: 65 × 109/L). KC is referred to an oncologist for further
workup
45. Cont.….
45
A bone marrow biopsy is performed and reveals
hypercellular marrow with 13% (0.05) blasts. FISH
analysis is positive for Ph.
1. What are the first-line treatment options for chronic
phase CML patient?
2. Which specific treatment do you recommend for this
patient and why?
3. Identify your treatment goals for this patient?
46. Treatment of CML
46
The goal in the treatment of CML is eradication of the Ph
clone.
Most pts will initially be placed on imatinib therapy
More than 85% of pts will achieve a complete
cytogenetic response on imatinib and will remain on
imatinib until dx progression
A small percentage of pts will choose allogeneic HSCT,
which is the only treatment shown to permanently
47. 47
Three types of treatment responses for CML are
described:
Hematologic: normalization of peripheral blood counts
and is the earliest type of response.
Cytogenetic responses: are based on the percentage
of cells positive for Ph in the BM
Complete cytogenetic remission defined as the elimination
of Ph and
Major cytogenetic response defined as fewer than 35% Ph-
positive cells.
48. Conventional Chemotherapy
48
Conventional cytotoxic CT can be used in chronic-
phase CML to reduce high circulating WBCs, but
has only modest effects on median survival.
Agents used to normalize WBCs are busulfan and
hydroxyurea.
Hydroxyurea rapidly lowers high circulating WBCs
in chronic phase CML.
49. 49
Hudroxyurea 1000mg initiated and will be continued
until the WBC count falls to approximately 10,000
cells/mm3.
Hydroxyurea may be discontinued once adequate
control of the WBC count is achieved and imatinib
has been initiated.
Imatinib is emerged as the drug with the best oral
bioavailability and high binding affinity for the BCR-
50. CHRONIC LYMPHOCYTIC LEUKEMIA
(CLL)
50
CLL is a lymphoproliferative disorder characterized
by accumulation of functionally incompetent clonal B
lymphocytes
CLL is a dx of the elderly, with a median age of onset
between 65 & 75 yrs although 20% to 30% of CLL
occurs in patients who are younger than 55 years of
age.
51. 51
Risk factor:
Occasional family clusters have been recognized,
and first-degree relatives of patients with CLL are at
3x the risk of developing a lymphoid malignancy as
compared with the general population.
52. Pathogenesis
52
CLL cells are believed to be a neoplastic clone of CD5+
cells, which express low levels of surface-membrane IgM
and IgD compared to normal peripheral blood B cells.
Normal CD5+ B lymphocytes are present in the lymph
nodes and in the blood.
Cytogenetic abnormalities correlate with disease
progression in CLL.
The chromosomes that are most frequently involved include
chromosomes 13, 12, 11, and 17.
55. Staging and Prognosis
55
Survival times for pts with CLL are widely variable, with
some pts dying within 2 years and others living two
decades from the time of diagnosis.
Prognosis depends on:
Stage and tumor burden at diagnosis
Presence of biomarkers: ZAP 70 mutation or 17P-
Low risk (stage 0)
Intermediate risk (stage I & II)
High risk (stage III & IV)
Based on the prognostic factors
56. Treatment of CLL
56
CLL is considered to be an incurable dx, thus primary goals
of treatment are to improve quality and duration of life.
The decision to begin treatment is based on:
Age of the patient, symptoms, aggressiveness of the tumor,
and high risk molecular features.
Most stage 0 pts do not require treatment and can be
managed with observation.
57. 57
In pts with stage I or II dx, treatment is
controversial.
• Therapy should be considered in pts with
symptomatic disease.
• In stages III and IV disease, treatment is required,
with the goal of achieving a partial or complete
remission.
Treatment of CLL
58. 58
Oral Chlorambucil alone or with corticosteroids ( e.g
prednisolone)
Oral cyclophosphamide alone or with corticosteroids (
e.g prednisolone)
Fludarabine + cyclophosphamide
Fludarabine +rituximab
Fludarabine +cyclophosphamide +rituximab
Alemtuzumab alone or with fludarabine
CT options for CLL
59. 59
Patients may become hypogammaglobinemic as a
consequence of disease progression or treatment
will need routine monitoring of serum IgG.
If the serum IgG falls below 5 g/L, then monthly
replacement doses of 300 to 500 mg/kg of
intravenous immune globulin is warranted.
Evaluation of therapy for CLL
There is no tumor in leukemia so it is cancer of blood cells
Multiple myeloma (MM) is a malignancy of plasma cells or immunoglobulin-producing B lymphocytes the presence of an abnormal proliferation of myelopoietic cells (from bone marrow)
Leukemia affects the blood, bone marrow, and lymphoid system but it originates from the bone marrow.
physical discomfort
the detection of tumour cell DNA aneuploidy, the analysis of tumour cell proliferation and the immunophenotyping of leukemias.
Fluorescence in situ hybridization (FISH): to visualize and map the genetic material in an individual's cells, including specific genes or portions of genes
cyclophosphamide, methotrexate, or cytarabine can also be added in place of daunorubicin
Maintenance therapy usually consists of daily mercaptopurine and weekly methotrexate for 12-week courses, at doses that produce relatively little myelosuppression, with monthly "pulses" of vincristine and a steroid for 5 days per month.
Intrathecal therapy consists of methotrexate and cytarabine, given either alone or in combination. When given together, hydrocortisone is commonly added (triple intrathecal therapy) to decrease the incidence of arachnoiditis.
Swollen lymph nodes
low risk (stage 0), intermediate risk (stages I and II), and high risk (stages III and IV) with median survivals of greater than 10 years, 7 years, and 2 to 4 years, respectively.