NEOPLASTIC DISEASES OF

THE BLOOD

Dr. Ma. Luisa D. Concepcion

 LEUKEMIAS

 Neoplastic expansion of mature or

immature cells in the blood and marrow
 Classification

A. Natural history  Acute (immature)

Chronic (mature)
B. Cell type  Myelogenous
Lymphocytic
Etiology of Leukemias

A.Radiation
(high doses)  genetic damage
immunosuppression
B. Chemicals - e.g benzene, alkylating agents
C. Viruses - HTLV I & II
D. Hereditary influences – may inc. risk
e.g. Trisomy 21, Fanconi’ anemia,
LEUKEMOGENESIS Defective
Maturation &
Transformation Event Differentiation

(initiation, promotion, progression)

Normal
Malignant
Progenitor
Progenitor

Uninhibited Cellular
Replication & Expansion
A. ACUTE LEUKEMIAS
Clinical Course :

- 25 % AML pts. (+) for MDS (mos to yrs)

- Manifestations (< 3 mos.)
* Pallor, easy fatigue, exertional dyspnea
(anemia)
ACUTE LEUKEMIAS
* Bleeding diathesis ( thrombocytopenia +/-
coagulation defect )
* Cough, dysuria etc… - prone to infections
(leucopenia +/- leukocyte dysfunction)
 ACUTE LEUKEMIAS

* Bone pains, sternal tenderness,

lymphadenopathy, organomegaly (leukemic
infiltration; ALL) .
* Testicular enlargement
 ACUTE LEUKEMIAS
* Chloromas
* Headache, cranial nerve palsies, seizure
(leukemic infiltration of subarachnoidspace)
* Fever / weight loss (hypercatabolic state)
* Hyperuricemia (rapid cell turnover)
 ACUTE LEUKEMIAS

Diagnosis:
* Clinical manifestations
* 20 % or more bone marrow blasts (morphology,
cytochemical, immunophenotyping, molecular).
 FAB Classification of AML
M0 Undifferentiated / minimally differentiated
M1 AML (-) differentiation (20 %)
M2 AML (+) differentiation (30 %)
M3 APL (5 %)  assoc w/ DIC
M4Eo Variant
M4 AMMoL (30 %)  assoc w/ tissue
M5 AMoL (10 %) infiltration
M6 Erythroleukemia or Di Guglielmo’s Disease (5 %)
M7 Acute Megakaryoblastic Leukemia (5 %)
*prominent marrow fibrosis

WHO Classification Harrison’s 16th ed p.632 table 96-1.

FAB Classification of ALL

L1 Homogenous small blasts

L2 Heterogenous blasts
L3 Burkitt-like blasts

* Biphenotypic Leukemia
SIGNS IN POOR PROGNOSTIC ADULTS

ALL AML
*Older age * Older age (> 60 yrs)
* Male * Chromosomal abn.
* Leukocytosis * M4, M5 subtype
* Organomegaly * Secondary AML
* Bleeding diathesis
* CNS involvement
* Longer time to CR
 TREATMENT OF ACUTE LEUKEMIAS
A. Standard Chemotherapy
* Stages
1. Induction of Remission
- leukemic cells below detectable level.
2. Consolidation / Intensification
- to further leukemic cell mass
3. Maintenance
4. CNS Treatment / Prophylaxis
- Intrathecal vs. Craniospinal irradiation
 TREATMENT OF ACUTE LEUKEMIAS
B. Supportive
- Antibiotics, transfusions, correction of
metabolic problems.
C. Hematopoietic Stem Cell Transplant
( Bone Marrow vs Peripheral Blood )
1. Allogeneic
2. Autologous
 B. CHRONIC HEMATOPOIETIC MALIGNANCIES

Chronic Myeloid Chronic Lymphoid

Malignancies Malignancies
* Myeloproliferative Disorders •CLL
1. CML 3. IMF • HCL
2. PV 4. ET • Sezary Syndrome/
*aCML Mycosis Fungoides
*CMMol • Lymphomas
*CNL 1. HD
*CEoL 2. NHL
*CBL * Plasma cell myeloma
*CBF
 Chronic Myelogenous Leukemia
 Clonal hematopoietic stem cell disorder
 1.3/100,000 ; M:F = 1.7:1 ; 4th-6th decade
 Characteristics : Marked splenomegaly

Panmyelosis in PB & BM
Ph 1 (+)
 Triphasic course : AML
Chronic stable  Accelerated  Blastic
ALL
 Chronic Myelogenous Leukemia
Ph 1 -
Reciprocal t : BCR-Abl
Chr 9 (Abl) &  fusion gene  p 210
Chr 22 (BCR) t(9:22)q34;q11
Tyrosine kinase
actvity

LAP Score = or nil

 Chronic Myelogenous Leukemia

Treatment:
• IFN alpha +/- Ara C or HU

• Imatinib (STI 571;Gleevec)

• HSCT
 Chronic Myelogenous
Leukemia
 Supportive :
 Allopurinol, Transfusions,

Leukopheresis , antibiotics.
 *Blastic crisis – treat as acute leukemia
 *Splenectomy (limited)
 Polycythemia Vera

 A clonal disorder of MPSC  panmyelosis

(-) stimulus
 Most common CMPD (2 / 100,00)
 Gradual onset; chronic, slowly progressive
course.
 Polycythemia Vera
 M:F = 2;1 ; > common in elderly but
may be seen in younger age group.
 Etiology ?, PV erythroid precursors
over express Bcl-xl (anti –apoptotic
protein).
 Clinical Manifestations of
Polycythemia Vera

• Erythrocytosis  hyperviscosity  Poor CNS &

CP circulation  Phlethora, headache, dizziness,
visual, alterations, tinnitus, dyspnea, angina.
2. Myeloproliferation  organomegaly  early
satiety, abdominal fullness.
Clinical Manifestations of Polycythemia Vera

3. Thrombocytosis, +/- platelet dysfunction

Thrombo-hemorrhagic complications :
bleeding PU, CVD, Budd Chiari,
digital ischemia / erythromelagia
Clinical Manifestations of
Polycythemia Vera
4 Hypermetabolic state  Arthralgias,
fever, weight loss.

5 Histamine release  Aquagenic

pruritus , PUD
 Diagnostic Criteria for
Polycythemia Vera
Category A Category B
M1 - Total rbc mass m1 - Thrombocytosis
Male 35 cc/kg & > > 400,000/cu.mm

Female 32 cc/kg & > m2 - Leukocytosis

M2 - Arterial O2 sat 92 %
&>
M3 – Splenomegaly
* PV
All 3 in category A present
> 12,000/cumm
m3 - LAP score > 100
m4 - Serum B12 conc.
> 900 pg or B12
binding capacity
> 2.000 pg/ cc
 Secondary Erythrocythosis

a. Physiologic (dec tissue O2)

COPD, R L shunts, high altitudes,
Hgb-O2 dissociation abn. (hemo -
globinopathy, carboxyhemoglobin)
b. Abn. Inc. in EPO w/ normal tissue O2
Renal diseases, hepatoma, uterine
leiomyoma, cerebellar hemangioblastoma
c. Relative (pseudo or spurious)
Stress
 Polycythemia Vera
Treatment

1. Phlebotomy
- hyperviscosity;
- MS to 10 - 12 yrs vs. 2 yrs w/o.
- Preferred regardless of etiology of erythrocytosis
sp. young patients w/ mild disease.
< 50 yrs (-) hx of thrombosis - 450 cc EOD
> 70 yrs w/ CVS disease - 250 cc bi-weekly
 Polycythemia Vera
Treatment

2. Myelosuppressive agents – best for pts w/ :

a. Symptomatic thrombocytosis /
hypermetabolism.
b. Rapidly enlarging spleen.
c. History of thrombosis (sp. If elderly)
* incidence of sec. malignancies ( > 10 %)
 Polycythemia Vera
Treatment

3. Allopurinol
4. Antihistamines
ASA ?
 Polycythemia Vera

 Morbidity/ Mortality
1. Thrombosis
2. Hemorrhage
3. Dev’t. of Acute Leukemia & other
malignancies
4. Marrow failure  spent phase
 Agnogenic Myeloid Metaplasia with
Myelofibrosis ( AMMMF )

 Extramedullary hematopoiesis
hypocellular / fibrotic marrow
 0.5 : 100,000 ; M: F = 1.2:1 ; Median age 60 yrs. @ dx.
 ? etiology ; exposure to petroleum derivatives
(benzene , toluene )
 Agnogenic Myeloid Metaplasia with
Myelofibrosis ( AMMMF )
 Gradual, chronic but progressive course

marrow failure (transfusion dependent )

+
organomegaly.

 Prone to infections (sp. Pulmonary)

 Agnogenic Myeloid Metaplasia
with Myelofibrosis ( AMMMF )
 Fibrosis is reactive & not part of abn. clone.
 PDGF is inappro. released  B. M. fibroblast
stimulation  fibrosis.
 Excess of TGF B - > potent mediator of
collagen accumulation.

*Secondary causes of myelofibrosis Harrison’s 16th

ed. Table 95-3, p. 629
 Agnogenic Myeloid Metaplasia
with Myelofibrosis ( AMMMF )
Manifestations :
1. Myeloproliferation  Hepatosplenomegaly
2. Cytopenias  fatigue, pallor, bleeding,
suceptability to infections
3. Hypercatabolism  night sweats, fever,
weight loss.
4. Leukemic transformation ( 0 – 15 % )
 Agnogenic Myeloid Metaplasia
with Myelofibrosis ( AMMMF )
 PB smear : leukoerythroblastosis
 MS up to 7 yrs fr. dx. (low risk grp);
(+) anemia +/- / wbc = 1 yr.
 30% of cases with a prior MPD
 Major causes of death: CHF, RF, hge, portal
hpn ( sec. to hepatic fibrosis & splenic BF).
 Agnogenic Myeloid Metaplasia
with Myelofibrosis ( AMMMF )
 Treatment :
1. Hydroxyurea
2. Androgens / Epo
3. Steroids
 Agnogenic Myeloid Metaplasia
with Myelofibrosis ( AMMMF )
3. Splenectomy* / splenic irradiation – for
splenic infarction; hypersplenism
4. Supportive - transfusions; allopurinol
5. HSCT – younger pts.
 Essential Thrombocythemia

 2.5 / 100,000 ; M > F ; Median age @ dx : 60 yrs

 25 % asymptomatic @ dx, (+) thrombocytosis .
 S/sx : 1. Arterial / venous thrombosis : eg TIAs
( headache , dizziness, neuro deficits);
PE (tachypnea); digital ischemia; etc.
2. Erythromelalgia
3. Spontaneous bleeding –rare (NSAIDs)
4. Hepatosplenomegaly
 Essential Thrombocythemia

 (+) Ineffective clearance of TPO ( sec. to c-Mpl

expression in plts. & megakaryocytes).
 Causes of thrombocytosis:

1. Clonal : MPDs
2. Non clonal : Reactive (iron def., post surgery/
trauma, bleeding, infections/inflammation, malignancy).
 Dx by exclusion
 Treatment of Essential
Thrombocythemia
* Young & asymptomatic - observe/ ffup
* To plt cts : Hydroxyurea, Anagrelide, Plateletpheresis, IFN
* ASA – high risk. Strictly avoid NSAIDs.
* Thrombo-hgic episodes w/ age (terminal event in majority).
1- 2 % risk of leukemic conversion.
CHRONIC HEMATOPOIETIC MALIGNANCIES
Chronic Myeloid Chronic Lymphoid
Malignancies Malignancies
*Myeloproliferative • CLL
Disorders • HCL
1. CML 3. IMF
2. PV 4. ET • Sezary Syndrome/
*aCML
*CMMol Mycosis Fungoides
*CNL • Lymphomas
*CEoL
*CBL 1. HD 2. NHL
*CBF
* Plasma cell myeloma
 Chronic Lymphocytic Leukemia

 # of mature lymphocytes (CD 5 B cells 95%) in PB

& BM.
 M>F
 Asymptomatic or +/- pallor, signs of bleeding, infection
lymphadenopathy, splenomegaly,
 May progress to aggressive type of lymphoma

(Richter’s syndrome)
 Chronic Lymphocytic Leukemia
Diagnosis
 The International CLL Workshop Grp (1989)
1. Sustained PB lymphocytosis ( 10,000 or > ) mostly
mature.
2. BM > 30 % lymphocytes
3. PB lymphocytes CD 5 (+).

Dx : 1 + 2 or 3
If PB lymphocytes is < 10,000 = 2 & 3 must be +
 Chronic Lymphocytic Leukemia
Diagnosis

NCI –WG ( 1996 )

1. PB lymphocyte > 5,000 ( < 55 % atypical).
a. B cell specific; (-) Pan T markers.
b. Monoclonal ( either Kappa or Lambda chain
surface Ig ).
c. Low density surface Ig
2. BM > 30 % lymphocytosis
 CLL Staging (International
Workshop Group)
Risk Stage Median
Survival (yrs)
Low A Lymphocytosis < 3 10
L.n. grps ; (-) anemia
or thrombocytopenia
Inter- B > 3 L.n. grps 7
mediate
High C (+) Anemia or 5
Thrombocytopenia
 Treatment of Chronic
Lymphocytic Leukemia
 Indications:
1. Hemolytic anemia
2. Important cytopenias
3. Disfiguring lymphadenopathy
4. Symptomatic organomegalies
5. Marked systemic symptoms
 Treatment of Chronic
Lymphocytic Leukemia
 Chlorambucil + prednisone
 COP or CHOP
 Fludarabine +/- chemotherapeutic agents
 HSCT
 IV Ig
 Lymphomas
 M > F ( 3:2 )
 Etiology: Viral (EBV), Chemical (Benzene,
Herbicides), Hereditary, Immunofeficiency
 S/sx: Painless enlarged lymphadenopathy,
+/- fever, night sweats, wt. Loss
 Lymphomas
Hodgkin’s
 Orderly spread by contiguity
 Extranodal site: rare
 Systemic symptoms of
prognostic importance
 Involves axial & central l.n.
Cure
possible for all types
NHL
 Random, hematogenous
 E. N sites in unfavorable types
 Systemic symptoms are
< common
 Peripheral, mesenteric l.n.,
blood, Waldermyer’s ring
 Cure rare in low grade tumors
 Lymphomas
 Diagnosis :
Lymph node or E.N. mass biopsy
FNAB (+) Limitations
Histopathology :RS cell in Hodgkin’s.
Immunohistochemistry
 Lymphomas
 DDx : Reactive l.n. hyperplasia (infections)
Undifferentiated carcinoma
 Staging: Ann Arbor (Hodgkin’s Disease)
(Table 97-8, p. 647 Harrison’s 16 th ed )
 Prognosis: Hodgkin’s better than NHL
IPI for NHL
 International Prognostic Index
for NHL

5 Clinical factors
1. Age 60 or >
2. Serum LDH levels elevated
3. Performance status
4. Ann Arbor Stage III or IV
5. Extranodal site inolvement
 International Prognostic Index
for NHL

Cont’n…
For Diffuse Large B cell lymphoma
0, 1 factor = low risk 35 % SR 5 yrs 73 %
2 low – intermediate 27 % 51 %
3 high - intermediate 22 % 43 %
4. 5 high 16 % 26 %
 Tx depend on histopathology, stage, type of
lymphoma.
Radiotherapy
Combination chemotherapy
Rituximab