Pedia - Neoplastic Diseases Of The Blood3

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,

Defective

LEUKEMOGENESIS Transformation Event

Maturation & Differentiation

(initiation, promotion, progression)

Normal Progenitor

Malignant 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 * Male * Leukocytosis * Organomegaly * Bleeding diathesis * CNS involvement * Longer time to CR

* Older age (> 60 yrs) * Chromosomal abn. * M4, M5 subtype * Secondary AML

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 Malignancies * Myeloproliferative Disorders 1. CML 3. IMF 2. PV 4. ET *aCML *CMMol *CNL *CEoL *CBL *CBF

Chronic Lymphoid Malignancies •CLL • HCL • Sezary Syndrome/ Mycosis Fungoides • Lymphomas 1. HD 2. NHL * Plasma cell myeloma

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  Chr 22 (BCR) t(9:22)q34;q11

LAP Score =

or nil

p 210 Tyrosine kinase actvity

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 - Arterial O2 sat 92 % &> M3 – Splenomegaly

m2 - Leukocytosis > 12,000/cumm m3 - LAP score > 100 m4 - Serum B12 conc. > 900 pg or B12 * PV binding capacity All 3 in category A present > 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 Disorders 1. CML 3. IMF 2. PV 4. ET *aCML *CMMol *CNL *CEoL *CBL *CBF

• CLL • HCL • Sezary Syndrome/

Mycosis Fungoides • Lymphomas 1. HD 2. NHL * 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 Low

Stage A Lymphocytosis < 3 L.n. grps ; (-) anemia or thrombocytopenia

Median Survival (yrs) 10

Intermediate

B > 3 L.n. grps

7

High

C (+) Anemia or Thrombocytopenia

5

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 2 low – intermediate 27 % 3 high - intermediate 22 % 4. 5 high 16 %

73 % 51 % 43 % 26 %



Tx depend on histopathology, stage, type of lymphoma. Radiotherapy Combination chemotherapy Rituximab