Acute Leukemia is hematological malignancy

Awesome

1. ACUTE LEUKEMIA

MEKOYA D MENGISTU
MD, INTERNIST, ASSIST PROF OF INTERNAL MEDICINE

2. ACUTE LEUKEMIA

is the result of a malignant event occurring in an early
hematopoietic precursor

the affected cells fail to differentiate but continue to proliferate in
an uncontrolled fashion

Blasts—rapidly accumulate and progressively replace the BM,
diminishing the production of normal red cells, white cells, and platelets

Number of blasts in BM > 20% of the total cells of the bone marrow aspirate
OR
Number of blasts in PM > 20% of nucleated cells in p/film

3. common clinical complications of leukemia: anemia, infection,
and bleeding

With time, the leukemic blasts pour out of the blood stream and
infiltrating the lymph nodes, spleen, and other vital organs

If untreated, acute leukemia is rapidly fatal; most patients die
within weeks to months after diagnosis

With appropriate therapy many patients can be cured

4. @--@

Hematopoietic
stem cell

—
6-

Lymphoid
progenitor

Myeloid

ante 7

Eosinophils

Basophils

Monocytes

Platelets

Red cells

5. EPIDEMIOLOGY OF ACUTE LEUKEMIA

+ The annual incidence of AML( in Western pop): 80% of AL
* The annual incidence of ALL: 20% of AL
* The incidence of AML
= Increases with age
= Median age at presentation 60-65yrs
« The peak incidence of ALL
= 3-4yrs of age
= Incidence decreases after 9yrs of age
= Rare after 40

ae

ES

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« Sex distribution: More common in males

+ The relative frequency of the 4 leukemias in the west
= ALL(11%) AML (46%)
= CLL (29%) CML (14%)

« Ethiopia: CML accounts for 50% of leukemias in our country

6. CLASSIFICATION OF ACUTE LEUKEMIA

« The classification is based on biological features
— Clinical feature
— Morphology based on Wright or Giemsa stain
— Cytochemical studies
— Flow cytometry
— Cytogenetics
— molecular study

7. 1-Morphologic classification (microscopic)

Lymphoblast / myeloblast

— Blast size :small — Large

— Cytoplasm: Scanty — Moderate

— Chromatin: Dense — Fine, Lacy €
— Nucleoli :Indistinct - Prominent o®

— Auer-rods: Never present - Present in 50% O € = @ -

8. 2-Immunological classification (flow cytometry)

« can quickly identify the abnormal cell population,
= characterize its phenotype, give lineage classification,
= make the diagnosis, or narrow down the differential list.

+ Based on this flow cytometry , AL is classified into
= Acute Myelogenous Leukemia(AML)
= Acute Lymphoblastic Leukemia(ALL)
= Biphenotypic Leukemia—have both AML and ALL feature
= Undifferentiated leukemia
Based on cell surface markers of ALL
= Classifies into B or T cell types
= Determines their maturation

9. 3-cytochemistry

Different chemicals are used to stain enzymes specific to some leukemias

e.g. Peroxidase staining, sudan black B,
Esterase

Ld

+ Positive for myeloblast and
+ negative for lymphoblast

Currently not commonly used, and Replaced
by immunophenotyping(flowcytometery)

10. 4-Cytogenetics
In most cases of acute leukemia, an abnormality in chromosome number or
structure is detected
often they include
— gain or loss of whole chromosomes
— chromosomal translocations,
— deletions, or
— Inversions
the chromosomal abnormality disappears
— when patients receive treatment and enter into complete remission (CR),
— when relapse occurs, the abnormality reappears
a favorable prognosis is seen in leukemias (AML) with :
— t(8;21)
— inv(16)
— t(15;17), invariably associated with APL
unfavorable prognosis seen in leukemias with
— Deletions of part or all of chromosomes 5 or 7

11. 5-Molecular analysis

Used for

— diagnosis,

— prognosis,

— As target for therapy

The BCR/ABL fusion (Philadelphia chromosome) can be detected in the lab
— ALL with t(9;22) has a poor prognosis when treated with conventional

chemotherapy

Ph+ ALL patients are treated with the
same regimens as other types of ALL,
with poor results.

However, tyrosine kinase inhibitors
(TKIs) inhibit the bcr-abl fusion
protein of Ph+ ALL

Normal
chromosome 9

Changed chromosome 9

Chromosomes break

Normal
chromosome 22

ABL

BCR

ä
u

>

Changed
chromosome 22

| Philadelphia

Chromosome)

-

13. AML is a neoplasm characterized by infiltration of the blood,
bone marrow, and other tissues by proliferative, clonal, poorly
differentiated cells of myeloid line of the hematopoietic system.

comprises a spectrum of malignancies that, untreated, are
uniformly fatal.

AML is the most common acute leukemia in older patients,
— median age at diagnosis of 65-67 years.

Long-term survival is infrequent;
— U.S. registry data report that only 27% of patients survive 5 years.

14. ETIOLOGY

+ Most cases of AML are idiopathic.
+ AML cases with established etiology are relatively rare.

+ Risk factors implicated in the development of AML are
— Genetic predisposition,
— radiation, chemical exposures,

+ Exposure to ionizing radiation, benzene, chloramphenicol, phenylbutazone, and
other drugs can uncommonly result in BM failure that may evolve into AML.

— Drugs Hx- Anticancer drugs are the leading cause of therapy-associated AML.
* Alkylating agent[eg. Chlorambucil]—associated leukemias
— occur on average 4-6 years after exposure
+ Topoisomerase ll inhibitors[Eg. Anthracyclines]—associated leukemias
— occur 1-3 years after exposure

» No direct evidence suggests a viral etiology.

15. CLINICAL PRESENTATION

Patients with AML usually present with nonspecific symptoms that begin gradually,
or abruptly,
— are the consequence of
Y anemia,
y leukocytosis, leukopenia/leukocyte dysfunction, or
Y” thrombocytopenia.
Y pancytopenia

50% of AML pts have symptoms up to 3 months before the AML diagnosed.
— Fatigue is a frequent first symptom among AML patients.
— Anorexia and weight loss are common.
— Fever with or without identifiable infection is the initial symptom in “10% of pts.
— Bone pain, LAP, nonspecific cough, headache, or diaphoresis may also occur.

Signs of abnormal hemostasis (bleeding, easy bruising) are common.

16. * Rarely, patients may present with symptoms from a myeloid sarcoma
— Isatumor mass consisting of myeloid blasts
— occur at anatomic sites other than bone marrow
* most common sites: skin, lymph node, GIT, soft tissue, and testis.

often characterized by chromosome aberrations (e.g., monosomy 7,
trisomy 8, 11q23 rearrangement, inv[16], trisomy 4, t[8;21]),

may precede or coincide with blood and/or BM involvement by AML.

+ Patients who present with isolated myeloid sarcoma typically develop blood
and/or marrow involvement quickly thereafter and

* cannot be cured with local therapy (radiation or surgery) alone.

17. PHYSICAL FINDINGS

Fever, Tachycardia, Tachypenia
less commonly: splenomegaly, hepatomegaly, LAP, and “bone tenderness”

Hemorrhagic complications are most commonly and, classically, found in APL

APL patients often present with DIC-associated minor hemorrhage

but may have significant Gl bleeding, intrapulmonary hemorrhage, or
intracranial hemorrhage.

Retinal hemorrhages are detected in 15% of patients.

Likewise, thrombosis is another less frequent but well recognized clinical
feature of DIC in APL.

Infiltration of gingiva, skin, soft tissues, or meninges with leukemic blasts

is characteristic of the monocytic subtypes (monoblastic leukemia) and
those with 11q23 chromosomal abnormalities.

18. Gingival infiltration in acute monoblastic leukemia

Marked gingival enlargement affecting both upper and lower
gingivae in our patient affected by acute monoblastic leukemia.
Reprinted by permission from: Macmillan Publishers Ltd: Gallipoli, P, Leach, M.
Gingival infiltration in acute monoblastic leukaemia. Br Dental J 2007;
203:507. Copyright © 2007.

18

Leukemia cutis: extensor forearms.
Reproduced with permission from: Stedman's Medical Dictionary. Copyright
©2008 Lippincott Williams & Wilkins.

19. HEMATOLOGIC FINDINGS
+ CBC:

+ Hb: Anemia is usually present at diagnosis though it is not typically severe.
— The anemia is usually normocytic normochromic.
— Active blood loss may rarely contribute to the anemia.
+ WBC: 60% of pts have an elevated, 25% low and 15% normal wbc
— The median presenting leukocyte count is “15,000/pL.
— 20% have >100,000/uL.
— Aleukemic leukemia: <5% of pts have no detectable leukemic cells in the blood.

.

+ Platelet: <100k/uL at diagnosis in 75% of pts, and “25% have <25,000/uL.

«<* Peripheral Morphology and BM in AML: Myeloblasts
— Myeloblasts contain primary (nonspecific) granules,
— Have fine nuclei, lacy chromatin with one or more nucleoli characteristic of immature
cells.
— Abnormal rod-shaped granules called Auer rods present in 50% of cases
+ when they are present, AML is virtually certain

20. Myeloblasts with Auer rod in acute myeloid leukemia

Peripheral smear from a patient with acute myeloid leukemia.
There are two myeloblasts, which are large cells with high nuclear-
to-cytoplasmic ratio and nucleoli. Each mobles: has a pink/red
rod-like structure (Auer rod) in the

Source: Longo DL, Fauci AS, Kasper DL, Mauser SL, Jameson JL, Loscazo 3: Harrison's
Principles of Internal Medicine, 18th Edition: www.accessmedicine.com
DR NT A LT AE E

21. Other investigation

+ Uric acid
» Liver 4 renal functions
+ Serum LDH
+ Serum electrolytes,
— Hypo/hyper kalemia
— Hypomagnesemia
— hyperphosphatemia

* Coagulation profile

+ Serological screening ( HIV)

TABLE 100-5 Initial gnostic Evaluation and Management of
Adult Patients with AML

History

Increasing fatigue or decreased exercise tolerance (anemia)

Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)
Fevers or recurrent infections (neutropenia)

Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia
or bleed)

Early satiety (splenomegaly)

Family history of AML (Fanconi, Bloom, or Kostmann syndromes or
ataxia-telangiectasia)

History of cancer (exposure to alkylating agents, radiation, topoisomerase II
inhibitors)
Occupational exposures (radiation, benzene, petroleum products, paint,
smoking, pesticides)
Performance status (prognostic factor)
Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic
leukemia)
Fever and tachycardia (signs of infection)
Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)
Poor dentition, dental abscesses
¡Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia)
‘Skin infiltration or nodules (leukemia infiltration, most common in monocytic
leukemia)
Lymphadenopathy, splenomegaly, hepatomegaly
Back pain, lower extremity weakness (spinal granulocytic sarcoma, most likely
in {8;21] patients)
‘CBC with manual differential cell count
‘Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid,
hepatic enzymes, bilirubin, LDH, amylase, lipase)
conte: studies (prothrombin time, partial thromboplastin time, fibrinogen,
limer)
Viral serologies (CMV, HSV-1, vancella-zoster)

22. TREATMENT OF AML

Rx of the newly diagnosed AML is usually divided into two phases,
— Induction : cytarabine and anthracyclines

+ The initial goal is to induce Complete Remission(CR).

+ Virtually all pts in CR will relapse within months unless additional therapy is given

— Postremission (consolidation)
* Once CR obtained, further Rx is must to prolong survival and achieve cure.

The initial induction treatment and subsequent postremission therapy are chosen
based on the patient’s age, overall fitness, and cytogenetic/molecular risk.

Intensive therapy with cytarabine and anthracyclines in younger patients (<60
years) increases the cure rate of AML.

= In older pts, its benefit is controversial in all except favorable-risk pts;

23. Specific Rx for AML

“ Chemotherapy

ME Remission induction

+ 7+3 regimen ( Cytarabine + Daunorubicin/doxorubicin)
V Cytarabin Iv infusion for 7 days + Doxorubicin IV 3days(d1-d3)

+ CR can be achieved in 70% of patients usually after 1 month
+ Alternative ( cytarabin + Idarubicin + etoposide)

E Postremission therapy
+ The best regimen not yet settled
+ Consolidation/Intensification chemotherapy
* Allo-SCT
+ Auto-SCT

< Treatment of M3(APL): High risk(initial WBC>10K), Low risk(WBC<10k)
= APL(acute promyelocytic leukemia) is a highly curable AML
= 85% of patients achieve long term survival with curative approach
= Special entity(t(15;17)) & Favourable outcome
= High Risk: All- Trans-Retinoic Acid(ATRA)+other chemo (Cytarabin + Daunrubicin)
= Low Risk: ATRA + Arsenic TriOxide(ATO)
= Maintenance therapy

23

24. Ml Criteria for complete remission(CR) of AML
1. Granulocyte, RBC and platelet counts normalized
2. No blast in peripheral blood
3. Normal bone marrow (normal cellularity, <5%blasts)
"= Molecular complete remission: no evidence with molecular studies

*

+ Adverse prognostic factors
— Age>50

— Poor performance status

— High wbc count

— Secondary AML

— MDR

— Unfavourable karyotypes—deletions of chromosome 5 and 7

24

25. +» Among candidates for intensive therapy With the 7 and 3 regimen,
— 60-80% of younger and 33-60% of older patients achieve CR.
+ Of patients who do not achieve CR, most have drug-resistant leukemia,

— Induction death is more frequent with advancing age and medical
comorbidity.

+ In older pts (age 260-65 years), the outcome is generally poor
— due toa higher frequency of resistant disease and increased rate of
treatment-related mortality.
= This is especially true in patients with
* prior hematologic disorders (MDS or myeloproliferative neoplasms),

+ therapy-related AML, or
+ cytogenetic and genetic abnormalities that adversely impact on clinical outcome.

26. ACUTE LEUMPHOCYTIC LEUKEMIA (ALL)

27. ACUTE LEUMPHOCYTIC LEUKEMIA (ALL)

Is the malignant clone arises from lyphoid progenitors in the BM
or lymphatic system resulting in an increase of immature
nonfunctioning leukemic cells.

Infiltration of bone marrow leads to
— anemia, granulocytopenia, and thrombocytopenia
— C/m: fatigue, infection, and hemorrhages.

These symptoms are often the reason a patient first seeks medical advice
— rather than consequences of tumor bulk caused by leukemic infiltration, such as
+ lymph node enlargement,
+ hepatosplenomegaly, or
* symptoms of the CNS (meningeosis leukemica)

28. ALL: INCIDENCE AND AGE

ALL is the most frequent neoplastic disease in children
— early peak at the age of 3-4 years.

The incidence in adults ranges from 0.7 to 1.8/100,000 per year,
— higher in younger adults for the age group 15-24 years and
— decreasing thereafter, only to increase again in elderly (>65 yrs).

The frequency of immunological, cytogenetic, and genetic
subtypes changes with age.

29. ETIOLOGY OF ALL

The etiology is unknown.
However, internal and external factors influence the incidence

Risk factors associated with an increased risk of ALL:

— inheritance of certain diseases
* e.g., Klinefelter’s syndrome, Fanconi’s anemia, Bloom’s syndrome,
ataxia telangiectasia, and neurofibromatosis.
exposure to ionizing radiation or
Exposure to chemicals, including prior chemotherapy,

Factors having less association to ALL are
Human T-cell leukemia virus | (HTLV-1) is etiological agent for adult T-cell
leukemia/lymphoma, an aggressive adult T-cell leukemia

30. CLINICAL PRESENTATION OF ALL

+ Non specific: Wt loss, fever, night sweating loss of appetite ..
+ Symptoms associated with low blood count.

+ Anemia: easy fatigability, lightheadness...

« Sxs of thrombocytopenia: Bleeding tendency

“* Increased susceptibility for infection

Vv High grade Fever ---- due to infections
V Low grade Fever ----- due to the ALL

« Signs of tissue or organ infiltration
< Prominent LAP including signs of mediastinal LAP
+ Hepatosplenomegaly---causing Abdominal fullness,
& Cranial nerve palsies
< Meningeal irritation signs----common in ALL
« Bone and joint pain
« It rarely spread to the skin, eye, testicles, kidney
“+ T subtype can affect thymus: may lead to tracheal obstruction, SVC syndrome.

31. CLASSIFICATION OF ALL

F-A-B classification: use microscopic feature to classify in to L1,L2,L3
Y L-1:85%, L-2:14%, L-3 (Burkitt's leukemia): - 1%

The second method of classification uses immunophenotyping and

cytogenetic studies

It classifies based the type of involved cells and the level of maturity.

pro-B ALL

— The most immature group

— expresses CD19 but not other B-lineage antigens
Early pre-B-cell (CALLA-positive) ALL

— most common ALL

— Have the best therapeutic outcomes
among B-cell ALL

pre-B-cell ALL:
— have intracytoplasmic immunoglobulin
Mature B-cell ALL:

— signified by the presence of immunoglobulin
on the cell surface

T cell ALL
— Pre T ALL=5-10%
— Mature T cell ALL=15-20%

Immunological Cla:

B-Linenge(75% of ALL)
Precursor B ( Pro-B ALL)

Common(early pre-B) ALL

Pre-B ALL
Mature B-ALL

TLineage(25% of ALL

Early T (T-Precursor) ALL
Cortical (Thymic) T-ALL

Mature T-ALL

1

51

10

7

1

32. INVESTIGATION IN ALL

CBC:
“= 60% of pts have an elevated, 25% low and 15% normal wbc
— 95% have blast in the periphral blood film
— Aleukemic leukemia-- absence of leukemic cells in the peripheral blood.

Peripheral smear and BM examination: Lymphoblast
— Blasts: Cytoplasm:- Scant, Nucleoli:- Indistinct, Auer-rods:-Never present

Uric acid

Liver & renal functions
Serum LDH

Serum electrolytes,

— Hypo/hyper kalemia
— Hypomagnesemia

— hyperphosphatemia
Coagulation profile
Serological screening ( HIV)

33. i.
howing
small lymphoblasts with rare nucleoli and vacuoles, as
seen in acute lymphocytic leukemia (ALL) of the L-1
morphologic type. Courtesy of Robert Baehner, MD.

33

34. > ® 00

Lymphoblasts (FAB L2) Bone marrow aspirate from a

patient with acute lymphoblastic leukemia of the L2 type. The
blast cells have more abundant cytoplasm that those of the L1
type. The nucleus is often fissured or indented. (Wright- 5
Giemsa). Courtesy of David S Rosenthal, MD.

35. aspirate from a patient with the L3 variant of acute
lymphoblastic leukemia. The blasts have vacuolated cytoplasm
(small arrows) and their nuclei have large prominent nucleoli
(large arrows). Courtesy of David S Rosenthal, MD.

35

36. + Radiology:
— CXR: mediastinal mass (T-cell ALL)
— Osteopenia or lytic lesion in 50% of patients with ALL

— CT Scan if symptomatic

+ Lumbar puncture ----should be done in:
Y all ALL pts,
v selected AML pts (monocytic, high blast number, <2yrs old)

37. DIAGNOSIS OF ALL

Detailed Hx &P/E

CBC with differential

Peripheral morphology: lymphoblasts

Blood chemistry

BM aspiration and biopsy: used in diagnosis and follow up.
— Dx of ALL generally requires at least 20%-30% of cells are blasts,
— under normal circumstance blasts in BM are <5%.

Lumbar puncture

Cytochemistry

— Flow cytometry:

— Immunocytochemistry

Cytogenetic studies: FISH, PCR

LN biopsies: rarely used kin leukemia unlike lymphoma
Imaging: usually not helpful b/c tumors are less likely in leukemia.

38. TREATMENT OF ALL

Goals:
— Give supportive care
— Eradicate the leukemic cell mass: Complete remission, Cure if possible
+ General options : chemotherapy, Target therapy, SCT, Radiation

< Criteria for complete remission

1. Granulocyte, RBC and platelet counts normalized
2. No blast in peripheral blood
3. Normal bone marrow (normal cellularity, <5%blasts)

Treatment is given over a period of two years.
— Incase of chemotherapy given in 3 phases over 2 yrs.

Target therapy uses tryosine kinase inhibitors in addition to chemo
— E.g: imatinbin, nilotinbin etc in those with Ph+ chromosome to assist in rapid remission

Radiation: not usually used except in the cases of brain/spinal cord metastasis

39. SUPPORTIVE CARE

Treatment of fluid & electrolyte disturbance
Treatment of anemia and thrombocytopenia
— Packed red cells transfusion
— Platelet transfusion

Treatment of infection/Neutropenic fever
— Culture and other studies
— Broad spectrum IV antibiotics ( empiric/emergency)

Prevention of uric acid nephropathy & tumor lysis syndrome
— hydration

— Allopurinol

— Rasburicase

Treatment of Hyperleukocytosis/hyperviscosity
— Cytoreduction: Hydroxyurea, steroids

40. SPECIFIC TREATMENT IN ALL

* Chemotherapy
— Several phases
* Remission Induction
* Consolidation/Intensification
* CNS prophylaxis or Treatment
+ Maintenance

+ Remission Induction
— weekly cycles with the aim of complete remission
* Vincristine + Prednisolone + daunorubicin + L-Asparaginase
* Continued until patient achieves complete remission
— 75-85% of adults achieve Complete Remission

— Cure rate : Children-2/3, Adults -1/3
+ Reason for poor outcome in adults with ALL
— High rate of Philadelphia chromosome in adults
— high degree of toxicity with the drugs in adults

41. Clinical characteristics

Presenting WBC

Immunophenotype

Cytogenetics/molecular
genetics

Treatment response

Children: <1yr and >9yrs
Adult: >60yrs

High WBC
>30000/uL in B-lineage,
>50000 in T-cell

Pro-B cell, Early T-cell

t(9;22)/BCR-ABL(Ph+)
Late CR achievement(Time to CR) > 4 wks

MRD (minimal residual disease) positivity

41

42. ° Consolidation/Intensification

— Refers to admin of high dose of induction regimen or high dose of multiple
regimens not used during induction phase for 4-6wks

— Based on the poor prognostic factors pts are classified into
* Standard risk—without any risk factor(no bad prognostic factors)
* High risk----one or more risk factor
* Very high risk---philadelphia chromosome positive
— Pts in very high or high risk categories are treated more
intensively or may proceed to stem cell transplantation

° Maintenance therapy: This phase typically includes:
Y” Weekly methotrexate (Po/IM) + daily oral 6- mercaptopurine
Y” This phase typically lasts approximately 2 -2.5years

43. CNS prophylaxis or Treatment

+ Adults who don't receive prophylaxis have CNS relapse rate of 30%
* CNS leukemia occurs in

— 5% of patients with ALL at diagnosis

— 80% in the disease course

+ Do LP in all patients of ALL

The options of CNS treatment/ prophylaxis include
1. Intrathecal: Methotrexate alone or combination of Methotrexate, Cytarabine, prednisolone)
2. High dose systemic chemotherapy
3. Cranial Irradiation