Last edited: 5/7/2023

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Acute Lymphoblastic Leukemia (ALL) Medical Editor: Aldrich Christiandy and Jude Loyola

OUTLINE
I) PATHOPHYSIOLOGY AND II) DIAGNOSTIC APPROACH III) TREATMENT
CLINICAL FEATURES (A) CBC WITH PBS (A) SYSTEMIC CHEMOTHERAPY
(A) HEMATOPOIESIS PATHWAY (B) BONE MARROW BIOPSY (B) INTRATHECAL CHEMOTHERAPY
(B) CAUSES OF INCREASED (C) IMMUNOPHENOTYPING (C) ADVANCED THERAPIES
LYMPHOBLASTS (D) GENETIC STUDIES (D) COMPLICATIONS
(C) EFFECTS OF INCREASED LYMPHOBLASTS IN (E) TESTS FOR LEUKEMIC INFILTRATION IV) APPENDIX
BONE MARROW V) REVIEW QUESTIONS
(D) EFFECTS OF INCREASED LYMPHOCYTES IN
VI) REFERENCES
BLOOD AND TISSUES

I) PATHOPHYSIOLOGY AND CLINICAL FEATURES

(A) HEMATOPOIESIS PATHWAY

Normal hematopoiesis pathway Pathology

Hematopoiesis is the production of blood cells In ALL, there’s a problem with B-lymphoblast and T-
o Happens in red bone marrow lymphoblast differentiation
Stem cell that generates all blood cells → o Gets stuck in the division stage and can’t differentiate
hemocytoblast (pluripotent stem cell) to become functional T cells and B cells
 Continue replicating and dividing without dying
1) Myeloid stem cell o So we end up with
In the presence of  Decreased functional T cells and functional B cells
o Erythropoietin → red blood cell  Tons of T lymphoblasts and B lymphoblasts
o Thrombopoietin (TPO) → platelet
o Colony-stimulating factor (CSF) → myeloblast
And then myeloblast, in the presence of other colony-
stimulating factors and interleukins, will become
granulocytes
o Neutrophil
o Eosinophil
o Basophil
2) Lymphoid stem cell
→ Lymphoblast
o B-lymphoblast → B-cells (B-lymphocyte)
 Go to lymph nodes
o T-lymphoblast → T-cell (T-lymphocyte)
 Differentiate in the thymus
 Go to lymph nodes

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 (B) CAUSES OF INCREASED LYMPHOBLASTS

(1) Chemoradiation (2) Genetic

Causes DNA mutation (i) Down syndrome (trisomy 21)
o Gene has gained the capacity to continue to
replicate without the cell dying Associated with AML and ALL
Causes tons of DNA replication without the cell dying (ii) Translocation
o End up with a massive amount of T lymphoblast and
B lymphoblast 1) t(12;21)
o Without completely becoming differentiated, T cell We have chromosomes 12 and 21
and B cell And we swap some of the genetic material
o Form weird fusion gene → gains the capacity to
(3) Infection
continue to keep replicating and dividing without
Human T-lymphotropic virus (HTLV) dying
o Associated with T-cell ALL Common in children
So, we have 2 types of ALL o So, this translocation is more common
o T lymphoblast (20%) 2) t(9;22)
 Remember HTLV as the cause
o B lymphoblast (80%) We have chromosomes 9 and 22
We swap some of the genetic material
o We get the Philadelphia chromosome
 Fusion gene → BCR-ABL gene
Common in adults
o Less common
o But it’s important to be able to determine this
 Due to different treatment regiment

Remember, these fusion genes gain the capacity to

continue to allow for excessive amounts of DNA
replication without the cell dying

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 (C) EFFECTS OF INCREASED LYMPHOBLASTS IN BONE MARROW

T lymphoblasts and B lymphoblasts are populated within bone marrow due to

o Chemoradiation causing mutations
o Genetic abnormalities associated with
 Trisomy 21 (Down syndrome)
 Translocations
• Cause weird fusion genes that cause excessive DNA replication
• Evade apoptosis and become immortal
o Human T-cell lymphotropic virus
Epidemiology
o B cell ALL (80%) VS T cell ALL (20%)
Lymphoblasts populate in the bone marrow and cause a lot of problems
o Taking so much space in the bone marrow
o Taking all the nutrients that are needed for red blood cell and platelet production
So, these cell lines become affected, and their production is dropped due to
o Decreased space
o Decreased nutrients available for them to continue to undergo their production process

(1) Increased lymphoblast → decreased functional (3) Thrombocytopenia (low platelet)

white blood cells We could see this on CBC showing low levels of platelet
Platelets are supposed to clog up holes in blood
Aren’t able to perform normal functions below
vessels if they’re broken or ripped up
o Fight off pathogens
o If we can’t do this, we’ll bleed through those holes
→ release cytokines
 Develop little bruising on the skin → Petechiae
→ promote an inflammatory reaction
 Bigger one → purpura
→ fight off infection
 Even bigger one → ecchymosis
High risk of infections o Or bleeding
o One of the higher mortality causes  Nose bleeding
o They may present with  Gingival bleeding
 Pneumonia  GI bleeding
 Urinary tract infection (UTI)
Look for features of
 Cellulitis
Bruising
(2) Anemia (low red blood cell) o Petechiae (Diameter ≤ 3mm)
o Purpura (Diameter 3-10mm)
Dropping the amount of red blood cells causes
o Ecchymosis (Diameter > 10mm)
anemia
Anemia would be evident if we got CBC and showed low Bleeding
numbers of red blood cell o Epistaxis
Clinical features o Gingival bleeding
o GI bleeding
1) Pallor
o Decreased hue of the skin (4) Bone pain
o If red blood cell is oxygenated properly and has
Increased lymphoblast → compensate and expand to
enough of them
make space for these lymphoblasts
 They should give a pinky-reddish hue to the skin
Distension and activation of pain receptors and
2) Fatigue, dyspnea nerves → Bone pain
o Remember, red blood cells are supposed to supply o May present with limping
O2 to tissues o Or complaining of particular bone pain in the areas
o To help us to be able to perform normal functions where red bone marrow is present
(producing energy)

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 (D) EFFECTS OF INCREASED LYMPHOCYTES IN BLOOD AND TISSUES

We know that B lymphoblasts and T lymphoblasts are made particularly within the bone marrow
They should get pushed into the bloodstream → supposed to go to some organs

(1) Liver and spleen → hepatosplenomegaly (3) Meninges → meningeal leukemia

Deposit lymphoblasts cause hepatosplenomegaly Unique and important to differentiate between AML
The liver and spleen are getting bigger and ALL
o Taking up a lot of spaces within the GI tract → o Deposit into meninges → meningeal leukemia
Compress stomach and bowels Present with features of meningitis
 Food is supposed to go through without any o Headache
compression or restriction o Photophobia
o Now we have things compressing GI organs like o Phonophobia
the stomach and bowels o Nausea/vomiting
 Not going to be able to push food along easily o Focal neural deficits
 These will cause o Altered mental status
• Nausea/vomiting
• Abdominal fullness The cranial nerve that moves through and around the
area of the meninges, especially CN VI
(2) Lymph nodes → lymphadenopathy o Lots of deposition into meninges and
compressing cranial nerve → cranial nerve palsy
B cells and T cells naturally go into lymph nodes  Specifically, CN VI → CN VI palsy
Deposit lots of them cause lymphadenopathy o If CN VI isn’t able to work
o May see in any lymphocyte-predominant leukemia  Can’t abduct the eye
o May see this within the cervical region or other areas  Related to extraocular movement
of the body
Generally, it’s a large, non-painful (non-tender) type of
swollen lymph node

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 QUICK RECAP

Depositing into the liver and spleen causes big swelling

Lymphadenopathy
o Large, non-painful, non-tender type of swollen lymph node
Meningeal leukemia presents with
o Meningitis
o Cranial nerve palsy, specifically CN VI palsy
 Inability to abduct the eye

(1) Testicular enlargement (3) Leukostasis

Not as common as meningeal leukemia
o But this is something to think about
AML vs. ALL
Biggest features to differentiate from AML
o Lymphadenopathy
o Meningeal leukemia
o Testicular enlargement
We can rarely see splenomegaly in AML
o But not that common
o Hepatosplenomegaly is more commonly seen in
ALL than in AML
(4) Tumor lysis syndrome
(2) Thymus (T-cell ALL only) → thymic enlargement
Only see this in T-cell ALL
Thymus sits on the top of the heart
o T lymphoblasts deposit in the thymus
o Thymus will get larger → Thymic enlargement
Compressing these structures
Way more common in AML than in ALL
Tons of blast cells stuck within the bloodstream
o Occlude the blood flow
o Block the circulation to brain tissues, causing
 Stroke
 Headache
o Blockage of pulmonary vessels causing
 Hypoxemia
 Dyspnea
o Block the retina vessel
 Vision change or vision loss
o Block off the drainage vein of the penis
 Priapism
High tumor burden (massive amount of
lymphoblasts)
o Present and stuck in capillaries and popping open
o Getting chemotherapy and busting the cell open
 Releasing K+, PO43- , uric acid
o May get acute kidney injury associated with this

1) Trachea and bronchi → Dyspnea and stridor May see this in AML and ALL

2) Esophagus → dysphagia
3) Superior vena cava → SVC syndrome
o We have subclavian and internal jugular veins
draining into the brachiocephalic vein, → drains into
the superior vena cava
o Symptoms
 Very large neck vein
 Enlargement of veins with blue discoloration
• Chest
• Face
• Arms

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 II) DIAGNOSTIC APPROACH

(A) CBC WITH PBS (B) BONE MARROW BIOPSY

Figure 4. Bone marrow biopsy reveals hypercellular bone

Figure 1. CBC shows anemia, thrombocytopenia, and marrow with >20% lymphoblasts.
increased lymphoblasts.
Definitive diagnostic test
General screening test Take a chunk of the bone marrow which then shows
o Tell us the effect of crowding of lymphoblast on the hypercellular BM with >20% lymphoblasts
bone marrow o Highly diagnostic of ALL
(1) Effect of Lymphoblast Crowding on CBC:
↓↓CBC = anemia
↓↓platelets = thrombocytopenia
↑↓mature WBCs
o Very variable; sometimes you have leukopenia or
leukocytosis
↑↑lymphoblasts
o On PBS, there is evidence of ↑↑lymphoblasts
o In AML, there is ↑↑myeloblast with Auer rods

Figure 5. Lymphoblasts on bone marrow biopsy.

Figure 2. PBS shows lymphoblasts indicating acute

lymphoblastic leukemia.

Figure 3. PBS showing myeloblasts with their characteristic

Auer rods (Raj & Mehta, 2022).

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 (C) IMMUNOPHENOTYPING (D) GENETIC STUDIES
To determine the specific chromosomal abnormality in
ALL because it affects the management
(1) Cytogenetics

Figure 7. Cytogenetics shows different chromosomal

Figure 6. Flow cytometry and immunohistochemistry can abnormalities in ALL.
determine which ALL subtype is present. Taking the nuclear material and then checking for any
To determine the subtype of ALL chromosomal abnormality
Is there a specific type of molecule present in lymphoblast (12:21)t
that is not seen in myeloid stem cells? o Associated with children
o More common
(1) Immunohistochemistry
(9:22)t or the Philadelphia chromosome
Checks for specific proteins inside the lymphoblasts o Associated with adults
Lymphoblasts = Tdt (+) and MPO (-) o Less common
o MPO (myeloperoxidase) is only seen in myeloblasts o Involves a very specific treatment process !!
(2) Flow Cytometry (2) PCR
What kinds of CD proteins are present on the surface of
the cells?
Checks for specific proteins outside the lymphoblasts =
CD proteins
o The type of CD determines whether it is a B-cell or a
T-cell
Running these cells through a column and putting Abs
that bind to these proteins, and lighting them up
More beneficial in ALL than AML

(i) T-lymphoblast (T-ALL)

Highly suggestive if there is CD2-CD8 Figure 8. PCR reveals the BCR-ABL fusion gene, which may
o Most important is CD3 indicate a different treatment regimen for ALL.
(9:22)t → there is a specific fusion gene present called
(ii) B-lymphoblast (B-ALL) BCR-ABL
Highly suggestive if there is CD10, CD19 or CD20 (+) BCR-ABL → treated with tyrosine kinase inhibitors
(TKI)
o BCR-ABL gene hyperactivates tyrosine kinases →
Low numbers indicate T-ALL, ↑↑stimulation and replication
high numbers indicate B-ALL

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 (E) TESTS FOR LEUKEMIC INFILTRATION

Figure 9. Different diagnostic modalities for leukocytic infiltration.

Check for leukemic infiltration in the organs

Table 1. Tests or imaging to check for organ involvement in ALL.

Check for features of
meningitis →
CT/MRI
enhancement of
CNS
meninges

Lumbar puncture ↑↑lymphoblasts in CSF

Check for testicular

infiltration of
Testicles Testicular UTS
lymphoblasts resulting
in a testicular mass

(+) thymic enlargement

Thymus Chest Xray or CT → mediastinal widening
and mass effect

Liver
Ultrasound or CT
and/or Hepatosplenomegaly
of the abdomen
Spleen Figure 12. Thymoma from ALL in coronal CT scan.

Figure 10. Cranial MRI showing enhancement of meninges

indicating meningeal leukemia.
Figure 13. Hepatomegaly as seen in abdominal CT scan.

Figure 11. Testicular involvement in ALL as shown in testicular

ultrasound.

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 III) TREATMENT

(A) SYSTEMIC CHEMOTHERAPY (C) ADVANCED THERAPIES

Figure 14. Chemotherapeutic regimen for ALL.

Same with AML to start with combination systemic Figure 16. Advanced ALL therapies use TKI or BM transplant.
chemotherapy (1) TKIs
Induction → consolidation → maintenance
o The goal is to reach complete remission Tyrosine kinase inhibitors: imatinib
o Most common agent
Agents: CVADD
o Cyclophosphamide (+) (9:22)t
o Vincristine (+) BCR-ABL gene
o Asparaginase (+/-) (2) Bone Marrow Transplant
o Daunorubicin
o Dexamethasone If patients fail chemotherapy, TKIs, or if there is a poor
prognostic

(B) INTRATHECAL CHEMOTHERAPY (D) COMPLICATIONS

(1) Tumor Lysis Syndrome (TLS)

Figure 17. Tumor lysis syndrome is the most common

Figure 15. Intrathecal chemotherapy for ALL. complication of ALL.

Prophylactic for meningeal leukemia During chemotherapy, leukemic cells pop out and release
o Chemotherapy ↑↑PO4, ↑↑K+, and ↑↑uric acid → causes AKI
o Radiation (+/-)
(i) Treatment
(1) Chemotherapy
IV fluids
Agents: Allopurinol
o Methotrexate (MTX)* o Prevents conversion of purines to uric acid
 May be asked in exams
o Cytarabine Rasburicase
o Steroids o Converts uric acid to its non-toxic metabolite

It may be delivered intrathecally: through a lumbar drain

or through the EVD
(2) Radiation (+/-)
Cranial irradiation therapy

Acute Lymphoblastic Leukemia (ALL) Hematology Pathology: Note #3. . 9 of 11

 IV) APPENDIX

Liver

V) REVIEW QUESTIONS 7) Which indicates T-ALL in flow cytometry?

a) Tdt (+)
1) Both B-lymphoblasts and T-lymphoblasts migrate b) MPO (-)
into the thymus for differentiation c) CD10 (+)
a) True d) CD3 (+)
b) False
8) What gene translocation is the Philadelphia
2) Which are the etiologies of the increased chromosome? What fusion gene is the result of this
lymphoblasts? (May choose more than 1) translocation?
a) Chromosome 12 and 22 translocation
b) Chemoradiation 9) What agent is used in intrathecal chemotherapy of
c) Cytomegalovirus infection ALL?
d) Down syndrome a) Methotrexate
e) Klinefelter syndrome b) Vincristine
f) Human T-lymphotropic virus infection c) Cyclophosphamide
g) Steven-Johnson syndrome d) All of the above

3) Acute lymphoblastic leukemia can cause anemia and 10) What is the specific therapy for patients who are
thrombocytopenia due to decreased bone marrow positive for the Philadelphia chromosome?
size and decreased nutrients for production a) Methotrexate
a) True b) Imatinib
b) False c) Pembrolizumab
d) Vincristine
4) Superior vena cava syndrome can be found in both
acute lymphoblastic leukemia and acute myeloid 11) What is the most common complication of ALL?
leukemia patients
a) True VI) REFERENCES
b) False
5) The following can be seen in the CBC of patients
● Harrison, T. R., & Kasper, D. L. (2015). Harrison's Principles of
Internal Medicine. McGraw-Hill Medical Publ. Division.
with ALL EXCEPT?
a) Increased lymphoblasts
● Raj, K., & Mehta, P. (2022, March 4). Acute myeloid leukemia.
Retrieved from BMJ Best Practice:
b) Decreased RBC https://bestpractice.bmj.com/topics/en-us/274
c) Increased platelets
d) Increased leukocytes
6) What is the definitive diagnostic test for ALL?
a) PBS
b) Bone marrow biopsy
c) CT scan
d) Flow cytometry

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