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ACUTE PROMYELOCYTIC
LEUKAEMIA
UNIT V PRESENTATION
• Acute promyelocytic leukemia (APL) is a unique
subtype of the acute leukemias.
• It has distinct cytogenetics, clinical features, and
biologic characteristics. Acute promyelocytic
leukemia (APL) is caused by an arrest of leukocyte
differentiation at the promyelocyte stage.
• The discovery and elucidation of the molecular
pathogenesis for APL has led to the first and only
targeted therapy for leukemia
HAEMATOPOIESIS
EPIDEMIOLOGY
• AML comprises 11% of the cases of leukemia in
childhood in the United States, with approximately 380
children diagnosed with AML annually.
• APL is more common in certain other regions of the
world, but incidence of the other types is generally
uniform.
• Affects males and females equally
• Several chromosomal abnormalities associated with
AML are identified, but no predisposing genetic or
environmental factors can be identified in most
patients
Prognosis
• Very good survival rates (up to 90% molecular
remmission) in developed countries where
cytotoxics are given together with retinoic
acid (ATRA)
• Still very poor in our setting
PATHOGENESIS
• Acute myelogenous leukemias, characterized by
the accumulation of immature myeloid forms in
the bone marrow and the suppression of normal
hematopoiesis
• Most AMLs are associated with acquired genetic
alterations that inhibit terminal myeloid
differentiation. As a result, normal marrow
elements are replaced by relatively
undifferentiated blasts exhibiting one or more
types of early myeloid differentiation
• Acute promyelocytic leukemia (APL) is defined
by its cytogenetic properties. Over 95% of
cases are characterized by a balanced
translocation between chromosome 17q21
and chromosome 15q22.
• This leads to an abnormal fusion protein
called PML-RAR alpha
• In APL the translocation occurs
between genes that would
normally help to restrict tumor
growth and help white blood
cells to mature in a healthy way.
• When these genes trade places,
a mutant gene is formed.
• This mutant gene encodes for a
protein that prevents
maturation of the promyelocyte
CLASSIFICATION OF APL
• It is classified as AML M3 by the old FrenchAmerican-British (FAB) system
• Acute promyelocytic leukemia (APL) with
translocation between chromosomes 15 and
17, ie t(15;17) in the World Health
Organization (WHO) classification system.
FAB vs WHO
• FAB classification is the most widely used system in current use where
AML is divided into eight (M0 to M7) categories.This scheme takes into
account both the degree of maturation (M0 to M3) and the lineage of the
leukemic blasts (M4 to M7).
• The FAB classification categorized leukemia based on cell morphology,
including cytochemical stains, whereas the WHO system also includes flow
cytometry, cytogenetic studies and, in some cases, clinical information.
• A recently proposed WHO classification for AML retains the FAB categories
M0 to M7 but also creates special categories for AMLs associated with
particular chromosomal aberrations (e.g., the t(15;17), t(8;21), inv(16), or
11q23 rearrangements), which arise after prior chemotherapy or follow a
myelodysplastic syndrome.
• This classification thus attempts to define forms of AML according to
molecular pathogenesis and outcome. Given the increasing role of
cytogenetic and molecular features in directing therapy, a further shift
toward molecular genetic classifications of AML seems inevitable and
desirable
WHO classification
CLINICAL FEATURES - leukemias
• The production of symptoms and signs of
AML, is due to replacement of bone marrow
by malignant cells and to secondary bone
marrow failure.
• Thus, patients with AML may present with any
or all of the findings associated with marrow
failure.
History is rather short
• Short (<3-month) history of symptoms due to
bone marrow failure (e.g. of anaemia, abnormal
bruising/bleeding or infection).
• DIC with bleeding is particularly common in acute
promyelocytic leukaemia
• Increased cellular catabolism may cause
sweating, fever and general malaise.
• Lymphadenopathy and hepatosplenomegaly are
less frequent than in ALL
• Tissue infiltration of skin, bones, gums with
hypertrophy (AML M5 or M4).
• Initially there are non-specific symptoms are
present for less than 3 mo
• As the disease progresses, signs and symptoms of
bone marrow failure become more obvious with
the occurrence of pallor, fatigue, bruising, or
epistaxis, as well as fever, which may be caused
by infection.
• On physical examination, findings of pallor,
listlessness, purpuric and petechial skin lesions,
or mucous membrane hemorrhage may reflect
bone marrow failure
AML clinical features
• subcutaneous nodules or “blueberry muffin”
lesions, infiltration of the gingiva, signs and
discrete masses, known as chloromas or
granulocytic sarcomas.
• Patients can present with neurologic deficits
or headaches if there is central nervous
system (CNS) involvement.
APL
• In APL is set apart from other forms of AML many patients present
with coagulopathy. The coagulopathy has been described as DIC
with associated hyperfibrinolysis.
• APL has been associated with
– low levels of plasminogen,
– Low levels alpha2-plasmin inhibitor, and
– plasminogen activator inhibitor 1 found in fibrinolytic states.
• There is increased expression of annexin II, a receptor for
plasminogen and plasminogen-activating factor, on the surface of
leukemic promyelocytes.This leads to overproduction of plasmin
and fibrinolysis.
• It is important to treat the coagulopathy as a medical emergency. In
40% of untreated patients, pulmonary and cerebral hemorrhages
can occur.
DIAGNOSIS
• FBC & DC – may be normal, may have low platelets and Hb but
raised WCC, or all the 3 celllines may be depleted (aleukemic
leukemia). Anemia and thrombocytopenia may indicate bone
marrow failure.
• Peripheral smear – blasts in the PS suggest a leukemic process.
Occasionally, the peripheral smear might not contain any blasts
(aleukemic leukemia). For this reason, bone marrow examination is
essential to exclude acute leukemia in pancytopenic patients
• Bone marrow aspiration - When the results of an analysis of
peripheral blood suggest the possibility of leukemia, a bone marrow
examination should be done promptly to establish the diagnosis.
– Bone marrow aspiration alone is usually sufficient, but sometimes a
bone marrow biopsy is needed to provide adequate tissue for study or
toexclude other possible causes of bone marrow failure.
OTHER INVESTIGATIONS
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U & Es
LFTs
CSF studies – esp in hyperleukocytosis
Imaging studiesProthrombin time (PT) and activated partial
thromboplastin time (aPTT), fibrinogen
measurements.
The diagnosis is based on finding that myeloid
blasts make up more than 20% of the cells in the
marrow
• Several types of myeloid blasts are recognized.
• Myeloblasts have
–
–
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delicate nuclear chromatin
two to four nucleoli
more voluminous cytoplasm than lymphoblasts
The cytoplasm often contains fine, azurophilic, peroxidasepositive granules. Distinctive red-staining peroxidasepositive structures called Auer rods, which represent
abnormal azurophilic granules, are present in many cases
and are particularly numerous in AML associated with the
t(15;17).
• The presence of Auer rods is taken to be definitive
evidence of myeloid differentiation
promyeloblast
Histologic variants of APL
• The hypergranular subtype (classic M3) has
frequent Auer rods, clumps of granular material
containing lysosomes, peroxidase, lysosomal
enzymes, and large crystalline inclusion. The
nucleus is folded or bilobed, and the cytoplasm
contains prominent azurophilic granules. The
bone marrow is usually hypercellular. The cells
stain intensely for Sudan black and
myeloperoxidase, but not for periodic acid-Schiff
(PAS) and HLA-DR.
• The microgranular variant (M3v) also has a folded
nucleus, but the cytoplasm has fine, dusky granules
and Auer rods are rare. It is seen in 25% of cases
• The hyperbasophilic subtype shows an increased
nucleocytoplasmic ratio and strongly basophilic
cytoplasm with blebs. There are few granules and no
Auer rods.
• The last variant is PLZF-RAR alpha (M3r), and it has
regular, condensed chromatin in the nucleus. There are
fewer granules and rare Auer rods when compared
with the hypergranular subtype
• BM aspirate samples can be sent for flow
cytometry, cytogenetics or FISH for the usual
translocations.
• The typical phenotype of acute promyelocytic
leukemia (APL) is myeloperoxidase positive
and CD33 positive, human leukocyte antigen
(HLA)-DR negative.
PROCEDURE
• BONE-MARROW
ASPIRATION
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Informed consent needed
Sterile procedure
Pt lies prone on abd
1% lignocaine is used to
numb the area
– Using special bone marrow
aspiration needle
– Posterior superior iliac
spine, or sternum
Bone marrow aspiration
• An aspirate needle is inserted through the skin and forced down till
it abuts the bone
• The clinician the advences the needle though the bony cortex into
the marrow cavity by a twisting motion of the hand
• Once the needle is in the cavity, the needle is removed and a
syringe is attached and used to aspirate marrow
• Some of the aspirate is used to make slides and the remainder put
into an EDTA bottle and sent to the lab for cytology
• Remember to give the patient analgesia
TREATMENT
• Patients with acute leukemia should be treated in
centers staffed by specially trained physicians
with access to adequate supportive care eg
platelet transfusion and adequate nursing care.
• Patients need to be nursed in a sterile
environment when their bone-marrow cells are
depleted
• Access to a well equipped laboratory is also
crucial.
• High-risk patients with acute promyelocytic
leukemia (APL) (WBC >10,000/μL) should
undergo induction and consolidation
chemotherapy with an anthracycline (eg,
idarubicin), cytarabine, and ATRA.
• ATRA should be started immediately to control
coagulopathy.
• Chemotherapy can be started within 3 days, but
it should be started as soon as possible for highrisk patients.
• Four small studies performed in China, India,
Iran, and the United States at MD Anderson
have investigated the role of ATO with ATRA as
induction therapy with complete remission
rates from 86-95%.
• However, a randomized controlled trial is
needed to compare chemotherapy with ATRA
versus ATO with ATRA to determine which
therapy is ideal for induction.
ATRA
• ATRA was first demonstrated to be effective in acute
promyelocytic leukemia (APL) in China during the mid
1980s.
• Pharmacologic doses of ATRA (45 mg/m2 divided into bid
doses) led to terminal differentiation of malignant
promyelocytes to mature neutrophils.
• However, ATRA alone cannot eradicate the malignant clone.
There can be complete hematologic and molecular
remission with the addition of chemotherapy to ATRA.
• studies have shown that extended ATRA treatment
improved complete remission rates, improved overall
survival, and reduced relapse rates.
ATRA induced differentiation
Other benefits
• ATRA helps to rapidly control the DIC
associated with acute promyelocytic leukemia
(APL).
Adverse effect - RAS
• About 25-50% of patients can develop retinoic
acid syndrome (RAS) during treatment with
ATRA
• This syndrome can occur within the first 21 days of treatment and is
characterized by fever, hypotension, weight gain, respiratory
distress, serositis with pleural or pericardial effusions, hypoxemia,
radiologic infiltrates, acute renal failure, and hepatic dysfunction.
• Other side effects of ATRA include headache, nasal stuffiness, dry
red skin and, rarely, pseudotumor cerebri.
• RAS should be treated with intravenous (IV) dexamethasone for at
least 3 days.
• Resistance to ATRA has been seen with the other cytogenetics
variants of acute promyelocytic leukemia (APL), especially the PLZFRAR alpha mutation, but the resistance may also develop as a
secondary event in garden variety APL.
Arsenic trioxide
• ATO induces differentiation of acute promyelocytic leukemia (APL)
cells at low concentrations and apoptosis at higher concentrations
by interacting with the PML-RAR alpha protein.
• ATO has been studied as part of induction therapy and in the
relapsed setting.
• In 2004, Shen et al randomized 61 patients to ATRA versus ATO
versus ATO and ATRA. All groups demonstrated high complete
remission rates (>90%), but the combination group had the fastest
time to complete remission, greater molecular reduction of disease,
and lower relapse rates.
• However, ATO has not yet been compared to standard induction or
consolidation chemotherapy in a randomized clinical trial. It is
recommended that ATO is used in first-line setting if the patient
cannot tolerate chemotherapy.
BONE MARROW TRANSPLANT
• The cure rate for acute promyelocytic leukemia (APL) is
high, such that BMT is not the first option.
• There is also significant transplant-related mortality,
especially with allogeneic transplants.
• BMT should be offered to patients in the relapsed setting.
– Patients who achieve molecular remission with salvage therapy
should be offered high-dose chemotherapy, followed by
autologous stem cell transplantation (SCT) for consolidation.
– Patients who have persistent molecular or hematologic disease
after salvage therapy should be offered allogeneic SCT if they
have a good performance status and an HLA-matched donor can
be found.
So what is bone marrow transplant?
• Bone marrow transplantation (BMT) is a
relatively new medical procedure being used
to treat diseases once thought incurable.
Since its first successful use in 1968, BMTs
have been used to treat patients diagnosed
with leukemia, aplastic anemia, lymphomas
such as Hodgkin's disease, multiple myeloma,
immune deficiency disorders and some solid
tumors such as breast and ovarian cancer
• Although BMTs now save thousands of lives
each year, 70 percent of those needing a BMT
using donor marrow are unable to have one
because a suitable bone marrow donor cannot
be found.
• Large doses of chemotherapy and/or radiation are
required to destroy the abnormal stem cells and
abnormal blood cells found in cancers and aplastic
conditions.
• These therapies, however, not only kill the abnormal
cells but can destroy normal cells found in the bone
marrow as well.
• A bone marrow transplant enables physicians to treat
these diseases with aggressive chemotherapy and/or
radiation by allowing replacement of the diseased or
damaged bone marrow after chemo or radiation
• While bone marrow transplants do not
provide 100 percent assurance that the
disease will not recur, a transplant can
increase the likelihood of a cure or at least
prolong the period of disease-free survival for
many patients.
How it is done
• In a bone marrow transplant, the patient's diseased bone marrow is
destroyed and healthy marrow is infused into the patient's bloodstream.
• In a successful transplant, the new bone marrow migrates to the
cavities of the large bones, engrafts and begins producing normal
blood cells.
• If bone marrow from a donor is used, the transplant is called an
"allogeneic" BMT, or "syngeneic" BMT if the donor is an identical
twin.
• In cases where the disease afflicting the bone marrow is in
remission or if the condition being treated does not involve the
bone marrow, patients may be their own bone marrow donors,
autologous BMT
• In an allogeneic BMT, the new bone marrow infused into
the patient must match the genetic makeup of the patient's
own marrow as perfectly as possible.
• Special blood tests are conducted to determine whether or
not the donor's bone marrow matches the patient's.
• If the donor's bone marrow is not a good genetic match, it
will perceive the patient's body as foreign material to be
attacked and destroyed. This condition is known as graftversus-host disease (GVHD) and can be life-threatening.
• Alternatively, the patient's immune system may destroy the
new bone marrow. This is called graft rejection