AML LECTURE

1. Acute myeloid leukaemias
• Acute myeloid leukaemia (AML) is a clonal
expansion of myeloid blast cells (myeloblasts) in
the bone marrow.
• Myeloblasts vary in size from slightly larger than a
lymphoblast to the size of a monocyte (12-15 μm).
• They have variable amounts of basophilic or light
grey cytoplasm which may contain azurophilic
granules or Auer rods, the latter being myeloid-
specific.
• The nuclei vary from round to ovoid, indented or
convoluted, and the nuclear chromatin is fine with
one or more nucleoli.

3. Acute Myeloid Leukemia(AML)
CLINICAL PRESENTATION
Symptoms
• 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)

4. Physical Examination
• 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

5. Physical Examination
• 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 t(8;21)
patients]

6. Physical Findings
• Fever, splenomegaly, hepatomegaly,
lymphadenopathy, sternal tenderness, and
evidence of infection and hemorrhage are often
found at diagnosis.
• Significant GI bleeding, intrapulmonary
hemorrhage, or intracranial hemorrhage occurs
most often in APL.
• Bleeding associated with coagulopathy may also
occur in monocytic AML and with extreme
degrees of leukocytosis or thrombocytopenia in
other morphologic subtypes.

7. Physical Findings
• Retinal hemorrhages are detected in 15% of
patients.
• Infiltration of the gingivae, skin, soft tissues,
or meninges with leukemic blasts at diagnosis
is characteristic of the monocytic subtypes
and those with 11q23 chromosomal
abnormalities.

8. Laboratory and Radiologic Studies
• CBC with manual differential cell count
• Chemistry tests (electrolytes, creatinine, BUN,
calcium, phosphorus, uric acid, hepatic
enzymes, bilirubin, LDH, amylase, lipase)
• Clotting studies (prothrombin time, partial
thromboplastin time, fibrinogen, d-dimer)
• Viral serologies (CMV, HSV-1, varicella-zoster)
• RBC type and screen

9. • HLA typing for potential allogeneic HSCT
• Bone marrow aspirate and biopsy
(morphology, cytogenetics, flow cytometry,
molecular studies for NPM1 and CEBPA
mutations and FLT3-ITD)
• Cryopreservation of viable leukemia cells
• Myocardial function (echocardiogram or MUGA
scan)
• PA and lateral chest radiograph
• Placement of central venous access device

10. Interventions for Specific Patients
• Dental evaluation (for those with poor
dentition)
• Lumbar puncture (for those with symptoms of
CNS involvement)
• Screening spine MRI (for patients with back
pain, lower extremity weakness, paresthesias)
• Social work referral for patient and family
psychosocial support

11. Hematologic Findings
• Anemia is usually present at diagnosis and can
be severe.
• The anemia is usually normocytic
normochromic.
• Decreased erythropoiesis often results in a
reduced reticulocyte count, and red blood cell
(RBC) survival is decreased by accelerated
destruction.
• Active blood loss also contributes to the
anemia.

12. Hematologic Findings
• The median presenting leukocyte count is about
15,000/μL.
• Between 25 and 40% of patients have counts <5000/μL,
and 20% have counts >100,000/μL.
• Fewer than 5% have no detectable leukemic cells in the
blood.
• The morphology of the malignant cell varies in different
subsets.
• In AML, the cytoplasm often contains primary
(nonspecific) granules, and the nucleus shows fine, lacy
chromatin with one or more nucleoli characteristic of
immature cells.
• Abnormal rod-shaped granules called Auer rods are not
uniformly present, but when they are, myeloid lineage is
virtually certain.

13. Hematologic Findings
• Poor neutrophil function may be noted functionally
by impaired phagocytosis and migration and
morphologically by abnormal lobulation and
deficient granulation.
• Platelet counts <100,000/μL are found at diagnosis
in 75% of patients, and about 25% have counts
<25,000/μL.
• Both morphologic and functional platelet
abnormalities can be observed, including large and
bizarre shapes with abnormal granulation and
inability of platelets to aggregate or adhere
normally to one another.

14. Pretreatment Evaluation
• Once the diagnosis of AML is suspected, a rapid
evaluation and initiation of appropriate therapy should
follow.
• Initial studies should evaluate the overall functional
integrity of the major organ systems, including the
cardiovascular, pulmonary, hepatic, and renal systems.
• Factors that have prognostic significance, either for
achieving CR or for predicting the duration of CR, should
also be assessed before initiating treatment, including
cytogenetics and molecular markers.
• Leukemic cells should be obtained from all patients and
cryopreserved for future use as new tests and
therapeutics become available.
• All patients should be evaluated for infection.

15. Pretreatment Evaluation
• Most patients are anemic and thrombocytopenic at
presentation.
• Replacement of the appropriate blood components,
if necessary, should begin promptly.
• About 50% of patients have a mild to moderate
elevation of serum uric acid at presentation, while
Only 10% have marked elevations, but renal
precipitation of uric acid results in the nephropathy,
a serious but uncommon complication.
• Initiation of chemotherapy may aggravate
hyperuricemia, and patients are usually started
immediately on allopurinol and hydration at
diagnosis.

16. Pretreatment Evaluation
• Rasburicase (recombinanturic oxidase) is also
useful for treating uric acid nephropathy and
often can normalize the serum uric acid level
within hours with a single dose of treatment.
• The presence of high concentrations of lysozyme,
a marker for monocytic differentiation, may be
etiologic in renal tubular dysfunction, which
could worsen other renal problems that arise
during the initial phases of therapy.

17. TREATMENT of AML
• Treatment of the newly diagnosed patient with
AML is usually divided into two phases,
• Induction and
• Postremission management
The initial goal is to induce CR. Once CR is
obtained,
• further therapy must be used to prolong survival
and achieve cure.
• The initial induction treatment and subsequent
postremission therapy are often chosen based
on the patient’s age.

18. • Intensifying therapy with traditional
chemotherapy agents such as cytarabine and
anthracyclines in younger patients (<60 years)
appears to increase the cure rate of AML.
• In older patients, the benefit of intensive
therapy is controversial; novel approaches for
selecting patients predicted to be responsive to
treatment and new therapies are being
pursued.

19. INDUCTION CHEMOTHERAPY
• The most commonly used CR induction regimens
(for patients other than those with APL) consist of
combination chemotherapy with cytarabine and an
anthracycline (e.g., daunorubicin, idarubicin,
mitoxantrone).
• Cytarabine is a cell cycle S-phase–specific
antimetabolite that becomes phosphorylated
intracellularly to an active triphosphate form that
interferes with DNA synthesis.
• Anthracyclines are DNA intercalators. Their primary
mode of action is thought to be inhibition of
topoisomerase II, leading to DNA breaks.

20. INDUCTION CHEMOTHERAPY
• In younger adults (age <60 years), cytarabine is
used either at standard dose (100–200 mg/m2)
administered as a continuous intravenous
infusion for 7 days or higher dose (2 g/m2)
administered intravenously every 12 h for 6
days.
• With standard-dose cytarabine, anthracycline
therapy generally consists of daunorubicin (60–
90 mg/m2) or idarubicin (12 mg/m2)
intravenously on days 1, 2, and 3.
• Other agents can be added (i.e., cladribine)
when 60 mg/m2 of daunorubicin is used.

21. INDUCTION CHEMOTHERAPY
• High-dose cytarabine-based regimens have also
been shown to induce high CR rates.
• When given in high doses, higher intracellular levels
of cytarabine may be achieved, thereby saturating
the cytarabine-inactivating enzymes and increasing
the intracellular levels of 1-β-d-
arabinofuranylcytosine-triphosphate, the active
metabolite incorporated into DNA.
• Thus, higher doses of cytarabine may increase the
inhibition of DNA synthesis and thereby overcome
resistance to standard-dose cytarabine.
• With high-dose cytarabine, daunorubicin 60
mg/m2 or idarubicin 12 mg/m2 is generally used.

22. INDUCTION CHEMOTHERAPY
• The hematologic toxicity of high-dose cytarabine-
based induction regimens has typically been
greater than that associated with 7 and 3
regimens.
• Toxicity with high-dose cytarabine also includes
pulmonary toxicity and significant and
occasionally irreversible cerebellar toxicity.

23. • All patients treated with high-dose cytarabine
must be closely monitored for cerebellar
toxicity.
• Full cerebellar testing should be performed
before each dose, and further high dose
cytarabine should be withheld if evidence of
cerebellar toxicity develops.
• This toxicity occurs more commonly in patients
with renal impairment and in those older than
age 60 years.
• The increased toxicity observed with high-dose
cytarabine has limited the use of this therapy in
older AML patients.

24. Target Agents
• Incorporation of novel and molecular targeting agents
into these regimens is currently under investigation.
• Trials with tyrosine kinase inhibitors are ongoing.
• Patients with CBF AML may benefit from the combination
of gemtuzumab ozogamicin, a monoclonal CD33 antibody
linked to the cytotoxic agent calicheamicin, with induction
and consolidation chemotherapies.
• This agent, initially approved for older patients with
relapsed disease, has been withdrawn at the request of
the U.S. FDA due to concerns about the toxicity, including
myelosuppression, infusion toxicity, and venoocclusive
disease.
• However, the aforementioned recent results are
encouraging and support the reintroduction of this agent
into the therapeutic armamentarium for AML.

25. • In older patients (age ≥60 years), the outcome is
generally poor likely due to a higher induction
treatment–related mortality rate and frequency
of resistant disease, especially in patients with
prior hematologic disorders (MDS or
myeloproliferative syndromes) or who have
received chemotherapy treatment for another
malignancy or harbor cytogenetic and genetic
abnormalities that adversely impact on clinical
outcome.

26. • Alternatively, older patients can be also treated
with the 7 and 3 regimen with standard-dose
cytarabine and idarubicin (12 mg/m2),
daunorubicin (45–90 mg/m2), or mitoxantrone
(12 mg/ m2).
• For patients older than 65 years, higher dose
daunorubicin (90 mg/m2) has not shown benefit
due to the increased toxicity and is not
recommended.
• The combination of gemtuzumab ozogamicin
with chemotherapy reduces the risk of relapse
for patients age 50–70 years with previously
untreated AML.

27. • Finally, older patients may be considered for
single-agent therapies with clofarabine or
hypomethylating agents (i.e., 5-azacitidine or
decitabine), oftenly used for patients unfit for
more intensive therapies
• After one cycle of the 7 and 3 chemotherapy
induction regimen, if persistence of leukemia is
documented, the patient is usually retreated
with the same agents (cytarabine and the
anthracycline) for 5 and 2 days, respectively.

28. POSTREMISSION THERAPY
• Induction of a durable first CR is critical to long-
term disease free survival in AML.
• However, without further therapy, virtually all
patients experience relapse.
• Thus, postremission therapy is designed to
eradicate residual leukemic cells to prevent
relapse and prolong survival.
• The type of post remission therapy in AML is
often based on age and cytogenetic and
molecular risk.

29. POSTREMISSION THERAPY
• For younger patients, most studies include intensive
chemotherapy and allogeneic or autologous
hematopoietic stem cell transplantation (HSCT).
• In the postremission setting, high-dose cytarabine for
three to four cycles is more effective than standard-
dose cytarabine.
• The Cancer and Leukemia Group B (CALGB), for example,
compared the duration of CR in patients randomly
assigned after remission to four cycles of high (3 g/m2,
every 12 h on days 1, 3, and 5), intermediate (400
mg/m2 for 5 days by continuous infusion), or standard
(100 mg/m2 per day for 5 days by continuous infusion)
doses of cytarabine.
• A dose-response effect for cytarabine in patients with
AML who were age ≤60 years was demonstrated.

30. POSTREMISSION THERAPY
• High-dose cytarabine significantly prolonged CR
and increased the fraction cured in patients with
favorable [t(8;21) and inv(16)] and normal
cytogenetics, but it had no significant effect on
patients with other abnormal karyotypes.
• As discussed, high-dose cytarabine has increased
toxicity in older patients.
• Therefore, in this age group, for patients without
CBF AML, exploration of attenuated chemotherapy
regimens has been pursued.
• However, because the outcome of older patients is
poor, allogeneic HSCT, when feasible, should be
strongly considered.

31. POSTREMISSION THERAPY
Postremission therapy is also a setting for introduction
of new agents
• Autologous HSCT preceded by one to two cycles of
high-dose cytarabine is also an option for intensive
consolidation therapy.
• Autologous HSCT has been generally applied to AML
patients in the context of a clinical trial or when the
risk of repetitive intensive chemotherapy
represents a higher risk than the autologous HSCT
(e.g., in patients with severe platelet
alloimmunization) or when other factors including
patient age, comorbid conditions, and fertility are
considered.

32. POSTREMISSION THERAPY
• Allogeneic HSCT is used in patients age <70–75
years with a human leukocyte antigen (HLA)-
compatible donor who have high risk
cytogenetics.
• Selected high-risk patients are also considered
for alternative donor transplants (e.g.,
mismatched unrelated, haploidentical related,
and unrelated umbilical cord donors).
• For older patients, exploration of reduced-
intensity allogeneic HSCT has been pursued.

33. POSTREMISSION THERAPY
• Trials comparing intensive chemotherapy and
autologous and allogeneic HSCT have shown
improved duration of remission with allogeneic
HSCT compared to autologous HSCT or
chemotherapy alone.
• In fact, relapse following allogeneic HSCT occurs in
only a small fraction of patients, but treatment-
related toxicity is relatively high; complications
include venoocclusive disease, graft-versus-host
disease (GVHD), and infections.
• Autologous HSCT can be administered in young and
older patients and uses the same preparative
regimens.
• Patients subsequently receive their own stem cells
collected while in remission.

34. POSTREMISSION THERAPY
• The toxicity is relatively low with autologous
HSCT (5% mortality rate), but the relapse rate is
higher than with allogeneic HSCT, due to the
absence of the graft-versus leukemia (GVL)
effect seen with allogeneic HSCT and possible
contamination of the autologous stem cells
with residual tumor cells.

35. • Patients with the favorable CBF AML [i.e., t(8;21),
inv(16), or t(16;16)] are treated with repetitive
doses of high-dose cytarabine, which offers a high
frequency of cure without the morbidity of
transplant.
• Among AML patients with t(8;21) and inv(16),
those with KIT mutations, who have a worse
prognosis, may be considered for novel
investigational studies, including tyrosine kinase
inhibitors.
• The inclusion of gemtuzumab ozogamicin in
induction and consolidation chemotherapy-based
treatment has been reported to be beneficial in
this subset of patients.

36. • For patients in morphologic CR,
immunophenotyping to detect minute populations
of blasts or sensitive molecular assays (e.g.,
reverse transcriptase polymerase chain reaction
[RT-PCR]) to detect AML-associated molecular
abnormalities (e.g., NPM1 mutation, the CBF AML
RUNX1/RUNX1T1 and CBFB/MYH11 transcripts, the
APL PML/RARA transcript), and the less sensitive
metaphase cytogenetics or interphase
cytogenetics by fluorescence in situ hybridization
(FISH) to detect AML-associated cytogenetic
aberrations, can be performed to assess whether
clinically meaningful minimal residual disease.

37. • Minimal residual disease (MRD) is present at
sequential time points during or after treatment.
• Detection of MRD may be a reliable discriminator
between patients who will continue in CR and
those who are destined to experience disease
recurrence and therefore require early therapeutic
intervention before clinical relapse occurs.
• Although assessment of MRD in bone marrow
and/or blood during CR is routinely used in the
clinic to anticipate clinical relapse and initiate
timely salvage treatment for APL patients, for other
cytogenetic and molecular subtypes of AML, this is
an area of current investigation.

38. • Adequate and prompt blood bank support is critical
to therapy of AML.
• Platelet transfusions should be given as needed to
maintain a platelet count ≥10,000/μL.
• The platelet count should be kept at higher levels in
febrile patients and during episodes of active
bleeding or DIC.
• Patients with poor post transfusion platelet count
increments may benefit from administration of
platelets from HLAmatched donors.
• RBC transfusions should be administered to keep
the hemoglobin level >80 g/L (8 g/dL) in the
absence of active bleeding, DIC, or congestive heart
failure, which require higher hemoglobin levels.

39. • Blood products leukodepleted by filtration
should be used to avert or delay
alloimmunization as well as febrile reactions.
• Blood products should also be irradiated to
prevent transfusion-associated GVHD.
• Cytomegalovirus (CMV)-negative blood
products should be used for CMV-seronegative
patients who are potential candidates for
allogeneic HSCT.
•

40. • Neutropenia (neutrophils <500/μL or <1000/μL and
predicted to decline to <500/μL over the next 48 h)
can be part of the initial presentation and/or a side
effect of the chemotherapy treatment in AML
patients.
• Thus, infectious complications remain the major
cause of morbidity and death during induction
and postremission chemotherapy for AML.
• Antibacterial (i.e., quinolones) and antifungal (i.e.,
posaconazole) prophylaxis in the absence of fever
is likely to be beneficial.
• For patients who are herpes simplex virus or
varicellazoster seropositive, antiviral prophylaxis
should be initiated (e.g., acyclovir, valacyclovir).

41. • Fever develops in most patients with AML, but
infections are documented in only half of febrile
patients.
• Early initiation of empirical broad-spectrum
antibacterial and antifungal antibiotics has
significantly reduced the number of patients dying
of infectious complications.
• An antibiotic regimen adequate to treat gram-
negative organisms should be instituted at the
onset of fever in a neutropenic patient after clinical
evaluation, including a detailed physical
examination with inspection of the indwelling
catheter exit site and a perirectal examination, as
well as procurement of cultures and radiographs
aimed at documenting the source of fever.

42. • Acceptable regimens for empiric antibiotic therapy include
monotherapy with imipenem-cilastatin, meropenem,
piperacillin/ tazobactam, or an extended-spectrum
antipseudomonal cephalosporin (cefepime or ceftazidime).
• Combination of an aminoglycoside with an
antipseudomonal penicillin (e.g., piperacillin) or an
aminoglycoside in combination with an extended-spectrum
antipseudomonal cephalosporin should be considered in
complicated or resistant cases.
• Empirical vancomycin should be added in neutropenic
patients with catheter-related infections, blood cultures
positive for gram-positive bacteria before final identification
and susceptibility testing, hypotension or shock or known
colonization with penicillin/cephalosporin-resistant
pneumococci or methicillin-resistant Staphylococcus aureus..

43. • In special situations where decreased
susceptibility to vancomycin, vancomycin-
resistant organisms, or vancomycin toxicity is
documented, other options including
linezolid, daptomycin, and quinupristin/
dalfopristin need to be considered.

44. • Caspofungin (or a similar echinocandin), voriconazole, or
liposomal amphotericin B should be considered for
antifungal treatment if fever persists for 4–7 days
following initiation of empiric antibiotic therapy.
• Amphotericin B, Although liposomal formulations have
improved the toxicity profile, its use has been limited to
situations with high risk of or documented mold
infections.
• Caspofungin has been approved for empiric antifungal
treatment.
• Voriconazole has also been shown to be equivalent in
efficacy and less toxic than amphotericin B.
• Antibacterial and antifungal should be continued until
patients are no longer neutropenic, regardless of
whether a specific source has been found for the fever.

45. • Recombinant hematopoietic growth factors
have been incorporated into clinical trials in
AML,to lower the infection rate after
chemotherapy.
• Both G-CSF and granulocyte-macrophage
colony-stimulating factor (GM-CSF) have
reduced the median time to neutrophil
recovery.
• This accelerated rate of neutrophil recovery,
however, has not generally translated into
significant reductions in infection rates or
shortened hospitalizations.

46. • In most randomized studies, both G-CSF and
GM-CSF have failed to improve the CR rate,
disease-free survival, or overall survival.
• Although receptors for both G-CSF and GM-CSF
are present on AML blasts, therapeutic efficacy
is neither enhanced nor inhibited by these
agents.

47. TREATMENT FOR REFRACTORY OR RELAPSED
AML
• With the 7 and 3 regimen, 65–75% of younger and 50–
60% of older patients with primary AML achieve CR.
• Two-thirds achieve CR after a single course of therapy,
and one-third require two courses.
• Of patients who do not achieve CR, approximately 50%
have a drug resistant leukemia, and 50% do not
achieve CR because of fatal complications of bone
marrow aplasia or impaired recovery of normal stem
cells.
• Because these patients are usually not cured even if
they achieve second CR with salvage chemotherapy,
allogeneic HSCT is a necessary therapeutic step.

48. • In patients who relapse after achieving CR, the length of first
CR is predictive of response to salvage chemotherapy
treatment; patients with longer first CR (>12 months)
generally relapse with drug-sensitive disease and have a
higher chance of attaining a CR, even with the same
chemotherapeutic agents used for first remission induction.
• Whether initial CR was achieved with one or two courses of
chemotherapy and the type of postremission therapy may
also predict achievement of second CR.
• Similar to patients with refractory disease, patients with
relapsed disease are rarely cured by the salvage
chemotherapy treatments.
• Therefore, patients who eventually achieve a second CR and
are eligible for allogeneic HSCT should be transplanted.

49. Target therapy
• In addition to kinase inhibitors for FLT3- and KIT-
mutated AML, other compounds targeting the
aberrant activity of mutant proteins (e.g., IDH2
inhibitors) or biologic mechanisms deregulating
epigenetics (e.g., histone deacetylase and DNA
methyltransferase inhibitors),
• cell proliferation (e.g., farnesyl transferase
inhibitors),
• protein synthesis (e.g., aminopeptide inhibitors)
and
• folding (e.g., heat shock protein inhibitors), and
ubiquitination, or

50. • with novel cytotoxic mechanisms (e.g.,
clofarabine, sapacitabine), are being tested in
clinical trials.
• Furthermore, approaches with antibodies
targeting commonly expressed leukemia blasts
(e.g., CD33) or leukemia initiating cells (e.g.,
CD123) and immunomodulatory agents (e.g.,
lenalidomide) are also under investigation.

51. TREATMENT OF ACUTE PROMYELOCYTIC
LEUKEMIA
• APL is a highly curable subtype of AML, and
approximately 85% of these patients achieve long-term
survival with current approaches.
• APL has long been shown to be responsive to
cytarabine and daunorubicin, but previously patients
treated with these drugs alone frequently died from DIC
induced by the release of granule components by the
chemotherapy-treated leukemia cells.
• However, the prognosis of APL patients has changed
dramatically from adverse to favorable with the
introduction of tretinoin, an oral drug that induces the
differentiation of leukemic cells bearing the t(15;17),
where disruption of the RARA gene encoding a retinoid
acid receptor occurs.

52. Tretinoin
• Tretinoin decreases the frequency of DIC but produces another
complication called the APL differentiation syndrome.
• Occurring within the first 3 weeks of treatment, it is characterized by
fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates,
pleural and pericardial effusions, and hypoxemia.
• The syndrome is related to adhesion of differentiated neoplastic cells
to the pulmonary vasculature endothelium.
• Glucocorticoids, chemotherapy, and/ or supportive measures can be
effective for management of the APL differentiation syndrome.
• Temporary discontinuation of tretinoin is necessary in cases of severe
APL differentiation syndrome (i.e., patients developing renal failure or
requiring admission to the intensive care unit due to respiratory
distress).
• The mortality rate of this syndrome is about 10%.

53. Tretinoin
• Tretinoin (45 mg/m2 per day orally until remission is
documented) plus concurrent anthracycline-based (i.e.,
idarubicin or daunorubicin) chemotherapy appears to be
among the most effective treatment for APL, leading to CR
rates of 90–95%.
• The role of cytarabine in APL induction and consolidation
is controversial.
• The addition of cytarabine, although not demonstrated to
increase the CR rate, seemingly decreases the risk for
relapse.
• Following achievement of CR, patients should receive at
least two cycles of anthracycline based chemotherapy.

54. • Arsenic trioxide has significant antileukemic
activity and is being explored as part of initial
treatment in clinical trials of APL.
• Patients receiving arsenic trioxide are at risk of
APL differentiation syndrome, especially
when it is administered during induction or
salvage treatment after disease relapse.
• In addition, arsenic trioxide may prolong the
QT interval, increasing the risk of cardiac
arrhythmias.

55. • A study compared the gold standard (tretinoin
plus chemotherapy) in newly diagnosed non-
high-risk APL with a chemotherapy-free
combination of tretinoin and arsenic trioxide.
• An equivalent outcome was demonstrated
between the two arms, and the
chemotherapy-free regimen will likely become
a new standard for non-high-risk APL patients.

56. • Combinations of tretinoin, arsenic trioxide, and/or
chemotherapy and/or gemtuzumab ozogamicin have
shown favorable responses in high-risk APL patients at
diagnosis.
• Assessment of residual disease by RT-PCR amplification
of the t(15;17) chimeric gene product PML-RARA
following the final cycle of chemotherapy is an
important step in the management of APL patients.
• Disappearance of the signal is associated with long-
term disease-free survival; its persistence documented
by two consecutive tests performed 2 weeks apart
invariably predicts relapse.
• Sequential monitoring of RT-PCR for PML-RARA is now
considered standard for postremission monitoring of
APL, especially in high-risk patients.

57. • Patients in molecular, cytogenetic, or clinical
relapse should be salvaged with arsenic trioxide
with or without tretinoin; it produces
meaningful responses in up to 85% of patients
and can be followed by autologous or, less
frequently, especially if RT-PCR positive for PML-
RARA, allogeneic HSCT.

58. A. Uniform population of primitive myeloblasts with immature
chromatin,nucleoli in some cells, and primary cytoplasmic
granules.

59. B. Leukemic myeloblast containing an
Auer rod.

60. C. Promyelocytic leukemia cells with prominent cytoplasmic
primary granules.

61. D. Peroxidase stain shows dark blue color characteristic
of peroxidase in granules in AML.

62. Therapy of newly diagnosed acute
myeloid leukemia (AML).
• For all forms of AML except acute promyelocytic leukemia (APL),
standard therapy includes a regimen based on a 7-day continuous
infusion of cytarabine (100–200 mg/m2 per day) and a 3-day course
of daunorubicin (60–90 mg/m2 per day) with or without additional
drugs. Idarubicin (12–13 mg/m2 per day) could be used in place of
daunorubicin .
• Patients who achieve complete remission (CR) undergo
postremission consolidation therapy, including sequential courses
of high-dose cytarabine, autologous hematopoietic stem cell
transplantation (HSCT), allogeneic HSCT, or novel therapies, based
on their predicted risk of relapse (i.e., risk-stratified therapy).
• Patients with APL usually receive tretinoin and arsenic trioxide–
based regimens with or without anthracycline-based chemotherapy
and possibly maintenance with tretinoin.