Acute Promyelocytic Acute Promyelocytic Leukemia (APL)Leukemia (APL)

ByBy

Maged Abd El Fattah AmineMaged Abd El Fattah AmineAssistant Lecturer Of Medical Oncology Assistant Lecturer Of Medical Oncology

South Egypt Cancer InstituteSouth Egypt Cancer Institute

3.20143.2014

18/3/2014

*Outline:*Outline:

- Hematopoiesis.- Hematopoiesis.- Introduction and Epidemiology of APL.- Introduction and Epidemiology of APL.- Pathogenesis of APL.- Pathogenesis of APL.- Diagnosis of APL.- Diagnosis of APL.- Treatment of APL. - Treatment of APL. - Conclusions.- Conclusions.

2APL

HematopoiesisHematopoiesis

18/3/2014 3APL

- Hematopoiesis- Hematopoiesis is a term describing the formation and is a term describing the formation and development of blood cells.development of blood cells.

- The hematopoietic system must have the capacity - The hematopoietic system must have the capacity for self renewal, which involves:for self renewal, which involves:1- 1- ProliferationProliferation of progeny stem cells. of progeny stem cells.2- 2- Differentiation and maturation Differentiation and maturation of the stem cells of the stem cells into the functional cellular elements.into the functional cellular elements.

- Normally hematopoiesis is limited to the - Normally hematopoiesis is limited to the bone bone marrow and the widespread lymphatic system marrow and the widespread lymphatic system and and only only mature cells mature cells are released into the peripheral are released into the peripheral blood. blood.

18/3/2014 4APL

18/3/2014 5APL

- All cells are derived from a pool of stem cells that- All cells are derived from a pool of stem cells thatare are self-renewingself-renewing..- Pluripotential & multipotential stem cells give rise- Pluripotential & multipotential stem cells give riseto to committed stem cells committed stem cells for each cell line.for each cell line.

- - Committed stem cells have receptors for specific Committed stem cells have receptors for specific growth factorsgrowth factors, respond to stimulation by division & , respond to stimulation by division & maturation maturation (precursor cell stages) (precursor cell stages) into into end-stage cellsend-stage cells..- Growth factor stimulation increases with need.- Growth factor stimulation increases with need.

18/3/2014 6APL

18/3/2014 7APL

18/3/2014 8APL

18/3/2014 9APL

18/3/2014

IntroductionIntroductionAnd And

Epidemiology of APLEpidemiology of APL

10APL

- - Acute promyelocytic leukemia (APL)Acute promyelocytic leukemia (APL), is a distinct subtype of , is a distinct subtype of acute myeloid leukemia, represents about acute myeloid leukemia, represents about 10-12%10-12% of adult AML of adult AML cases, and cases, and 8% - 15% 8% - 15% of pediatric AML.of pediatric AML.

- The median age is approximately - The median age is approximately 30-40 years30-40 years, which is , which is considerably considerably younger than younger than the other subtypes of AML (70 yrs).the other subtypes of AML (70 yrs).

- It- It was first described in was first described in 1957 1957 byby “Hillestad (Sweden)” “Hillestad (Sweden)”,, as a as a hyperacute fatal illness.hyperacute fatal illness.

- laboratory evidence of DIC is present in - laboratory evidence of DIC is present in 70% to 90% 70% to 90% of of patients at diagnosis or shortly after.patients at diagnosis or shortly after.

- Hemorrhagic events contribute - Hemorrhagic events contribute 10% to 15% 10% to 15% excess mortality excess mortality during induction chemotherapy for APL.during induction chemotherapy for APL.

18/3/2014 11APL

-- MorphologicallyMorphologically, it is identified as , it is identified as AML-M3AML-M3 by the French- by the French-American-British (FAB) classification.American-British (FAB) classification.

-- Cytogenetically (WHO)Cytogenetically (WHO), APL is characterized by a balanced , APL is characterized by a balanced reciprocal translocation abnormality, reciprocal translocation abnormality, t(15;17)(q22;q12); t(15;17)(q22;q12); PML-RARAPML-RARA. .

- Currently it is one of the most treatable forms of leukemia with - Currently it is one of the most treatable forms of leukemia with a a 12-yr PFS rate, 12-yr PFS rate, is estimated to be approximately is estimated to be approximately 70%70%..

18/3/2014 12APL

Pathogenesis of APLPathogenesis of APL

18/3/2014 13APL

- In Acute promyelocytic leukemia (APL), - In Acute promyelocytic leukemia (APL), there is an abnormal there is an abnormal accumulation of immature granulocytes called accumulation of immature granulocytes called promyelocytes.promyelocytes.

- - APLAPL is characterized a balanced reciprocal translocation is characterized a balanced reciprocal translocation abnormality, abnormality, t(15;17)(q22;q12); PML-RARAt(15;17)(q22;q12); PML-RARA, which results in , which results in fusion of fusion of the retinoic acid receptor (RARA) gene on chromosome the retinoic acid receptor (RARA) gene on chromosome 17 17 with the with the promyelocytic leukemia (PML) gene on chromosome promyelocytic leukemia (PML) gene on chromosome 1515. .

- The fusion of PML and RARA results in expression of a hybrid - The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein binds with protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, enhanced affinity to sites on the cell's DNA, blocking blocking transcription and differentiation of granulocytestranscription and differentiation of granulocytes. .

18/3/2014 14APL

Physiologic Physiologic quantities of quantities of retinoic acid no retinoic acid no longer sufficient longer sufficient to allow for cell to allow for cell differentiation.differentiation.

18/3/2014

t(15;17); PML-RARAt(15;17); PML-RARA

15APL

- PML/RARa gene product - PML/RARa gene product forms homodimer.forms homodimer.

- Homodimer represses - Homodimer represses target genes needed for target genes needed for differentiation.differentiation.

- Mechanisms act via - Mechanisms act via aberrant histone aberrant histone modification and DNA modification and DNA methylation.methylation.

- Proliferation via FLT3 - Proliferation via FLT3 and KIT as well are and KIT as well are required.required.

18/3/2014 16APL

- Although the chromosomal translocation involving RARA is - Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are believed to be the initiating event, additional mutations are required for the development of leukemia. required for the development of leukemia.

- This translocation abnormality could be detected by - This translocation abnormality could be detected by karyotypingkaryotyping, , FISH FISH oror PCR PCR techniques, which is useful for techniques, which is useful for both diagnosis and evaluation of minimal residual disease.both diagnosis and evaluation of minimal residual disease.

-- EightEight other rare gene rearrangements have been described in other rare gene rearrangements have been described in APL fusing RARA to other genes “APL fusing RARA to other genes “Variant chromosomal Variant chromosomal translocationstranslocations” [e.g., ” [e.g., t(11;17)t(11;17), , t(5;17)t(5;17)], can be detected in no ], can be detected in no less than less than 5%5% of APL patients. of APL patients.

18/3/2014 17APL

18/3/2014 18APL

clinicaloptions.com/oncologyClinical Focus: Acute Promyelocytic Leukemia

PML-RARat(15;17)(q22;q21)

92%

PML-RAR+ insertions4%

PML-RAR+ variants2%

PZLF-RARt(11;17)(q23,q21)

0.8%

NPM-RARt(5;17)(q35,q21)

0.2%

NuMa-RARt(11;17)(q13,q21)

< 0.1%

Stat5b-RARder(17)

< 0.1%

No RAR1%

4 .Grimwade D, et al. Leukemia. 2002;16:1959-1973.

APL: Molecular Variants

Diagnosis of APLDiagnosis of APL

18/3/2014 20APL

Diagnosis of APLDiagnosis of APL

18/3/2014

Clinical

Morphological

Immunophenotyping

Molecular genetics

Cytogenetics

21APL

18/3/2014

Clinical- S&S of pancytopenia (fever, anemia, bleeding)- Coagulopathy (DIC). - Weakness, and malaise.- S&S of Organ infiltration.

Morphological(Blood & BM)

- Abnormal promyelocytes predominate (blastsmay be <20%), packed with granules, numerous Auer rodsin single cell (Hypergranular variant ).

- In M3v, reniform, bilobed nuclei with scant granules.

Immunophenotyping

- Classically CD33+, CD13+, MPO+, CD34–, HLA-DR–.- CD2 and CD34 expression common in microgranular var.- CD56 in 20% of cases; associated with worse outcome.

Cytogenetics- t(15;17)(q22;q12); PML-RARA.

Molecular genetics

- Molecular for PML-RARA needed in rare cases with negative cytogenetics and FISH.

- FLT3 mutations (~30% - 40%); likely adverse effect.

22APL

# Karyotype:# Karyotype:- Detects translocation variant.- Detects translocation variant.

# FISH or immunostaining:# FISH or immunostaining:- Fast – often within - Fast – often within 2-4 hours2-4 hours..- Immunostaining is inexpensive and can be done at - Immunostaining is inexpensive and can be done at smaller centers. smaller centers.

# RT-PCR:# RT-PCR:- Can detect minimal residual disease (MRD).- Can detect minimal residual disease (MRD).- - “Gold Standard”.“Gold Standard”.

18/3/2014 23APL

18/3/2014

Hypergranular variant

Microgranular variant

Incidencemajority of cases(80%)

20% of cases

Clinical Presentation

LeukopeniaLeukocytosis

Pathologypacked with granules, numerous Auer rods

in single cell

reniform, bilobed nuclei with scant to

inconspicuous granules

FlowcytometryCD13+, CD33+, MPO+, wCD45+, CD34–,

HLA-DR–

CD34, is often positive

24APL

18/3/2014 25APL

18/3/2014 26APL

18/3/2014 27APL

Anti-PML Immunofluorescent Anti-PML Immunofluorescent Antibody Test (“POD” Test)Antibody Test (“POD” Test)

Sensitivity and specificity of 98.7% and 98.9%Sensitivity and specificity of 98.7% and 98.9%

5 .Dimov N, et al. Cancer. 2010;116:369-376.18/3/2014 28APL

Treatment of APLTreatment of APL

18/3/2014 29APL

18/3/2014

APL

Leukemic Infiltration

Coagulopathy

30APL

*Coagulopathy:*Coagulopathy:

- It occurs in - It occurs in 70% to 90% 70% to 90% of cases.of cases.- It occurs due to release of several procoagulants, mainly - It occurs due to release of several procoagulants, mainly tissue tissue factor (TF), factor (TF), and and cancer procoagulant (CP).cancer procoagulant (CP).

# Def:# Def:- Fibrinogen level < 150 mg / dl.- Fibrinogen level < 150 mg / dl. OROR 2 of the following criteria; 2 of the following criteria;

(1) Fibrinogen 150-200 mg / dl.(1) Fibrinogen 150-200 mg / dl.(2) FDP (D-dimer).(2) FDP (D-dimer).(3) PT 3 sec. Longer than control.(3) PT 3 sec. Longer than control.18/3/2014

Coagulopathy

31APL

# TTT of Coagulopathy:# TTT of Coagulopathy:

1- Keep PLT count 1- Keep PLT count > 50 000.> 50 000.2- Maintain fibrinogen level 2- Maintain fibrinogen level > 150 mg/dl, > 150 mg/dl, byby -- FFP FFP 15 ml/kg 15 ml/kg (max infusion rate = 200 ml/hr).(max infusion rate = 200 ml/hr). - Cryoprecipitate. - Cryoprecipitate. - Fibrinogen ( - Fibrinogen (2 gm I.V2 gm I.V) may be given instead of ) may be given instead of plasma if available. plasma if available.

- Heparin - Heparin is of no documented value.is of no documented value. - packed RBCs - packed RBCs transfusion may worsen the condition.transfusion may worsen the condition. - - Avoid Avoid invasive procedures invasive procedures if possible (if possible (leukapheresis, leukapheresis, LP LP, and , and central line placementcentral line placement).).

18/3/2014

NoteNote::

32APL

18/3/2014 33APL

- Using - Using “Sanz” “Sanz” criteria (Sanz score).criteria (Sanz score).- - Depending on WBCs and Platelets count at presentation.Depending on WBCs and Platelets count at presentation.

18/3/2014

WBC countPlatelet count3-yr relapse-free survival

Low Risk<10>4098%

Intermediate<10<4089%

High Risk>10<4070%

Risk stratification of APL

34APL

18/3/2014 35APL

clinicaloptions.com/oncologyClinical Focus: Acute Promyelocytic Leukemia

APL Therapy: History

Discovery t(15;17) in APL

Discovery t(15;17) in APL

Differentiation of APL cells with

RA

Differentiation of APL cells with

RA

ATRA therapyATRA therapy

ATRA + CTATRA + CT

ATO in relapseATO in relapse

Daunorubicin in APL

Daunorubicin in APL

First description: Hyperacute fatal

illness associated with hemorrhagic

syndrome

First description:Hyperacute fatal

illness associated with hemorrhagic

syndrome

In vivo leukemic cell

differentiation

In vivo leukemic cell

differentiation

ATO frontline

ATO frontline

ATRA + ATO ± GO

ATRA + ATO ± GO

HIGHLY FATAL

HIGHLY CURABLE

1950 1960 1970 1980 1990 2000

6 .Chen Y, et al. Cancer. 2012;118:5811-5818. 7. Nowak D, et al. Blood. 2009;113:3655-3665.

18/3/2014

TTT of APL

Induction Therapy

Consolidation

Maintenance

37APL

- Several established treatment protocols offer - Several established treatment protocols offer excellent excellent outcomesoutcomes..

- Important not to - Important not to “mix and match” “mix and match” induction from one trial induction from one trial with consolidation from another.with consolidation from another.

- - ATRAATRA ((all-trans retinoic acidall-trans retinoic acid) ) is the is the cornerstonecornerstone in each in each protocol, whatever the protocol, whatever the risk statusrisk status..

- Treatment must begin before the diagnosis is confirmed in - Treatment must begin before the diagnosis is confirmed in patients with suspected APL, patients with suspected APL, as early ttt as early ttt is the key for survival.is the key for survival.

18/3/2014

Induction/Consolidation therapy in Induction/Consolidation therapy in APLAPL

38APL

18/3/2014 39APL

Treatment of APLTreatment of APL

18/3/2014 40APL

# ATRA [Vesanoid Caps.(10 mg)]:# ATRA [Vesanoid Caps.(10 mg)]:- - 45 mg/m45 mg/m22 P.O. daily P.O. daily in 2 divided/12hs, till CR or for a max. ofin 2 divided/12hs, till CR or for a max. of

90 days90 days..

#Anthracyclines ( DAN or IDA):#Anthracyclines ( DAN or IDA):- Daunorubicin (- Daunorubicin (50 mg/m50 mg/m2 2 I.V. x 4dI.V. x 4d), or), or ( (60 mg/m60 mg/m22 I.V. x 3d I.V. x 3d).).- I- Idarubicin (darubicin (12 mg/m12 mg/m22 I.V. x 2,4,6,8 days I.V. x 2,4,6,8 days). ).

# Cytarabine (Ara-C):# Cytarabine (Ara-C): 200 mg/m2 CIVI x 7 days200 mg/m2 CIVI x 7 days, could be , could be added according to the protocol.added according to the protocol.

18/3/2014

Induction Therapy in APL

41APL

- - 2 or 3 cycles 2 or 3 cycles of an of an anthracycline (daunorubicin or idarubicin) anthracycline (daunorubicin or idarubicin) plus plus 1 to 2 weeks of ATRA 1 to 2 weeks of ATRA are administered until are administered until molecular CRmolecular CR..

- - Intermediate- or high-dose Ara-C Intermediate- or high-dose Ara-C can be administered can be administered depending on age as a first consolidation, as in (depending on age as a first consolidation, as in (GIMEMA, APL GIMEMA, APL 2000 study2000 study);); or or Arsenic Trioxide (ATO) for 2 courses of 25 days Arsenic Trioxide (ATO) for 2 courses of 25 days each as in each as in ((second North American Intergroup C9710 studysecond North American Intergroup C9710 study).). - To consider - To consider LPLP and and IT CTR IT CTR for for 5 doses (weekly) 5 doses (weekly) in high risk in high risk patients. patients.

18/3/2014

Consolidation Treatment in APL

42APL

18/3/2014 43APL

18/3/2014 44APL

18/3/2014 45APL

- - ATRA and low-dose chemotherapy with 6-ATRA and low-dose chemotherapy with 6-mercaptopurine and methotrexate is given for mercaptopurine and methotrexate is given for 2 years2 years.. --ATRA (ATRA (45 mg/m45 mg/m22 P.O/day P.O/day) for ) for 2 weeks2 weeks every 3 months. every 3 months.- - 6-MP (6-MP (60 mg/m60 mg/m22, P.O/day, P.O/day). ). - MTX (- MTX (15 mg/m15 mg/m22, IM/ week, IM/ week).).

- There is some debate around maintenance ttt in APL, - There is some debate around maintenance ttt in APL, as some studies showed no difference in DFS and OS, as some studies showed no difference in DFS and OS, but it is but it is still the standard of care still the standard of care till now.till now.

18/3/2014

Maintenance Treatment in APL

46APL

- - Elderly patients (> 60y) Elderly patients (> 60y) have poorer outcomes with have poorer outcomes with standard treatment.standard treatment.

- In the PETHEMA trial, the - In the PETHEMA trial, the last dose of idarubicin last dose of idarubicin was omittedwas omitted during induction; consolidation should be during induction; consolidation should be altered to liposomal altered to liposomal ATRA and ATOATRA and ATO..

- Another option is - Another option is ATRA + ATO ATRA + ATO for induction for induction without anthracyclines.without anthracyclines.

18/3/2014

Treatment of APL in Elderly pts

47APL

1- Document complete molecular remission by PCR 1- Document complete molecular remission by PCR after consolidationafter consolidation..

2- Monitor PCR every 2- Monitor PCR every 3 months 3 months up to up to 2 years2 years..

3- If 3- If PCR was –vePCR was –ve, continue maintenance ttt., continue maintenance ttt.

4- If 4- If PCR was +vePCR was +ve, repeat , repeat within 4 weeks within 4 weeks to confirm.to confirm.

5- If 5- If PCR still +vePCR still +ve, proceed to ttt of relapse., proceed to ttt of relapse.

18/3/2014

Post- remission Monitoring in APL

48APL

18/3/2014 49APL

- - Arsenic Trioxide (ATO) Arsenic Trioxide (ATO) is the standard ttt of relapsed APL, is the standard ttt of relapsed APL, +/- ATRA+/- ATRA..

- If CR2 and - If CR2 and PCR was -vePCR was -ve, consider , consider ASCTASCT, or , or ATO x 6 cyclesATO x 6 cycles..- If - If PCR was +vePCR was +ve, or No CR, consider , or No CR, consider AlloSCTAlloSCT or or clinical trialclinical trial, , (Gemtuzumab followed by allo SCT).(Gemtuzumab followed by allo SCT).

- Strongly consider - Strongly consider CNS-directed treatment CNS-directed treatment with intrathecal with intrathecal chemotherapy.chemotherapy.

- - Gemtuzumab ozogamicin (GO) Gemtuzumab ozogamicin (GO) is also an effective agent for is also an effective agent for patients with relapsed APL. Although this drug is no longer patients with relapsed APL. Although this drug is no longer commercially available.commercially available.

18/3/2014

Treatment of Relapsed APL

50APL

18/3/2014 51APL

- - "Differentiation syndrome" (formerly known as ATRA "Differentiation syndrome" (formerly known as ATRA syndrome) syndrome) develops in approximately develops in approximately 25%25% of patients with APL. of patients with APL.

- - Symptoms of this syndrome are; Symptoms of this syndrome are; fever, respiratory distress with pulmonary infiltrates or pleural fever, respiratory distress with pulmonary infiltrates or pleural effusions, and cardiovascular collapse. Temporary pseudotumor effusions, and cardiovascular collapse. Temporary pseudotumor cerebri is a fairly common (10%) adverse effect of ATRA. cerebri is a fairly common (10%) adverse effect of ATRA.

- Although these symptoms most often correlate with leukocytosis - Although these symptoms most often correlate with leukocytosis (WBC > 10,000/μL(WBC > 10,000/μL), many patients develop symptoms with WBC ), many patients develop symptoms with WBC counts between 5,000/μL and 10,000/μL. The syndrome is seen in counts between 5,000/μL and 10,000/μL. The syndrome is seen in patients treated with patients treated with arsenic trioxide arsenic trioxide as well as in those treated as well as in those treated with with ATRAATRA..

18/3/2014

APL syndrome

52APL

(1) Fever + rigors.(1) Fever + rigors.(2) Capillary leak (dyspnea, pleural (2) Capillary leak (dyspnea, pleural effusion, pericardial effusion, HF).effusion, pericardial effusion, HF).(3) CXR: pulmonary infiltrates.(3) CXR: pulmonary infiltrates.(4) Renal failure.(4) Renal failure.(5) Hypotension.(5) Hypotension.(6) Edema & gain of weight.(6) Edema & gain of weight.(7) Lymphadenopathy & tonsillitis.(7) Lymphadenopathy & tonsillitis.(8) Leucocytosis.(8) Leucocytosis.

18/3/2014 53APL

# Incidence: # Incidence: Day Day 2-202-20 after start of ATRA. after start of ATRA.

#Treatment of this syndrome involves prompt use of:#Treatment of this syndrome involves prompt use of:

1- high-dose corticosteroids, 1- high-dose corticosteroids, Dexamethazone 10 mg I.V. every Dexamethazone 10 mg I.V. every 12 hrs for at least 3 days 12 hrs for at least 3 days, then gradual tapering over 2 ws. , then gradual tapering over 2 ws.

2- initiation of conventional Ara-C/daunorubicin chemotherapy 2- initiation of conventional Ara-C/daunorubicin chemotherapy to control leukocytosis, and; to control leukocytosis, and;

3- temporary discontinuation of ATRA or arsenic trioxide.3- temporary discontinuation of ATRA or arsenic trioxide.

4- Continue treatment with ATRA after controlling the 4- Continue treatment with ATRA after controlling the situation.situation.

18/3/2014 54APL

Arsenic trioxide adverse effects:Arsenic trioxide adverse effects:- ECG alterations, especially - ECG alterations, especially prolongations of the QT intervalprolongations of the QT interval. .

- - Electrolyte shifts Electrolyte shifts commonly involve potassium and magnesium. commonly involve potassium and magnesium. potassium should exceed potassium should exceed 4mmol/l4mmol/l and magnesium should be and magnesium should be above above 1.8mg/dl1.8mg/dl. .

- Regular ECG checks are indicated. If a QT interval exceeds - Regular ECG checks are indicated. If a QT interval exceeds 500msec therapy will have to be discontinued due to the 500msec therapy will have to be discontinued due to the increased risk of cardiac arrhythmias (torsade de pointes). Any increased risk of cardiac arrhythmias (torsade de pointes). Any co-medication which might prolong the QT interval in a way co-medication which might prolong the QT interval in a way similar to ATO should be avoided.similar to ATO should be avoided.

- Other frequently occurring, however, not life-threatening - Other frequently occurring, however, not life-threatening adverse effects are nausea, vomiting, exanthema, fatigue, fever, adverse effects are nausea, vomiting, exanthema, fatigue, fever, neuropathy, functional liver disorders and increase of neuropathy, functional liver disorders and increase of transaminase activities, and diarrhea.transaminase activities, and diarrhea.18/3/2014 55APL

# Ongoing trials: # Ongoing trials: - US Intergroup trial S0535- US Intergroup trial S0535,evaluating, Concurrent ATRA, ,evaluating, Concurrent ATRA, ATO, and GO for induction, then 3 courses of consolidation with ATO, and GO for induction, then 3 courses of consolidation with daunorubicin plus ATRA, ATO, and GO than maintenance.daunorubicin plus ATRA, ATO, and GO than maintenance.

- - GIMEMA[b]/DSIL-APL0406 protocolGIMEMA[b]/DSIL-APL0406 protocol, which compares ATRA, which compares ATRAplus ATO with minimal chemotherapy to standard ATRA plusplus ATO with minimal chemotherapy to standard ATRA plusanthracycline.anthracycline.

# Two novel agents:# Two novel agents:- - Oral arsenicOral arsenic appears very effective, and the combination with appears very effective, and the combination with ATRA will be an attractive strategy. ATRA will be an attractive strategy. - - Tamibarotene (AM-80) Tamibarotene (AM-80) that seems less toxic than ATRA .that seems less toxic than ATRA .

18/3/2014

Future DirectionsFuture Directions

56APL

ConclusionsConclusions

18/3/2014 57APL

** Acute promyelocytic leukemia(APL) Acute promyelocytic leukemia(APL) was first identified as a was first identified as a distinct subtype of acute myeloid leukemia in distinct subtype of acute myeloid leukemia in 19571957..

** APL is characterized by APL is characterized by three featuresthree features;; - accumulation of abnormal - accumulation of abnormal promyelocytespromyelocytes. . - occurrence of - occurrence of fibrinogenopenia and DICfibrinogenopenia and DIC.. - presence of the specific chromosomal translocation - presence of the specific chromosomal translocation t(15;17)(q22;q21).t(15;17)(q22;q21).

** Currently it is one of the Currently it is one of the most treatablemost treatable forms of acute forms of acute leukemia (shift from highly fatal to highly curable subtype). leukemia (shift from highly fatal to highly curable subtype).

** Treatment must begin before the diagnosis is confirmed in Treatment must begin before the diagnosis is confirmed in patients with suspected APL, patients with suspected APL, as early ttt as early ttt is the key for survivalis the key for survival..

18/3/2014 58APL

** ATRAATRA ((all-trans retinoic acidall-trans retinoic acid) ) is the is the cornerstonecornerstone in in each protocol, whatever the each protocol, whatever the risk statusrisk status. .

* * Several established treatment protocols offer Several established treatment protocols offer excellent excellent outcomesoutcomes..

* * Important not to Important not to “mix and match” “mix and match” induction from induction from one trial with consolidation from another. one trial with consolidation from another. * * Good supportive care during induction is essential to Good supportive care during induction is essential to control control DICDIC and and ATRA syndromeATRA syndrome..

18/3/2014 59APL

** To consider evaluation and prophylaxis for To consider evaluation and prophylaxis for CNS CNS involvementinvolvement after achievement of remission after achievement of remission. .

* * Several ongoing trials to evaluate new ttt modalities Several ongoing trials to evaluate new ttt modalities including including low or no CTR low or no CTR ..

* * Novel agents in ttt of APL as Novel agents in ttt of APL as Oral arsenic Oral arsenic and and Tamibarotene (AM-80). Tamibarotene (AM-80).

18/3/2014 60APL

THANK YOUTHANK YOU

18/3/2014 61APL