1) The patient, a 6-year-old female, presented with generalized petechiae and prolonged epistaxis. Laboratory results showed high white blood cell count with 46% blasts and 44% promyelocytes containing Auer rods, consistent with acute promyelocytic leukemia (APL). 2) She received induction therapy for APL per the TPOG-APL-2001 protocol including all-trans retinoic acid (ATRA) and chemotherapy. She experienced complications including fever, pleural effusion, and later pseudotumor cerebri, thought to be related to a drug-drug interaction between ATRA and fluconazole. 3) Her course

1. All-trans retinoic acid related
complications in a patient with acute
promyelocytic leukemia
1
2013. 05. 16
臨床藥學與藥物科技所 陳秋縈
指導老師 鄭兆能 醫師
Case report

2. Patient profile
2
Name 戴XX Admission date 2013/02/18
Age 6 y/o HT 124.3cm (50-75th%)
Gender female BW 25.8kg (75-90th%)
BSA 0.94 Allergy history NKDA
Past history
• Hospitalization: pneumonia 3y/o
Chief complaint
• Suffered from Generalized petechiae for recent one week
• Prolonged epistaxis this morning
She was referred from ENT LMD, and AOM left side was found at LMD
Physical examination and ROS
• T/P/R: 36.4/148/24 BP: 117/88mmHg
• Petechiae over trunk and extremities, especial anterior neck
• Ear drum: left side injected

3. Lab data on 2/18
3
檢驗名稱 參考值 單位 結果
WBC 4.27-13.18 10^3/μL H 52.8
RBC 3.84-5.01 10^6/μL L 2.97
Hb 10.2-13.2 g/dL L 8.2
Hct 30.9-37.9 % L 23.9
MCV 72.3-87.6 fl 80.7
MCH 23.7-29.5 pg 27.5
MCHC 33.2-35.2 g/dL 34.1
RDW 12.2-15.1 % 13.1
Plt 189-459 10^3/μL L 20
Blast % 46
Pro % 44
Myelo % 0
Meta % 0
Band % 0
Seg 22.4-69 % 1
Eos 0-3.6 % 0
Baso 0-0.7 % 0
Mono 4.1-11.4 % 0
Lymph 18.1-68.6 % 9
Aty-lym % 0
NRBC /Count WBCs 0
*Auer rods in the cytoplasm as found
檢驗名稱 參考值 單位 結果
CRP 0-8 mg/L H 32.2
FIB 276-471 mg/dL L 238.5
BIL-T 0.2-1.4 mg/dL 0.7
ALK-P 30-110 U/L H 147
CA 8.6-10.1 mg/dL 9.8
P 2.5-4.5 mg/dL 4.1
BIL-D 0-0.3 mg/dL 0.3
NA 135-148 mmol/L 145
K 3.5-5 mmol/L 4.5
BUN 7-21 mg/dL 12
CREA 0.6-1.2 mg/dL 0.46
URIC 2-6 mg/dL 6.3
AST 0-39 U/L 35
ALT 0-54 U/L 24
LD 100-200 U/L H 866
Impression：
1. Lab: Blast and promyelocyte with auer rods was
found from peripheral blood
 Suspect acute leukemia
2. Acute otitis media (AOM)
APTT 26-38 secs 28
MNAPTT secs 32.7
PT 9.4-12.5 secs H 16
PT(MNPT) secs 10.5

4. Hospital course-1
4
Date Event Management
2/18 • WBC: 52800/μL, Blast: 46%, Pro: 44%
Blast and promyelocyte with auer rods was
found
 Acute leukemia was suspected (APL)
• Perform bone marrow aspiration, biopsy and
chromosome for diagnosis
night • Fever up to 39.5, CRP: 27.4 mg/L
 Suspect AOM, r/o tumor fever
• B/C, UA
• Unasyn, Gentamicin
• Acetaminophen, Diclofenac EM
2/20 • BM biopsy and cytogenetic report:
t(15,17), PML-RAR alpha: positive
 Acute promyelocytic leukemia (APL, M3)
Start TPOG-APL-2001 induction therapy
• ATRA 20mg QD 10mg HS
2/21 • Fever, pleural effusion, hyperleukocytosis
CXR: bilateral pleural effusion, no dyspnea
BT: 38.4
WBC: 52800→ 96600/μL
• Idarubicin 8.5 mg IVD 2/21-23
MTX IT 2/21
Granisetron 3mg IVD before CT
• Dexamethasone 10mg q12h x 3 days
for prevent DS (differentiation syndrome)
2/22 • Fever subside, no pleural effusion, dyspnea
• AOM improved
• Peripheral edema with BW gain
(25.8 28.8kg)
• Furosemide 10mg ivd stat

5. Hospital course-2
5
Date Event Management
2/24 • WBC: 71200→ 15900/μL • Taper dexamethasone 5mg qd
2/25 • No fever for 3 days • DC ABX
2/26 • WBC↓: 1100/μL • DC dexamethasone
2/28 • BT: 39, WBC: 1300 /μL
 Neutropenic fever
• CRP: 27.6 mg/L
• B/C from peripheral and CVP
• Amikacin, Cefazolin, Piperacillin
3/1 • UA, CXR: normal
• WBC: 500/μL
• Oral ulcer, gingiva swelling
 Suspect HSV or oral infection
• Acyclovir 250 mg IVD q8h
• Nystatin 1# qid when
3/2 • CRP: 62.9 mg/L, Still fever
• Blood culture from CVP: GPC
 Highly suspect CVP related infection
• Remove CVP
• Shift cefazolin to Vancomycin (3/2-8)
3/4 • Persist high fever and elevated CRP • Fluconazole 250 mg qd
3/5 • Blood culture from CVP: CoNS
• CRP: 79.9 mg/L
• Persist neutropenic fever
• CXR: R’t lung infiltration
• Shift piperacillin, amikacin to meropenen
Neutropenic
Fever

6. Hospital course-3
6
Date Event Management
3/8 • Procalcitonin: 0.324 ng/ml • DC vancomycin after 7-day-use
• Metronidazole 200 mg q6h ivd
• Baktar 1# bid 1,3,5
3/10 • HTN was noted 150/99mmHg
3/13 • Fever subside, CRP↓ 161.3 45mg/L
• Visual diplopia(+), papilloedema(+), N/V
 Suspect ATRA and fluconazole DDI related
pseudotumor cerebri
• DC metronidazole, meropenem (9d), acyclovir
(14d) de-escalate to penicillin, ceftazidime
• Discontinued ATRA
• Acetazolamide 125mg qd
Mannitol 6mg q8h ivd
Dexamethasone 7.5 mg q6h ivd for IICP
• CSF study or brain image survey
3/16 • Hypertension improved, still blurred vision
• Stable condition
• Discharge
Nystatin 1# qid
Dexamethasone 4mg bid po
Acetazolamide 125mg qd
Augmentin 1# bid
3/18 • Diplopia improved
Fever

7. 7
60
80
100
120
140
160
180
35
36
37
38
39
40
41
18 19 20 21 22 23 24 25 26 27 28 3/1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
BT BP
Unasyn + Gentamicin
ATRA
Idarubicin
MTX
Dexamethasone
 edema
Furosemide
Piperacillin + Amikacin
Acyclovir
 oral ulcer
Cefazolin Vancomycin
 CVP: GPC
Fluconazole
Meropemen
TMP/SMX
 HTN
Metronidazole
 Diplopia,N/V
 pleural effusion
PCN + ceftazidime
Acetazolamide
Mannitol
Dexamethasone
47.2 52.9 96.6 91.6 71.2 15.9 2.4 1.1 1.7 1.3 0.5 0.6 0.7 1.1 0.9 1.1 2.5 2.1 1.5
27 35 28 37 63 80 150 142 161 45 24
WBC (103/μl)
CRP (mg/L)
Fever Neutropenic Fever

8. Outline
8
 Acute Promyelocytic Leukemia (APL)
 Differentiation syndrome (DS)
 Overview
 Case discussion
 Pseudotumor cerebri (PC)
 Overview
 Case discussion
 Summary

9. Acute myeloid leukemia (AML)
9
 AML is characterized by a clonal proliferation of hematopoietic
progenitor with reduce ability to differentiate into mature
elements
 Leukemic blasts or immature forms in bone marrow and periphery
 RBCs, platelets, and neutrophils
Anemia, bleeding, infection
Our patient
• Generalized petechiae
• Prolonged epistaxis
• Fever, suspect AOM

10. Classification of acute myeloid leukemia
Blood 2009;114:937 10
APL is a biologically and clinically distinct variant of AML
• French American British (FAB) classification: M3 subtype of AML
• WHO 2008 classification: APL with t(15;17)(q22;q12), (PML/RAR)
(Classified based upon morphology, immunophenotype, genetics, and clinical features)
4 major subtypes Examples
With recurrent genetic abnormalities t(8;21); inv(16); t(15;17); 11q23 anomalies
With myelodysplasia-related features Antecedent myelodysplastic syndrome (MDS)
Therapy-related AML Alkylating agents or topoisomerase inhibitors
Not otherwise specified With minimal differentiation, maturation,
myelomonocytic, monoblastic, erythroid

11. Pathogenesis
Nat Med 2001 Jun;7(6):680 11
Translocation of retinoic acid
receptor gene (RARα) to
promyelocytic gene (PML) leading
to chimeric oncogene PML-RARα
PML-RARa fusion protein forms a homodimer
 Binds to RARα target genes and ehnance
co-repressors binding
 Blocked differentiation and enhanced
self-renewal of the promyelocytes
PML-RARa fusion protein

12. Epidemiology of APL
Hematol Oncol Clin North Am. 2009 Aug;23(4):633-54
Blood. 2009 Feb 26;113(9):1875-91
12
Who is most affected: Most common in young adults
 Very uncommon in children < 10 years old
 Incidence increases during teen years
 Incidence plateaus in early adulthood and remains steady up to about age
60 years
 Incidence decreases after age 60 years
Incidence/Prevalence:
 Rare
 5%-8% of all AML
 4%-8% of all pediatric AML in united states
 Estimated 600-800 new cases per year in United States
Our patint: 6 y/o

13. Clinical manifestations
Br J Haematol. 2006 Nov;135(4):450-74
Blood. 2009 Feb 26;113(9):1875-91
N Engl J Med. 1993;329(3):177.
13
General
 Symptoms related to complications of pancytopenia
(anemia, neutropenia, and thrombocytopenia)
 Weakness and easy fatigue, infections, Hemorrhage
 Leukostasis (when blast count > 50,000/L)
 Dyspnea, chest pain, headache, blurred vision, altered mental status
Especially with APL
 Disseminated intravascular coagulation (DIC)
 Life-threatening complications: intracerebral or pulmonary hemorrhage
 10-20% incidence of early fatal hemorrhagic
 Requires emergent therapy

14. Acute Promyelocytic Leukemia (APL)
N Engl J Med. 1997;337(15):1021.
Blood. 2011;118(5):1248.
14
 Diagnosis of APL is confirmed by the identification of the
t(15;17) PML-RARα fusion gene
 Most severe (but also most treatable) type of AML
 Median survival of less than one month
 Treatment of APL differs from other types of AML
 ATRA/As2O3 + anthracycline-based chemotherapy
 CR rates: 85-90%
ATRA: all-trans retinoic acid

15. Effect of ATRA on APL cells
15
As a differentiation agent
 Addition of ATRA or As2O3 results in degradation of the PML-RARα fusion
protein and release of the corepressors
 Allows the normal RARα to bind to target genes and promote transcription
 Lead to differentiation of the promyelocyte to a mature granulocyte

16. TPOG-APL-2001
16
 Induction Therapy (repeat q3w until CR)
 ATRA 30mg/m2/d PO, BID, started D1 (<90 days)
 Idarubicin 9mg/m2/d, IV 5-10 minutes D1-3
 IT MTX D1
 Consolidation Therapy (q4W x 3 cycles)
If ANC >1,000/mm3, platelet >100,000/mm3
 Idarubicin 9mg/m2/d, IV 5-10 minutes D1-3
 IT MTX D1
 Probably needs prophylactic G-CSF
 Maintenance Therapy (2 years)
 ATRA 25mg/m2/d PO, BID, for 15 days every 3 months
 6-MP 90mg/m2/d PO
 MTX 15mg/m2/w PO
- If WBC <3,500/mm3, 6-MP and MTX 50% dose
- If WBC <2,500/mm3, discontinue 6-MP and MTX
 Differentiation agent
Started immediately if suspected

17. Complications of treatment
Blood. 2009 Feb 26;113(9):1875-91
J Clin Oncol 2010 Aug 20;28(24):3872
17
 APL differentiation syndrome (retinoic acid syndrome, RAS)
 May be caused by ATRA or arsenic trioxide treatment
 Pseudotumor cerebri
 More common in children treated with ATRA
 Therapy-related myeloid neoplasms (t-MNs)
 Infrequent: 1.9%
 Complications of treatment with arsenic trioxide
 Leukocytosis: 50%
 Prolonged QT interval

18. Differentiation syndrome (DS)
18

19. Differentiation syndrome (DS)
Blood. 1998;92(8):2712.
J Clin Oncol. 2000;18(13):2620.
Ann Intern Med. 1992;117(4):292.
19
 Previously called "retinoic acid syndrome“ (RAS)
 Caused by ATRA or As2O3 treatment during APL induction therapy
 Not observed when ATRA/As2O3 are used in non-APL malignancies
 Incidence:
 2-27% with ATRA
 30% with As2O3
 Onset:
 Median of 7 days (range 2-46 days) after treatment initiation
 Potential life-threatening

20. Pathophysiology
J Oncol Pharm Pract 2012 18: 109 20
 Three general theories have been proposed to explain the
infiltration of myeloid cells into the lung and other tissues:
 Release of cytokines from differentiating myeloid cells that cause a
capillary leak syndrome
 Sudden increase in differentiated myelocytes and neutrophils
 Upregulation of the expression of cellular adhesion molecules, which
increase adherence to endothelial cells

21. Clinical presentation and diagnosis
J Clin Pharm Ther. 2008 Aug;33(4):331-8.
21
 The diagnosis is made based on clinical features and findings in the
absence of other causes
 At least three of the following signs and symptoms
 Differential diagnosis: lung infection, sepsis, thromboembolism, and
heart failure
 A rapid improvement with initiation of treatment supports the
diagnosis of differentiation syndrome
Symptoms and signs
Unexplained fever Pleural/pericardial effusions
Weight gain (Peripheral edema ) Hypotension
Respiratory distress Renal/hepatic dysfunction
Pulmonary infiltrates

22. Management of differentiation syndrome
Blood. 2009;113(9):1875.
J Natl Compr Canc Netw. 2006;4(1):37.
22
 Principle: early recognition and aggressive management
 Without treatment: high mortality 30%
 With treatment: mortality 5%
improve ≤ 12 hours and complete resolution of symptoms ≤ 24 hours
 Glucocorticoids
 Given at the first suspicion of RAS appear to reduce morbidity and
mortality (in presence of any of symptoms)
 Dexamethasone 10 mg q12h for at least 3 days until the complete
disappearance of symptoms and then tapered

23. Case discussion
23
Literature review Our patient
Cause
ATRA or As2O3 treatment during
APL induction therapy
ATRA 20mg QD, 10mg HS during
APL induction therapy
Onset
Median of 7 days
(range 2-46 days)
Day 2
• Pleural effusion
• WBC: 52800→ 96600/μL
Day 3
• Peripheral edema with BW gain
(25.8 28.8kg)
Day 9
• Persisted high fever at the regular time
(morning and night)
• Progressed increased CRP level although
antibiotics use
Symptoms
and signs
• Leukocytosis
• Unexplained fever
• Pleural/pericardial effusions
• Weight gain (Peripheral edema )
• Hypotension
• Respiratory distress
• Renal/hepatic dysfunction
• Pulmonary infiltrates
Outcome
A rapid improvement with initiation
of treatment
Day 2 Dexamethasone
Day 3 no pleural effusion, WBC decreased
Day 7 normal BW

24. Problem list
24
 Whether ATRA should be continued or discontinued
when differentiation syndrome develops ?
 Can we use ATRA as maintenance therapy in this patient ?
 What are the predictive factors of DS ?
 Do we need prophylaxis or what can we do if patient is
at high risk?
?

25. Literature review-1
25
 Purpose
To examined the incidence, clinical course, and outcome of patients with
newly diagnosed APL who developed DS
Blood. 2000;95(1):90.
167 patient receive
ATRA for APL induction
44 (26%) developed RAS
• Onset
Median of 11 days of ATRA (range 2-47)
• WBC count
1450/μL (at diagnosis)  31000/μL (at develop RAS)
123 (74%) without RAS

26. Outcome of 44 patients with DS
Blood. 2000;95(1):90. 26
Resumed ATRA
19 (53%)
Not resumed ATRA
17 (47%)
1 death
Continued ATRA
8 (18%)
all syndrome resolved
with steroid
• 2 deaths definitely attributed to DS
• None of the patients who subsequently received ATRA as maintenance therapy
developed differentiation syndrome
3 recurred
(1 death, resumed
without steroid)
Discontinued ATRA
at the earliest signs of RAS
36 (82%)
44 patients with DS

27. Q & A
Blood. 2000;95(1):90.
Blood. 2009 Feb 26;113(9):1875-91
27
Whether ATRA should be continued or discontinued when
differentiation syndrome develops?
 For most patients, ATRA can be safely continued as long as prompt treatment
with glucocorticoids is implemented
 Temporary discontinuation of ATRA indicated only in case of severe DS
(renal failure, respiratory distress lack of response to dexamethasone)
 Once symptoms have completely resolved, ATRA can be restarted, but under
the cover of steroids and closely monitor for signs and symptoms of DS
because the syndrome may recur
Can we use ATRA as maintenance therapy in this patient ?
 Yes. DS is not observed when ATRA used as maintenance therapy for APL

28. Problem list
28
 Whether ATRA should be continued or discontinued
when differentiation syndrome develops ?
 Can we use ATRA as maintenance therapy in this patient ?
 What are the predictive factors of DS ?
 Do we need prophylaxis or what can we do if patient is
at high risk?
?

29. Literature review-2
29
 A retrospective review
 Patients
739 newly diagnosed APL patients treated with ATRA plus
idarubicin for induction therapy
 Purpose
analyze the incidence, characteristics, prognostic factors, and outcome
Blood. 2009;113(4):775.

30. Results-incidence
Blood. 2009;113(4):775. 30
 DS occurred in 183 patients (24.8%)
 93 patients (12.6%) had severe DS
 90 patients (12.2%) had moderate DS
 Bimodal incidence of DS was observed,
with peaks occurring in the first and third
weeks after the start of ATRA therapy
 More frequently in patients with a high
WBC at diagnosis
Signs and symptoms: Severe DS: ≥ 4 Moderate: 2-3
• Dyspnea
• Unexplained fever
• Weight gain ≥ 5 kg
• Unexplained hypotension
• Acute renal failure
• CXR: pulmonary infiltrates or
pleuropericardial effusion
Time to occurrence of DS

31. Results-characteristics
Blood. 2009;113(4):775. 31
 The most frequent clinical manifestations of severe DS were dyspnea,
pulmonary infiltrates, edema, unexplained fever
 Hypotension is more frequent in late severe DS than in early severe DS
(P= .007)
Clinical signs and symptoms of moderate and severe DS
Occurred ≤ 7 days > 7 days

32. Results-prognostic factors, and outcome
Blood. 2009;113(4):775.
32
Outcome and complications of DS
No DS
(n=556)
Moderate
(n =90)
Severe
(n=93)
P
Early severe
(n=50)
Late severe
(n=43)
P
Death during induction (%) 37 (7) 5 (6) 24 (26) < .001 20 (40) 4 (9) .001
Death due to DS (%) 0 (0) 0 (0) 10 (11) < .001 8 (16) 2 (5) .08
Thrombosis during induction (%) 18 (3) 3 (3) 9 (10) .008 5 (10) 4 (9) .91
Grade 3-4 hepatotoxicity (%) 24 (5) 5 (6) 11 (14) .01 5 (12) 6 (15) .65
Outcome
 Severe DS was significantly associated with mortality (higher in early severe
DS), thrombosis, and hepatotoxicity
Factors OR (95% CI) of Severe DS P
WBC count > 5000 /μL 1.8 (1.1-2.7) .021
Creatinine > 1.4 mg/dL 5.8 (1.9-16.9) .004
Factors predicting severe DS
 WBC > 5000/μL, abnormal serum creatinine level

33. Other potential risk factors for DS
33
Study N Incidence of DS Potential risk factors for DS
Blood.
2009;113(4):775.
739 25%
• WBC > 5000/μL (p= 0.021) for severe DS
• Scr > 1.4 mg/dL (p= 0.004) for severe DS
Leukemia.
2003;17(2):339-342
306 13%
• Sequential (18%) versus concomitant (9%)
chemotherapy (p= 0.035)
Leuk Res.
2010;34(4):545.
36 31%
• WBC ≥ 20000/μL (p= 0.025)
• BMI ≥ 30 (67%) versus BMI < 30 (19%)
(p= 0.012)

34. Literature review-3
34
 Compare two trials (APL 93 and APL 2000) in patients with high WBC counts
to evaluated outcome improvement in such patients
J Clin Oncol. 2009 Jun 1;27(16):2668-76.
Prophylaxis of DS Treatment of DS
Early death
due to DS in
WBC > 10,000/μL
APL 93 X
Both receive dexamethasone
for treatment of DS
until resolution of symptoms
8/139 (6%)
APL 2000
If WBC > 10,000/μL
Dexamethaone 10 mg q12h
for 3-5 days
2/133 (1.5%)

35. Q & A
Blood. 2000;95(1):90.
Blood. 2009 Feb 26;113(9):1875-91
35
What are the predictive factors of DS ?
 High WBC count
 Abnormal serum creatinine level
 BMI ≥ 30
Do we need prophylaxis or what can we do if patient is at high
risk?
 Prophylactic glucocorticoids for patients with initial WBC > 10,000/μL
Suggested regimen: Dexamethasone 10 mg q12h for 3–5 days, followed by
2-week taper
 Consider start chemotherapy immediately if hyperleukocytosis

36. Pseudotumor cerebri
36

37. Pseudotumor cerebri (PC)
J Neuroophthalmol. 2001;21(1):12.
Case Rep Oncol Med. 2012;2012:313057
37
PC is characterized by
 Symptoms and signs of increased intracranial pressure
 Headache: most common
 Ocular signs: transient visual obscurations, diplopia
 Papilledema: usually bilateral and symmetric, severity is associated with the risk of
permanent visual loss
 N/V
 But with normal cerebrospinal fluid composition and normal brain imaging
Epidemiology
 Incidence: 1 per 100,000 /year
 Predominantly affects obese women of childbearing age
 Medications associated with PC: growth hormone, tetracycline, retinoids

38. ATRA associated pseudotumor cerebri
Case Rep Oncol Med. 2012;2012:313057 38
 Exact pathogenesis has not been established
 Onset
 Median 14 days (range: 7 days-10 months) after initiate ATRA
 Occurrence
 Most often during induction therapy (78%)
 Predominantly in the pediatric
 Concurrent medications such as triazole antifungals may increase risk
 Management
 Temporary ATRA discontinuation
 Diuretics– mannitol, glycerin, acetazolamide
 Lumbar puncture
 Analgesics
 Corticosteroid

39. Common drug interactions with ATRA
39
 ATRA is Metabolized by CYP isoenzymes (CYP2C8, CYP2C9, CYP3A4)
 Concomitant use of drugs that affect CYP isoenzymes can lead to toxic ATRA
concentrations
Drug Severity Interaction
Tranexamic acid
Aminocaproic acid
aprotinin
Major Increased risk of thrombosis
Paclitaxel Major Increased risk of paclitaxel toxicity
Tetracycline Major Increased risk of pseudotumor cerebri
Fluconazole
Ketoconazole
Voriconazole
Moderate Increased risk of tretinoin toxicity
Methotrexate Moderate Increased hepatotoxicity
Glucocorticoids Moderate Decreased efficacy of tretinoin

40. Case discussion
PC associated with interaction of ATRA with fluconazole
Case Rep Oncol Med. 2012;2012:313057
J Pediatr Hematol Oncol. 2003 May;25(5):403-4.
40
Case 1 Case 2 Our patient
Patient 38 y/o female 4 y/o male 6 y/o female
Therapy ATRA 45mg/m2/d ATRA 45mg/m2/d ATRA 30mg/m2/d
PC onset
• On day 17
• 10 days after Fluconazole
400mg/d
• [induction]
• On day 21
• 1 day after Fluconazole
100mg/d
• [induction]
• On day 22
• 9 days after Fluconazole
250mg/d
• [induction]
Presentation
Headache, photosensitivity,
N/V, bilateral papilledema
CSF pressure: 300mmH2O
Headache, papilledema, N/V
CSF pressure > 200mmH2O
Visual diplopia, NV
Papilloedema
CSF study??
Management
Discontinue ATRA
Acetazolamide
Antiemetics and analgesics
Discontinue ATRA Discontinue ATRA
Acetazolamide, Mannitol
Dexamethasone
Resolution The next week 1 day after 5 days after
Rechallenge
ATRA
No recurrent
Recurred under concurrent
with fluconazole ?
2nd 75% dose: 2 days onset, headache, N/V
 discontinued ATRA
3rd 30% dose: 3 days onset, headache
 discontinued fluconazole, resolve within 24 h

41. Q & A
41
Can we use ATRA as maintenance therapy in this patient ?
Yes.
 ATRA associated pseudotumor cerebri occurred most often during
induction therapy but also during consolidation and maintenance
therapy
 Cases of successful rechallenge ATRA, and some rechallenge successful
with prophylactic acetazolamide (500 mg/day)
 Increased risk of PC when concomitant use of other medications that
affect the cytochrome P-450 system (triazole antifungals)
 Rechallenge without concomitant these drugs, or carefully monitor for
the side effects of ATRA

42. Summary
42
 ATRA is an important component in the treatment of acute
promyelocytic leukemia
 Use of ATRA can lead to several side effects such as differentiation
syndrome(DS) and pseudotumor cerebri (PC)
 For differentiation syndrome
 Prophylactic steroids can be given in patients with hyperleukocytosis
 Steroids should be started immediately at earliest suspicion of DS
 Temporary discontinuation of ATRA indicated only in case of severe DS
 For pseudotumor cerebri
 Concomitant use of drugs that affect CYP isoenzymes may increase risk of
ATRA associated PC (tetracyclines, triazole antifungals)

43. Thank you for your attention
43

44. 44
2/20 Induction therapy ATRA 2/20-3/13 + Idarubicin + MTX
3/22 1st Consolidation Idarubicin + MTX
Bone marrow survey: remission but MRD(+)
 Add ATRA
3/25
4/18 2nd Consolidation Idarubicin + MTX
ATRA + dexamethasone prophylaxis
2/13 Discontinued ATRA due to pseudotumor cerebri
4/6~
4/14
Infection, fluconazole use
4/29