All-trans retinoic acid relatedcomplications in a patient with acutepromyelocytic leukemia12013. 05. 16臨床藥學與藥物科技所 陳秋縈指導老師 ...
Patient profile2Name 戴XX Admission date 2013/02/18Age 6 y/o HT 124.3cm (50-75th%)Gender female BW 25.8kg (75-90th%)BSA 0.9...
Lab data on 2/183檢驗名稱 參考值 單位 結果WBC 4.27-13.18 10^3/μL H 52.8RBC 3.84-5.01 10^6/μL L 2.97Hb 10.2-13.2 g/dL L 8.2Hct 30.9-37...
Hospital course-14Date Event Management2/18 • WBC: 52800/μL, Blast: 46%, Pro: 44%Blast and promyelocyte with auer rods was...
Hospital course-25Date Event Management2/24 • WBC: 71200→ 15900/μL • Taper dexamethasone 5mg qd2/25 • No fever for 3 days ...
Hospital course-36Date Event Management3/8 • Procalcitonin: 0.324 ng/ml • DC vancomycin after 7-day-use• Metronidazole 200...
760801001201401601803536373839404118 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 15BT BPUnasyn + Gent...
Outline8 Acute Promyelocytic Leukemia (APL) Differentiation syndrome (DS) Overview Case discussion Pseudotumor cerebr...
Acute myeloid leukemia (AML)9 AML is characterized by a clonal proliferation of hematopoieticprogenitor with reduce abili...
Classification of acute myeloid leukemiaBlood 2009;114:937 10APL is a biologically and clinically distinct variant of AML•...
PathogenesisNat Med 2001 Jun;7(6):680 11Translocation of retinoic acidreceptor gene (RARα) topromyelocytic gene (PML) lead...
Epidemiology of APLHematol Oncol Clin North Am. 2009 Aug;23(4):633-54Blood. 2009 Feb 26;113(9):1875-9112Who is most affect...
Clinical manifestationsBr J Haematol. 2006 Nov;135(4):450-74Blood. 2009 Feb 26;113(9):1875-91N Engl J Med. 1993;329(3):177...
Acute Promyelocytic Leukemia (APL)N Engl J Med. 1997;337(15):1021.Blood. 2011;118(5):1248.14 Diagnosis of APL is confirme...
Effect of ATRA on APL cells15As a differentiation agent Addition of ATRA or As2O3 results in degradation of the PML-RARα ...
TPOG-APL-200116 Induction Therapy (repeat q3w until CR) ATRA 30mg/m2/d PO, BID, started D1 (<90 days) Idarubicin 9mg/m2...
Complications of treatmentBlood. 2009 Feb 26;113(9):1875-91J Clin Oncol 2010 Aug 20;28(24):387217 APL differentiation syn...
Differentiation syndrome (DS)18
Differentiation syndrome (DS)Blood. 1998;92(8):2712.J Clin Oncol. 2000;18(13):2620.Ann Intern Med. 1992;117(4):292.19 Pre...
PathophysiologyJ Oncol Pharm Pract 2012 18: 109 20 Three general theories have been proposed to explain theinfiltration o...
Clinical presentation and diagnosisJ Clin Pharm Ther. 2008 Aug;33(4):331-8.21 The diagnosis is made based on clinical fea...
Management of differentiation syndromeBlood. 2009;113(9):1875.J Natl Compr Canc Netw. 2006;4(1):37.22 Principle: early re...
Case discussion23Literature review Our patientCauseATRA or As2O3 treatment duringAPL induction therapyATRA 20mg QD, 10mg H...
Problem list24 Whether ATRA should be continued or discontinuedwhen differentiation syndrome develops ? Can we use ATRA ...
Literature review-125 PurposeTo examined the incidence, clinical course, and outcome of patients withnewly diagnosed APL ...
Outcome of 44 patients with DSBlood. 2000;95(1):90. 26Resumed ATRA19 (53%)Not resumed ATRA17 (47%)1 deathContinued ATRA8 (...
Q & ABlood. 2000;95(1):90.Blood. 2009 Feb 26;113(9):1875-9127Whether ATRA should be continued or discontinued whendifferen...
Problem list28 Whether ATRA should be continued or discontinuedwhen differentiation syndrome develops ? Can we use ATRA ...
Literature review-229 A retrospective review Patients739 newly diagnosed APL patients treated with ATRA plusidarubicin f...
Results-incidenceBlood. 2009;113(4):775. 30 DS occurred in 183 patients (24.8%) 93 patients (12.6%) had severe DS 90 pa...
Results-characteristicsBlood. 2009;113(4):775. 31 The most frequent clinical manifestations of severe DS were dyspnea,pul...
Results-prognostic factors, and outcomeBlood. 2009;113(4):775.32Outcome and complications of DSNo DS(n=556)Moderate(n =90)...
Other potential risk factors for DS33Study N Incidence of DS Potential risk factors for DSBlood.2009;113(4):775.739 25%• W...
Literature review-334 Compare two trials (APL 93 and APL 2000) in patients with high WBC countsto evaluated outcome impro...
Q & ABlood. 2000;95(1):90.Blood. 2009 Feb 26;113(9):1875-9135What are the predictive factors of DS ? High WBC count Abno...
Pseudotumor cerebri36
Pseudotumor cerebri (PC)J Neuroophthalmol. 2001;21(1):12.Case Rep Oncol Med. 2012;2012:31305737PC is characterized by Sym...
ATRA associated pseudotumor cerebriCase Rep Oncol Med. 2012;2012:313057 38 Exact pathogenesis has not been established O...
Common drug interactions with ATRA39 ATRA is Metabolized by CYP isoenzymes (CYP2C8, CYP2C9, CYP3A4) Concomitant use of d...
Case discussionPC associated with interaction of ATRA with fluconazoleCase Rep Oncol Med. 2012;2012:313057J Pediatr Hemato...
Q & A41Can we use ATRA as maintenance therapy in this patient ?Yes. ATRA associated pseudotumor cerebri occurred most oft...
Summary42 ATRA is an important component in the treatment of acutepromyelocytic leukemia Use of ATRA can lead to several...
Thank you for your attention43
442/20 Induction therapy ATRA 2/20-3/13 + Idarubicin + MTX3/22 1st Consolidation Idarubicin + MTXBone marrow survey: remis...
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All-trans retinoic acid related complications in a patient with acute promyelocytic leukemia

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All-trans retinoic acid related complications in a patient with acute promyelocytic leukemia

  1. 1. All-trans retinoic acid relatedcomplications in a patient with acutepromyelocytic leukemia12013. 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. 2. Patient profile2Name 戴XX Admission date 2013/02/18Age 6 y/o HT 124.3cm (50-75th%)Gender female BW 25.8kg (75-90th%)BSA 0.94 Allergy history NKDAPast history• Hospitalization: pneumonia 3y/oChief complaint• Suffered from Generalized petechiae for recent one week• Prolonged epistaxis this morningShe was referred from ENT LMD, and AOM left side was found at LMDPhysical 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. 3. Lab data on 2/183檢驗名稱 參考值 單位 結果WBC 4.27-13.18 10^3/μL H 52.8RBC 3.84-5.01 10^6/μL L 2.97Hb 10.2-13.2 g/dL L 8.2Hct 30.9-37.9 % L 23.9MCV 72.3-87.6 fl 80.7MCH 23.7-29.5 pg 27.5MCHC 33.2-35.2 g/dL 34.1RDW 12.2-15.1 % 13.1Plt 189-459 10^3/μL L 20Blast % 46Pro % 44Myelo % 0Meta % 0Band % 0Seg 22.4-69 % 1Eos 0-3.6 % 0Baso 0-0.7 % 0Mono 4.1-11.4 % 0Lymph 18.1-68.6 % 9Aty-lym % 0NRBC /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 32.2FIB 276-471 mg/dL L 238.5BIL-T 0.2-1.4 mg/dL 0.7ALK-P 30-110 U/L H 147CA 8.6-10.1 mg/dL 9.8P 2.5-4.5 mg/dL 4.1BIL-D 0-0.3 mg/dL 0.3NA 135-148 mmol/L 145K 3.5-5 mmol/L 4.5BUN 7-21 mg/dL 12CREA 0.6-1.2 mg/dL 0.46URIC 2-6 mg/dL 6.3AST 0-39 U/L 35ALT 0-54 U/L 24LD 100-200 U/L H 866Impression:1. Lab: Blast and promyelocyte with auer rods wasfound from peripheral blood Suspect acute leukemia2. Acute otitis media (AOM)APTT 26-38 secs 28MNAPTT secs 32.7PT 9.4-12.5 secs H 16PT(MNPT) secs 10.5
  4. 4. Hospital course-14Date Event Management2/18 • WBC: 52800/μL, Blast: 46%, Pro: 44%Blast and promyelocyte with auer rods wasfound Acute leukemia was suspected (APL)• Perform bone marrow aspiration, biopsy andchromosome for diagnosisnight • Fever up to 39.5, CRP: 27.4 mg/L Suspect AOM, r/o tumor fever• B/C, UA• Unasyn, Gentamicin• Acetaminophen, Diclofenac EM2/20 • 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 HS2/21 • Fever, pleural effusion, hyperleukocytosisCXR: bilateral pleural effusion, no dyspneaBT: 38.4WBC: 52800→ 96600/μL• Idarubicin 8.5 mg IVD 2/21-23MTX IT 2/21Granisetron 3mg IVD before CT• Dexamethasone 10mg q12h x 3 daysfor 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. 5. Hospital course-25Date Event Management2/24 • WBC: 71200→ 15900/μL • Taper dexamethasone 5mg qd2/25 • No fever for 3 days • DC ABX2/26 • WBC↓: 1100/μL • DC dexamethasone2/28 • BT: 39, WBC: 1300 /μL Neutropenic fever• CRP: 27.6 mg/L• B/C from peripheral and CVP• Amikacin, Cefazolin, Piperacillin3/1 • UA, CXR: normal• WBC: 500/μL• Oral ulcer, gingiva swelling Suspect HSV or oral infection• Acyclovir 250 mg IVD q8h• Nystatin 1# qid when3/2 • 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 qd3/5 • Blood culture from CVP: CoNS• CRP: 79.9 mg/L• Persist neutropenic fever• CXR: R’t lung infiltration• Shift piperacillin, amikacin to meropenenNeutropenicFever
  6. 6. Hospital course-36Date Event Management3/8 • Procalcitonin: 0.324 ng/ml • DC vancomycin after 7-day-use• Metronidazole 200 mg q6h ivd• Baktar 1# bid 1,3,53/10 • HTN was noted 150/99mmHg3/13 • Fever subside, CRP↓ 161.3 45mg/L• Visual diplopia(+), papilloedema(+), N/V Suspect ATRA and fluconazole DDI relatedpseudotumor cerebri• DC metronidazole, meropenem (9d), acyclovir(14d) de-escalate to penicillin, ceftazidime• Discontinued ATRA• Acetazolamide 125mg qdMannitol 6mg q8h ivdDexamethasone 7.5 mg q6h ivd for IICP• CSF study or brain image survey3/16 • Hypertension improved, still blurred vision• Stable condition• DischargeNystatin 1# qidDexamethasone 4mg bid poAcetazolamide 125mg qdAugmentin 1# bid3/18 • Diplopia improvedFever
  7. 7. 760801001201401601803536373839404118 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 15BT BPUnasyn + GentamicinATRAIdarubicinMTXDexamethasone edemaFurosemidePiperacillin + AmikacinAcyclovir oral ulcerCefazolin Vancomycin CVP: GPCFluconazoleMeropemenTMP/SMX HTNMetronidazole Diplopia,N/V pleural effusionPCN + ceftazidimeAcetazolamideMannitolDexamethasone47.2 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 1.527 35 28 37 63 80 150 142 161 45 24WBC (103/μl)CRP (mg/L)Fever Neutropenic Fever
  8. 8. Outline8 Acute Promyelocytic Leukemia (APL) Differentiation syndrome (DS) Overview Case discussion Pseudotumor cerebri (PC) Overview Case discussion Summary
  9. 9. Acute myeloid leukemia (AML)9 AML is characterized by a clonal proliferation of hematopoieticprogenitor with reduce ability to differentiate into matureelements Leukemic blasts or immature forms in bone marrow and periphery RBCs, platelets, and neutrophilsAnemia, bleeding, infectionOur patient• Generalized petechiae• Prolonged epistaxis• Fever, suspect AOM
  10. 10. Classification of acute myeloid leukemiaBlood 2009;114:937 10APL 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 ExamplesWith recurrent genetic abnormalities t(8;21); inv(16); t(15;17); 11q23 anomaliesWith myelodysplasia-related features Antecedent myelodysplastic syndrome (MDS)Therapy-related AML Alkylating agents or topoisomerase inhibitorsNot otherwise specified With minimal differentiation, maturation,myelomonocytic, monoblastic, erythroid
  11. 11. PathogenesisNat Med 2001 Jun;7(6):680 11Translocation of retinoic acidreceptor gene (RARα) topromyelocytic gene (PML) leadingto chimeric oncogene PML-RARαPML-RARa fusion protein forms a homodimer Binds to RARα target genes and ehnanceco-repressors binding Blocked differentiation and enhancedself-renewal of the promyelocytesPML-RARa fusion protein
  12. 12. Epidemiology of APLHematol Oncol Clin North Am. 2009 Aug;23(4):633-54Blood. 2009 Feb 26;113(9):1875-9112Who 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 age60 years Incidence decreases after age 60 yearsIncidence/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 StatesOur patint: 6 y/o
  13. 13. Clinical manifestationsBr J Haematol. 2006 Nov;135(4):450-74Blood. 2009 Feb 26;113(9):1875-91N Engl J Med. 1993;329(3):177.13General 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 statusEspecially with APL Disseminated intravascular coagulation (DIC) Life-threatening complications: intracerebral or pulmonary hemorrhage 10-20% incidence of early fatal hemorrhagic Requires emergent therapy
  14. 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 thet(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. 15. Effect of ATRA on APL cells15As a differentiation agent Addition of ATRA or As2O3 results in degradation of the PML-RARα fusionprotein 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. 16. TPOG-APL-200116 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 agentStarted immediately if suspected
  17. 17. Complications of treatmentBlood. 2009 Feb 26;113(9):1875-91J Clin Oncol 2010 Aug 20;28(24):387217 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. 18. Differentiation syndrome (DS)18
  19. 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. 20. PathophysiologyJ Oncol Pharm Pract 2012 18: 109 20 Three general theories have been proposed to explain theinfiltration of myeloid cells into the lung and other tissues: Release of cytokines from differentiating myeloid cells that cause acapillary leak syndrome Sudden increase in differentiated myelocytes and neutrophils Upregulation of the expression of cellular adhesion molecules, whichincrease adherence to endothelial cells
  21. 21. Clinical presentation and diagnosisJ Clin Pharm Ther. 2008 Aug;33(4):331-8.21 The diagnosis is made based on clinical features and findings in theabsence of other causes At least three of the following signs and symptoms Differential diagnosis: lung infection, sepsis, thromboembolism, andheart failure A rapid improvement with initiation of treatment supports thediagnosis of differentiation syndromeSymptoms and signsUnexplained fever Pleural/pericardial effusionsWeight gain (Peripheral edema ) HypotensionRespiratory distress Renal/hepatic dysfunctionPulmonary infiltrates
  22. 22. Management of differentiation syndromeBlood. 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 andmortality (in presence of any of symptoms) Dexamethasone 10 mg q12h for at least 3 days until the completedisappearance of symptoms and then tapered
  23. 23. Case discussion23Literature review Our patientCauseATRA or As2O3 treatment duringAPL induction therapyATRA 20mg QD, 10mg HS duringAPL induction therapyOnsetMedian of 7 days(range 2-46 days)Day 2• Pleural effusion• WBC: 52800→ 96600/μLDay 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 althoughantibiotics useSymptomsand signs• Leukocytosis• Unexplained fever• Pleural/pericardial effusions• Weight gain (Peripheral edema )• Hypotension• Respiratory distress• Renal/hepatic dysfunction• Pulmonary infiltratesOutcomeA rapid improvement with initiationof treatmentDay 2 DexamethasoneDay 3 no pleural effusion, WBC decreasedDay 7 normal BW
  24. 24. Problem list24 Whether ATRA should be continued or discontinuedwhen 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 isat high risk??
  25. 25. Literature review-125 PurposeTo examined the incidence, clinical course, and outcome of patients withnewly diagnosed APL who developed DSBlood. 2000;95(1):90.167 patient receiveATRA for APL induction44 (26%) developed RAS• OnsetMedian of 11 days of ATRA (range 2-47)• WBC count1450/μL (at diagnosis)  31000/μL (at develop RAS)123 (74%) without RAS
  26. 26. Outcome of 44 patients with DSBlood. 2000;95(1):90. 26Resumed ATRA19 (53%)Not resumed ATRA17 (47%)1 deathContinued ATRA8 (18%)all syndrome resolvedwith steroid• 2 deaths definitely attributed to DS• None of the patients who subsequently received ATRA as maintenance therapydeveloped differentiation syndrome3 recurred(1 death, resumedwithout steroid)Discontinued ATRAat the earliest signs of RAS36 (82%)44 patients with DS
  27. 27. Q & ABlood. 2000;95(1):90.Blood. 2009 Feb 26;113(9):1875-9127Whether ATRA should be continued or discontinued whendifferentiation syndrome develops? For most patients, ATRA can be safely continued as long as prompt treatmentwith 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 underthe cover of steroids and closely monitor for signs and symptoms of DSbecause the syndrome may recurCan we use ATRA as maintenance therapy in this patient ? Yes. DS is not observed when ATRA used as maintenance therapy for APL
  28. 28. Problem list28 Whether ATRA should be continued or discontinuedwhen 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 isat high risk??
  29. 29. Literature review-229 A retrospective review Patients739 newly diagnosed APL patients treated with ATRA plusidarubicin for induction therapy Purposeanalyze the incidence, characteristics, prognostic factors, and outcomeBlood. 2009;113(4):775.
  30. 30. Results-incidenceBlood. 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 thirdweeks after the start of ATRA therapy More frequently in patients with a highWBC at diagnosisSigns and symptoms: Severe DS: ≥ 4 Moderate: 2-3• Dyspnea• Unexplained fever• Weight gain ≥ 5 kg• Unexplained hypotension• Acute renal failure• CXR: pulmonary infiltrates orpleuropericardial effusionTime to occurrence of DS
  31. 31. Results-characteristicsBlood. 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 DSOccurred ≤ 7 days > 7 days
  32. 32. Results-prognostic factors, and outcomeBlood. 2009;113(4):775.32Outcome and complications of DSNo DS(n=556)Moderate(n =90)Severe(n=93)PEarly severe(n=50)Late severe(n=43)PDeath during induction (%) 37 (7) 5 (6) 24 (26) < .001 20 (40) 4 (9) .001Death due to DS (%) 0 (0) 0 (0) 10 (11) < .001 8 (16) 2 (5) .08Thrombosis during induction (%) 18 (3) 3 (3) 9 (10) .008 5 (10) 4 (9) .91Grade 3-4 hepatotoxicity (%) 24 (5) 5 (6) 11 (14) .01 5 (12) 6 (15) .65Outcome Severe DS was significantly associated with mortality (higher in early severeDS), thrombosis, and hepatotoxicityFactors OR (95% CI) of Severe DS PWBC count > 5000 /μL 1.8 (1.1-2.7) .021Creatinine > 1.4 mg/dL 5.8 (1.9-16.9) .004Factors predicting severe DS WBC > 5000/μL, abnormal serum creatinine level
  33. 33. Other potential risk factors for DS33Study N Incidence of DS Potential risk factors for DSBlood.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 DSLeukemia.2003;17(2):339-342306 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. 34. Literature review-334 Compare two trials (APL 93 and APL 2000) in patients with high WBC countsto evaluated outcome improvement in such patientsJ Clin Oncol. 2009 Jun 1;27(16):2668-76.Prophylaxis of DS Treatment of DSEarly deathdue to DS inWBC > 10,000/μLAPL 93 XBoth receive dexamethasonefor treatment of DSuntil resolution of symptoms8/139 (6%)APL 2000If WBC > 10,000/μLDexamethaone 10 mg q12hfor 3-5 days2/133 (1.5%)
  35. 35. Q & ABlood. 2000;95(1):90.Blood. 2009 Feb 26;113(9):1875-9135What are the predictive factors of DS ? High WBC count Abnormal serum creatinine level BMI ≥ 30Do we need prophylaxis or what can we do if patient is at highrisk? Prophylactic glucocorticoids for patients with initial WBC > 10,000/μLSuggested regimen: Dexamethasone 10 mg q12h for 3–5 days, followed by2-week taper Consider start chemotherapy immediately if hyperleukocytosis
  36. 36. Pseudotumor cerebri36
  37. 37. Pseudotumor cerebri (PC)J Neuroophthalmol. 2001;21(1):12.Case Rep Oncol Med. 2012;2012:31305737PC 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 ofpermanent visual loss N/V But with normal cerebrospinal fluid composition and normal brain imagingEpidemiology Incidence: 1 per 100,000 /year Predominantly affects obese women of childbearing age Medications associated with PC: growth hormone, tetracycline, retinoids
  38. 38. ATRA associated pseudotumor cerebriCase 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. 39. Common drug interactions with ATRA39 ATRA is Metabolized by CYP isoenzymes (CYP2C8, CYP2C9, CYP3A4) Concomitant use of drugs that affect CYP isoenzymes can lead to toxic ATRAconcentrationsDrug Severity InteractionTranexamic acidAminocaproic acidaprotininMajor Increased risk of thrombosisPaclitaxel Major Increased risk of paclitaxel toxicityTetracycline Major Increased risk of pseudotumor cerebriFluconazoleKetoconazoleVoriconazoleModerate Increased risk of tretinoin toxicityMethotrexate Moderate Increased hepatotoxicityGlucocorticoids Moderate Decreased efficacy of tretinoin
  40. 40. Case discussionPC associated with interaction of ATRA with fluconazoleCase Rep Oncol Med. 2012;2012:313057J Pediatr Hematol Oncol. 2003 May;25(5):403-4.40Case 1 Case 2 Our patientPatient 38 y/o female 4 y/o male 6 y/o femaleTherapy ATRA 45mg/m2/d ATRA 45mg/m2/d ATRA 30mg/m2/dPC onset• On day 17• 10 days after Fluconazole400mg/d• [induction]• On day 21• 1 day after Fluconazole100mg/d• [induction]• On day 22• 9 days after Fluconazole250mg/d• [induction]PresentationHeadache, photosensitivity,N/V, bilateral papilledemaCSF pressure: 300mmH2OHeadache, papilledema, N/VCSF pressure > 200mmH2OVisual diplopia, NVPapilloedemaCSF study??ManagementDiscontinue ATRAAcetazolamideAntiemetics and analgesicsDiscontinue ATRA Discontinue ATRAAcetazolamide, MannitolDexamethasoneResolution The next week 1 day after 5 days afterRechallengeATRANo recurrentRecurred under concurrentwith fluconazole ?2nd 75% dose: 2 days onset, headache, N/V discontinued ATRA3rd 30% dose: 3 days onset, headache discontinued fluconazole, resolve within 24 h
  41. 41. Q & A41Can we use ATRA as maintenance therapy in this patient ?Yes. ATRA associated pseudotumor cerebri occurred most often duringinduction therapy but also during consolidation and maintenancetherapy Cases of successful rechallenge ATRA, and some rechallenge successfulwith prophylactic acetazolamide (500 mg/day) Increased risk of PC when concomitant use of other medications thataffect the cytochrome P-450 system (triazole antifungals) Rechallenge without concomitant these drugs, or carefully monitor forthe side effects of ATRA
  42. 42. Summary42 ATRA is an important component in the treatment of acutepromyelocytic leukemia Use of ATRA can lead to several side effects such as differentiationsyndrome(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 ofATRA associated PC (tetracyclines, triazole antifungals)
  43. 43. Thank you for your attention43
  44. 44. 442/20 Induction therapy ATRA 2/20-3/13 + Idarubicin + MTX3/22 1st Consolidation Idarubicin + MTXBone marrow survey: remission but MRD(+) Add ATRA3/254/18 2nd Consolidation Idarubicin + MTXATRA + dexamethasone prophylaxis2/13 Discontinued ATRA due to pseudotumor cerebri4/6~4/14Infection, fluconazole use4/29

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