Advances in the Treatment of APL in Children SLOP Vina del Mar April 2014

Transcription

1 Advances in the Treatment of APL in Children SLOP Vina del Mar April 2014

2 Outline Advances in suppor3ve care of pediatric acute promyelocy3c leukemia (APL) Advances in specific treatment of pediatric APL

3 SLE por Riesgo, abandono como evento (No.75)

4 Estatus N=75 Bajo Riesgo No.(35) Primer Evento % % Alto Riesgo No.(40) Primer Evento % % Vivo Abandono Enfermedad Resistente Recaída Fallecido Total

5 Case 13- year old girl with altered mental status 2 weeks prior had sinus symptoms Progressive weakness and body aches Eye pain and blurry vision Somnolent and confused Syncope in bathroom followed by emesis

6 Physical Vitals: T37.7, HR 127, BP 148/78, RR20 General: Asleep, comba3ve when aroused; obese HEENT: Pupils 3mm, reac3ve, equal; bilateral papilledema and re3nal hemorrhages Neurological: Uncoopera3ve, difficult to understand speech

7 Laboratory Studies WBC count 93.7x 10 9 /L; ANC 2.8 x 10 9 /L ; Hgb 6.3 g/dl; platelet count /dl; differen3al: 2% segs, 3% lymph, 1% mono, 88% blast Coagula3on: PT 20 sec, INR 1.86, aptt 25.2 sec, fibrinogen 114 mg/dl Uric acid 5.2 mg/dl

8 Intracranial Ischemic Infarcts

9 Intracranial Ischemic Infarcts

10 Coagulopathy in APL It manifests as hemorrhage or thrombosis Mechanism is not known Ac3va3ng of the coagula3on system Non- specific protease s3mula3on The predominant feature at diagnosis is fibrinolysis

11 Management of Coagulopathy Blood Products Platelets (> 50 x 10 9 /l) Fibrinogen (>100 mg/dl) No proven benefit for use of heparin or an3- fibrinoly3c agents An3- fibrinoly3c agents when combined with ATRA could increase the risk of thrombo3c complica3ons Leukapheresis is not recommended for hyperleukocytosis

12 Coagulopathy Fibrinogen/dL Platelet count x 10 9 /L

13 Induc3on Atra

14 Should ATRA be held? Day 3: Tachypnea and 0 2 satura3on drop Day 3: Started dexamethasone Day 4: Oxygen via nasal cannula Day 5: Transi3oned to high- frequency nasal cannula (HFNC) Day 7: Off HFNC, fever resolved Steroids weaned over 4 day

15 ATRA + Idarubicin (AAML0631)

16 Pathogenesis Luesink M. Br J Haematol :209-20

17 Management of Syndrome Ini3ate dexamethasone at the very earliest suspicion of RA syndrome Temporary discon3nua3on of ATRA only in case of severe RA syndrome Prophylaxis with prednisone 1 mg/kg/day

18 ATRA Weaned off oxygen WBC decreased Intense rehab for strokes, becoming more interac3ve Day 15: new spots in visual fields, L>R. BP 160/100 MRI- prior infarcts, no new findings LP- opening pressure too high to measure

19 Pseudotumor Cerebri More common in children Impair of CSF absorp3on at the level of the arachnoid villi or granula3on Headaches Diplopia 6 th cranial nerve palsy Papilledema

20 Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) Stopped ATRA Started dexamethasone and Diamox Serial therapeu3c taps ATRA restarted at 75% dose when opening pressure decreased to goal 30-35mm H2O Con3nued Diamox through induc3on

21 of Intracranial Ischemic Infarcts

22 Specific Management of APL Historic Halmarkers Pa3ents receiving ATRA had significantly greater EFS compared with those in chemotherapy- only arms ATRA plus chemotherapy was superior that ATRA alone, par3cularly in individuals with WBC > 10,000/µL

23 APL European Group Role of Chemotherapy in N (%) Median ATRAà CT ATRA+CT No. of pa3ents Male sex 59 (48.4) 87 (47.3) Age, y (range) 46 (35-54) 44 (33-55) WBC count, 10 9 /L (range) 1.3 ( ) 1.4 ( ) CR: N (%) 113 (92.6) 177 (96.2) 10- year CI of relapse 21.6% 13.2% 10- year CI of deaths in CR 6.6% 6.7% 10- year EFS 64.4% 76.3% 10- year survival 81.8% 85.0% Adès L et al. Blood 2010;115:

24 Cytarabine in LPA99 and 2005 Sanz M A et al. Blood 2010;115:

25 Incidence of Relapse in High- Risk according to PETHEMA Trial Sanz M A et al. Blood 2010;115:

26 Long- Term Outcome APL European Group Role of Maintenance ATRA No maintenance ATRA+CT CT alone p Number Relapse % % % % < year EFS 62.9% 51.4% 79.7% 72.6% < year OS 88.0% 74.4% 94.4% 93.4% Adès L et al. Blood 2010;115:

27 Maintenance ATRA- based maintenance shown to reduce relapse It is uncertain whether pa3ents who achieve complete remission ajer induc3on and are nega3ve for the PML/RARα fusion gene ajer consolida3on benefit from maintenance

28 Overall survival of Children Treated on the PATHEMA Trials N=66 Ortega, J. J. et al. J Clin Oncol; 23:

29 Anthracycline Dosage in Contemporary Pediatric AML trials Study MRC10/12 Anthracycline mg/m France AIEOP CCG BFM SHOP

30 Arsenic Trioxide (ATO) an for Therapy Ref. 1 No. of Pa@ents Induc@on therapy CR rate 20 ATRA 25 mg/m 2 (CT 11 pts) ATO 0.16 mg/kg (CT 12 pts) ATO + ATRA (CT 14 pts) ATO 0.16 mg/kg + ATRA 25 mg/m ATO 10 mg (CT 6 pts; hydrea 37 pts) ATO 0.16 mg/kg ATO 0.15 mg/kg (GO 19 pts) Shen et al. PNAS, 2004; 2. Hu et al. Blood, 2005; 3. Mathews et al. Blood, 2006; 4. Ghavamzadeh et al. Ann Oncol, 2006; 5. Estey et al. Blood, 2006

31 with ATO significantly improves RR, EFS and OS among with newly diagnosed APL (US Intergroup C9710 trial) 1.0 Event- free survival % 66% p=0.001 ATO No ATO 0.4 p=0.09 Pediatric Time (months) Powell et al. ASCO 2007

32 Arsenic Trioxide in Therapy of the Evidence In some countries where locally produced arsenic compounds exists, it lead to the cure of many pa3ents with APL Excellent preliminary results from rela3vely small and selected series in single ins3tu3ons Clinical trials to determine the efficacy, safety, and cost- effec3veness is warranted

33 156 patients with low/intermediate risk were randomized Lo- Coco F et al. N Engl J Med 2013;369:

34 Lo- Coco F et al. N Engl J Med 2013;369: Probability of Event- Free Survival

35 Lo- Coco F et al. N Engl J Med 2013;369: Probability of Overall Survival

36 Lo- Coco F et al. N Engl J Med 2013;369: Probability of Relapse

37 Lo- Coco F et al. N Engl J Med 2013;369: Hematologic Toxic Effects

38 Future Integra3on of ATO in front- line treatment in childhood APL Oral ATO Liposomal ATRA Other re3noid drugs: Tamibarotene

39 Conclusions APL in children is highly curable with current strategies Early mortality and long- term sequelae remain concerns par3cularly in low- income countries Con3nue research to understand the pathogenesis of early complica3on is necessary Treatment op3miza3on to decrease the poten3al for anthracycline- cardiac toxicity