New APL Strategy for Children BFM-Recommendation

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New APL Strategy for Children BFM-Recommendation Ursula Creutzig Nils von Neuhoff Dirk Reinhardt Medical High School Hannover UK Essen

AML FAB M3 / AML FAB M3 variant AML FAB M3v t(15;17) Cantú Rajnoldi A, Biondi A, Jankovic M, Masera G, Rovelli A, Uderzo C, Head D, Raimondi S, Creutzig U, Ritter J. Diagnosis and incidence of acute promyelocytic leukemia (FAB M3 and M3 variant) in childhood. Blood 1993; 81: 2209-2210 2

1. Frequency 7-8% of AML`s in < 18 years old in Germany ca 8 pat. /year (G) 20% in Italy Rare in infants < 2 years Selten bei < 2 Jährigen

Standard treatment until 2012 Chemotherapy + ATRA Standard treatment until 2012

Mechanismen of ATRA in APL Normal Mutation PML/RARa The functional consequence of the PML-RARA fusion protein is a more difficult detachment of the co-repressor that can be overcome with higher concentrations of ATRA. Die RARE verhindern/hemmen die Ablesung der DNA. Normalerweise reichen physiologische Konzentrationen von ATRA aus, den Co-repessor komplex abzulösen und so die Fortsetzung der DNA Ablesung zu ermöglichen und damit die weitere Differenzierung der Zelle. Liegt das Fusionprotein PML/RARa vor, so ist die Ablösung des Corepressors erschwert. Erst höhere Konzentrationen von ATRA ermöglichen die weitere Transcription. Bei den selteneren anderen Mutation wie PLZF/RARa bewirken auch hohe ATRA-Konzentrastion keinen Effekt, die Zellen sind ATRA resistent. Mutation PLZF/RARa Abb. nach Guidez et al. Blood 1998; 91, 2634-42

Chemotherapy + ATRA: AML-BFM 2004 KMP Chemotherapy + ATRA: AML-BFM 2004 Tag -3 Tag 1 15 21-28 42-56 ~88 ~112 3 Mo 6 Mo 9 Mo MRD MRD MRD MRD MRD MRD 12 Gy vs. 18 Gy1 HAE Induktion 1 ADxE haM Erhaltungstherapie 1 Jahr und Cytarabin i.th.1 Intensivierung A: ARA-C; Cytarabin Dx: liposomales Daunorubicin; L-DNR I: Idarubicin E: Etoposid-Phosphat HA: Hochdosis Cytarabin M: Mitoxantron HAE: Hochdosis Cytarabin/ Etoposid-Phosphat R: Randomisierung SR: Standardrisikogruppe HR: Hochrisikogruppe MRD: Minimal residual disease KMP: Knochenmarkpunktion Konsolidierung AIE R1 R3 AI ATRA Tag –3 bis 11 Tag 18-31 Tag 38-51 AT RA Parallel HAE 14 Tage Alle 3 Monate je 14 Tage FAB M3 Strategy APL children no anthracycline-monotherapy But limited cum. Anthracycline doses and combination with Ara-C (+ ATRA) Anthrazykline: 3x12mg IDR, 2x7 IDR, 2x10mg MITOX = (Faktor 5) = 350mg/m² DNR kum. Dosis

Results - APL Study 2004-2012 EFS (3 years) 1.0 OS 96% + 2% (4 events) 0.9 0.89, SE= 0.04 0.8 0.7 Results N % Total pat. 77 100 Early death* 3 4 Relapse 5 Lfu in CCR CCR 60 80 0.6 0.5 P 0.4 apl_2014.tab 15JUL14 0.3 0.2 *All ED were HR pts., died by cerbral bleeding, bleeding sepsis, 1x?, at day 0, 9 and 10 0.1 Creutzig et al. BJH 2010 0.0 1 2 3 4 5 6 7 8 9 years All Patients (N= 77, 7 events) Testi et al BLOOD 2018

APL-Risk Groups Standard High Risk Early death and relapse WBC /µl <10 000 >10 000 In addition: M3v (associated with high WBC) About 1/3 APL children HR pts.

ATO = As2O3 Dosis dependend dual effect* Apoptose: higher concentration partial differentiation: lower concentration Synergistic to ATRA by reduction of LICs (leukemia-initiating cells)** ATO is licensed in Europe and US for relapsed/refractary APL and de novo SR-APL in in adults ATO monoth. CR 80% *Lallemand-Breitenbach , J Exp Med 1999 **Nasr, Nature Medicine 2008

Mode of Action of ATO and ATRA in APL PML-RARa-Protein: Transkriptionfactor → dominant negative effect on myeloid differentiation, apoptosis, DNA-replication and DNA-repair Synergististic effects: ATO/ATRA Leukemia-inducing cells (LICs) Mi et al. (2012) Leukemia 26: 1743-1751

Weight gain, fluid retention leukocytosis Dynamic changes of peripheral WBC counts during As2O3 treatment in five patients presenting hyperleukocytosis. Side effects ATO Weight gain, fluid retention leukocytosis prolongation of the QT-interval. ECG control at start of each ATO cycle rare: peripheral neuropathy hyperglycemia skin rash Dynamic changes of peripheral WBC counts during As2O3 treatment in five patients presenting hyperleukocytosis. Shen Z et al. Blood 1997;89:3354-3360 ©1997 by American Society of Hematology

Differentiation Syndrom after ATRA and ATO Unexplained Fever Respiratory distress Interstitial pulmonary infiltrates and pleural or pericardial effusion weight gain (fluid retention) hypotension +/- hyperleukocytosis Therapy Stop ATRA and ATO Dexamethason 10 -15 mg/m² iv in 2-3 doses/day for min. 3 days No single feature is diagnostic of the syndrome, but suggestive

APL-BFM recommendation Standard Risk FAB M3 (PML/RARA): ATRA + ATO in pat. with WBC < 10 000/µl Induction maintenance CR If PML/RARA remains positive, perform another cycle. If still posisive additional therapy is required if NR consultation molecular remission from day 2-6 to day 42 4 weeks 4 Wochen ATO 2 weeks break ATO 4 weeks break ATO total 4x ATO following CR ATRA 14 days, 14 days break day 1 -14 day 21-42 day 56 - 70 day 84 – 98 day 112 - 126 day 140 - 154 total 7x ATRA following CR ATRA ATRA ATRA ATRA ATRA ATRA BMP i.th. starting day 10, every 4 weeks, in total 7x i.th. MRD monitoring from BM before the 4. ATO course and after the 5. ATO course (=end of therapy), afterwords from blood for 12 month (min. every 3-month) MRD Tag MRD 1 MRD 28 MRD 56 MRD 84 MRD 112 In case of symptoms of differentiation syndrome immediately start dexamethason 10 to 15mg/m² ATRA: All trans-retinoid acid 25mg/m²/day oral twice a day, each day for 14 days, followed by a break of 14 days, in total 7x following CR (exception 2. ATRA course!) ATO: Arsentrioxid 0.15 mg/kg/day i.v.; 1-2 hours starting at day 2-6 until morphologic CR. Concomitant prednison 0.5 mg/kg day 1 – day 15 as prophylaxis of the differentiation syndrome After 2 weeks break: 4 cycles with ATO: Monday - Friday 0.15 mg/kg/day i.v. for 4 weeks – 4 weeks break Side effects ATO: Weight gain, fluid retention, leukocytosis, prolongation of the QT-interval. ECG control at start of each ATO cycle rare: peripheral neuropathy, hyperglycemia, skin rash CR: complete remission MRD: minimal residual disease BMP: bone marrow aspiration i.th. intrathecal cytarabin age dependent Modified from the adult protocol, see Lo-Coco et al, NEJM13 AML-BFM 05/2018

APL-BFM recommendation High Risk FAB M3 (PML/RARA): ATRA + ATO in pat. with WBC > 10 000/µl Induction maintenance CR If PML/RARA remains positive, perform another cycle. If still posisive additional therapy is required if NR consultation molecular remission ICC APL study 2x GO ADx from day 2-6 to day 42 4 weeks 4 Wochen ATO 2 weeks break ATO 4 weeks break ATO total 4x ATO following CR ATRA 14 days, 14 days break day 1 -14 day 21-42 day 56 - 70 day 84 – 98 day 112 - 126 day 140 - 154 total 7x ATRA following CR ATRA ATRA ATRA ATRA ATRA ATRA BMP i.th. starting day 10, every 4 weeks, in total 7x i.th. MRD monitoring from BM before the 4. ATO course and after the 5. ATO course (=end of therapy), afterwords from blood for 18 month (min. every 3-month) MRD Tag MRD 1 MRD 28 MRD 56 MRD 84 MRD 112 In case of symptoms of differentiation syndrome immediately start dexamethason 10 to 15mg/m² ATRA: All trans-retinoid acid 25mg/m²/day oral twice a day, each day for 14 days, followed by a break of 14 days, in total 7x following CR (exception 2. ATRA course!) ATO: Arsentrioxid 0.15 mg/kg/day i.v.; 1-2 hours starting at day 2-6 until morphologic CR. Concomitant prednison 0.5 mg/kg day 1 – day 15 as prophylaxis of the differentiation syndrome After 2 weeks break: 4 cycles with ATO: Monday - Friday 0.15 mg/kg/day i.v. for 4 weeks – 4 weeks break Side effects ATO: Weight gain, fluid retention, leukocytosis, prolongation of the QT-interval. ECG control at start of each ATO cycle rare: peripheral neuropathy, hyperglycemia, skin rash CR: complete remission MRD: minimal residual disease BMP: bone marrow aspiration i.th. intrathecal cytarabin age dependent AML-BFM 05/2018

SR WBC < 10 000/µl – PCR follow-up ATRA – ATO Group (APL-BFM Recommendation) SR WBC < 10 000/µl – PCR follow-up PCR (Pos > 10 E -4) Pos Neg 1 6y 2m WBC 3.67 2 5 y 3m WBC 3.2 3 14y 11m WBC 1.3 4 3y 4m WBC 3.11 5 7y 8m WBC 4.2 6 1y 2m WBC 2.9 7 14y 2m WBC 0.79 8 16y 3m WBC 1.9 9 8y 6m WBC 1.9 10 11y 2m WBC 3.0 w16 11 1y 3m WBC 3.8 12 4y 6m WBC 2.0 13 14y 6m WBC 2.6 ATO ATO ATO total 4* ATO and 7 * ATRA from CR ATRA ATRA ATRA ATRA ATRA ATRA Initial 4w 12w 16w 20w 28w 9m 12m 15m 18m 8w Creutzig et al.(2017) First experience of the AML-BFM group in pediatric patients with standard-risk APL treated with ATO and ATRA. Pediatr Blood Cancer, 64. 9/2016

Course and Toxicity in SR APL Patients WBC (/µl) WBC increase Therapeutic action toxicity 1 3,7 48,6 (ATRA) HU, Ara-C Trans. thrombocytosis 1419,000/µl 2 3,2 79,0 (ATO) Break of ATO, Ara-C 2x focal gen. seizure, posterior reversible encephalopathy syndrome (PRES), asept. Osteonecrosis 3 1,3 22,5 - 4 3,1 22,4 Skin reaction (facial), 5 4,2 135,0 (ATRA) Ara-C (does escalation) * L-DNR ATRA syndrome, knee pain, QTc time prolongation gr. 1 6 3,8 (AIE Ukraine) Otitis media (4. ATO cycl.) 7 0,8 10,4 8 1,9 24,2 9 40,0 (ATO) Break of ATO double vision, congested papilla, abducens paresis 10 3,0 ADxE first (M2) QTc time borderline 11 37,2 (infection) Facial eczema 12 2,0 75,0 (ATO) HU 13 2,6 14,0 (ATO) Stop of ATRA (diff. syndrome) Deep vein thromb., after 2 yrs. hair loss

Increase of WBC until day 33 6 pat. with different. Syndrome 4x after ATO WBC data are incomplete in patient (Pat) 4 and 6

Summary ATRA+ATO Leukemia can be cured without ChTH! (SR) All 13 (in between 20 pts.) SR pts. are in molec. CR Till now no difference in MRD kinetics – (time until PCR neg.) between ChTh. - and ATRA/ATO All pts. achieved hyperleukocytosis after ATRA / ATO – (Pred. propylaxis and early HU needed) After 1 week outpatient care!

Early Death in APL Summary of Findings Bleeding and thrombosis are the leading causes (72%) of ED in child- hood APL – CNS bleed: 85% chance ED Higher ED rate in patients not receiving induction ATRA Initial high WBC count, increased BMI and M3v morphology were independently associated with ED Abla O. et al. – Predictors of thrombohemorrhagic early death… Ann. Hematol 2017 YOU ARE NOT SHOWING BLACK RACE – SO REMOVE FROM SUMMARYT

Early Death in APL Highest risik: Initially ED by bleeding/ DIC Early diagnosis - Suspicion on APL – ATRA at once Teaching – for pediatricians Initial absolut nessessary - morphology! WBC high risk > 10 000/µl Bleeding? Coagulation - (Quick, PTT, Fibrinogen, D-Dimere) Supportive Care Guidelines intensive monitoring Substitution of platelets diagnostic LP after blast cell reduction

APL – to consider! ATRA always immediately ATO as soon as possible (ATO leads besides differentiation also to apoptosis) Because of danger of differentiation syndrome: hydroxyurea (2x20mg / m² / day) already in case of WBC increase to 5 000/μl At WBC increase to 10 000/μl, hydroxyurea (2x40mg/m²) + cytarabine (2x40mg/m²/day)

Concomitant therapies Prednisone 0.5 mg/kg from day 1 until day 15 of induction to prevent differentiation syndrome. Dexamethasone if APL differentiation syndrome develops Platelet concentrate transfusions to maintain platelets >50x109/l during the first 10 days. After day 10, platelets transfusion when platelets count is <20x109/l or in presence of hemorrhagic symptoms. Packed red cell concentrates must be transfused to maintain Hb levels > 8 g/dl. Supplemental electrolytes administered i.v., to maintain potassium concentrations above 4 mEq/l and magnesium concentrations above 1.8 mg/dl (0.74 mmol/l) in order to reduce the risk of cardiac arrhythmia

During follow-up In case of non-response – other fusion gene? ZBTB16-RARA (past PLZF-RARA) – ChTh! MRD (PCR) relapse diagnosis every 3 months 12 m. (SR) and 18 m. (HR) patients After end of therapy from blood

Relapse treatment according to time of rel. </> 18->36 months Algorithm for Early Relapse – Consensus Guideline COG/I-BFM BJH 2016 Abla O. et al. Relapse treatment according to time of rel. </> 18->36 months or > 3 years and the firstline treatment: ATRA + chemoth. or ATRA + ATO Early APL Relapse (<18 m) Prior ATO? Ind ATO/ATRA no 3x Consol ATRA/ATO/GO Auto SCT PCR neg Consol.: hAM, ATRA PCR pos Allo SCT Ind ATO/ATRA/Ida yes Consol 1: HD-Ara-c, ATRA, GO Consol 2: ATRA-ATO Consol 3: hAM, ATRA Consol.: HD-Ara-c ATRA 2x ITT

Algorithm for Late Relapse – Consensus Guideline COG/I-BFM BJH 2016 Oussama A. et al. APL Relapse (>18 m) Prior ATO? Ind ATO/ATRA no 3x Consol ATRA/ATO/GO 4x ATRA/ATO PCR neg Consol.: hAM, ATRA PCR pos Allo SCT Ind ATO/ATRA/Ida yes Consol 1: ATO/ ATRA, GO Consol. 2: ATRA + ATO Consol 3: hAM, ATRA Auto SCT Consol.: HD-Ara-c ATRA 2x ITT

Very Late Relapse (>3 yrs.) ATO/ATRA regimen + GO (see de novo APL) Persistent MRD after 3 courses – allo SCT Thank`s for your attention!

Information for patients and their families – about the diseases and therapies ...

Risk Groups LR WBC <10 000 HR WBC >10 000 AIEOP/AIDA93* N=110 64 % 36 % M3v 11 % 5 yrs. OS >90 % 81 % 5 yrs. EFS 83 % 59 % AML-BFM 93-04** N=81 70 % 30 % CNS pos. 5 % (1 CNS rel) 86 % more HR in children vs adults (25%) *Testis, BLOOD 2005 ** Creutzig, BJH 2010