Acute Promyelocytic Leukemia

Transcription

1 Acute Promyelocytic Leukemia A chemotherapy-free zone? Francesco Lo-Coco, MD University Tor Vergata, Rome GIMEMA Cooperative Group, Italy 32 nd Annual Meeting of the BSH Brussels, February 10, 2017

2 Disclosures Research Support/P.I. Employee Stockholder Consultant Advisory Board Speakers Bureau Other (Specify) No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Teva Novartis, Teva Lundbeck, Novartis, Teva No relevant conflicts of interest to declare

3 L.S., a professional cyclist, came second one spring Sunday in the race from Paris to Tours, in which he averaged 40 Km/h The following Monday, he was tired and the fatigue was attributed to his physical effort On Wednesday he had serious hemorrhages and was taken to hospital On Thursday, promyelocytic leukemia was diagnosed He died on Saturday of more hemorrhages Bernard J, History of APL, Leukemia 1993

4 Continuing Early Death in APL Population-based studies Study ED rate (< 30 d) Swedish Registry 1 29 % SEER (USA) 2 17 % Stanford University 3 26 % Canadian Registry 4 22 % 1 Lehman, Leukemia 2011; 2 Park, Blood 2011; 3 McClellan, Haematologica 2011; 4 Paulson, BJH 2014

5 Percent ED ED by WBC at diagnosis Swedish Registry WBC > 10 WBC < courtesy of S. Lehman, (unpublished)

6 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable 1957 First description

7 .. Evidence is here presented for the existence of a special type of acute myelogenous leukemia It is suggested that this type is named acute promyelocytic leukemia (APL). It seems to be the most malignant form of acute leukemia

8 Epidemiology 10%-15% of acute myeloid leukemias (AMLs) cases/year in Italy Median age 40 (vs 70 in other AMLs) Same incidence in M/F De novo and therapy-related

9 Main presenting features Life-threatening bleeding tendency Dysplastic promyelocytes in the marrow Usually abrupt onset, with rapidly progressing coagulopathy (medical emergency)

10 Thrombo-Hemorrhagic Syndrome of APL Variability of Clinical Manifestations Catastrophic internal hemorrhage Intracranial, pulmonary, other Muco-cutaneous hemorrhage Thrombosis - DVT, cerebral, myocardial, cerebral, splancnic, other Laboratory DIC only None of the above

11 Thrombosis as initial manifestation of APL (Not all APLs bleed) Cancer Res Ther Oct-Dec;6(4): Acute Budd-Chiari syndrome as an initial presentation of acute promyelocytic leukemia. Bandyopadhyay S, Bandyopadhyay D. Leuk Res Jul;35(7):e Transient ischemic attack as initial manifestation of acute promyelocytic leukemia. Cicconi L, Madeo G, Ramadan SM, Forte V, Mercuri N, Lo- Coco F.

12 Early Death What can be done? More awareness/education (emergency & ICUs) Foster registry studies Improve early diagnosis & ATRA / ATO availability Specialized care (important Center effect!) More investigation on coagulopathy

13 Morphologic Diagnosis of APL: it can be easy, it can be tough Diagnostic refinement: 1. Flow cytometry 2. Cytogenetics/FISH 3. The undisputed molecular confirmation

14 CD33 CD34

15 Recommended actions in case of APL suspicion Start treatment with Atra Start supportive care with plts/plasma transfusions Send a marrow sample to reference lab for genetic dx

16 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo First description

17 Jean Bernard

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19 GIMEMA trials in newly diagnosed APL 77-81: DNR 82-88: IDA 89-93: IDA vs IDA+AraC 93-99: AIDA : MyAIDA 00-05: AIDA 2000 (risk-adapted) 06-12: AIDA vs ATO+RA

20 151 Clinical Centers 9 Centralizing Labs Established in 1982 by F. Mandelli - Non-profit clinical studies - Homogenize rx in the country - Reference laboratories - Diagnostic standardization - International collaborations

21 Randomized APL0389 Trial (pre-atra era) Avvisati et al. Blood 2002

22 Mode of action of chemotherapy in vivo on human acute leukemia. I. Daunomycin. Stryckmans P, Manaster J, Lachapelle F, Socquet M. J Clin Invest Jan;52(1): Daunorubicin in patients with relapsed and refractory acute nonlymphoblastic leukemia previously treated with anthracycline. Velu T, Debusscher L, Stryckmans P. Am J Hematol Mar;27(3):224-5

23 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo First description Specific chromosome lesion identified

24 t(15;17) is the Diagnostic Hallmark of AML M3 (J Rowley 1977)

25 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo Response to ATRA (Vit. A derivative) First description Specific chromosome lesion identified

26 From Confucius to differentiation therapy If you use laws to direct the people, and punishments to control them, they will merely try to evade the laws, and will have no sense of shame. But if by virtue you guide them, and by the rites you control them, there will be a sense of shame and of right. Confucius B.C. Malignant cells induced to differentiate with ATRA. ME Huang, Blood 1988 Retinoic Acid (ATRA)

27 2015 Nobel Prize awarded to achievements of Traditional Chinese Medicine (antimalaric treatment) Tu you you

28 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo Response to ATRA (Vit. A derivative) First description Specific chromosome lesion identified Altered genes identified

29 Cloning of the t(15;17) Novel Retinoic Acid Receptor-a Transcripts in Acute Promyelocytic Leukemia Responsive to RARα RAR locus All-frans-Retinoic Acid locus Wilson H. Miller, Jr, Raymond P. Warrell, Jr* Stanley R. Frankel, Ann Jakubowski, Janice L. Gabrilove, Josephia Muindi, Ethan Dmitrovsky Journal of National Cancer Institute Vol 82, No.24, December 1990, fusion gene 15q+ 17q-

30 PML locus RARα locus RAR locus PML/RARα RARα/PML fusion gene 15q+ 17q-

31 The PML/RAR fusion protein Why so important in clinical practice? Unique to APL (disease hallmark) Strongly correlated with pathogenesis Targeted by specific therapies Detection predicts response to ATRA & ATO Ideal marker for residual disease monitoring

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33 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo 1973 Response to ATRA 1987 High cure rates with ATRA + Chemo First description Specific chromosome lesion identified Altered genes identified

34 G. Avvisati

35 AIDA protocol is exported (and refined) Miguel A Sanz

36 Definition of Relapse Risk Groups

37 AIDA Long-term results 76 % at 12 yrs. low: 81%. intermediate: 75% high: 53%. p< Avvisati et al., Blood 2011

38 Survival (%) Survival (%) Reported outcomes for APL pre- and after ATRA Chemotherapy era Time (mo) Fenaux et al, 1993; Mandelli et al, 1997; Sanz et al, 1999; Burnett et al, 1998;Tallman et al 2002, Asou et al, 2007; Lengfelder et al 2009, Iland et al, 2012

39 Problems with ATRA and Chemotherapy Induction death Death in remission Toxicity of consolidation therapy Therapy-related MDS/AML (t-mn)

40 Cumulative incidence of relapse elderly vs young P=0.16 <60 years >60 years by courtesy of M Sanz (unpublished)

41 Non-relapse mortality elderly vs young P<0.001 >60 years <60 years by courtesy of M Sanz (unpublished)

42 PETHEMA-HOVON APL trials Post-remission events by courtesy of M Sanz (unpublished)

43 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo Response to ATRA (Vit. A derivative) High cure rates with ATRA + Chemo First description Specific chromosome lesion identified Altered genes identified Response to Arsenic Trioxide (ATO)

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45 From Poisons to Remedies Streptomyces: Toxin interferes in DNA biosynthesis Daunorubicin: Antineoplastic antibiotic Black Mamba: Seven steps poison Mambalgins: Anesthetic Arsenicals: Multiorgan failure Arsenic trioxide (ATO): Treatment of leukemia

46 PML PML RXR RAR RAR Antileukemic Mechanisms of ATO in APL PML-RARα degradation (via PML sumoylation); phosphorilation of NCoR and transcriptional activation Increased production of reactive oxygen species (ROS); induction of caspases ATO As 2 O 3 Co-Activators RA 10-6 M P ROS ATO R A RARE Apaf-1 Caspase9 SUMO SUMO Cytochrome C Caspase3 Differentiation Apoptosis

47 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo Response to ATRA (Vit. A derivative) High cure rates with ATRA + Chemo Improved ATRA + Chemo combinations First description Specific chromosome lesion identified Altered genes identified Response to Arsenic Trioxide (ATO)

48 AIDA 2000 Vs AIDA 0493 (historical) A: all patients AIDA 2000 AIDA 0493 p< DFS time since CR (years) B: Low/Intermediate C: High AIDA 2000 AIDA 2000 AIDA 0493 AIDA 0493 p= p< DFS time since CR (years) DFS time since CR (years) Lo-Coco et al, Blood 2010

49 Post-Induction toxicity in the AIDA in CR after induction 377/420 (90%) evaluable after consolidation 362/377 (96%) tested for RT-PCR post-consolidation 358/362 (99%) PCR-negative proceeded to maintenance 43 (10%) off-study for: 17 toxicity (11 deaths) 14 missing data 7 major protocol violation 3 lost to follow-up 1 refusal 1 other Lo-Coco et al, Blood 2010

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51 Elihu Estey

52 Experience with Arsenic in APL (Estey et al.)

53 PML/RARα: functional domains de Thé et al. J Cell Biol 2012

54 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo Response to ATRA (Vit. A derivative) High cure rates with ATRA + Chemo Improved ATRA + Chemo combinations First description Specific chromosome lesion identified Altered genes identified Response to Arsenic Trioxide (ATO)

55 Acute Promyelocytic Leukemia: From Highly Fatal to Highly Curable Responses with anthracycline chemo Response to ATRA (Vit. A derivative) High cure rates with ATRA + Chemo Improved ATRA + Chemo combination First description Specific chromosome lesion identified Altered genes identified Response to Arsenic Trioxide (ATO) Chemo-free (ATO + ATRA) results

56 Front-line Therapy of APL State of the art in 2006 Retinoic Acid + Arsenic? Retinoic Acid + Chemotherapy Target therapy High efficacy Reduced toxicity % of cure? Non specific therapy High toxicity 80% of cure

57 APL 0406 Italian-German Phase III Study Acute Promyelocytic Leukemia Low-intermediate risk R ATRA + Arsenic Trioxide ATRA + Chemotherapy

58 APL-0406 Study in non-high risk (GIMEMA-AMLSG-SAL) Induction Consolidation ATO arm ATO ATRA ATO ATO ATO ATO R Estey et al. Blood 2006 Induction Consolidation Maintenance Chemo arm ATRA IDA IDA MTZ IDA MTX + 6MP Lo-Coco et al. Blood 2010

59 Haematological Toxicity Grade 3 4 thrombocytopenia >15 days Grade 3 4 neutropenia >15 days NEJM 319; , 2013

60 APL0406 trial original series Follow-up (34 months) Lo-Coco et al. NEJM 2013

61 APL: Less is Just as Good Alan K Burnett School of Medicine, Cardiff University United Kingdom Rome, October 2013

62 6 th INTERNATIONAL SYMPOSIUM ON ACUTE PROMYELOCYTIC LEUKEMIA Rome, September 29 th - October 2 nd, 2013

63 AML17: CI of Molecular Relapse Burnett et al, Lancet Oncol 2015

64 AML 17: Overall Survival Burnett et al, Lancet Oncol 2015

65 APL 0406: Updated and extended series Follow-up (41.9 mos) p= p= Platzbecker et al., J Clin Oncol 2016

66 APL0406 extended series Study Outcomes Survival probability (95% CI) p-value 24 months 50 months OS ATRA-ATO 99.2% ( ) 99.2% ( ) ATRA-CHT 94.8% ( ) 92.6% ( ) EFS ATRA-ATO 98.3% ( ) 97.3% ( ) <0.000 ATRA-CHT 86.8% ( ) 80% ( ) 1 DFS ATRA-ATO 98.3% ( ) 97.3% ( ) ATRA-CHT 89.4% ( ) 82.6% ( ) CIR ATRA-ATO 0.9% (0-2.7) 1.9% ( ) ATRA-CHT 8.2% ( ) 13.9% ( ) Platzbecker et al., J Clin Oncol 2016

67 APL 0406 Update. Post-remission events ATO arm (n=3) 1 death in CR (H1N1 pneumonia) 2 relapses Chemo arm (n=23) 5 deaths in CR (1 sec. AML) 1 additional sec. AML 15 relapses 2 molecular resistance

68 Haematological Toxicity Grade 3-4 thrombocytopenia >15 days Grade 3-4 neutropenia >15 days P< P< P< P< P< P< P< P< ATRA-ATO ATRA-CHT ATRA-ATO ATRA-CHT

69 APL0406. Non-haematologic toxicities Side effect ATRA+ATO ATRA+CHT P-value QTc prolongation 15.6% 0% P<0.001 Hyperleukocytosis 47% 24% P=0.007 Hepatic toxicity (grade 3-4) Gastrointestinal toxicity (grade 3-4) Oral toxicity (grade 3-4) 63.2% 5.8% P< % 9.9% P=0.33 0% 19.4% P<0.001

70 APL0406. Molecular studies Kinetics of PML/RARA clearance Impact of FLT3 status

71 Differential log-reduction of PML-RARa transcripts in the ATO-ATRA (arm A) and ATRA-CHT (arm B) Log reduction PML/RARa transcript Median diagnosis-post induction (range) ATRA-ATO 3.00 ( ) P-value 0.09 Median post inductionpost III cons (range) 5.81 (0 8.67) P-value ATRA-Chemo 3.47 ( ) 5.30 (0 8.74) Cicconi L, Leukemia

72 EFS probability at 2-years for FLT3-ITD positive and negative patients in the two treatment arms. Cicconi et al., Leukemia 2016

73 November 2016 EU Commission grants extension of indication to first line use of Trisenox in combination with retinoic acid

74 November 2016 EU Commission grants extension of indication to first line use of Trisenox in combination with retinoic acid Decision solely based on published academic data endorsing the benefit of Trisenox as first chemotherapy-free treatment for APL and marks important advancement for patients in Europe

75 ATO+ATRA vs ATRA+CHT for high-risk APL APOLLO-Trial A European Intergroup Randomized Trial (started in January 2017)

76 Phase III European trial for high-risk APL Treatment Arms IDA ATO ATO ATO ATO ATO 4 weeks on / 4 weeks off 2 weeks on / 2 weeks off IDA: d 1 & 3 ATO: d 5 until CR IDA: d 1,3,5,7

77 High-risk APL trial. Participating groups GROUPS Country PI GIMEMA Italy F. Lo Coco SAL Germany U. Platzbecker AMLSG Germany R. Schlenk ALSG Germany E. Lengfelder OSHO Germany D. Niederwieser French-Belgian-Swiss France P. Fenaux PETHEMA Spain M. Sanz HOVON Netherlands E. Vellenga EORTC EU F. Baron Swedish AL Sweden S. Lehman

78 A few key features of the APL saga must be stressed: Hallmark findings made by chance more than design Progress relied primarily on the academic world Basic science accompanied clinical explorations providing a spectacular illustration of the power of translational research International cooperation was the key to success H de Thé, Blood 2013

79 Acknowledgements (I) M. Breccia D. Diverio M. Divona E. Ammatuna L. Cicconi S.K.Hasan

80 Acknowledgements (II) F. Ferrara E. Di Bona G. Rossi M. Breccia F. Fabbiano G. Leone S. Orlando M.C. Petti G. Specchia P. Fazi M. Vignetti S. Amadori G. Avvisati F. Mandelli C.Ciardi L. Cicconi M. Divona S. Iacobelli A.Venditti J.Digiandomenico M. Alcalay S. Minucci P.G. Pelicci (Milan, Italy) E. Rego P. Muxi, R Uriarte S Undurraga J. Zarza (IC-APL) D. Grimwade A.K. Burnett (NCRI, UK) P. Fenaux H. de Thé (St. Louis, Paris) E. Estey (Seattle, USA) P. Montesinos M.A. Sanz (Valencia, Spain) G. Ehninger C. Thiede U. Platzbecker (SAL, Germany) H. Döhner A. Ganser R. Schlenk (AMLSG, Germany)

81 7 th INTERNATIONAL SYMPOSIUM ON ACUTE PROMYELOCYTIC LEUKEMIA Save the date! Rome, September 24-27, 2017 Chairmen: F. Lo-Coco, M.A. Sanz