State of the Art Therapy of Acute Promyelocytic Leukemia

Transcription

1 State of the Art Therapy of Acute Promyelocytic Leukemia Francesco Lo-Coco, MD University Tor Vergata, Rome; GIMEMA Cooperative Group, Italy DGHO Annual Congress Hamburg, October 10-14, 2014

2 Outline Early death: an unsolved issue Current standard Rx in first line Latest advances using chemo-free Rx Future perspectives in high risk disease

3 Early Death in APL: Real World Data 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, Br J Haematol 2014

4 Percent ED ED by WBC at diagnosis WBC > 10 WBC < Lehman S, 6 Intl. Symposium on APL, Rome Oct. 2013

5 Leukemia Referral Centers (Canada) Early era Late era ( ) ( ) Time since dx Survival% Survival % Survival % 30 days* year year Significant improvement in ED and OS over time Paulson K, Br J Haematol 2014

6 Canadian Cancer Registry Results for APL ( ) Early Death % OS at 1 Year, % OS at 5 Yrs, % All patients <50 years old years old No improvement in ED or OS over time Paulson K, Br J Haematol 2014

7 Strategy at Emory Univ Hospital Developed a simple 1.5 page treatment algorithm Quick diagnosis Ad hoc meeting and treatment planning Rapid initiation of therapy Aggressive management of coagulopathy Prevention of differentiation syndrome; early recognition and management Implemented in 2010 A. Jillella et al., EHA 2014

8 Strategy at Affiliated Sites Affiliates contact us when a patient is diagnosed with APL or fax our algorithm Discuss patient with treating physician and recommend a treatment plan Follow up by phone, or texting at least 3 to 4 times in the first 10 days- during which 70% of the deaths take place. A. Jillella et al., EHA 2014

9 Survival Pre and Post Algorithm A. Jillella et al, EHA 2014

10 Outline Early death, an unsolved issue Current standard Rx in first line Latest advances using chemo-free Rx Future perspectives in high risk disease

11 Current treatment options in APL Cure CHT ATRA of ATRA ATO APL Third Way CHT ATRA ATO

12 Front-line Management of APL ATRA and CHT: Some Open Issues CNS prophylaxis Ara-C (high-risk only?) Role of Maintenance Cost-effectiveness of MRD smds/aml Elderly pts

13 Current treatment options in APL Conventional approach Cure of APL Alternative approach CHT ATRA ATRA ATO Third Way Four studies reported good results with the triple combination CHT ATRA ATO of ATO, ATRA & CHT 1. Hu J, et al. PNAS. 2009;106: Powell BL, et al. Blood. 2010;116: Iland HJ, et al. Blood. 2012;120: Zhu H-H, et al. JCO. 2013;31:

14 ATRA + ATO + CHT Australasian Leukemia and Lymphoma Group Induction Consolidation Maintenance ATRA + ATO + CHT 2 cycles of ATRA + ATO 5 cycles of sequential use of ATRA and LD/CHT Iland HJ, et al. Blood 2010

15 ATO+ATRA+CHT Chinese Cooperative Group Randomized comparison of oral arsenic vs. IV ATO * * Mitoxantrone was added at a dose of 1.4 mg/m 2 /day on 5 days 4, 5, 6, 7, and 8 (if WBC >10 x 10 9 /L start on day 1). ATRA = all-trans retinoic acid; ATO = arsenic trioxide; RIF = Realgar-Indigo naturalis formula; HA = homoharringtonine and cytarabine; DA = daunorubicin and cytarabine; MA = mitoxantrone and cytarabine Zhu H et al. JCO 2013

16 ATO+ATRA Vs. RIF+ATRA Chinese APL Cooperative Group 3-year OS 99.1% (95% CI, 97.2% to 99.9%) 3-year OS 96.6% (95% CI, 93.0% to 99.8% n = 114; CR 113; Relapse 1; Death in CR 1 n = 117; CR 114; Relapse 1 Zhu H et al. JCO 2013

17 Outline Early death, an unsolved issue Current standard Rx in first line Latest advances using chemo-free Rx Future perspectives in high risk disease

18 ATO+ATRA without CHT Randomized Studies GIMEMA-SAL-AMLSG MRC AML 17

19 APL0406: Treatment Arms ATO arm Induction ATO ATRA Until CR Consolidation ATO ATO ATO ATO 4 weeks on / 4 weeks off 2 weeks on / 2 weeks off R Estey et al. Blood 2006;107: Induction Consolidation Maintenance Chemo arm IDA IDA MTZ IDA ATRA ATRA ATRA ATRA Until CR 3 monthly cycles MTX + 6MP ATRA 2 years Lo-Coco et al. Blood 2010;116:3171-9

20 0406 Trial Results (n=162, median f.up 34m) Lo-Coco et al. NEJM 2013

21 What about QoL of patients treated with Arsenic? APL 0406: QoL Outcomes

22 EORTC QLQ-C30 Questionnaire 5 functioning scales: physical, role, emotional, cognitive, social 3 symptom scales: fatigue, nausea/vomiting, pain 6 single-item scales: dyspnoea, sleep disturbances, appetite loss constipation, diarrhea, financial impact Global QoL scale

23 Results and QoL compliance A total of 162 pts enrolled between Oct 2007 and Sept patients received at least one dose of the assigned Rx 156 patients ATRA- Chemotherapy ATRA-ATO N= 150 expected Compliance 77% Post induction N= 62 Post induction N= 53 N= 142 expected Compliance 84% Post consolidation Post consolidation N= 61 N= 58

24 Estimated differences in EORTC QLQ-C30 mean scores and 95% CIs between Rx arms Functional aspects / Global QoL *Clinically meaningful difference; (based on Cocks K, et al., JCO 2011).

25 Estimated differences in EORTC QLQ-C30 mean scores and 95% CIs between Rx arms Symptoms *Clinically meaningful difference; (based on Cocks K, et al., JCO 2011).

26 Results on QoL in APL0406 study Post-induction: Overall, current QoL findings further support the use of ATRA plus ATO as preferred first-line treatment in low-intermediate risk APL patients. Patients treated with ATRA-ATO reported statistically significant less fatigue, and other clinically relevant better outcomes for appetite loss, nausea/vomiting, constipation, physical and cognitive functioning Post-consolidation: No major difference in QoL between treatment at the end of 3 rd consolidation course

27 MRC-AML17 APL Protocol: Best AIDA (Italian) APL patients (Low/Int and high risk) R Chemo-free (ATRA-ATO)

28 APL: Less is just as good Alan K Burnett School of Medicine, Cardiff University United Kingdom Rome, October 2013

29 MRC-AML17 APL Protocol: CHEMO-FREE PCR Week ATO ATRA 3-monthly BM for PCR to 36mo from diagnosis d1 d60 Week AIDA PCR Ida Ida Mitox Ida ATRA 3-monthly BM for PCR to 36mo from diagnosis

30 ATO Schedule in AML17 Induction: ATO 0.3mg/kg days 1-5 week mg/kg X 2 per week Consolidation: ATO 0.3mg/kg X2 per week, in wk1 0.25mg/kg X2 per week x3 weeks (4 courses)

31 Outline Early death, an unsolved issue Current standard Rx in first line Latest advances using chemo-free Rx Future perspectives in high risk disease

32 ATO+ATRA+Ida vs ATRA+CHT for high-risk APL APOLLO-Trial Open label, randomized, prospective, intergroup phase III study Inclusion criteria: Newly diagnosed and genetically confirmed APL Age: 18 and 65 yrs WBC at diagnosis > 10 x 10 9 /L ECOG performance status 0-2

33 Treatment Arms The first 4 days of therapy are identical in the two arms

34 Aim to show superiority of the experimental arm: clinically relevant increase of 10% in EFS at 2 yrs (from 77% in the AIDA study* to 87%) * Lo-Coco et al, Blood 2010

35 Primary efficacy endpoint: EFS Key secondary endpoint(s): Objectives CR, OS and CIR Quality of life Toxicity profile Rate of early death Kinetics of MRD Cumulative incidence of secondary MDS or AML Hospitalization Cost analysis

36 Participating groups GROUPS Country PI SAL Germany U.Platzbecker GIMEMA Italy F. Lo-Coco 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 NCIC-CTG Canada S. Couban

37 Conclusions Early death is still the main obstacle to cure High cure rates can be achieved with optimized combinations of: ATRA + CHT ATRA + ATO ATRA + CHT + ATO ATO+ATRA appears superior to ATRA-CHT for Low-intermediate risk. However: Not yet approved for this indication in most countries Not yet assessed in high-risk (R studies needed)

38 Acknowledgements S.K. Hasan M. Divona L. Cicconi M. Breccia

39 Acknowledgements F. Ferrara E. Di Bona M. Breccia A.M. Carella F. Fabbiano G. Leone S. Orlando E. Morra G. Specchia P. Fazi M. Vignetti A. Rambaldi G. Rossi S. Amadori C. Ciardi M. Divona S. Iacobelli F. Mandelli G.Ehninger C. Thiede C. Brandts H. Link W. Aulitzky M. Hänel K. Schäfer-Eckart S. Krause K.-H. Pflüger N. Schmitz M. Sauer E. Estey (Seattle, USA) M.A. Sanz P. Montesinos (Valencia, Spain) A.K. Burnett D. Grimwade (NCRI, UK) G. Avvisati U. Platzbecker H. Döhner A. Ganser K. Dohner J. Krauter R.F. Schlenk