Objectives. I do not have anything to disclose.

Transcription

1 Treatment of APL

2 Objectives I do not have anything to disclose.

3 Objectives 1. Urgency of early recognition and treatment 2. Treatment based on risk stratification 3. Monitoring for relapse 4. Treatment of relapse 5. Long-term toxicities

4 Acute Promyelocytic Leukemia Distinguishing Features 10-15% of adult AML Leukopenia (85%) Complex coagulopathy t(15;17) PML-RAR fusion transcript Sensitivity to anthracyclines Differentiation with retinoic acid Apoptosis with arsenic trioxide

5 Bleeding in APL Oral mucosal bleeding Subcutaneous bleeding Retinal hemorrhages Intracerebral hemorrhage

6 Early Death Rate in APL Population-Based Studies Study N ED Jeddi 41 16% Lehmann 99 31% Alizadeh % McClellan 70 26% Park 1,400 18% Jeddi et al. Hematology, 2008; Lehmann et al. Leukemia, 2010; Alizadeh et al. ASH, 2009; McClellan et al. Haematologica, 2012; Park et al. Blood, 2011

7 Early Death Rate in APL Progress! 2018 by American Society of Hematology Ana C. Xavier et al. Blood 2018;132:710

8 Molecular Basis of Leukemogenesis in APL RAR fuses to PML Fusion protein shows increased affinity for nuclear corepressor protein complex (N-coR) including histone deacetylase High doses of retinoic acid (RA) induces release of N- cor permitting transcription RAR RARE msin3 N-CoR HD RA RAR RARE msin3 N-CoR HD PML PML Grignani et al. Nature, 1998

9 DFS OS Milestones in the Development of Curative Strategies in APL Initial Description, Highly Fatal Daunorubicin ATRA ATRA + Chemo Arsenic Highly Curable ATRA + Arsenic s s ECOG Data Pre-ATRA era Years Tallman et al. Blood, APL WBC < 10,000/ L WBC 10-50,000/ L 0.2 WBC > 50,000/ L P = Years Kelaidi et al. J Clin Oncol, 2009

10 All-trans Retinoic Acid Natural vitamin A derivative Induces leukemic promyelocytes to differentiate in vitro Induces CR in most pts with APL as single agent No marrow aplasia Biggest side effect headache / pseudotumor At diagnosis Day 12 Day 37

11 Arsenic Trioxide The most active agent in APL Single-agent CR rate (including molecular CR) very high even in relapsed setting Dual mechanism (differentiation at lower dose, apoptosis at higher dose) Biggest concerns are QTc prolongation and elevated LFTs

12 Patients with MR ( %) Molecular Response to Arsenic Trioxide in Relapsed APL: US Multicenter Study Baseline N=29 48% 86% Induction Consolidation 90% Maintenance Soignet et al. J Clin Oncol, 2001

13 Prevention of Early Death in APL ATRA at first suspicion (based on clinical hx and review of peripheral smear), before marrow and before diagnosis is confirmed Frequent platelet transfusions to > 50,000/ L Cryoprecipitate to maintain fibrinogen > 150 mg/dl No routine heparin No routine antifibrinolytics No leukopheresis Rodeghiero et al. Blood, 1990; Tallman et al. Leukemia Res, 2004; Sanz et al. Blood, 2008

14 Risk Stratification Treatment is primarily based on risk stratification. Risk stratification is easy based on initial WBC > 10 = high risk 10 = standard risk

15 Induction in APL Differentiation Syndrome fever, weight chain, volume overload treat with steroids (dexamethasone 10 mg IV BID) QT prolongation electrolyte repletion, hold ATO if QTc > 500 NO marrow at day 14. Molecular positivity on day 28 does NOT mean treatment failure.

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18 Inclusion Criteria APL 0406 Study Newly diagnosed APL Age years WBC 10 x 10 9 /L (low-risk disease) WHO performance status 2 Trial designed to assess a non-inferiority margin difference between the group proportions of 5%

19 APL0406 Study: Treatment ATO arm Induction ATO ATR Consolidation ATO ATO ATO ATO 4 weeks on / 4 weeks off 2 weeks on / 2 weeks off R Estey et al, Blood 2006 Induction Consolidation Maintenance Chemo Arm IDA IDA IDA MTZ ATR ATR ATR ATR MTX + 6MP ATR Until CR 3 monthly cycles 2 years Lo Coco et al. NEJM, 2013

20 Induction Outcome ATRA + ATO ATRA + Chemo No. of patients CR, (%) 75 (100%) 75 (95%) Induction death 0 4* Resistant disease 0 0 *Differentiation syndrome (2), ischemic CVA (1) and pneumonia (1) Lo Coco et al. NEJM, 2013

21 APL 0406: Hematologic Toxicity Grade 3-4 thrombocytopenia >15 d p= <.0001 Grade 3-4 neutropenia >15 d p= p= < p= < p=.0185 p= p= <.0001 p= < IND I CONS II CONS III CONS ATO IND I CONS II CONS III CONS Chemo Lo Coco et al. NEJM, 2013

22 APL 0406: Other Toxicities Toxicity ATRA+ATO ATRA+Chemo P value QTc prolongation 1,% Hepatic toxicity 1 (Grade 3-4), % Leukocytosis 2 (>10x10 9 /L), % 57 5 < Managed with temporary discontinuation and dose modification of ATO 2. Hydroxyurea 500 mg qid if WBC <50K and 1 g qid if >50K

23 Event-free survival probability Disease-free survival probability APL Event-free Survival 97.1% 100 Disease-free Survival 97.1% % % ATRA+ATO ATRA+Chemo p= ATRA+ATO ATRA+Chemo p= Months from diagnosis Months after CR Lo Coco et al. NEJM, 2013 Type of event Relapse Death in CR ATRA+ATO 2 1 ATRA+Chemo 5 3

24 Overall survival probability APL 0406: Overall Survival % 91.1% Lo Coco et al. NEJM, 2013 ATRA+ATO ATRA+Chemo p= Months from diagnosis

25 APL 0406 Long-term Final analysis A total of 276 patients were ultimately enrolled. Median follow-up 66.4 months 72 month EFS 96.6% vs. 77.4% (p < ) 72 month OS 98.3% vs % (p = 0.004) No relapse post 48 months in the ATRA-ATO group Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Platzbecker U, et al. J Clin Onc 2017.

26 APML4 Single-arm phase 2 trial for newly diagnosed APL (any risk) 124 patients were treated Less anthracycline than AIDA, C9710 regimens Consolidation with ATRA/ATO alone All patients received 2 years of maintenance therapy. Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Iland H, et al. Blood 2012.

27 APML4 INDUCTION CONSOLIDATION (1) MAIN ATRA D 1-35 ATRA D 1-28 ATRA, 6-MP IDA D 2,4,6,8 ATO D 1-28 MTX ATO D 9-36 PRED D 1-10 CONSOLIDATION (2) ATRA D 1-7, 15-21, ATO D 1-5, 8-12, 22-26, Iland H et. al, Blood 2012

28 % alive and % relapse free relapse-free APML4 DFS by Sanz Risk Category Low 100% High 95% Intermediate 93% Low Intermediate High P [ trend ] =.30 Low Inter High 0-0 P value (trend) = year relapse free rate: 100%, 97%, 95%, 5 year: 100%, 93%, 95% Years from documented HCR Number at risk Years 57 from 46 documented HCR

29 APML update (5-year data): 5-yr OS 94% overall (high-risk 87%) 5-yr DFS 95% 5-yr EFS 90% 3 patients relapsed between the interim 2-year analysis and the 5-year update. Iland H et. al, Lancet Oncol Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010

30 High-Risk APL ATRA + Risk-Adapted Chemo vs APML4 Number Median follow-up IDA equivalent AraC DFS CIR OS (months) (mg/m 2 ) (g/m 2 ) PETHEMA LPA % 14% 79% European APL % 88% GIMEMA AIDA % 9% 83% ALLG APML % 5% 87% Sanz et al. Blood, 2010; Adès et al. Am J Hematol, 2013; Lo Coco et al. Blood, 2010; Sanz et al. Best Pract Res Clin Haematol, 2003; Iland et al. ASH, 2014

31 Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol AML17 Randomized phase 3 trial ATRA/ATO vs. ATRA + chemotherapy for newly diagnosed APL Differences with APL0406: 1) Twice weekly schedule for ATO 2) Inclusion of high-risk patients High risk patients randomized to ATRA/ATO could receive one dose of gemtuzumab ozogamicin 9 mg/m2 3) Patients relapsing on ATRA/chemo could receive ATRA/ATO 4) No maintenance for ATRA/chemo

32 AML17 ATRA/ATO Burnett AK, et al. Lancet Oncol 2015.

33 AML17 - AIDA Burnett AK, et al. Lancet Oncol 2015.

34 AML17 Trial Profile Burnett AK, et al. Lancet Oncol 2015.

35 AML17 - Results Russell N, et al. Blood 2018.

36 Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol AML17 - Results With median follow-up of 30.5 months: CR rate 94% vs. 89% (p = 0.18) 30-day mortality 4% vs. 6% (p = 0.56) 60-day mortality 5% vs. 9% (p = 0.22) 4-year EFS 91% vs. 70% (p = 0.002) 4-year OS 93% vs. 89% (p = 0.25) 4-year incidence of tmds/taml 0% vs. 3% (p = 0.34)

37 Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol AML17 Long-term results Subsequent update (Blood 2018) Median follow-up 67.4 months 5-year RFS 97% vs. 78% (p = ) includes molecular relapse only (morphologic relapse 96 vs. 86%) No patient achieving molecular negativity with ATRA/ATO relapsed. 5-year OS 92% vs. 86% (p = 0.4)

38 Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol AML17 Conclusions: Relapse rate lower with ATRA + ATO. Overall survival remains unchanged in either low-risk or high-risk cohort (at least in part because of effective salvage from ATRA + ATO) Toxicities decreased overall with ATRA + ATO. QOL unchanged

39 MRD Monitoring Document molecular CR from marrow after consolidation (More sensitive than PB) Monitor from PB every 3 months for 2 yrs If positive PCR, repeat in 2-4 weeks; if persistent positive, treat as relapse Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010; Grimwade Best Pract Res Clin Haematol 2015

40 Relapsed APL Achieve a second molecular remission and consolidate with autologous transplant Consider CNS prophylaxis (ATO does penetrate the bloodbrain barrier with 30-50% of serum levels in the CSF) Lo Coco Blood, 1999 and 2004; Esteve Leukemia, 2007, Estey Blood, 2002; Meloni Blood,1997; de Botton J Clin Oncol, 2005; Thomas Haematologica, 2006; Kohno Int J Hem, 2008, Kharfan-Dabaja BBMT, 2007; Au J Clin Oncol 2000; Knipp Leuk Res, 2007; Sanz Blood, 2009

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42 Probability Adjusted Probability of Overall Survival APL in CR allohsct autohsct Months Chakrabarty et al. BBMT, 2014

43 Late Toxicities 3-5% death rate in CR reported in PETHEMA and European APL trials 1,2 Heart failure, secondary malignancies, especially as historical APL regimens have included a lot of anthracycline Possible late toxicities with ATO hypertension, DM, arrhythmia 3 1 Sanz MA, et al. Blood Ades L, et al. Blood Shetty AV, et al. ASH 2014.

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45 Future Directions Reducing early death rate! Lower dose ATRA? (25 mg/m2 vs. 45 mg/m2) Lower dose ATO? Minimizing cytotoxic chemotherapy in high-risk patients Need for maintenance therapy in high-risk patients?

46 Future Questions Current therapy is directed at less chemotherapy and can be cured with NO chemotherapy Current strategies focus early (ED) and late (maintenance) phases of treatment Disease is as sensitive among older adults as younger Risk stratification is very simple ONY AML WHERE Treatment of relapsed disease is highly effective Autologous transplant is treatment of choice in CR2