Treatment of APL M a tth e w M e i, M.D. A s s is ta n t P ro fe s s o r C ity o f H o p e C o m p re h e n s iv e C a n c e r C e n te r
Disclosures I have nothing to disclose
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
Acute Promyelocytic Leukemia Distinguishing Features 10-15% of adult AML Leukopenia (85%) Complex coagulopathy t(15;17) chrom translocation Sensitivity to anthracyclines PML-RAR fusion transcript Differentiation with retinoic acid Apoptosis with arsenic trioxide
Bleeding in APL Oral mucosal bleeding Subcutaneous bleeding Retinal hemorrhages Intracerebral hemorrhage
Early Death Rate in APL Population-Based Studies Study N ED Jeddi 41 16% Lehmann 99 31% Alizadeh 137 14% 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
Molecular Basis of Leukemogenesis in APL RAR fuses to PML Increased affinity for nuclear co-repressor protein complex (N-coR) Histone deacetylase alters chromatin conformation inhibiting transcription 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
DFS OS Milestones in the Development of Curative Strategies in APL Initial Description, Highly Fatal Daunorubicin ATRA ATRA + Chemo Arsenic Highly Curable ATRA + Arsenic 1957 1973 1985 1990 s 1997 2000 s 2009 1.0 0.8 0.6 0.4 0.2 ECOG Data Pre-ATRA era 1973-1989 0.0 0 5 10 15 20 Years Tallman et al. Blood, 2002 1.0 0.8 APL2000 0.6 0.4 WBC < 10,000/ L WBC 10-50,000/ L 0.2 WBC > 50,000/ L P =.14 0.0 0 1 2 3 Years 4 5 6 Kelaidi et al. J Clin Oncol, 2009
All-trans Retinoic Acid Natural vitamin A derivative Induces leukemic promyelocytes to differentiate in vitro Induces CR in almost all pts with APL as single agent No imposition of marrow aplasia At diagnosis Day 12 Day 37
Arsenic Trioxide Single most active agent in APL Single-agent CR rate very high in frontline and relapsed setting Dual mechanism (differentiation at lower dose, apoptosis at higher dose) Biggest concerns are QTc prolongation and elevated LFTs
Patients with MR ( %) Molecular Response to Arsenic Trioxide in Relapsed APL: US Multicenter Study 100 90 80 70 60 50 40 30 20 10 0 Baseline N=29 48% 86% Induction Consolidation 90% Maintenance Soignet et al. J Clin Oncol, 2001
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
Risk Stratification Treatment is primarily based on risk stratification. Risk stratification is easy Initial WBC > 10 = high risk (probably needs some chemotherapy besides just ATRA + ATO) Initial WBC 10 = standard risk (induce with ATRA + ATO)
Caveats for Induction in APL Differentiation Syndrome steroid prophylaxis built a number of the regimens Do NOT do marrow on Day 14 or Day 21! Cytogenetic / molecular positivity on day 28 does NOT mean treatment failure. Initial rise in WBC with rising neutrophils represents differentiation of the malignant clone, not true count recovery
Inclusion Criteria APL 0406 Study Newly diagnosed APL Age 18-70 years WBC 10 x 10 9 /L WHO performance status 2 Trial designed to assess a non-inferiority margin difference between the group proportions of 5%
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
Induction Outcome ATRA + ATO ATRA + Chemo No. of patients 75 79 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
APL 0406: Hematologic Toxicity Grade 3-4 thrombocytopenia >15 d p= <.0001 Grade 3-4 neutropenia >15 d 70 60 69 70 60 p=.0001 62 p= <.0001 50 p= <.0001 50 54 40 45 46 40 30 30 35 p=.0185 p=.0117 20 10 0 p= <.0001 p= <.0004 13 10 4 4 2 IND I CONS II CONS III CONS ATO 20 10 0 4 4 3 IND I CONS II CONS III CONS Chemo 25 17 Lo Coco et al. NEJM, 2013
APL 0406: Other Toxicities Toxicity ATRA+ATO ATRA+Chemo P value QTc prolongation 1,% 13 0 0.0005 Hepatic toxicity 1 (Grade 3-4), % Leukocytosis 2 (>10x10 9 /L), % 57 5 <0.0001 47 24 0.007 1. Managed with temporary discontinuation and dose modification of ATO 2. Hydroxyurea 500 mg qid if WBC <50K and 1 g qid if >50K
Event-free survival probability Disease-free survival probability APL 0406 100 Event-free Survival 97.1% 100 Disease-free Survival 97.1% 75 85.6% 75 90.3% 50 50 25 0 ATRA+ATO ATRA+Chemo p=0.02 0 12 24 36 48 60 25 0 ATRA+ATO ATRA+Chemo p=0.14 0 12 24 36 48 60 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
Overall survival probability APL 0406: Overall Survival 100 75 98.7% 91.1% 50 25 0 Lo Coco et al. NEJM, 2013 ATRA+ATO ATRA+Chemop=0.02 0 12 24 36 48 60 Months from diagnosis
APL 0406 Long-term After initial 2013 publication, more patients were enrolled (total n = 276). OS at 50 months was 99.2% vs. 92.6% (p = 0.0073) EFS at 50 months was 97.3% vs. 80% (p < 0.003) ATRA + ATO is clear standard of care for newly diagnosed standard risk APL. Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Platzbecker U, et al. J Clin Onc 2016.
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015. AML17 Randomized phase 3 trial of ATRA + ATO vs. ATRA + chemotherapy for newly diagnosed APL Patients with high risk disease receiving ATRA + ATO only could receive one dose of gemtuzumab ozogamicin 235 patients, 57 high risk
AML17 ATRA + chemotherapy arm induction / consolidation regimen as per low-risk arm of AIDA2000 ATRA + ATO Induction: ATRA 45 mg/m2 until remission, ATO 0.3 mg/kg D1-5, then twice weekly on weeks 2-8 Consolidation: ATRA 45 mg/m2 D1-14, ATO 03. mg/kg D1-5, twice weekly on weeks 2-4 Gemtuzumab ozogamicin 6 mg/m2 on D1 for highrisk in ATRA + ATO patients Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015.
AML17 results Burnett AK, et al. Lancet Oncol 2015.
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015. AML17 Conclusions: Relapse rate lower with ATRA + ATO. Overall survival unchanged in either low-risk or high-risk cohort. Toxicities decreased overall with ATRA + ATO. QOL unchanged. Update at ASH 2016 confirmed above findings.
North American Intergroup C9710 Randomized trial for newly diagnosed APL patients. 481 patients enrolled Two randomizations: ATO consolidation (yes/no) Maintenance (ATRA alone vs. ATRA + 6-MP/MTX) Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Powell BL, et al. Blood 2010.
North American Intergroup C9710 Powell BL, et al. Blood 2010.
North American Intergroup C9710 Powell BL, et al. Blood 2010.
North American Intergroup C9710 Fairly sizeable advantage realized with addition of ATO consolidation in high and low risk disease for diseasefree and event-free survival. OS not different but p-value 0.059 (86% vs. 81% at 3 years) Not enough events to evaluate the differential effect of maintenance therapy (p-value for PFS 0.11) Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Powell BL, et al. Blood 2010.
APML4 Australasian Leukaemia and Lymphoma Group Single-arm phase 2 trial with 124 patients, median followup for 2 years. Both low and high-risk patients were included. Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Iland H, et al. Blood 2012.
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, 29-35 ATO D 1-5, 8-12, 22-26, 29-33 Iland H et. al, Blood 2012
APML4 DFS by Sanz Risk Category Low Inter High 100 relapse-free100- % alive and % relapse free 80-60- 40-20- 0-0 Low Intermediate High P [ trend ] =.30 P value (trend) = 0.30 2 year relapse free rate: 100%, 97%, 95%, 5 year: 100%, 93%, 95% 0 0 1 2 3 4 5 6 7 8 Years from documented HCR 1 2 3 4 5 6 7 8 Number at risk 32 31 30 22 12 8 3 1 0 60 58 Years 57 from 46 documented 32 15 HCR 8 2 0 19 18 18 12 8 6 2 0 0 Low 100% High 95% Intermediate 93%
APML4 2015 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 2015. Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
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 LPA2005 118 28 122 5.8 82% 14% 79% European APL2000 74 103 99 22.8-7% 88% GIMEMA AIDA2000 129 59 122 6.3 85% 9% 83% ALLG APML4 23 50 48 0 95% 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
MRD Monitoring Document molecular CR from marrow after consolidation (slightly more sensitive than PB by 1.5 logs) Unclear benefit in low-risk disease Potential benefit in high-risk disease, never prospectively validated, but treatment of molecular relapse is easier than hematologic relapse Monitor from PB q3 mo. for 2 yrs for high-risk, age >60, therapy interruptions or intolerance Low-risk: may not be necessary If pos 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
Relapsed APL Molecular relapse ATO x 2 cycles Autograft in CR2 Morphologic relapse ATO x 2 cycles: CR 85% Autograft in CR2: 5-yr DFS 70-80% Isolated CNS relapse ATO crosses into CNS 30-50% serum levels ATO x 2 cycles, IT MTX/ara-C, autograft 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
Probability Adjusted Probability of Overall Survival APL in CR2 1.0 0.8 0.6 0.4 0.2 0 allohsct autohsct 0 12 24 36 48 60 72 84 96 108120 Months Chakrabarty et al. BBMT, 2014
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 2008 2 Ades L, et al. Blood 2010. 3 Shetty AV, et al. ASH 2014.
ASH 2016 Updates Two trials for high risk patients: 1) APL2006 Induction with ATRA + ida 12mg/m2 x 3 days + ara-c 200 mg/m2 x 7 days (7+3) Randomization between consolidation chemotherapy with or without ATO, ara-c later removed from ATO arm due to toxicity, results ultimately comparable 2) SWOG/Alliance/ECOG S0535 Untreated high-risk patients, GO 9 mg/m2 on D1, ATRA + ATO until remission. Consolidation ATO x 2, ATRA + dauno x 2, GO x 2, maintenance ATRA + 6MP/MTX 3y EFS 79% Lu et al. Blood, 2002; Kumana et al. Eur J Clin Pharmacol, 2002; Au et al. Leukemia Res, 2007; Au et al. Blood 2006 and 2008
Provocative Thoughts Regarding Treatment of APL Current therapy is directed at less chemo and can be cured with NO chemo 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 Autograft is treatment of choice in CR2 not allograft