Clinical Focus: Acute Promyelocytic Leukemia Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Clinical Focus: Acute Promyelocytic Leukemia Farhad Ravandi, MD Professor of Medicine Department of Leukemia University of Texas M. D. Anderson Cancer Center Houston, Texas This program is supported by an educational grant from Image: Meullemiestre/Copyright©2012 Photo Researchers, Inc. All Rights Reserved

Acute Promyelocytic Leukemia 5% to 15% of all adult acute leukemias in the US More common Young/middle age adults Hispanics and obese (BMI > 30) Incidence worldwide: 0.6/106 people FAB: AML M3 Caused by balanced translocation, usually t(15;17) Chromosome 17 Chromosome 15 AML, acute myeloid leukemia; BMI, body mass index; FAB, French-American-British. der 15 + der 17 1. Chen Y, et al. Cancer. 2012;118:5811-5818. 2. Wang ZY, et al. Blood. 2008;111:2505-2515.

APL Diagnosis: Pathology Leukopenia M3v often hyperleukocytosis Circulating promyelocytes Irregular azurophilic granules Auer rods (bundle of sticks) Bilobed or reniform nucleus Immunophenotype CD33+, CD13+ Neg/low: CD34, CD11b, CD117, HLA-DR M3v (microgranular) often CD2+, CD34+ DIC common APL, acute promyelocytic leukemia; DIC, disseminated intravascular coagulation. 3. Sanz MA, et al. Blood. 2009;113:1875-1891.

APL: Molecular Variants PML-RARa+ insertions 4% PML-RARa+ variants 2% PZLF-RARa t(11;17)(q23,q21) 0.8% NPM-RARa t(5;17)(q35,q21) 0.2% NuMa-RARa t(11;17)(q13,q21) < 0.1% Stat5b-RARa der(17) No RARa 1% APL, acute promyelocytic leukemia; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha. PML-RARa t(15;17)(q22;q21) 92% 4. Grimwade D, et al. Leukemia. 2002;16:1959-1973.

Anti-PML Immunofluorescent Antibody Test (“POD” Test) Sensitivity and specificity of 98.7% and 98.9% APL, acute promyelocytic leukemia. 5. Dimov N, et al. Cancer. 2010;116:369-376.

APL Therapy: History 1960 1970 1980 1990 2000 HIGHLY FATAL Discovery t(15;17) in APL ATO frontline ATRA therapy First description: Hyperacute fatal illness associated with hemorrhagic syndrome Daunorubicin in APL Differentiation of APL cells with RA ATO in relapse ATRA + ATO ± GO In vivo leukemic cell differentiation ATRA + CT APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CT, chemotherapy; GO, gemtuzumab ozogamicin. 1960 1970 1980 1990 2000 HIGHLY FATAL HIGHLY CURABLE 6. Chen Y, et al. Cancer. 2012;118:5811-5818. 7. Nowak D, et al. Blood. 2009;113:3655-3665.

Survival Functions by Diagnosis Time Periods Life Table Survival Curves 1.0 Log-rank P = .0002 x 0.8 0.6 Survival Probability 0.4 Diagnosis yr: 1992-1995 Diagnosis yr: 1996-2001 Diagnosis yr: 2002-2007 0.2 x 10 20 30 Survival Time (Mos) 8. Park JH, et al. Blood. 2011;118:1248-1254.

North American Intergroup Protocol I0129: DFS and OS 1.0 0.8 ATRA → CT 0.6 Probability of DFS 0.4 0.2 CT → CT 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Yr 1.0 ATRA, all-trans-retinoic acid; CT, chemotherapy; DFS, disease-free survival; OS, overall survival. 0.8 ATRA → CT 0.6 Probability of OS 0.4 CT → CT 0.2 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Yr 9. Tallman MS, et al. N Engl J Med. 1997;337:1021-1028.

North American Intergroup Protocol I0129 1.0 ATRA → CT → ATRA 0.8 ATRA→ CT → Observation 0.6 Probability of DFS 0.4 CT→ CT → ATRA ATRA, all-trans-retinoic acid; CT, chemotherapy; DFS, disease-free survival. CT = daunorubicin + cytarabine ATRA→ CT →ATRA ATRA→ CT →Observation CT→ CT →ATRA CT→ CT →Observation 0.2 CT→ CT → Observation 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Yr 10. Tallman MS, et al. N Engl J Med. 1997;337:1021-1028.

North American Intergroup Protocol I0129: Maintenance 1.0 0.8 0.6 ATRA Probability of DFS Observation 0.4 ATRA, all-trans-retinoic acid; DFS, disease-free survival. 0.2 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Yr 11. Tallman MS, et al. N Engl J Med. 1997;337:1021-1028.

ATRA + CT: Sequential vs Concurrent European APL Group: Relapse and EFS 1.0 1.0 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 Proportion of Patients Relapsing Proportion of Patients Event Free 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; CT, chemotherapy; EFS, event-free survival. 1 2 3 4 1 2 3 4 Yrs Yes Patients, n 101 93 Events, n 16 7 Patients, n 101 99 Events, n 32 19 ATRA → CT ATRA + CT ATRA → CT ATRA + CT Log-rank P = .04 Log-rank P = .10 16. Fenaux P, et al. Blood. 1999;94:1192-1200.

Cumulative Incidence of (A) Relapse, (B) EFS, and (C) OS by Ara-C or No Ara-C 1.0 1.0 1.0 0.8 0.8 0.8 P = .011 0.6 0.6 0.6 Cumulative Incidence of First Relapse Ara-C No Ara-C EFS Ara-C No Ara-C OS Ara-C No Ara-C 0.4 0.4 0.4 P = .0066 0.2 Ara-C, cytarabine; EFS, event-free survival; OS, overall survival. 0.2 0.2 P = .0021 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 Mos Mos Mos 17. Ades L, et al. J Clin Oncol. 2006;24:5703-5710.

Cumulative Incidence of (A) Relapse, (B) EFS, and (C) OS of Younger Pts With WBC > 10 x 109/L 1.0 1.0 1.0 0.8 0.8 0.8 0.6 0.6 0.6 Cumulative Incidence of First Relapse EFS OS 0.4 0.4 0.4 0.2 EFS, event-free survival; OS, overall survival; WBC, white blood cell. 0.2 0.2 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 Mos Mos Mos 18. Ades L, et al. J Clin Oncol. 2006;24:5703-5710.

ATO in Relapsed Disease: OS and RFS 100 100 80 80 60 60 Patients Achieving OS (%) Patients Achieving RFS (%) 40 40 ATO, arsenic trioxide; OS, overall survival; RFS, relapse-free survival. At Risk, n Deaths, n 18-Mo OS, % At Risk, n Deaths, n 18-Mo OS, % 20 20 40 14 66 34 13 56 6 12 18 24 30 6 12 18 24 30 Mos Mos 19. Soignet SL, et al. J Clin Oncol. 2001;19:3852-3860.

5-Yr KM Product Limit Estimate of (A) OS of the Entire Cohort (N = 72) 1.0 B 1.0 74.2 ± 5.2% 0.8 0.8 69 ± 5.5% 0.6 0.6 OS (Proportion) EFS (Proportion) 0.4 0.4 0.2 0.2 24 48 72 96 120 144 24 48 72 96 120 144 C 1.0 GR (n =11) D 1.0 GR (n = 22) 100 ± 0% 0.8 IR (n = 45) 0.8 0.6 0.6 HR (n =50) EFS (Proportion) OS (Proportion) 63 ± 7% 0.4 HR (n = 16) 0.4 0.2 0.2 DFS, disease-free survival; EFS, event-free survival; GR, good-risk group; HR, high-risk group; IR, intermediate-risk group; KM, Kaplan-Meier; OS, overall survival. P = .158 P = .003 24 48 72 96 120 144 24 48 72 96 120 144 E 1.0 F 1.0 (n = 23) 0.8 91 ± 6% 0.8 0.6 (n = 39) Cumulative Incidence of Relapse (Proportion) 0.6 DFS (Proportion) 73.5 ± 7.2% 0.4 0.4 0.2 0.2 P = .062 24 48 72 96 120 144 24 48 72 96 120 144 Mos Mos 20. Mathews V, et al. J Clin Oncol. 2010;28:3866-3871

DFS and OS for 197 New Cases of Acute Promyelocytic Leukemia B 1.0 1.0 0.8 0.8 0.6 0.6 DFS (Proportion) OS (Proportion) 0.4 0.4 DFS, disease-free survival; OS, overall survival. 0.2 0.2 20 40 60 80 100 120 20 40 60 80 100 120 Mos Mos 21. Ghavamzadeh A, et al. J Clin Oncol. 2011;29:2753-2757.

DFS With 1 Consolidation Course vs 4 Consolidation Courses 1.0 1 consolidation course 4 consolidation courses 0.8 0.6 DFS (Proportion) 0.4 DFS, disease-free survival. 0.2 20 40 60 80 100 120 Mos 22. Ghavamzadeh A, et al. J Clin Oncol. 2011;29:2753-2757

PML-RARα Negative Post CR % ATRA + ATO Study N CR, % PML-RARα Negative Post CR % EFS/DFS/RFS, OS, Hu et al China 85 94 NR 89 (5-yr DFS) 91 (5-yr) Ravandi et al MD Anderson 82 90* 100 80 (2-yr RFS) (2-yr) Dai et al 90 93 92 (3-yr EFS) ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission; DFS, disease-free survival; EFS, event-free survival; NR, not reported; OS, overall survival; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha. *95% in low risk, 81% in high risk. 23. Hu J, et al. Proc Natl Acad Sci U S A. 2009;106:3342-3347. 24. Ravandi F, et al. J Clin Oncol. 2009;27:504-510. 25. Dai CW, et al. Acta Haematol. 2009;121:1-8.

Gemtuzumab Ozogamicin CD33 conjugated to calicheamicin CD33 heavily expressed on APL cells Single agent Induced molecular response in high proportion of relapsed patients ATRA + gemtuzumab ozogamicin (19 patients) 84% CR Remissions more durable than ATRA alone APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; CR, complete remission. 26. Takeshita A, et al. Leukemia. 2005;19:1306-1311. 27. Estey EH, et al. Blood. 2002.99:4222-4224. 28. Lo-Coco F, et al. Blood. 2004;104:1995-1999.

Kaplan-Meier Curve of EFS and OS for the Entire Group 1.0 + 0.8 0.6 Survival (Probability) 0.4 EFS, event-free survival; OS, overall survival. Survival OS EFS Patients, n 82 82 Events, n 13 14 0.2 52 104 156 208 260 Wks 29. Ravandi F, et al. J Clin Oncol. 2009; 27:504-510.

ATRA + ATO ± GO: Longer Follow-up 1.0 0.8 0.6 Survival Probability 0.4 ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; GO, gemtuzumab ozogamicin. Survival Overall Remission Event Free Total 104 102 Events 10 5 13 0.2 52 104 156 208 260 312 364 416 Wks 30. Ravandi F, et al. ASH 2010. Abstract 1080.

PML-RARα newly diagnosed APL ATRA/CT → ATO vs ATRA/CT in Newly Diagnosed APL Intergroup Protocol C9710 PML-RARα newly diagnosed APL confirmed by RT-PCR (N = 480, adults) RANDOMIZED ATRA Ara-C Daunorubicin ATO x 2 ATRA DNR x 2 RANDOMIZED ATRA CR ATRA Ara-C Daunorubicin ATRA DNR x 2 ATRA 6-MP MTX APL, acute promyelocytic leukemia; Ara-C, cytarabine; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission; CT, chemotherapy; IV, intravenous; MTX, methotrexate; PCR, polymerase chain reaction; PML, promyelocytic leukemia; PO, orally; RARα, retinoic acid receptor alpha; RT, reverse transcriptase; 6-MP, 6-Mercaptopurine; DNR, daunorubicin. Induction Consolidation Maintenance Agent Induction Consolidation Maintenance ATRA 45 mg/m2 PO on Days 1-CR 45 mg/m2 PO on Days 1-7 45 mg/m2 PO on Days 1-7 every other wk Ara-C 200 mg/m2 IV on Days 3-9 DNR 50 mg/m2 IV on Days 3-6 50 mg/m2 IV on Days 1-3 ATO 0.15 mg/kg 5 days/wk x 5 wks 6-MP 60 mg/m2/day PO MTX 20 mg/m2 once/wk 31. Powell BL, et al. ASCO 2007. Abstract 2.

EFS by Treatment and Risk Group Event-Free Survival EFS by Treatment EFS by Treatment and Risk Group 1.0 1.0 0.8 0.8 0.6 0.6 EFS (Proportion) EFS (Proportion) 0.4 0.4 0.2 0.2 EFS, event-free survival. 6 18 30 42 54 66 78 90 102 114 6 18 30 42 54 66 78 90 102 114 Mos From Study Entry Mos From Study Entry Arsenic No arsenic n = 244 n = 237 Events: 51 Events: 97 Log-rank P < .0001 Arsenic low/inter risk No arsenic low/inter risk Arsenic high risk No arsenic high risk n = 189 n = 179 n = 55 n = 58 Events: 31 Events: 59 Events: 20 Events: 38 32. Powell BL, et al. Blood. 2010;116:3751-3757.

Disease-Free Survival DFS by Treatment DFS by Treatment and Risk Group 1.0 1.0 0.8 0.8 0.6 0.6 DFS (Proportion) DFS (Proportion) 0.4 0.4 0.2 0.2 DFS, disease-free survival. 6 18 30 42 54 66 78 90 102 114 6 18 30 42 54 66 78 90 102 114 Mos From Study Entry Mos From Study Entry Arsenic No arsenic n = 213 n = 211 Events: 22 Events: 72 Log-rank P < .0001 Arsenic low/inter risk No arsenic low/inter risk Arsenic high risk No arsenic high risk n = 172 n = 163 n = 41 n = 48 Events: 16 Events: 44 Events: 6 Events: 28 33. Powell BL, et al. Blood. 2010;116:3751-3757.

OS for All 481 Randomized Patients by Treatment Arm OS by Treatment 1.0 0.8 0.6 OS (Proportion) 0.4 0.2 OS, overall survival. 6 18 30 42 54 66 78 90 102 114 Mos from Study Entry Arsenic No arsenic n = 243 n = 236 Events: 38 Events: 54 Log-rank P = .059 34. Powell BL, et al. Blood. 2010;116:3751-3757.

Kaplan-Meier Survival Curves 100 100 100 80 80 80 60 60 60 Low Intermediate High Alive and Failure Free (%) APML4 Surviving (%) APML4 Alive and Failure Free (%) 40 40 40 14 failures in 124 patients 2-yr FFS: 88.1% 95% CI: 80.7% to 92.8% 7 deaths in 124 patients 2-yr OS: 93.2% 95% CI: 85.8% to 96.8% 20 20 20 P (trend) = .03 2-yr FFS: 97%, 88%, 76% 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 ATRA, all-trans-retinoic acid; CI, confidence interval; FFS, failure-free survival; OS, overall survival. Yrs From Start of ATRA Therapy Yrs From Start of ATRA Therapy Yrs From Start of ATRA Therapy Pts at Risk, n 124 Pts at Risk, n 124 Pts at Risk, n 32 67 24 77 51 26 11 1 86 57 28 12 1 Low Inter High 20 45 11 10 31 9 7 13 6 2 7 1 35. Iland HJ, et al. Blood. 2012;120:1570-1580.

Overall Survival 98.7% 100 91.1% 75 ATRA + ATO ATRA + chemo OS Probability 50 P = 0.02 ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; OS, overall survival. 25 12 24 36 48 60 Mos From Diagnosis 37. Lo-Coco F, et al. ASH 2012. Abstract 6.

Minimal Residual Disease Monitoring in APL Best done by QT-PCR for PML-RARα Frequently positive at the time of achieving CR Must become negative after consolidation Best monitored by bone marrow initially Peripheral blood can be substituted later APL, acute promyelocytic leukemia; CR, complete remission; PCR, polymerase chain reaction; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha, QT, quantitative.

Therapy-Related APL 1.0 ATRA ± ATO ATRA ± Chemo 0.8 0.6 P = .35 0.4 Survival Probability 0.4 APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid. 0.2 12 24 36 48 60 72 84 96 108 120 132 Mos 38. Dayyani F, et al. Cancer. 2011;117:110-115.

Treatment of Relapsed APL European registry of ATO in relapsed APL (7 countries) 69 pts in first relapse (25 molecular, 42 hematologic, 2 isolated CNS/EMD) All treated with ATO Second molecular CR higher (and complications less—no coagulopathy, no hyperleukocytosis, no DS) with induction after molecular relapse rather than hematologic Importance of serial monitoring APL, acute promyelocytic leukemia; ATO, arsenic trioxide; CNS, central nervous system; CR, complete remission; EMD, extrameduallary disease; DS, differentiation syndrome. 39. Lengfelder E, et al. ASH 2010. Abstract 15.

GO in APL Salvage OS Treated With GO in APL and AML RFS Treated With 100 100 90 Log-rank P ≤ .0001 90 Log-rank P = .0074 80 80 APL 70 70 APL 60 60 OS (%) 50 RFS (%) 50 40 40 APL, acute promyelocytic leukemia; AML, acute myeloid leukemia; GO, gemtuzumab ozogamicin; RFS, relapse-free survival; OS, overall survival. 30 30 Non-APL Non-APL 20 20 10 10 6 12 18 24 6 12 18 24 Mos Mos 40. Takeshita A, et al. ASH 2011. Abstract 1532.

Remaining Challenges Early diagnosis to avoid early mortality 20% to 30% of patients relapse Extramedullary disease Therapy-related MDS Delayed cardiomyopathy Special populations Elderly patients Cardiac patients Underserved populations MDS, myelodysplastic syndromes.