RealLife Decisions An Interactive CaseBased Symposium on the

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Agenda CASE 1: Multiple Myeloma (MM) in the Nontransplant Setting Dr Harwin CASE 2: Biomarker-Guided Treatment for MDS Dr Schwartz CASE 3: Risk- and Age-Stratified Treatment for AML Dr Schwartz CASE 4: MM in the Transplant-Eligible Patient Dr Fishkin CASE 5: Chronic Myelomonocytic Leukemia (CMML) Dr Harwin CASE 6: Therapeutic Alternatives for Newly Diagnosed APL Dr Fishkin Panel Discussion and Response to Audience Questions Copyright © 2011 Research To Practice. All rights reserved.

Community Oncologist Participants Paul A S Fishkin, MD William N Harwin, MD Michael A

Copyright © 2011 Research To Practice. All rights reserved.

Audience members, please remember to take survey and ask questions Copyright © 2011 Research

Case 1: Dr Harwin (Discussant: Dr Bensinger) • 75 yo man: PMH – MGUS and chronic bronchiectasis • 2/09 – Mild anemia, no bone lesions, bone marrow 50% plasma cells no active therapy • 1/10 – Progressive anemia, M-spike to 3. 9 g/d. L and back pain solitary osteolytic lesion with compression fracture at T 7 • Vertebroplasty/biopsy showed plasmacytoma • Repeat bone marrow: Cytogenetics = t(11; 14) Copyright © 2011 Research To Practice. All rights reserved.

Case 1 continued: • Started on lenalidomide/dexamethasone (Rd) and zoledronic acid • Completed six cycles of Rd Len-maintenance (15 mg 3 wk on, 1 wk off) plus monthly bisphonate • M-spike down to 1. 0 g/d. L and Hgb stable • Referred to tertiary center for consideration of transplant considered not eligible due to chronic lung disease Copyright © 2011 Research To Practice. All rights reserved.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Management of Myeloma in Older Patients Presented by: Dr. William Bensinger, MD Professor of Medicine, University of Washington Member, Fred Hutchison Cancer Research Center

Genetic Classification of MM Genetics Hyperdiploid t(11; 14) t(6; 14) t(14; 16) t(14; 20) t(4; 14) Del(17 p) Fonseca, Cancer Research 2004 Incidence Del 13 Prognosis 45% - fair 10% ++ poor 15 -20% +++ poor

Initial Approach to Treatment of MM Clearly not a transplant candidate Potential transplant candidate MPT, clinical trial Non-alkylator based induction, clinical trial MPV and Len/Dex are additional options. Other options are under investigation. Stem cell harvest

Drugs for Myeloma Class Steroids Drugs IMi. Ds Dexamethasone, prednisone Cyclophosphamide, melphalan, bendamustine Doxorubicin, liposomal doxorubicin Thalidomide, lenalidomide Proteosome inhibitors Bortezomib Alkylators Anthracyclines

VMP vs. MP VISTA: Phase III Randomized, international phase 3 study: VMP vs MP in previously untreated MM patients, not candidates for SCT ► Endpoints: Primary: TTP; Secondary: CR rate, ORR, TTR, DOR, PFS, TNT, OS, Qo. L ► Study Schema: R A N D O M I Z E ARM A (VMP) VMP: 6 -week cycles: Cycles 1 -4 Bortezomib 1. 3 mg/m 2 days 1, 4, 8, 11, 22, 25, 29, 32; Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1 -4 Followed by 6 -week cycles: Cycles 5 -9 Bortezomib 1. 3 mg/m 2 days 1, 8, 22, 29; Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 once daily on days 1– 4 Max of 9 cycles (total 54 weeks) in both Arms ARM B (MP) MP: 6 -week cycles: Cycles 1 -9 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1 -4 Mateos MV et al. J Clin Oncol 2010; 28(13): 2259 -66. Assessment of Efficacy and Safety

VMP vs. MP Overall Survival (OS)* MP (n=233) VMP (n=178) Hazard Ratio (95% CI) 0. 688 Not Median OS 45. 0 mos reached (0. 500 -0. 948) Median Follow Up: 36. 7 months *OS for patients randomly assigned to VMP or MP who had received subsequent therapy by data cutoff for the present analysis. Mateos MV et al. J Clin Oncol 2010; 28(13): 2259 -66. p-value 0. 021

Thal-Dex vs. MP PFS MP (n=141) Median PFS Thal-Dex (n=142) 49. 4 mos 41. 5 mos Median Follow Up: 28. 1 months Dex dose 320 mg/cycle Ludwig H et al. Proc ASH 2007; Abstract 529. p-value 0. 024

MPT vs. MP in Patients >75 years ►IFM 01 -01 randomized, double blind study ►N=232 ►median age 78. 5 yrs ►Thal 100 mg/d x 72 weeks, no VTE prophylaxis ►MP q 6 wks X 12 Hulin C et al. J Clin Oncol 2009; 27(22): 3664 -70.

MP vs. MPT in Patients >75 Years of Age: PR VGPR CR 100 90 Patients (%) 80 70 P< 0. 001 60 62% 50 40 30 31% 20 10 0 1% 21% 7% 7% MP MPT Hulin C et al. J Clin Oncol 2009; 27(22): 3664 -70.

MP vs. MPT in Newly Diagnosed MM Patients Aged >75 Years: PFS and OS MP (n=116) MPT (n=113) p-value Median OS 29. 1 mos 44. 0 mos 0. 028 Median PFS 18. 5 mos 24. 1 mos 0. 001 Median Follow Up: 47. 5 months Hulin C et al. J Clin Oncol 2009; 27(22): 3664 -70.

E 4 A 03: Phase III Trial of Lenalidomide Plus High- Vs. Low-Dose Dexamethasone Newly diagnosed MM, Age 35 -87 years (median age 66 years) (N=445) Hi. Dex Lo. Dex Lenalidomide 25 mg days 1 -21 Dexamethasone 40 mg days 1 -4, 9 -12, 17 -20 28 -day cycle (N=223) Lenalidomide 25 mg days 1 -21 Dexamethasone 40 mg days 1, 8, 15, 22 28 -day cycle (N=222) x 4 <PR Thal/Dex 4 cycles CR/n. CR CR/PR/SD Rajkumar SV et al. Lancet Oncol 2010; 11(1): 29 -37. SCT

Landmark Analysis Median Follow up: 36 months 431 Patients Alive at 4 cycles Off therapy @ 4 cycles N=183 No transplant N=93 (Median Age 68) Transplant N=90 (Median Age 57) Rajkumar SV et al. Lancet Oncol 2010; 11(1): 29 -37. Primary therapy beyond 4 cycles N=248 Rd N=140 (Median Age 66) RD N=108 (Median Age 65)

Landmark Analysis Median Follow up: 36 months 431 Patients Alive at 4 cycles Off therapy @ 4 cycles N=183 No transplant N=93 (Median Age 68) Transplant N=90 (Median Age 57) Primary therapy beyond 4 cycles N=248 Rd N=140 (Median Age 66) RD N=108 (Median Age 65) 3 -yr OS rate = 79% Rajkumar SV et al. Lancet Oncol 2010; 11(1): 29 -37.

VMPT->VT maint vs. VMP->no maint Median time to next therapy (TTNT) TTNT (3 -year rate) Median OS* 3 -year OS rate VMPT → VT Hazard p. VMP (n=257) (n=254) ratio value Not reached 0. 58 0. 007 60% 72% Not reached 87% 89% Median Follow Up: 23. 2 months Palumbo A et al. J Clin Oncol 2010; 28(34): 5101 -9. 0. 92 0. 77

MRC Myeloma IX— Analysis Schematic for ZOL vs CLO N = 1, 960 Patients with newly diagnosed MM (stage I, III) R A N D O M N I Z A T I O Zoledronic acid (4 mga IV q 3 -4 wk) + intensive or non-intensive chemotherapy (n = 981) Treatment continued at least until disease progression Clodronate (1, 600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Endpoints (ZOL vs CLO) Primary: PFS, OS, and ORR Secondary: Time to first SRE, SRE incidence, and Safety Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid. a Dose-adjusted for patients with impaired renal function, per the prescribing information. With permission, Morgan G et al. Proc ASCO 2010; Abstract 8021.

MRC Myeloma IX — ZOL Significantly Reduced SREs vs CLOa 24% relative reduction P =. 0004 Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid. a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions. With permission, Morgan G et al. Proc ASCO 2010; Abstract 8021.

MRC Myeloma IX — ZOL Improved OS vs CLO After Adjustment for SREsa • Is the observed OS ↑ with ZOL because of SRE prevention, or does it represent an anti-myeloma effect? • Exploratory analysis that adjusted for SREs • ZOL reduced the risk of death by 15% vs CLO (HR = 0. 850; P =. 0178) 0. 850 OS 0 0. 2 0. 4 Risk reduction P value 15% . 0178 0. 6 0. 8 1 1. 2 1. 4 1. 6 Hazard ratio (ZOL versus CLO) In favor of ZOL 1. 8 2 In favor of CLO Abbreviations: CLO, clodronate; HR, hazard ratio; OS, overall survival; SRE, skeletal-related event; ZOL, zoledronic acid. a Time to first SRE was included as a time-dependent covariate in an exploratory Cox model examining OS. With permission, Morgan G et al. Proc ASCO 2010; Abstract 8021.

Conclusions ► 75 year old man h/o MGUS with symptomatic MM, co-morbidities, no high risk features MPV, MPT, Rd are all acceptable induction therapies Maintenance improved PFS in some trials; no clear survival benefits in current trials Compelling evidence for benefits of zoledronate for both skeletal disease and survival

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Life Expectancy in Older Men According to Health Status 88 Age = 70 82. 4 90. 8 Age = 80 86. 7 70 75 83. 3 80 85 90 95 80 85 90 89. 2 84. 3 Age = 75 92. 9 Age = 85 79. 9 75 80 95 89. 7 87. 2 85 90 95 85 Life expectancy, years Top 25 th percentile (healthy) 90 95 Life expectancy, years 50 th percentile (median) Lowest 25 th percentile (frail) Walter LC, Covinsky KE. JAMA 2001; 285: 2750 -6. Copyright © 2011 Research To Practice, All rights reserved.

(117) (42) (12) (38) (1)

(69) (54) (33) (6) (15) (23) (5)

Case 2: Dr Schwartz (Discussant: Dr Fenaux) • 71 yo man: PMH – Diabetes • 10/09 – Pancytopenia (ANC <1, platelets 63, 000/µL, Hgb 8. 8 g/d. L) • Bone marrow hypercellular, dysplastic changes, trisomy 8 and <5% blasts • IPSS 1. 0 = Intermediate-1 MDS • Patient is completely asymptomatic • Started on azacitidine 75 mg/m 2/day SQ x 7 days (MSun) on q 4 week intervals Copyright © 2011 Research To Practice. All rights reserved.

Case 2 continued: • Well-tolerated – mild nausea and slight pain at injection site • Difficulty with transportation to clinic treatment interval stretch to 5 weeks for C 5, 6 weeks for C 6 • Lab values normalized post C 6, but patient did not return to clinic for 4 mos • 10/10 – Follow-up visit, asymptomatic but declining blood counts and repeat biopsy MDS with trisomy 8 Copyright © 2011 Research To Practice. All rights reserved.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Current Treatment of MDS Pierre Fenaux Hôpital Avicenne Paris 13 University Inserm U 848 France ASH « super Friday » 2010

Cytogenetic Abnormalities in MDS No. of patients (%) –Y 17 (2) del(5 q) 48 (6) Normal 48 9 (60) del(20 q) 16 (2) Misc. single 74 (9) +8 38 (5) Double 29 (3) Misc. double 14 (2) Chrom 7 abn 10 (1) Misc. complex 15 (2) Complex 66 (8) Complex –Y del(5 q) Misc. complex Chrom 7 abn Misc. double Double +8 Misc. single del(20 q) Greenberg P et al. Blood. 1997; 89: 2079 -2088. Normal

MDS: « Higher » vs « Lower » Risk • Higher Risk – IPSS intermediate-2 or high • Lower Risk – IPSS low or intermediate-1

Treatment Objectives • • Delay disease progression Prolong survival Improve blood cytopenias Improve quality of life

Treatment of Anemia in Lower Risk MDS • First-Line Treatment – ESAs (EPO and darbepoetin) – Lenalidomide (del 5 q) • Second-Line Treatment – – Immunosuppression (ATG+/- ciclo) Thalidomide Lenalidomide (non del 5 q) Hypomethylating agents National Comprehensive Cancer Network, v 2. 2011.

Erythroid Response to Lenalidomide in Lower Risk MDS with or without del 5 q Erythroid response Transfusion independence ≥ 50% decrease in number of transfusions Total transfusion response Median time to transfusion independence (range) 1 List MDS with del 5 q deletion 1 (n = 148) MDS without del 5 q 2 (n = 214) 67% 26% 9% 17% 76% 43% 4. 6 weeks (1 -49) 4. 8 weeks (1 -39) A et al. N Engl J Med 2006; 355(14): 1456 -65; 2 Raza A et al. Blood 2008; 111(1): 86 -93.

Treatment of Higher Risk MDS • Allogeneic stem cell transplantation • Chemotherapy (intensive or not) • Hypomethylating agents

Phase III Trial: Efficacy of Azacitidine (AZA) vs Conventional Care Regimens (CCR) in the Treatment of Higher-Risk Myelodysplastic Syndromes AZA 75 mg/m 2/d x 7 d q 28 d Screening/Central Pathology Review Investigator CCR Tx Selection Randomization CCR • Best Supportive Care (BSC) or • Low Dose Ara-C (LDAC, 20 mg/m 2/d x 14 d q 28 -42 d) or • Intensive Chemo (7 + 3) BSC was included with each arm Tx continued until unacceptable toxicity or AML transformation or disease progression Fenaux P et al. Lancet Oncol 2009; 10: 223 -32.

Primary Endpoint: Median Overall Survival — AZA vs CCR (ITT Population) Log-Rank p = 0. 0001 HR = 0. 58 [95% CI: 0. 43, 0. 77] Deaths: AZA = 82, CCR = 113 Difference: 9. 4 months Proportion Surviving 1. 0 0. 9 0. 8 0. 7 50. 8% 24. 4 months 0. 6 0. 5 15 months 0. 4 26. 2% 0. 3 AZA CCR 0. 2 0. 1 0. 0 0 5 10 15 20 25 30 Time (months) from Randomization 35 40 Reprinted from the Lancet Oncology Vol. 10, Fenaux P et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study, pp 223 -232. Copyright 2009, with permission from Elsevier.

Secondary Endpoints: IWG (2000) CR, PR and HI Response Overall (CR+PR) CR PR IWG HI Major+Minor AZA N=179 (%) CCR N=179 (%) P-Value AZA vs CCR 29 17 12 12 8 4 0. 0001 0. 02 0. 009 49 29 <0. 0001 Fenaux P et al. Lancet Oncol 2009; 10: 223 -32.

Median Overall Survival Per Frequent Cytogenetic Abnormality AZA Karyotype CCR Patient n° Median OS HR - 7/ 7 q- not complex 16 24. 5 11 8. 1 0. 33 - complex 14 5. 3 16 3. 9 0. 45 +8 - not complex 16 26. 3 12 8. 7 0. 20 - complex 9 17. 3 9 4. 9 0. 44 Mufti GJ et al. Proc ASH 2009; Abstract 1755.

Azacitidine in Higher Risk MDS • Works slowly • Survival improvement may require a large number of cycles • Survival improvement for all responses (including « HI » ) • Prophylactic measures for side effects? – cytopenias

EORTC Trial: Decitabine versus BSC in Higher Risk MDS (Lubbert, 2010) Decitabine BSC HR, p-value Median PFS (mos) 6. 6 3 0. 68, 0. 004 Median OS (mos) 10. 1 8. 5 0. 88, 0. 38 PFS = progression free survival, OS = overall survival, BSC = best supportive care Wijermans P et al. Proc ASH 2008. Abstract 226

Decitabine Alternate Schedules 5 day IV (20 mg/m 2/d) (n = 64) 5 day SC (n = 14) 10 day IV (n = 17) CR 25 (39%) 3 (21%) 4 (24%) Median number of courses (range) 5 (1– 18) 8 (1– 17) 9 (1– 15) Median days to subsequent cycle 35 35 40 Courses requiring hospitalization 50 (12%) 14 (14%) 23 (23%) Parameter Kantarjian, et al. Blood 2007; 109: 52– 7

A Scoring System for Higher-Risk MDS Treated with Azacitidine Risk factor Point PS 0 -1 0 2+ 1 Karyotype: FAV 0 INT 1 UNFAV 2 Transfusions 0 -3 RBC units/8 weeks 0 > 3 RBC units/8 weeks 1 PB blasts absent 0 present 1 Itzykson R et al. Blood 2010. [Epub ahead of print]

ATU Initial cohort AZA-001 Validation cohort At risk Median OS 2 -year OS [95% CI] Low 30 (12%) NR 80% [63 -96] Int 182 (70%) 15. 0 31% [24 -39] High 48 (19%) 6. 1 0 Itzykson R et al. Blood 2010. [Epub ahead of print] At risk Median OS 2 -year OS [95% CI] Low 27 (17%) NR 83% [68 -98] Int 120 (73%) 20. 8 48% [37 -58] High 16 (10%) 14. 4 20% [0. 250]

Second-Line Treatment After Failure of Hypomethylating Agents • Median survival after failure of azacitidine: 6 months (Prébet, ASH 2010) • Treatment ? – Clofarabine – ON 01910 Na – Allogeneic SCT

Hypomethylating Agents in Lower Risk MDS • Silverman (2002), Wijermans (2005) Lyons (2007) – Patients generally resistant to EPO – 35– 40% HI-E, generally with transfusion independence • Italian group experience (Musto, Cancer 2010) – 63 patients, generally resistant to EPO – 41% erythroid responses

Alternative Regimens of AZA Phase II, prospective, multicenter, randomized, open-label, 3 -arm trial Screening Cycle 1 -6 AZA 5 -2 -2 75 mg/m 2 SC Day -21 to -1 AZA 5 -2 -5 50 mg/m 2 SC AZA 5 75 mg/m 2 SC q 28 or 42 days AZA 5 75 mg/m 2 SC Initial Randomization Repeat cycle every 28 days Lyons RM et al. J Clin Oncol 2009; 27(11): 1850 -56. Maintenance Randomization

Groupe Francophone des Myélodysplasies • Activates clinical trials in MDS (35 centers in France and Belgium + (recently) Switzerland, Tunisia) • Website: www. gfmgroup. org • Online registry of French MDS cases • Close cooperation with: - a patient support group - the International MDS Foundation - the European Leukemia Net

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Case 3: Dr Schwartz (Discussant: Dr Smith) • 72 yo man: PMH – CAD, but PS 0 • 12/09: High fever, obtunded, LP-negative, pancytopenia • Bone marrow = 24% blasts, hypocellular, CD 33+, monosomy 11, MML gene rearrangement • Inpatient tx: Azacitidine 75 mg/m 2/day x 7 days plus gemtuzumab 3 mg/m 2 on day 8 Copyright © 2011 Research To Practice. All rights reserved.

Case 3 continued: • Repeat bone marrow day 22 = hypocellular with <10% blasts • Discharged home • 2 nd cycle azacitidine/gemtuzumab outpatient blood counts and bone marrow normalized • Maintenance – 4 cycles azacitidine alone • In remission Copyright © 2011 Research To Practice. All rights reserved.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Management Strategies for Elderly Patients with AML B. Douglas Smith, MD Associate Professor, Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Elderly AML: Limited Improvements in Outcome Younger Older • Supportive care • Risk-adapted therapy • Intensifying therapy

ACUTE MYELOID LEUKEMIA Question #1: When is one really OLD?

Age ≥ 60 Years = Independent Risk Factor: Analysis From the German AMLCG 99 Study < 60 Years (n=1137) ≥ 60 Years (n=1367) P Value s. AML 17% 29% <. 0001 Unfavorable Cytogenetics 23% 29% . 0004 Favorable Cytogenetics 12% 4% <. 0001 nl Cyto, NPM mut, ITD wt 34% 26% <. 009 Median WBC/m. L 12. 600 7. 360 <. 0001 Median LDH U/L 413 340 <. 0001 CR Rate 70% 54% <. 001 Early and Hypoplastic Death 12% 16% <. 001 Persistent Leukemia 18% 30% <. 001 Patient Characteristics Buchner, T et al. ASH 2008, Abstract 555

Age ≥ 60 Years = Independent Risk Factor: Analysis From the German AMLCG 99 Study Overall Survival Relapse Rate Unfavorable Cytogenetics 2. 17 2. 08 Age ≥ 60 Years (all patients) 1. 96 2. 04 Age ≥ 60 Years (nl cytogenetics) 2. 0 LDH > 700 U/L 1. 32 1. 41 Multivariate Analysis Buchner, T et al. ASH 2008, Abstract 555

ACUTE MYELOID LEUKEMIA Question #2: Is your “old” pt ready for intensive induction chemotherapy? “FIT” vs “UNFIT”?

Choosing Patients Wisely • Age = continuous variable • Organ Function: • renal (cytarabine) • cardiac (anthracyclines) • History of previous chemotherapy • Performance status • nutritional parameters • Family / social support

ACUTE MYELOID LEUKEMIA Question #3: Is your “old” pt ready for intensive induction chemotherapy? Wild card = is the AML the problem?

ACUTE MYELOID LEUKEMIA Question #4: When is the AML really OLD?

AML: TWO Diseases 60 years ? ? De novo AML “MDS/AML” ? Age ** Courtesy of Dr. Mark Levis “MDS/AML” is more likely to have: - poor risk cytogenetics - antecedent marrow disorder - MDR 1 overexpression

Prognostic Factors in AML • • • CYTOGENETICS Molecular Mutations WBC @ presentation Preceding MDS CD 34 expression MDR 1 phenotype • • • Age Performance status Secondary AML Extramedullary AML Failure to achieve CR

Molecular Mutations in AML • FLT 3/ITD mutation • FLT 3/D 835 mutation Currently available • NPM 1 mutation • • Kit mutations CEBPa WT-1 BAALC The Future? ? ? Arriving SOON… TET 2 – impacts methylation status of cytosine… Jankowska, Ko, Huang, et al. ASH 2010, Abstract 1, Plenary Session

Prognostic Factors in AML • • • CYTOGENETICS Molecular Mutations WBC @ presentation Preceding MDS CD 34 expression MDR 1 phenotype • • • Age Performance status Secondary AML ? ? Extramedullary AML Failure to achieve CR What should this tell us AND what should we do? #1 Our patient is NOT likely to respond to traditional cytotoxics… #2 Start a direct dialog with your pt and consider a clinical trial…

ACUTE MYELOID LEUKEMIA Question #5: Are there better cytotoxic agents for older patients with AML? GOAL = increase induction success? Decrease toxicity? Improve survival?

Clinical Trials in Older Adults with AML AGE (YRS) CR(%) OVERALL SURVIVAL (MONTHS) ECOG 1490. Rowe 1995 64 52 7. 8 CALGB 8923. Stone 1995 69 52 9. 6 SWOG 9031. Godwin 1998 68 45 8. 5 HOVON AML 9. Löwenberg 1998 68 42 9. 5 MRC AML 11. Goldstone 2001 66 55 10% - 5 yrs CALGB 9720. Baer 2002 70 46 10 SWOG 9333. Anderson 2002 68 43 9 ECOG 3993. Rowe 2004 68 42 7. 5 STUDY German AML Coop Group Büchner 2009 66 59 16%- 4 yrs Induction Death ~ 15 – 20% Disease-Free Survival ~ 6 – 9 months

What’s New ASH 2010: AML Novel RX Monday, Dec 6, 4: 30 pm – 6 pm, room 311 ABCD • Abstract #655: Phase 2 B Randomized Study of CPX-351 Vs. Cytarabine (CYT) + Daunorubicin (DNR) (7+3 Regimen) In Newly Diagnosed AML Patients Aged 60 -75. Jeffery E. Lancet, MD, et al • Abstract #656: Phase I Study to Assess the Safety and Tolerability of AZD 1152 In Combination with Low Dose Cytosine Arabinoside In Patients with Acute Myeloid Leukemia (AML). Hagop M. Kantarjian, MD, et al • Abstract #657: A Multi-Center, Open-Label, Phase I Study of Single Agent RG 7112, A First in Class p 53 -MDM 2 Antagonist, In Patients with Relapsed/Refractory Acute Myeloid and Lymphoid Leukemias (AML/ALL) and Refractory Chronic Lymphocytic Leukemia/Small Cell Lymphocytic Lymphomas (CLL/SCLL). Michael Andreeff, MD, Ph. D, et al • Abstract #658: The Novel, Investigational NEDD 8 -Activating Enzyme Inhibitor MLN 4924 In Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study. Ronan T. Swords, MD, MRCPI, FRCPath, et al • Abstract #659: Anti-Leukemic Activity of PIK-75, a P 13 -Kinase p 110 a Selective Inhibitor, In Acute Myeloid Leukemia. François Vergez, et al • Abstract #660: Terminal Differentiation of FLT 3/ITD AML Blasts In Patients Treated with the FLT 3 Inhibitor AC 220. Mark J. Levis, MD, Ph. D, et al

CPX-351 Randomized Phase II Study 204: Newly Diagnosed AML, Elderly Patients • Liposomal formulation • Ara-C + daunorubicin • (fixed molar ratio = 5: 1) • Taken up in whole by cell • preferential = bone marrow • Phase IIB, Elderly AML • • Age btwn 60 -74, non-favorable risk, “fit” for chemo 2 to 1 randomization = CPX-351 (100 u/m 2 IV d 1, 3, 5) vs “ 7 + 3” 1˚ endpoint: % CR 2˚ endpoints: CR duration, EFS, survival at 12 mos, rate of SCT and mortality (30, 60, 90 d) Lancet J, et al. ASH 2009, Abstract 1033

CPX-351 Phase II: Interim Data Clinical Response and Toxicity Response: CPX-351 (n = 57) 7+3 (n = 28) CRm 23 (40%) CRi 12 (21%) 3 (11%) TOTAL 35 (61%) 14 (50%) Lancet J, et al. ASH 2009, Abstract 1033 11 (39%)

CPX-351 Phase II: Interim Data Clinical Response and Toxicity Response: CPX-351 (n = 57) 7+3 (n = 28) CRm 23 (40%) 11 (39%) CRi 12 (21%) 3 (11%) TOTAL 35 (61%) 14 (50%) </- 30 days 3 (5. 3%) 1 (3. 6%) 31 -60 days 0 (0%) 61 -90 days 2 (3. 5%) 1 (3. 6%) TOTAL 5 (8. 8%) 2 (7. 2%) Mortality: Lancet, et al. ASH 2009

ACUTE MYELOID LEUKEMIA Question #6: NON-cytotoxic agents for older patients with AML? GOAL = stabilize marrow function? Decrease toxicity? Improve survival?

DNA Methyltransferase Inhibitors • Abstract #1063: Decitabine for Older AML Patients: An Effective Therapy Associated with Short Hospitalization and No Invasive Fungal Infection (G. Ansstas, MD, W. Touma, MD, C. Adeimy, MD, G. Feng, P. Westevelt, MD, Ph. D, C. Abboud, MD, G. Uy, MD, K. Stockerl-Goldstein, MD, A. Cashen, MD, J. Di. Persio, MD, Ph. D, and R. Vij, MBBS, MD) • PLAN: Elderly AML pts Decitabine 20 mg/m 2 IV daily x 5 days every 28 days • 45 pts enrolled median age 71 (range 61 -83) years • Best response to therapy: CR/CRi = 13 (29%) SD/PR = 22 (49%) Progression = 10 (22%) • OVERALL SURVIVAL: CR/CRi = 18. 9 mos SD/PR = 7. 3 mos Progression = 1. 9 mos • Abstract #2181: 5 -AZA to Treat AML In Elderly or Frail Patients: A Phase II Study (SAKK 30/07). J. Passweg, MD, MS, T. Pabst, S. Blum, M. Bargetzi, H. Sun, D. Heim, MD, G. Stussi, MD, M. Gregor, L. Leoncini, S. Meyer-Monard, MD, P. Brauchli, and Y. Chaladon, MD • PLAN: Elderly AML pts (PS</= 3) Azacitidine 100 mg/m 2 SQ daily x 5 every 28 days • 45 pts enrolled median age 74 (range 55 -86) years >78% with PS 0 or 1 • 17 pts remain on study (authors concluded “feasible strategy” – updating outcomes) • 28 pts stopped early – reasons: progression, NR, toxicity, pt choice, infection, death (8)

ACUTE MYELOID LEUKEMIA Question #7: Can we extend our patients’ remissions? Maintenance strategies?

Potential Maintenance Regimens in AML AFTER OPTIMAL CONSOLIDATION • Low-dose cytarabine • Farnesyltransferase inhibitors • Hypomethylating agents • Gemtuzumab ozogamicin • Lenalidomide • Tyrosine kinase inhibitors: FLT 3 -ITD • Interferon • IL – 2 + Histamine • Immunomodulation / vaccines

ACUTE MYELOID LEUKEMIA Question #8: How are we going to make the next big discovery?

What’s New ASH 2010 – Elderly AML Monday, Dec 6, 10: 30 am – noon, room 311 ABCD • Abstract #331: Ph II Study of Bortezomib + Daunorubicin and Ara-C Induction and Dose Escalation of Bortezomib with Intermed-Dose Ara-C Consolidation Rx for Pts with Previously Untreated AML Age 60 -75 Years: Cancer and Leukemia Group B (CALGB) Study 10502 • Abstract #332: A Ph II Study of Lenalidomide for Previously Untreated Deletion (del) 5 q AML Pts Age 60 or Older Who Are Not Candidates for Remission Induction Chemotherapy (SWOG S 0605) • Abstract #333: Sorafenib In Combo with Induction and Consolidation Rx Elderly AML Pts: Results From a Randomized, Placebo-Controlled Ph II Trial • Abstract #334: Induction Rx in Elderly Pts w/AML: Random Comparison of Intermed-Dose Ara-C + Mitoxantrone vs Standard-Dose Ara-C + Dauno in 492 AML Pts >60 Years – the SAL 60+ Trial • Abstract #335: Induction Rx by Ara-C + Dauno vs Ara-C + Gemtuz: Interim Analysis of a Randomized Phase II Trial of the SAL In Elderly Pts with AML • Abstract #336: Frontline Rx for Older Pts with AML: Clofarabine + LD Ara-C Induction Followed by Prolonged Consolidation with Clofarabine Plus LD Ara-C Alternating with Decitabine

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Case 4: Dr Fishkin (Discussant: Dr Gertz) • 54 yo woman with pneumococcal sepsis and pancytopenia • Persistent serum protein elevation, SPEP with IFE = 9. 5 g/d. L Ig. G kappa • ß 2 -microglobulin 4. 6 mg/L • Bone marrow = plasma cells, normal cytogenetics • Enrolled in clinical trial: SWOG S 0777 RVd vs Rd Copyright © 2011 Research To Practice. All rights reserved.

Case 4 continued: • Randomized to RVd • Toxicity dose reduced x 2 and D/C after completing 4 cycles: Neuropathy with Bell’s palsy ↓ Na and ↓K Skin toxicity (lower extremity ulcer) • VGPR, stem cells collected and stored • Maintenance lenalidomide 10 mg/day Copyright © 2011 Research To Practice. All rights reserved.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Myeloma – Managing Younger Patients MA Gertz MD MACP Chair Medicine Mayo Rochester Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

m. SMART 2. 0: Classification of Active MM High-Risk 20% § FISH § Del 17 p § t(14; 16) § t(14; 20) § GEP §High risk signature Intermediate-Risk 20% § FISH § t(4; 14)* § Cytogenetic deletion 13 or hypodiploidy Standard-Risk 60%** All others including: § Hyperdiploid § t(11; 14)*** § t(6; 14) § PCLI >3% * Prognosis is worse when associated with high beta 2 M and anemia. ** LDH > ULN and beta 2 M > 5. 5 in standard risk may indicate worse prognosis. *** t(11; 14) is associated with plasma cell leukemia. Kumar SK et al. Mayo Clin Proc 2009; 84(12): 1095 -110. Revised and updated June 2010.

How to Treat Standard Risk Disease Standard-Risk All others including: § Hyperdiploid § t(11; 14) § t(6; 14) Mayo Clinic OS at 5 years is 60% (for 210 standard risk patients) in new drug era. Reproduced with permission from Kapoor S et al. Mayo Clin Proc 2010; 85(6): 532 -7. Quadrant Health. Com Inc.

How to Treat Standard Risk Disease Standard-Risk All others including: § Hyperdiploid § t(11; 14) § t(6; 14) 80% OS at 5 years in 150 transplant eligible standard risk patients treated with RD, CRD or CBD +/- HDM. Reproduced with permission from Kapoor S et al. Mayo Clin Proc 2010; 85(6): 532 -7. Quadrant Health. Com Inc.

m. SMART – Off-Study Transplant Eligible High Risk Intermediate Risk Standard Risk Experimental therapy Induction with bortezomib based regimen 4 cycles of Rda or bortezomib based regimen Collect stem cellsb If not available, then consider… Standard risk approach Allogeneic approach Intermediate risk approach Autologous stem cell transplant (ASCT) Continue Rdc Consider 2 nd ASCT if not in CR Bortezomib based maintenance for minimum of 1 year Consider lenalidomide maintenance a Bortezomib containing regimens preferred in renal failure or if rapid response needed b If age >65 years or ≥ 4 cycles of Rd consider G-CSF plus cyclophosphamide or plerixafor c Continuing Rd is option for patients responding and with low toxicities; Dex is usually discontinued after first year Kumar et al. Mayo Clin Proc 2009 84(12): 1095 -110. v 6 Revised and updated: Dec 2009

Transplant for Standard Risk Disease? Reproduced with permission of The American Society of Hematology from "How I treat multiple myeloma in younger

Efficacy of Lenalidomide, Bortezomib and Dexamethasone (RVD): A Phase 1/2 Study in Newly Diagnosed Myeloma Response ≥ PR ≥ VGPR CR + n. CR CR All Patients (N = 66) 100% 67% 40% 29% Phase 2 Population (N = 35)* 100% 74% 57% 37% Estimated 18 -Month Survival (with/without transplantation) Progression-free survival Overall survival 75% 97% *Bortezomib 1. 3 mg/m 2, lenalidomide 25 mg, dexamethasone 20 mg Richardson PG et al. Blood 2010; 116(5): 679 -86.

Select Adverse Events with Lenalidomide, Bortezomib and Dexamethasone (RVD): A Phase 1/2 Study in Newly Diagnosed Myeloma All Grades Grade 3/4 Sensory neuropathy 80% 2% Fatigue 64% 3% Neuropathic pain 32% 3% Motor neuropathy 18% 2% Lymphopenia 14% Thrombosis/embolism 6% 5% Richardson PG et al. Blood 2010; 116(5): 679 -86.

Maintenance therapy with thalidomide after ASCT N Initial dose, mg Maintenance versus no maintenance CR, % EFS or PFS, % OS, % Barlogie et al. 1 668 400 64 vs 43 5 -year EFS 8 -year OS 56 vs 45 57 vs 44 Attal et al. 2 597 400 67 vs 55* 3 -year EFS 4 -year OS 52 vs 36 87 vs 77 Spencer et al. 3 243 200 63 vs 40* 3 -year PFS 3 -year OS 42 vs 23 86 vs 75 * CR + VGPR rates. 1 Barlogie B et al. Blood 2008; 112(8): 3115 -21. 2 Attal M et al. Blood 2006; 108(10): 3289 -94. 3 Spencer A et al. J Clin Oncol 2009; 27(11): 1788 -93.

CALGB-100104: Median TTP: Not yet reached Median TTP 25. 5 mo Median follow up from ASCT is 12 months With permission, Mc. Carthy PL et al. Proc ASCO 2010; Abstract 8017.

CALGB-100104: Once again availability of len in the placebo arm at prog is critical There is not long enough follow-up to determine if there is a difference in OS; 11 deaths in lenalidomide arm and 17 deaths in the placebo arm (p<0. 2) With permission, Mc. Carthy PL et al. Proc ASCO 2010; Abstract 8017.

Results • Stratification by beta-2 microglobulin and previous thalidomide or lenalidomide exposure during induction demonstrated a benefit for lenalidomide over placebo in each stratification. • The study was un-blinded in December 2009 allowing patients (with physician support) to cross over to openlabel lenalidomide. • 77 of 89 eligible placebo patients have started lenalidomide therapy. Mc. Carthy PL et al. Proc ASCO 2010; Abstract 8017.

IFM 2005 -02: Study design Phase III randomized, placebo-controlled trial N = 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008 Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line Randomization: stratified according to beta-2 m, del 13, VGPR Consolidation: Lenalidomide alone 25 mg/day p. o. days 1 -21 of every 28 days for 2 months Arm A = Placebo Arm B = Lenalidomide (N=307) until relapse (N=307) 10 -15 mg/d until relapse Primary endpoint: PFS. Secondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide… Attal M et al. Proc ASCO 2010; Abstract 8018. IFM = Intergroupe Francophone du Myélome.

1. 00 0. 75 IFM 2005 -02: PFS from randomization 0. 25 0. 50 Len Placebo 0. 00 P < 10 -7 0 6 12 18 24 Placebo With permission, Attal M et al. Proc ASCO 2010; Abstract 8018. 30 36 Lenalidomide

IFM 2005 -02: First Interim Analysis (Cutoff date 4 th September 2009) § Maintenance therapy with lenalidomide: • Is well tolerated: ü Low discontinuation rate due to SAE (A = 4% vs B = 6%, NS) ü No increased incidence of DVT or peripheral neuropathy • Is superior to placebo: ü 54% reduction in risk of progression (p < 10 -7) üIn all stratified subgroups (VGPR, beta-2 m, del 13) § A longer follow-up is required to appreciate the impact of lenalidomide on OS (Final analysis: 8/2010) Attal M et al. Proc ASCO 2010; Abstract 8018.

Conclusions • SCT remains an important regimen capable of improving depth of response beyond that achievable with novel agents alone. • All patients fit for transplantation should have stem cells collected followed by a frank discussion of the pros & cons of early vs delayed transplant. • Maintenance lengthens PFS; impact on OS unknown.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Case 5: Dr Harwin (Discussant: Dr Vij) • 60 yo man: PMH – Pancreas NET since 1997 surgery, radioactive lutecium and temozolomide/ capecitabine • Rising WBC to 50, 000/mm 3 while on chemotherapy • 4/10: Bone marrow = 15% blasts, monosomy 7, negative for bcr-abl • Referred to tertiary center for diagnostic consult – CMML-2 Copyright © 2011 Research To Practice. All rights reserved.

Case 5 continued: • Azacitidine 75 mg/m 2/day IV x 7 days (M-Sat, +M) on q 4 week intervals • Bone marrow after C 5 = normocellular marrow, 2% blasts, monosomy 7 • WBC: 4, 400/mm 3, Hgb: 9. 9 g/d. L, platelets 107, 000/µL • Feeling well, continues on azacitidine Copyright © 2011 Research To Practice. All rights reserved.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

Chronic Myelomonocytic Leukemia (CMML) Ravi Vij MD Associate Professor Section of BMT and Leukemia Washington University School of Medicine St Louis, MO

CMML • • Affects 3 out of 100, 000 individuals in the US/year. 75% are > 60 years at diagnosis. Incidence in males is 2 X females. The defining features of CMML are: – Absolute monocytosis >1 X 109/l, increased numbers of monocytes in bone marrow, and a variable degree of dysplasia in all three lineages. – Myeloblasts and promonocytes comprise < 5% of nucleated cells in peripheral blood and < 20% in bone marrow. • 50% of patients present with an elevated white cell count >13 K, hepatomegaly and splenomegaly, the myeloproliferative form of the disease. • Patients lacking these features are considered to have the myelodysplastic form of the disease. www. leukemia-lymphoma. org, November 2010; www. atlasgeneticsoncology. org, November 2010.

Biology of CMML • Overall 20 -30% of cases show cytogenetic abnormalities. • These include: numerical and structural abnormalities +8, del(20 q), -7, del(11 q). • Rarely translocations have been identified in CMML. – Cases associated with eosinophilia commonly show t(5; 12)(q 33; 13) which fuses TEL to the platelet-derived growth factor receptor (PDGFb. R) (about 2 -5% of all CMML cases). – Fusions of the Huntington interacting protein 1(HIP 1) gene to PDGFb. R have also been described in CMML associated with t(5; 7)(q 33; q 11. 2). – Occasional cases of therapy-associated CMML are associated with the t(11; 16)(q 23; p 13) which fuses MLL to CBP. – Rare reports of CMML associated with t(1; 13)(p 36; q 21), t(7; 11)(p 15; p 15) and t(8; 9)(p 11; q 34) have been reported. • Targeted next generation sequencing detected frequent mutations in TET 2, CBL, RAS and RUNX 1, EZH 2, ASXL 1, IDH 2, NPM 1. www. atlasgeneticsoncology. org, November 2010.

FAB Classification Blasts, % MDS Subtype BM RA PB Ringed Sideroblasts Monocytosis (>1000/µL) <5 <1 <15% No RARS <5 <1 >15% No CMML 5 -20 <5 Variable Yes RAEB 5 -20 <5 Variable No RAEB-t* 21 -30 >5 Variable *With or without Auer rods. FAB = French-American-British; BM = bone marrow; PB = peripheral blood; RA = refractory anemia; RARS = RA with ringed sideroblasts; CMML = chronic myelomonocytic leukemia; RAEB = RA with excessive blasts; RAEB-t = RAEB in transformation. Bennett. Br J Haematol. 1982; 82: 358.

FAB Categories: Patient Distribution and Estimated Survival 12 mo CMML 16% 6 mo RAEB-t 9% RAEB 23% 18 mo 35 mo RA 28% RARS 24% 35 mo Bennett JM et al. Br J Haematol. 1982; 51: 189 Gallagher A et al. Haematologica. 1997; 82: 191

WHO-Revised MDS Classification • RA MDS/MPD MDS* • CMML-1 (<10% BM blasts) • CMML-2 (10 -19% blasts) • CMML-Eos (AEC >1500/ L) • JMML - RA - RCMD • RSA - RARS - RCMD-RS • RAEB-1 (5%-9% BM blasts) • RAEB-2 (10%-19% Auer rods) • 5 q– syndrome • MDS-U AML • 20% blasts *Single-lineage erythroid dysplasia. WHO = World Health Organization; MPD = myeloproliferative disease; Eos = eosinophils; AEC = absolute blood eosinophil count; JMML = juvenile myelomonocytic leukemia. Harris et al. J Clin Oncol. 1999; 17: 3835.

International Prognostic Scoring System All 3 prognostic variables required to generate IPSS score Score Value Prognostic variable Bone marrow blasts (%) Karyotype* Number of cytopenias** 0 0. 5 1. 0 1. 5 2. 0 <5 5– 10 – 11– 20 21– 30 Good Intermediate Poor – 0/1 2/3 – – *Good = normal, -Y, del(5 q), del(20 q); Intermediate = other karyotypic abnormalities; Poor = complex ( 3 abnormalities) or chromosome 7 abnormalities **Hgb <10 g/d. L; ANC <1800/ L; platelet count <100, 000/ L Greenberg P et al. Blood. 1997; 89: 2079 –

MDS: IPSS Risk* Categories Numeric Score IPSS Risk Category 0 Low 0. 5– 1. 0 Int-1 1. 5– 2. 0 Int-2 2. 5 High 8% Int-2 Risk 22% Low Risk 31% Int-1 Risk 39% *Estimated survival and risk of AML transformation Greenberg P et al. Blood. 1997; 89: 2079

Prognostic parameters for CMML Kaplan-Meier survival curves of CMML patients (n = 212) according to the MD Anderson Prognostic Score. Kaplan-Meier survival curves of CMML patients (n = 212) according to the Dusseldorf score. Reproduced with permission of The American Society of Hematology from "New prognostic parameters for chronic myelomonocytic leukemia? ” Germing et al. Blood 2002; 100(2): 731 -2. Permission conveyed through Copyright Clearance Center, Inc.

Goals of Therapy in MDS • • Select therapy best suited for the individual – Performance status, disease classification, IPSS score (cytogenetics, cytopenias, BM blasts), and treatment tolerance Low/Int-1 IPSS: Improve blood counts (decrease transfusions and infections) Improve quality of life Int-2/high-risk IPSS: Prolong survival and delay leukemic progression – Possible cure of disease List AF, et al. Hematology (Am Soc Hematol Educ Program). 2004; 297 -317. Cheson BD, et al. Blood. 2000: 96: 3671. NCCN Myelodysplastic Panel Members. Available at: http: //www. nccn. org/professionals/physician_gls/PDF/mds. pdf

% Survival The Decision HCT No HCT Time With Permission of C. Cutler, MD

The EBMT Experience • 50 allogeneic transplantations from related (n = 43) or unrelated (n =7) donors • Median age 44 years (range 19– 61) • The 5 -year estimated overall survival was 21% and the 5 -year estimated disease-free survival was 18% • Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, and acute Gv. HD favoured better DFS • The 5 -year estimated probability of relapse was 49%. The data showed a trend for a lower relapse with acute Gv. HD suggesting a graft-versus-CMML effect. Kroger et al, British Journal of Haematology, 2002, 118, 67– 73

Hypomethylating Cytosine Analogs NH 2 CH 3 N N O NH 2 N O N Ribose Cytosine 5 -methyl-cytosine 5 -aza-cytidine O Deoxyribose 5 -aza-2′-deoxycytidine (azacitidine) Santini V, et al. Ann Intern Med. 2001; 134(7): 573 -86. N N (decitabine)

Efficacy of Azacitidine in the Treatment of Chronic Myelomonocytic Leukemia (n = 35) n (%) Age (years) Median Range 70 33 -85 Gender M: F 19: 16 Splenomegaly Yes 13 (37. 1) Hemoglobin, g/dl < 10. 0 8 (22. 9) Platelets, X 109/L < 50 12(13. 3) <100 19 (54. 3) • ORR: 48. 6%: CR 5 (14. 3%), marrow CR 4 (11. 4%), PR 1 (2. 9%), HI 7 (20%) • The median OS was 25 months (95% CI 13. 8 -36. 1 mo). Teichman et al ASH 2010 Abstract # 4017

Treatment of Advanced CMML by Azacitidine in a Compassionate Program: the GFM Experience N = 38 • Median age was 71 y (range 50 -87) • Median interval from diagnosis to treatment: 22 months (range 0. 2 -74 months). • 20 pts (53%) responded including 9 CR, 3 marrow CR, 8 HI-E and 1 partial remission. • Median number of cycles of AZA to achieve best response was 4 (range 3 -12). • 9 of the 20 responders relapsed after a median of 10. 6 months (range 3 -23). • Median overall survival (OS) was 24 months in CMML compared to 7 months in AML arising from CMML (p = 0. 0081). • Presence of splenomegaly, WBC>13 G/l, previous treatment (excluding ESA), Sex, -7/del 7 q and normal karyotype had no impact on OS. Wolfromm et al ASH 2010 Abstract # 4023

Decitabine is Effective and Safe in Patients with Chronic Myelomonocytic Leukemia • A subset of patients with CMML from a pivotal phase III 3 -day dosing and an open-label trial of 5 -day dosing were identified Response Rates (N=17) n % 7 41. 1 Complete Response (CR) 3 17. 6 Marrow Complete Response (m. CR) 4 23. 5 Hematologic Improvement (HI) 2 11. 7 Overall Response Rate (CR + m. CR + PR) • Median survival was 391 (95% CI 239, 678) days and 2 (11. 7%) patients progressed to AML. Jabbour et al. ASH 2010 Abstract # 4032

A Phase II Study of Decitabine in Advanced CMML • 41 pts in 16 centers • Median age 71 years (range 54 -88) • Seventeen pts had CMML 1 and 22 had CMML 2 • Median number of cycles was 9 (range 1 -17) • Overall Response Rate (ORR) was 38. 6% with 4 (10. 3%) CR, 8 (20. 5%) marrow CR and 3 (7. 7%) with HI. • Overall Survival (OS) estimate was 60% at 2 years. By comparison, in a previous trial of HY in CMML where inclusion criteria were the same, 2 year survival was 43% (Blood 1996 88: 2480) • The only factor associated with response to DAC was WHO subtype: CMML 2 pts showing significantly better ORR (30. 8% vs 7. 7% in CMML 1; p = 0. 041). There was no difference in survival between CMML 1 and 2 pts. Braun et al ASH 2010 Abstract # 1873

Conclusions • Allogeneic transplant is the only known curative therapy for patients with CMML. However, few patients are eligible for such an approach. • DNA hypomethylating agents are a therapeutic option that most patients can tolerate and produce responses similar to that reported for other FAB categories of MDS.

Case 6: Dr Fishkin (Discussant: Dr Ravandi) • 48 yo woman with kidney stone • Thrombocytopenia, anemia and microgranules on pre-op evaluation • DIC panel mildly positive • Emergent bone marrow = t(15; 17) • Inpatient tx: Idarubicin + ATRA x 3 days • Discharged home to complete induction outpatient Copyright © 2011 Research To Practice. All rights reserved.

Case 6 continued: • Completed 3 cycles of induction therapy in 6/07 • Arsenic trioxide consolidation x 2 cycles • Maintenance with ATRA + MTX/6 MP D/C MTX/6 MP after one month b/c potential to exacerbate kidney stone disease 1 full year of ATRA • Remains in continuous cytogenetic and molecular remission Copyright © 2011 Research To Practice. All rights reserved.

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.

ACUTE PROMYELOCYTIC LEUKEMIA Farhad Ravandi, MD University of Texas – M. D. Anderson Cancer Center Friday, December 3, 2010

Distribution of APL Molecular Lesions PML/RARa t(15; 17)(q 22; q 21) 92% PML/RARa + insertions 4% PML/RARa + variants 2% PLZF/RARa t(11; 17)(q 23, q 21) 0. 8% NPM/RARa t(5; 17)(q 35, q 21) 0. 2% Nu. Ma/RARa t(11; 17)(q 13, q 21) < 0. 1% Stat 5 b/RARa der(17) < 0. 1% No RARa Grimwade D, Lo Coco F. Leukemia. 2002; 16(10): 1959 -1973 1%

Genetic Diagnosis • Confirm genetic diagnosis with leukemic cells from BM Level Method Chromosomal Karyotyping DNA FISH RNA RT-PCR Protein a-PML m. Ab Sanz MA, et al. Blood 2009; 113: 1875 -1891

The Role of Ara-C • Phase II, Idarubicin w/o Ara-C • PETHEMA ° 3 -yr DFS: 81% standard dose vs 90% intermediate/high-dose • ATRA/DNR/Ara-C vs ATRA/DNR • European APL group ° CR similar (99% vs 94%, P = 0. 12) ° Relapse higher w/o Ara-C (2 -yr CIR: 4. 7% vs 15. 9%, P = 0. 011) • ATRA /DNR/Etoposide/Ara-C vs ATRA/Idarubicin • MRC ° No difference in CR rate (91% vs 93%) ° No difference in 4 -year OS (81% vs 85%) ° ↓ myelosuppression w/o Ara-C/etoposide Sanz MA, et al. Blood. 2004; 103(4): 1237 -1243 Ades L, et al. J Clin Oncol. 2006; 24: 5703 -5710 Burnett AK, et al. Blood. 2007; 181 a; Abstract 589

2 -Yr Cumulative incidence of relapse, EFS, and OS by Ara-C or no Ara-C No Ara-C p-value Relapse 4. 7% 15. 9% 0. 011 EFS 93. 3% 77. 2% 0. 0021 OS 97. 9% 89. 6% 0. 0066 EFS = event-free survival; OS = overall survival Ades, L. et al. J Clin Oncol; 24: 5703 -5710 2006

2 -Yr Cumulative incidence of relapse, EFS, and OS of younger patients with WBC 10 x 109/L Relapse EFS OS 2. 9% 89% 91. 9% EFS = event-free survival; OS = overall survival Ades, L. et al. J Clin Oncol; 24: 5703 -5710 2006

UK MRC AML 15: Study Schema MRC Arm* Induction ADE and ATRA (2 courses) *MACE and Mid. AC Induction Ida and ATRA (2 courses) *Mitoxantrone/Ida and ATRA (2 courses) Pts with APL (N = 291) PETHEMA Arm* *Patients on both arms undergo second randomization to placebo or gemtuzumab ozogamicin in CR Burnett AK, et al. ASH 2007; Abstract 589. Maintenance 6 -mercaptopurine Methotrexate ATRA

UK MRC AML 15: Results • Outcomes: MRC vs PETHEMA – CR: 91% vs 93% (P =. 5) – OS: 81% vs 85% at 4 years (P =. 10) • Induction death: 10 patients in MRC vs 8 patients in PETHEMA • Resistance equal for 2 arms: 1 patient each • Relapse similar between 2 arms: 5 patients in MRC vs 6 patients in PETHEMA • Death in CR higher for MRC: 11 vs 2 (P =. 009) • More transfusions, infections, hospitalizations in the MRC arm (P <. 0001) • Better quality of life in the PETHEMA arm Burnett AK, et al. ASH 2007; Abstract 589.

ATO Monotherapy in Newly Diagnosed Patients N CR % PML-RARa negative post-CR % EFS % OS % Ghavamzadeh, et al 111* Iran 86 92 64 (2 -yr) 88† (3 -yr) Mathews, et al India 72 86 76 75 (3 -yr) 86 (3 -yr) George, et al India 11 91 100 82 (5 -yr) 91 (5 -yr) *94 of the 111 patients were newly diagnosed. †For patients in CR. Ghavamzadeh A, et al. Ann Oncol. 2006; 17(1): 131 -134. Mathews V, et al. Blood. 2006; 107(7): 2627 -2632. George B, et al. Leukemia. 2004; 18(10): 1587 -1590.

ATRA/CT→ATO vs ATRA/CT in Newly Diagnosed APL Intergroup Protocol C 9710 APL PML-RARa confirmed by RT-PCR N = 481 (adults) R A N D O M I Z E D ATRA Ara-C Daunorubicin ATO x 2 ATRA DNR x 2 CR Newly Diagnosed ATRA Ara-C Daunorubicin ATRA DNR x 2 Induction R A N D O M I Z E D Consolidation ATRA 6 -MP MTX Maintenance Agent Induction Consolidation Maintenance ATRA 45 mg/m 2 , PO, d 1 -CR 45 mg/m 2 , PO, d 1 -7, every other wk Ara-C 200 mg/m 2 , IV, d 3 -9 DNR 50 mg/m 2, IV, d 3 -6 ATO 50 mg/m 2, IV, d 1 -3 0. 15 mg/kg 5 d/week, x 5 wks 6 -MP 60 mg/m 2/d, PO, daily MTX 20 mg/m 2, once/week Powell BL, et al. Blood 2010; 116(19): 3751 -7

ATRA/CT→ATO vs ATRA/CT in Newly Diagnosed APL EFS, ITT Response + ATO n = 244 No ATO n = 237 P 3 -year EFS 80% 63% 0. 0001 3 -year OS 86% 81% 0. 07 Powell BL, et al. Blood 2010; 116(19): 3751 -7

ATRA and ATO Therapy N CR % PML-RARa negative EFS/DFS/RFS post-CR % % 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) 85 (2 -yr) Dai, et al China 90 93 100 92 (3 -yr EFS) NR *95% in low-risk, 81% in high-risk. Hu J, et al. Proc Natl Acad Sci U S A. 2009; 106(9): 3342 -3347. Ravandi F, et al. J Clin Oncol. 2009; 27(4): 504 -510. Dai CW, et al. Acta Haematol. 2009; 121(1): 1 -8. OS %

Randomized 3 arm study of ATRA vs ATO vs ATRA + ATO 20 20 21 Age in years (median, range) 30. 5 (14 – 74) 39. 5 (15 – 69) 34 (14 – 62) WBC x 109/L (median, range) 3. 0 (1. 2 – 49. 4) 2. 7 (0. 9 – 40) 2. 1 (0. 5 – 52. 6) 6 10 4 8 8 4 7 8 6 23 (4 -76) 27 (12 – 72) 30 (6 – 73) 19 (95) 18 (90) 20 (95. 2) 40. 5 (25 – 65) 31 (28 – 38) 25. 5 (18 – 35) Number < 2 2 – 10 > 10 Plt x 109/L (median, range) CR (%) Median days to CR (range) Shen ZX, PNAS, vol. 101 | no. 15 | 5328 -5335, 2004

Randomized 3 arm study of ATRA vs ATO vs ATRA + ATO Sample collection ATRA ATO ATRA + ATO Pretreatment N = 19 N = 18 N = 20 Median copy number 4, 595. 6 6, 655. 7 5, 155. 3 After CR N = 19 N = 18 N = 20 Median copy number 793. 5 286. 3 177. 3 Median reduction fold 6. 7 32. 1 118. 9 N = 14 N = 11 N = 14 Median copy number 71. 6 41. 3 15. 2 Median reduction fold 369. 5 521. 3 800 After consolidation Shen ZX, PNAS, vol. 101 | no. 15 | 5328 -5335, 2004

A DAY 10 BONE MARROW CR CR WBC < 10 x 109/l WBC ≥ 10 x 109/L B DAY 1 WBC < 10 x 109/l BONE MARROW CR CR ATRA ATO WBC ≥ 10 x 109/L Ravandi, F. et al. J Clin Oncol; 27: 504 -510 2009 GO

CR 4 8 Time in weeks after CR 12 16 PCR * * 20 24 28 PCR * • If PCR is positive, it is repeated 2 to 4 weeks later and if positive again, start GO once monthly ATRA ATO Ravandi, F. et al. J Clin Oncol; 27: 504 -510 2009

Patients Characteristics Number of patients Age in years; median, range Age ≥ 60 (%) Sex Male: Female Leukocyte count, x 109/L Median, range Platelet count, x 109/L Median, range Number 82 47, 14 -81 23 (28%) 44: 38 2. 5, 0. 4 -195. 0 32, 7 -261 Risk category High Low 26 56 Cytogenetics t(15; 17) + other Other (PCR +) Not Done (PCR +) Insufficient (PCR +) 14 58 3 5 2 FAB Morphology M 3 v 70 12 PML-RARA Isoforms Short Long Positive-Undefined Not Done/Suboptimal 30 33 8 11 Ravandi, F. et al. J Clin Oncol; 27: 504 -510 2009

Molecular status with follow-up Time (months) Patients (n) At CR PCR negative n % 13 5 38 1 -3 50 47 94 4 -6 49 49 100 7 -9 49 46 94* 10 -12 43 41 95* 13 -18 53 53 100 19 -24 37 36 97* 25 -36 36 35 97* 37 -48 17 17 100 49 -63 5 5 100 Legend – *Late PCR positive tests were seen in 3 patients with relapse as well as in 4 patients who had a transient weak positive PCR Ravandi, F. et al. J Clin Oncol; 27: 504 -510 2009

Outcome: ATRA+ ATO With permission, Ravandi F, ASH 2010; Abstract #1080

ASH 2010 APL papers • Paper #1083: Early events excluding pts from trial enrollment – Micol J -B, et al. 100 pts referred to single institution, 29 not enrolled, higher WBC ≥ 10 x 109/L, lower Plt < 40 x 109/L, lower CR (79% vs. 97%), 5 -year EFS (62% vs. 84%) and OS (63% vs. 85%; p = 0. 03) • Paper #872: Higher early death and lower OS in a population-based study; Park JH, et al. 1400 and 721 pts with APL in SEER and NY State cancer registry. ED rate 10 -20% with only modest change since 1992. Long-term survival, although improved, is less than reported in trials. More than 25% are not cured • Paper #506: Frontline therapy of APL by ATO; Iranian experience – Ghavamzadeh A, et al. 197 pts with newly dx APL treated with ATO. Induction followed by 4 courses of ATO consolidation. CR in 86% ED and DS in 15%. DFS and OS 67%± 4% and 64%± 4% at 5 years, respectively

ASH 2010 APL papers • Paper #505: ATO consolidation for newly diagnosed APL; European APL 2006 trial; Ades L, et al. Randomization with ATO replacing ara. C in pts with WBC< 10 x 109/L and with addition of ATO in pts with WBC> 10 x 109/L. Interim analysis CR 99. 3% and 100% in WBC< and > 10 groups. Very low relapse rate after a median f/u 2 years. • Paper # 15: Treatment of relapse of APL with ATO; European registry – Lengfelder E, et al. 69 pts in first relapse (25 molecular, 42 hematological, 2 isolated CNS/EMD). 2 nd molecular CR higher after induction with molecular relapse than hematological; Importance of monitoring • Paper #13: Is ara-C required in standard risk apl; Long-term f/u of European APL 2000 trial; Ades L, et al. 95 and 101 pts. CR in ara-C+: 99% and in no ara-C: 94%; CIR, EFS, and survival were all inferior in no ara-C group (p = 0. 013, p = 0. 01, and p = 0. 07, respectively)

Real-Life Decisions An Interactive Case-Based Symposium on the Management of Multiple Myeloma, Myelodysplastic Syndromes and Acute Myeloid Leukemias Friday, December 3, 2010 6: 30 PM – 9: 00 PM Orlando, Florida Moderator Neil Love, MD Faculty William I Bensinger, MD Pierre Fenaux, MD B Douglas Smith, MD Morie A Gertz, MD Ravi Vij, MD Farhad Ravandi, MD Copyright © 2011 Research To Practice. All rights reserved.