Oncology Highlights: Leukemia & Myelodysplastic Syndromes Jorge Cortes, MD Department of Leukemia The University of Texas, M.D. Anderson Cancer Center
Highlights of the Day Leukemia & MDS AML: The field is moving Optimal use of hypomethylating agents The rich (CML) get richer The incurable CLL
Prognostic Factors in AML For CR Cytogenetics Age AHD Secondary AML PS MDR For CR duration Cytogenetics Age AHD Secondary AML Slow response MDR WBC > 20 x 10 9 /L WBC > 20 x 10 9 /L High LDH
New Molecular Determinants in AML Marker Incidence Prognosis FLT3 mutations/itd 10-30% Worse CEBPA mutations 10% Better RAS mutations 10% Worse in subsets MLL gene PTD 6% Worse in intermediate CG NPM1 50% Better Kit mutations 30% Worse in CBF BAALC Worse
Prevalence of FLT3 Mutations in AML by Cytogenetic Group 481 patients with AML were analyzed treated at MDACC from 2003 to 2007 Median follow-up: 95 weeks (range 0-249) Cytogenetics N (%) FLT3-All FLT3-ITD FLT3-TKD CBF-AML 13 (20) 5 (8) 11 (17)* NK-AML 87 (32) 67 (25) 28 (10)** Poor Risk AML 11 (8) 3 (2) 8 (6) * 3 patients had double mutations ** 8 patients had double mutations Santos et al. ASCO 2009; abst# 7015
Outcome by FLT3 Status in Diploid AML Parameter % Response, or Median Survival [95% CI] FLT3-ITD FLT3-WT p CR rate 58 68 0.17 EFS, wk 19 [12-26] 41 [29-52] <0.001 OS, wk 33 [26-46] 90 [70-NR] <0.001 No difference in diploid FLT3 KD vs FLT3 WT No difference in CR, EFS or OS in CBP or poor risk cytogenetics (FLT3 ITD vs FLT3 WT) Santos et al. ASCO 2009; abst# 7015
Overall Survival by FLT3 Status in Diploid AML FLT3-ITD vs WT FLT3 KD vs WT Santos et al. ASCO 2009; abst# 7015
Multivariate Analysis for OS in Diploid AML Characteristic HR (CI 95%) P Age 1.04 (1.02-1.05) < 0.001 Platelets 1.0 (0.99-1.001) 0.22 Creatinine 1.67 (1.30-2.13) < 0.001 PS 1.32 (1.04-1.68) 0.02 FLT3-ITD (vs WT) 2.64 (1.84-3.80) < 0.001 Santos et al. ASCO 2009; abst# 7015
Standard Therapy AML Induction Ida 12 x 3 Ara-C 100 x 7 or HDAC Up to 2 courses Post CR 1-6 consolidation courses Results CR rate 30-90% Potential cure <5 - >50%
High-Dose Anthracycline in AML 20% CR with DNR 60 mg/m 2 /d x 5 days among pts with relapse AML Weil et al. Cancer Res 1973; 33: 921 3/6 previously treated pts responded (2 CR, 1 PR) with DNR 180 mg/m 2 x 2 Greene et al. Cancer 1972; 30: 1419 8% previously treated acute leukemia pts achieved CR with liposomal DNR (DNX) MTD 150 mg/m 2 /d x3 Cortes et al. Invest New Drugs 1999; 17: 81 40% in response rate (CR 29%) refractory/ relapsed AML with DNX 75-150 mg/m 2 x3 + Ara-C Cortes et al. Cancer 2001; 92: 7 68% CR with IDA 12-19 mg/m 2 + Ara-C in pts with AML Flomenberg et al. ASH 2000 (Abstract 4633)
Anthracycline Dose Intensification in AML ECOG Protocol E1900:Schema Risk Allocation Daunorubicin 45 mg/m 2 /d x 3 or 90 mg/m2/d x 3 + Cytarabine 100 mg/m2/day x 7 High Intermediate CR Persistent AML: 2 nd cycle: Daunorubicin 45mg/m 2 /d x3 Cytarabine 100mg/m2/d x7 Favorable Intermediate Indeterminate Allogeneic HSCT HiDAC x 2; PBSC Harvest after 2 nd course Autologous SCT Busulfan IV 0.8 mg/kg Every 6 hrs x16 doses Cyclophosphamide 60mg/kg/d x 2 Gemtuzumab Ozogamicin 6 mg/m 2 IV x 1 Closed 10/2007 Fernandez et al. ASCO 2009; abst#7003
Anthracycline Dose Intensification in AML - Results Percentage 45 mg/m 2 N=330 90 mg/m 2 N=327 Evaluable 89 88 CR 57 71 Induction Death 4.5 5.5 % Drop LVEF 0.3 1.6 Grade 3/4 toxicity Similar Delivery of SCT Not impacted Fernandez et al. ASCO 2009; abst#7003
OS by Dose in Prognostic Categories Median OS in Months 45 mg/m 2 90 mg/m 2 p value Overall 15.7 23.7 0.003 Age <55 yrs 16.5 28.6 0.002 55 yrs 12.6 16.3 0.63 CG Fav & Int 20.7 34.3 0.004 Unfav 10.2 10.4 0.45 FLT3 Positive 10.2 15.2 0.091 Negative 18.9 28.6 0.014 Fernandez et al. ASCO 2009; abst#7003
Daunorubicin vs Mitoxantrone vs Idarubicin in AML 2157 pts randomized by EORTC (1993-1999) Ara-C + VP16 + CR 70%, no difference by Rx Recovery time longer with IDA and MTZ (p<0.0001) If no donor DNR 50 mg/m 2 /Dx3 MTZ 12 mg/m 2 /Dx3 CT IDA 10 mg/m 2 /Dx3 DFS % 5-yr Surv DNR 29 35 MTZ 38 44 IDA 37 44 p=0.03 p=0.02 Allo SCT Auto SCT Vignetti et al, ASH 2003 (Abst 611)
Decitabine in Previously Untreated AML Age 60 Years 45 pts, median age 74 yrs (range, 60-84 yrs) 20 (44%) secondary AML; 14 (31%) complex karyotype Daily dose of decitabine (IV over 1 hr) No. of treatment days / cycle; cycles repeated Q 4-5 wks Induction(s) 20mg/m 2 10 consecutive days Maintenance 1 st cycle Subsequent cycles 20mg/m 2 20mg/m 2 5 consecutive days 5, 4, or 3 days (if ANC <500/uL for 14 days) Blum et al. ASCO 2009; abst# 7010
Response to Decitabine in Elderly AML No (%), or Median [range] Overall response (CR+CRi+Marrow CR) 28 (62) CR 21 (47) Induction cycles (responders) 2 [1-5] Total cycles 4 [1-15] Death within 8 weeks 7 (15) Febrile neutropenia in induction 34 (76) Febrile neutropenia in maintenance 0 (0) 19/21 CR patients achieved CRi initially, and then went on to achieve full CR with a median of one additional cycle (range, 1-3) Blum et al. ASCO 2009; abst# 7010
Response to Decitabine by CG Risk Group in Elderly AML CBF N=1 1 CR Normal N=19 9 CR, 2 CRi Complex N=14 7 CR, 2 CRi Other N=11 4 CR, 3 CRi CG CR in 9/11 (82%) pts with abnormal karyotype that achieved CR Blum et al. ASCO 2009; abst# 7010
Decitabine in AML 155 pts, median age 72.5 yrs (56-85); poor-risk CG 49% DAC 135 mg/m2 IV over 72 hours, Q6 weeks x 4 cycles (+ ATRA 45 mg/m2 in cycle #2 in SD) CR 15%, PR 10%; OR 54% Median OS 5.5 mos (0.3 38+) Lubbert et al. Blood 2007; 110: abst# 300
What Does This Mean? AML is a syndrome, not a disease Workup should include molecular and cytogenetic markers Molecular markers impact prognosis and might become therapeutic targets FLT3 inhibitors: sorafenib, CEP701, PKC-412, AC220 Dose intensification is important (younger) Includes ara-c What anthracycline to use? Decitabine useful in elderly AML Schedule?
Decitabine vs Supportive Care in MDS 170 pts randomized: DAC 45 mg/m 2 /d x3 vs SC Median age 70 y; prior Rx 28%; IPSS int2-high 70% Parameter DAC SC p value %CR+PR 9+8* 0 <.001 TTE (mos) Overall (n=170) 12.1 7.8.16 Int2-high (n=118) 9.3 5.2.039 Rx naïve (n=147) 12 5.2.028 11/27 (37%) responders had a cytogenetic response Kantarjian et al. Cancer 2006
DAC in MDS - CR by Treatment Arm Schedule No. CR/Total (%) 20 mg/m 2 IV x 5 25/64 (39) 20 mg/m 2 SQ x 5 3/14 (21) 10 mg/m 2 IV x 10 4/17 (24) Total 32/95 (34) Kantarjian et al. Blood 2007; 109: 52-7
Dosing Schedules of Decitabine in MDS Study Schedule D-0007 15 mg/m 2 IV over 3 hrs, Q 8 hrs x 3 d, Q 6 weeks EORTC-06011 15 mg/m 2 IV over 4 hrs, Q 8 hrs x 3 d, Q 6 wks DACO-020 ID03-0180 20 mg/m 2 IV over 1 hr Q day x 5 days, Q 4 wks 20 mg/m 2 IV over 1 hr Q day x 5 days, Q 4 wks Steensma et al. ASCO 2009; abst# 7011
Outcome with Decitabine in MDS by Schedule Overall Response, % 3-Day Decitabine Regimen D-0007 (N = 89) EORTC- 06011 (N = 119) 5-Day Decitabine Regimen DACO-020 (N = 99) ID03-0180 (N = 93) 30 34 43 65 CR 9 13 15 37 PR 8 6 1 2 HI 13 15 27 26 RBC Tf indep., % 23 34 33 NA Median PFS, mo 7.3 6.6 8.1 9.2 Median OS, mo 12.8 10.1 17.8 20.3 Steensma et al. ASCO 2009; abst# 7011
Grade 3/4 Adverse Events by Decitabine Schedule in MDS Adverse Event, n (%) 3-Day Regimen (n = 197) 5-Day Regimen (n = 192) G3 G4 G3 G4 Neutropenia 5 37 4 15 Thrombocytopenia 17 29 3 8 Febrile neutropenia 20 5 20 2 Anemia 12 2 7 4 Leukopenia 4 9 1 1 Infections 35 15 33 8 Hypertension 15 0 0 0 Fatigue 6 4 12 1 Dyspnea 5 2 4 1 Pyrexia 5 1 3 0 Pain in extremity 1 0 5 0 Steensma et al. ASCO 2009; abst# 7011
What Does This Mean? Hypomethylating agents are standard therapy in MDS (all stages) High response rate (mostly PR, HI) All patients with MDS should be offered therapy 3-day schedule standard 5-day schedule might improve outcome, tollerance Optimal pharmacodynamically Need randomized trial?
Dasatinib in CML Chronic Phase After Imatinib Failure (START-C) 387 pts; IM resistance 74%; dasatinib 70 mg BID; minimum follow-up 24 mo Parameter Percent MCyR / CCyR 60 / 51 IM Resistant 55 / 44 IM Intolerant 82 / 78 24-mo MMR 40 24-mo Duration MCyR 88 24-mo PFS 81 Baccarani et al. Blood 2008; 112: abst# 450
Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure Parameter 100mg QD N=166 50mg BID N=166 140mg QD N=163 70mg BID N=167 MCyR 63 61 63 61 CCyR 50 49 50 53 MMR 39 40 40 40 24-months PFS 73 72 60 67 24-months OS 87 84 84 80 Interruption 62 72 79 77 Reduction 39 46 62 62 Stone et al. ASCO 2009 (Abst # 7007)
% not progressed Landmark Analysis of PFS by Response at 12 Months (All Doses) 100 90 80 70 60 50 40 30 20 10 PFS at 36 months 12 months n % 95% CI MMR 119 94% 89 98 CCyR 49 88% 78 98 PCyR 67 81% 71 91 Other/no CyR 128 54% 43 64 MMR vs CCyR: P=0.30 MMR or CCyR vs PCyR: P=0.0065 MMR, CCyR, or PCyR vs other/no CyR: P<0.0001 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months Patients not assessed at the landmark (±1.5 months) or with Ph( ) BCR-ABL(+) disease were excluded Progression: WBC, loss of CHR or MCyR, 30% in Ph(+), AP/BP, or death Stone et al. ASCO 2009 (Abst # 7007)
Drug-Related Non-hematologic Side Effects with Dasatinib 100 mg Once Daily (n=165) Headache Diarrhea Fatigue Dyspnea Superficial edema Pleural effusion Musculoskeletal pain Nausea Rash Myalgia All grades 24 months 36 months Grade 3/4 24 months 36 months No pleural effusions were grade 4 Infection Arthralgia Abdominal pain 0 20 40 60 Percent Stone et al. ASCO 2009 (Abst # 7007)
Grade 3/4 Cytopenia With Dasatinib 100 mg Once Daily (n=165) Neutropenia Thrombocytopenia Leukopenia Months Anemia 12 24 36 0 20 40 60 Percent Stone et al. ASCO 2009 (Abst # 7007)
Nilotinib in CML Chronic Phase Post Imatinib Failure 321 pts with imatinib resistance (71%) or intolerance (29%) Median age 58 yrs; median exposure 19 mo Nilotinib 400mg PO BID 6 mos Outcome Percent - CHR 76 - MCyR / CCyR 59 / 44 Resistant 56 / 41 Intolerant 65 / 51-24-month OS / PFS 88 / 64 Median dose intensity 790 mg/d Grade 3-4 plts 31%, neuts 31%; lipase elevation 17% (pancreatitis <1%), bilirubin 8% Kantarjian et al. Blood 2008 (Abst# 3238)
Omacetaxine for CML with T315I Bcr-Abl mutations in ~50% of patients with imatinib failure T315I mutation represents up to 20% of mutations in this population Available TKIs ineffective against T315I Poor prognosis for patients with T315I 1 Omacetaxine inhibits protein synthesis and induces apoptosis 2 Effective in vitro against CML T315I 2 Clinical activity after imatinib failure 3 1 Nicolini et al. ASH 2008; Abstract# 188; 2 Chen et al. Cancer Res 2006; 66: 9059-66; 3 Quintas-Cardama et al. Cancer 2007; 109: 248-55
Omacetaxine for CML with T315I Response to Therapy No. (%) Response CP N=40 AP N=16 BP N=10 Hematologic 34 (85) 8 (50) 4 (40) CHR 34 (85) 5 (31) 2 (20) HI NA 2 (13) 1 (10) RCP NA 1 (6) 1 (10) Cytogenetic 11 (28) 1 (6) - MCyR 6 (15) - - CCyR 4 (10) 1 (6) - PCyR 2 (5) - - Minimal 5 (13) - - Data independently adjudicated by Data Monitoring Committee Cortes et al. ASCO 2009; abst# 7008
What Does This Mean? 2 nd generation TKI are effective and overall well tolerated in CML after imatinib failure Need to adequately monitor and optimize therapy more important than ever Once daily schedule optimal for CML-CP (and AP/BP) after imatinib failure Lack of MCyR at 12 months constitutes failure (depending on clinical setting) Options available for T315I CML SCT should be considered Omacetaxine clinically effective Others coming (DCC2036, AP24534, XL228, PHA739348)
Ofatumumab binding site Ofatumumab: A New Tool for CLL Rituximab binding site Human CD20 monoclonal antibody (mab) 1,2 Binds to small loop of CD20 Potent lysis of B cells More effective in vitro CDC versus rituximab Effective CDC of cells with low CD20 expression, including in CLL cells Promising activity in pilot CLL study: ORR 50% in high-dose group (N=26) 3 1 Teeling et al. J Immunol 2006; 177: 362; 2 Teeling et al. Blood 2004; 104: 1793; 3 Coiffier et al. Blood 2008; 111: 1094
Ofatumumab in Refractory CLL 138 pts with rafractory CLL: FA-ref (n=59): Fludarabine ( 2 cycles) and alemtuzumab ( 12 doses) refractory BF-ref (n=79): Fludarabine refractory ( 2 cycles) and large lymph nodes (>5 cm) Schedule: 2000mg IV weekly x 8 (1 st dose 300mg), then every 4 weeks x4) Patient characteristics FA-ref BF-ref Median age, yrs (range) 64 (41 86) 62 (43 84) Rai stage III / IV, n (%) 32 (54) 55 (70) Median prior Rx, n (range) 5 (1 14) 4 (1 16) Prior rituximab, n (%) 35 (59) 43 (54) Lymph nodes >5 cm, n (%) 55 (93) 79 (100) Kipps et al. ASCO 2009; abst# 7043
ORR (%) 100 Ofatumumab in Refractory CLL Overall Response Rate 80 58%* 47%* 60 99% CI 40 *p<0.0001 versus H 0 20 H 0 : ORR = 15% 0 FA-ref (N=59) BF-ref (N=79) All PRs except one CR in BF-ref group *The null hypothesis of ORR=15% was tested against the corresponding two-sided alternative hypothesis ORR 15% using an exact test. Kipps et al. ASCO 2009; abst# 7043
Ofatumumab in Refractory CLL Response by Prior Rituximab Exposure Prior RTX N ORR, % FA-ref Median PFS, mo N ORR, % BF-ref Median PFS, mo None 24 63 7.1 36 50 6.4 Any 35 54 5.5 43 44 5.5 FR 18 50 5.5 27 52 5.6 FCR 16 50 4.6 16 44 5.6 Wierda et al. ASCO 2009; abst# 7044
Patients (%) Patients (%) Improvements in Symptoms and Physical Findings ( 2 mo duration) with Ofatumumab 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 FA-ref Constitutional Symptoms (n=31) BF-ref Constitutional Symptoms (n=46) Lymphadenopathy (n=55) Lymphadenopathy (n=74) Hepatomegaly (n=18) Hepatomegaly (n=21) Complete Resolution 50% Improvement Splenomegaly (n=30) Splenomegaly (n=46) Kipps et al. ASCO 2009; abst# 7043
Patients (%) Patients (%) Improvements in Hematologic Parameters ( 2 mo duration) with Ofatumumab 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 FA-ref 5 ANC <1.5 (n=19) to >1.5 x 10^9/L BF-ref 29 ANC <1.5 (n=17) to >1.5 x 10^9/L 31 HGB <11 (n=26) to >11 g/dl 26 HGB <11 (n=42) to >11 g/dl Improvement or Normalization 41 PLT <100 (n=29) to >50% increase or >100 x10^9/l 39 PLT <100 (n=44) to >50% increase or >100 x10^9/l Kipps et al. ASCO 2009; abst# 7043
Ofatumumab in Refractory CLL Overall Survival by Response Landmark analysis 1 at Week 12* FA-ref BF-ref Median not reached Median not reached Median 9.8 mo Median 10.2 mo *Analysis included patients who were alive at the Week 12 time point. 1. Anderson et al. J Clin Oncol 2008; 26: 3913 Kipps et al. ASCO 2009; abst# 7043
What Does This Mean? Improved CLL therapy Ofatumumab: effective new agent for CLL Little cross-resistance with Rituximab Expect combination therapy Role of new agents in frontline therapy Cure for CLL is here (almost)
Questions? jcortes@mdanderson.org 713-794-5783