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 For CR duration Cytogenetics Cytogenetics Age Age AHD AHD Secondary AML Secondary AML PS Slow response MDR 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 Worse RAS mutations 10% in subsets Worse in MLL gene PTD 6% 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) N (%) Cytogenetics 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 % Response, or Median Survival [95% CI] Parameter p FLT3-ITD FLT3-WT 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 Up to 2 or HDAC 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 Autologous SCT High Allogeneic Daunorubicin Busulfan IV 0.8 mg/kg Intermediate HSCT 45 mg/m 2 /d x 3 Every 6 hrs x16 doses or Cyclophosphamide CR 90 mg/m2/d x 3 60mg/kg/d x 2 + HiDAC x 2; Cytarabine 100 Favorable PBSC Harvest mg/m2/day x 7 Intermediate after 2 nd Indeterminate course Gemtuzumab Persistent AML: Ozogamicin 2 nd cycle: 6 mg/m 2 IV x 1 Daunorubicin 45mg/m 2 /d x3 Cytarabine 100mg/m2/d x7 Closed 10/2007 Fernandez et al. ASCO 2009; abst#7003
Anthracycline Dose Intensification in AML - Results Percentage 45 mg/m 2 90 mg/m 2 N=330 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 p value 45 mg/m 2 90 mg/m 2 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 “Positive” FLT3 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) DNR 50 mg/m 2 /Dx3 Allo SCT • Ara-C + VP16 + MTZ 12 mg/m 2 /Dx3 CT IDA 10 mg/m 2 /Dx3 Auto SCT • CR 70%, no difference by Rx Recovery time longer with IDA and MTZ (p<0.0001) • If no donor % 5-yr DFS Surv DNR 29 35 MTZ 38 44 IDA 37 44 p=0.03 p=0.02 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 No. of treatment days / cycle; (IV over cycles repeated Q 4-5 wks 1 hr) 20mg/m 2 Induction(s) 10 consecutive days Maintenance 1 st 20mg/m 2 5 consecutive days cycle Subsequent 5, 4, or 3 days (if ANC 20mg/m 2 <500/uL for ≥14 days) cycles 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 15 mg/m 2 IV over 3 hrs, Q 8 D-0007 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 20 mg/m 2 IV over 1 hr Q day x DACO-020 5 days, Q 4 wks 20 mg/m 2 IV over 1 hr Q day x ID03-0180 5 days, Q 4 wks Steensma et al. ASCO 2009; abst# 7011
Outcome with Decitabine in MDS by Schedule 3-Day Decitabine 5-Day Decitabine Regimen Regimen EORTC- D-0007 DACO-020 ID03-0180 06011 (N = 89) (N = 99) (N = 93) (N = 119) Overall 30 34 43 65 Response, % CR 9 13 15 37 PR 8 6 1 2 HI 13 15 27 26 RBC Tf 23 34 33 NA indep., % 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 3-Day Regimen 5-Day Regimen Adverse Event, n (%) (n = 197) (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 100mg 50mg 140mg 70mg Parameter QD BID QD BID N=166 N=166 N=163 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)
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