Leukemia & Myelodysplastic Syndromes Jorge Cortes, MD - - PowerPoint PPT Presentation

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 109/L WBC > 20 x 109/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] 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

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

Multivariate Analysis for OS in Diploid AML

Santos et al. ASCO 2009; abst# 7015

Standard Therapy AML

• Induction Ida 12 x 3

Ara-C 100 x 7

• r HDAC
• Post CR

1-6 consolidation courses

• Results

CR rate 30-90% “Potential cure” <5 - >50%

Up to 2 courses

High-Dose Anthracycline in AML

• 20% CR with DNR 60 mg/m2/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/m2 x 2

Greene et al. Cancer 1972; 30: 1419

• 8% previously treated acute leukemia pts achieved

CR with liposomal DNR (DNX)

– MTD 150 mg/m2/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/m2 x3 + Ara-C

Cortes et al. Cancer 2001; 92: 7

• 68% CR with IDA 12-19 mg/m2 + Ara-C in pts with

AML

Flomenberg et al. ASH 2000 (Abstract 4633)

Anthracycline Dose Intensification in AML ECOG Protocol E1900:Schema

Gemtuzumab Ozogamicin 6 mg/m2 IV x 1 Daunorubicin 45 mg/m2/d x 3

• r

90 mg/m2/d x 3

+

Cytarabine 100 mg/m2/day x 7 Allogeneic HSCT CR High Intermediate HiDAC x 2; PBSC Harvest after 2nd course Autologous SCT

Busulfan IV 0.8 mg/kg Every 6 hrs x16 doses Cyclophosphamide 60mg/kg/d x 2

Favorable Intermediate Indeterminate

Closed 10/2007

Risk Allocation Persistent AML: 2nd cycle: Daunorubicin 45mg/m2/d x3 Cytarabine 100mg/m2/d x7

Fernandez et al. ASCO 2009; abst#7003

Anthracycline Dose Intensification in AML - Results

Percentage 45 mg/m2 N=330 90 mg/m2 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/m2 90 mg/m2 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

% 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)

DNR 50 mg/m2/Dx3 Allo SCT MTZ 12 mg/m2/Dx3 CT IDA 10 mg/m2/Dx3 Auto SCT

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/m2 10 consecutive days Maintenance 1st cycle 20mg/m2 5 consecutive days Subsequent cycles 20mg/m2 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)

• 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/m2/d x3 vs SC
• Median age 70 y; prior Rx 28%; IPSS int2-high 70%
• Parameter

DAC SC p value

–%CR+PR

9+8* <.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/m2 IV x 5 25/64 (39) 20 mg/m2 SQ x 5 3/14 (21) 10 mg/m2 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/m2 IV over 3 hrs, Q 8 hrs x 3 d, Q 6 weeks EORTC-06011 15 mg/m2 IV over 4 hrs, Q 8 hrs x 3 d, Q 6 wks DACO-020 20 mg/m2 IV over 1 hr Q day x 5 days, Q 4 wks ID03-0180 20 mg/m2 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

3-Day Decitabine Regimen 5-Day Decitabine Regimen D-0007 (N = 89) EORTC- 06011 (N = 119) DACO-020 (N = 99) ID03-0180 (N = 93) Overall Response, % 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 Fatigue 6 4 12 1 Dyspnea 5 2 4 1 Pyrexia 5 1 3 Pain in extremity 1 5

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 Months 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 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 3 6 9 12 15 18 21 24 27 30 33 36 39 42 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)

36 months 24 months Grade 3/4 36 months 24 months All grades

No pleural effusions were grade 4 Headache Diarrhea Fatigue Dyspnea Superficial edema Pleural effusion Musculoskeletal pain Nausea Rash Myalgia Infection Arthralgia Abdominal pain

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 Anemia

20 40 60 Percent Months 36 24 12

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

Kantarjian et al. Blood 2008 (Abst# 3238)

• Median dose intensity 790 mg/d
• Grade 3-4 ↓ plts 31%, neuts 31%; lipase elevation

17% (pancreatitis <1%), bilirubin 8%

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 T315I1
• Omacetaxine inhibits protein synthesis and

induces apoptosis2

• Effective in vitro against CML T315I2
• Clinical activity after imatinib failure3

1 Nicolini et al. ASH 2008; Abstract# 188; 2 Chen et al. Cancer Res 2006; 66: 9059-66; 3Quintas-Cardama et al. Cancer 2007; 109: 248-55

Omacetaxine for CML with T315I Response to Therapy

Data independently adjudicated by Data Monitoring Committee

Response

• No. (%)

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)

• Cortes et al. ASCO 2009; abst# 7008

What Does This Mean?

• 2nd 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: A New Tool for CLL

• 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

1Teeling et al. J Immunol 2006; 177: 362; 2Teeling et al. Blood 2004; 104: 1793; 3Coiffier et al. Blood 2008; 111: 1094

Ofatumumab binding site Rituximab binding site

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 (1st 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

Ofatumumab in Refractory CLL Overall Response Rate

20 40 60 80 100 FA-ref (N=59) BF-ref (N=79) ORR (%)

58%* 47%*

99% CI H0: ORR = 15%

*The null hypothesis of ORR=15% was tested against the corresponding two-sided alternative hypothesis ORR≠15% using an exact test.

• All PRs except one

CR in BF-ref group

*p<0.0001 versus H0

Kipps et al. ASCO 2009; abst# 7043

Ofatumumab in Refractory CLL Response by Prior Rituximab Exposure

Prior RTX FA-ref BF-ref N ORR, % Median PFS, mo N ORR, % 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

Improvements in Symptoms and Physical Findings (≥ 2 mo duration) with Ofatumumab

FA-ref

10 20 30 40 50 60 70 80 90 100

Constitutional Symptoms (n=31) Lymphadenopathy (n=55) Hepatomegaly (n=18) Splenomegaly (n=30)

Patients (%)

BF-ref

10 20 30 40 50 60 70 80 90 100

Constitutional Symptoms (n=46) Lymphadenopathy (n=74) Hepatomegaly (n=21) Splenomegaly (n=46)

Patients (%)

≥ 50% Improvement Complete Resolution

Kipps et al. ASCO 2009; abst# 7043

Improvements in Hematologic Parameters (≥ 2 mo duration) with Ofatumumab

FA-ref

5 41 31 10 20 30 40 50 60 70 80 90 100

ANC <1.5 (n=19) to >1.5 x 10^9/L HGB <11 (n=26) to >11 g/dL PLT <100 (n=29) to >50% increase or >100 x10^9/L

Patients (%)

BF-ref

29 39 26 10 20 30 40 50 60 70 80 90 100

ANC <1.5 (n=17) to >1.5 x 10^9/L HGB <11 (n=42) to >11 g/dL PLT <100 (n=44) to >50% increase or >100 x10^9/L

Patients (%)

Improvement or Normalization

Kipps et al. ASCO 2009; abst# 7043

*Analysis included patients who were alive at the Week 12 time point.

• 1. Anderson et al. J Clin Oncol 2008; 26: 3913

Landmark analysis1 at Week 12*

Ofatumumab in Refractory CLL Overall Survival by Response

FA-ref BF-ref

Median not reached Median 9.8 mo Median not reached Median 10.2 mo

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