Oncology Highlights: Leukemia & Myelodysplastic Syndromes

Transcription

1 Oncology Highlights: Leukemia & Myelodysplastic Syndromes Jorge Cortes, MD Department of Leukemia The University of Texas, M.D. Anderson Cancer Center

2 Highlights of the Day Leukemia & MDS AML: The field is moving Optimal use of hypomethylating agents The rich (CML) get richer The incurable CLL

3 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

4 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

5 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

6 Outcome by FLT3 Status in Diploid AML Parameter % Response, or Median Survival [95% CI] FLT3-ITD FLT3-WT p CR rate 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

7 Overall Survival by FLT3 Status in Diploid AML FLT3-ITD vs WT FLT3 KD vs WT Santos et al. ASCO 2009; abst# 7015

8 Multivariate Analysis for OS in Diploid AML Characteristic HR (CI 95%) P Age 1.04 ( ) < Platelets 1.0 ( ) 0.22 Creatinine 1.67 ( ) < PS 1.32 ( ) 0.02 FLT3-ITD (vs WT) 2.64 ( ) < Santos et al. ASCO 2009; abst# 7015

9 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%

10 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: % 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 mg/m 2 x3 + Ara-C Cortes et al. Cancer 2001; 92: 7 68% CR with IDA mg/m 2 + Ara-C in pts with AML Flomenberg et al. ASH 2000 (Abstract 4633)

11 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

12 Anthracycline Dose Intensification in AML - Results Percentage 45 mg/m 2 N= mg/m 2 N=327 Evaluable CR Induction Death % Drop LVEF Grade 3/4 toxicity Similar Delivery of SCT Not impacted Fernandez et al. ASCO 2009; abst#7003

13 OS by Dose in Prognostic Categories Median OS in Months 45 mg/m 2 90 mg/m 2 p value Overall Age <55 yrs yrs CG Fav & Int Unfav FLT3 Positive Negative Fernandez et al. ASCO 2009; abst#7003

14 Daunorubicin vs Mitoxantrone vs Idarubicin in AML 2157 pts randomized by EORTC ( ) 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 MTZ IDA p=0.03 p=0.02 Allo SCT Auto SCT Vignetti et al, ASH 2003 (Abst 611)

15 Decitabine in Previously Untreated AML Age 60 Years 45 pts, median age 74 yrs (range, 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

16 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

17 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

18 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 ( ) Lubbert et al. Blood 2007; 110: abst# 300

19 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?

20 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) Int2-high (n=118) Rx naïve (n=147) /27 (37%) responders had a cytogenetic response Kantarjian et al. Cancer 2006

21 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

22 Dosing Schedules of Decitabine in MDS Study Schedule D mg/m 2 IV over 3 hrs, Q 8 hrs x 3 d, Q 6 weeks EORTC mg/m 2 IV over 4 hrs, Q 8 hrs x 3 d, Q 6 wks DACO-020 ID 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

23 Outcome with Decitabine in MDS by Schedule Overall Response, % 3-Day Decitabine Regimen D-0007 (N = 89) EORTC (N = 119) 5-Day Decitabine Regimen DACO-020 (N = 99) ID (N = 93) CR PR HI RBC Tf indep., % NA Median PFS, mo Median OS, mo Steensma et al. ASCO 2009; abst# 7011

24 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 Thrombocytopenia Febrile neutropenia Anemia Leukopenia Infections Hypertension Fatigue Dyspnea Pyrexia Pain in extremity Steensma et al. ASCO 2009; abst# 7011

25 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?

26 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 / mo MMR mo Duration MCyR mo PFS 81 Baccarani et al. Blood 2008; 112: abst# 450

27 Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure Parameter 100mg QD N=166 50mg BID N= mg QD N=163 70mg BID N=167 MCyR CCyR MMR months PFS months OS Interruption Reduction Stone et al. ASCO 2009 (Abst # 7007)

28 % not progressed Landmark Analysis of PFS by Response at 12 Months (All Doses) PFS at 36 months 12 months n % 95% CI MMR % CCyR 49 88% PCyR 67 81% Other/no CyR % MMR vs CCyR: P=0.30 MMR or CCyR vs PCyR: P= MMR, CCyR, or PCyR vs other/no CyR: P< 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)

29 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 Percent Stone et al. ASCO 2009 (Abst # 7007)

30 Grade 3/4 Cytopenia With Dasatinib 100 mg Once Daily (n=165) Neutropenia Thrombocytopenia Leukopenia Months Anemia Percent Stone et al. ASCO 2009 (Abst # 7007)

31 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 / 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)

32 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: ; 3 Quintas-Cardama et al. Cancer 2007; 109:

33 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

34 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)

35 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

36 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

37 ORR (%) 100 Ofatumumab in Refractory CLL Overall Response Rate 80 58%* 47%* 60 99% CI 40 *p< 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

38 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 Any FR FCR Wierda et al. ASCO 2009; abst# 7044

39 Patients (%) Patients (%) Improvements in Symptoms and Physical Findings ( 2 mo duration) with Ofatumumab 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

40 Patients (%) Patients (%) Improvements in Hematologic Parameters ( 2 mo duration) with Ofatumumab 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

41 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

42 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)

43 Questions?

44