What is New in Leukemia & MPN in 2011?

Transcription

1 Leukemia Update What Did We Learn from ASCO 211? Jorge Cortes, MD Department of Leukemia MD Anderson Cancer Center Houston, Texas What is New in Leukemia & MPN in 211? Cool things happening in MPN The rich (CML) get richer CLL: not only alkylators Acute leukemias: one step at a time 1

2 JAK2 (and Other) Mutations in MPD Estimated 6,328 new cases of MPD in 24 JAK2 V617F mutations first reported in 25 Prevalence in MPD: PV 95%, ET 5-6%, MF 5-6% JAK2 exon 12 mutations in PV, MPL W515L/K in MF Cytokine-independent independent cell proliferation Impact on survival, leukemic transformation and thrombotic events controversial 1,2 1 Barosi et al. Blood 27; 11: 43-6; 2 Tefferi et al. Leukemia 28; 22: JAK2 Inhibitors in the clinic Agent (Company) CEP71 (Cephalon) XL19 (Exelixis) TG1348 (TargeGen) INCB18424 (Incyte) Diseases and studies MF: phase II ET/PV: phase II MF: phase I - stopped MF: phase I/II MF: phase I/II, III ET/PV: phase II Biological Target JAK2 and FLT3 JAK2 JAK2 CYT387 MF: phase I/II JAK2 (YM BioSciences) SB1518 (S*Bio) AZD148 (AstraZeneca) MF: phase I MF: phase I JAK1 and JAK2 JAK2 and FLT3 JAK2 2

3 Phase I/II Study of INCB18424 in Myelofibrosis Potent, oral Jak1 and Jak2 inhibitor 153 patients treated for a median of 14.7 months Doses 1-5 mg BID & 5-2 mg QD DLT: Thrombocytopenia MTD: 25 mg BID & 1 mg QD 52% with 5% reduction in splenomegaly lasting 12 months Rapid imporvement in weight loss, fatigue, night sweats, and pruritus Significant reduction of circulating inflammatory cytokines Verstovsek et al. NEJM 21; 363: Phase 3 Study of Ruxolitinib (INCB18424) in Myelofibrosis - COMFORT-I PMF or PPV-MF, or PET-MF Intermediate-2 or High Risk by IWG-MRT Palpable spleen 5 cm Platelet count 1 x1 9 /L JAK2 V617F positive or negative 1:1 R a n d o m i z e Ruxolitinib 15 or 2 mg BID Placebo Spleen volume by MRI every 12 weeks Daily assessment of symptoms from Day -7 through week 24 Cross over to ruxolitinib was possible COMFORT: COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment; IWG-MRT, International Working Group for Myelofibrosis Research and Treatment; PET-MF, post-essential thrombocythemia-myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera-myelofibrosis. Verstovsek et al. ASCO 211; abstract #65 3

4 COMFORT I Primary Endpoint: % of Patients With 35% Decrease in Spleen Volume at Week 24 (ITT) Responders (%) P <.1 Odds ratio (95% CI) (17.97, 15) 87% still on Ruxolitinib Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as non-responders.7 Ruxolitinib (n = 155) Placebo (n = 153) Verstovsek et al. ASCO 211; abstract #65 COMFORT I - Proportion of Patients with 5% Reduction in Total Symptom Score Over Time 6 5 Ruxolitinib Placebo % of Patients Weeks From Day 1 Patients who discontinued or had missing data were considered non-responders Verstovsek et al. ASCO 211; abstract #65 4

5 COMFORT I - Change in Individual Symptoms ine Mean % Change From Baseli Ruxolitinib Placebo n=1 n=86 n=96 n=9 n=77 n=89 n=97 n=124 n=19 n=122 n=13 n=98 n=18 n= Abdominal discomfort -1 Pain under left ribs Early satiety Night sweats Itching 37.7 Bone/muscle pain Inactivity Worsening Imp provement For all individual symptoms above, comparisons between ruxolitinib- and placebotreated groups were highly statistically significant (P <.1) Verstovsek et al. ASCO 211; abstract #65 COMFORT-I Non-hematologic Adverse Events Ruxolitinib, n = 155 % With Adverse Event Placebo, n = 151 % With Adverse Event Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Fatigue Diarrhea Peripheral edema Ecchymosis 19 9 Dyspnea Dizziness Nausea Headache 15 5 Constipation Vomiting Pain in extremity Insomnia 12 1 Arthralgia Pyrexia Abdominal pain AEs observed in at 1% of Ruxolitinib-treated patients Verstovsek et al. ASCO 211; abstract #65 5

6 COMFORT I - Hematology Effects Ruxolitinib, n = 155 Placebo, n = 151 Grade 3 % Grade 4 % Grade 3 % Grade 4 % Hemoglobin Platelets Neutrophils *Patients are included at their worst on study grade regardless of whether this represents a change from their baseline. Grade 3 and grade 4 anemia and thrombocytopenia were more common in those with higher baseline grade Discontinuation of treatment because of anemia and thrombocytopenia was rare (1 patient in each treatment group for each event) Newly transfusion independent by IWG criteria: Ruxolitinib 41%, placebo 47% Verstovsek et al. ASCO 211; abstract #65 COMFORT I - Mean Hemoglobin and Red Blood Cell Products Over Time 12 Mean Hemoglobin ± SEM (g/l) 11 1 Ruxolitinib Placebo Study Week 5 Percent of Patients Receiving RBC Products in Prior 4 Weeks Weeks From Day 1 Verstovsek et al. ASCO 211; abstract #65 6

7 uction 35% spleen volume red % With COMFORT-II Efficacy Results (ITT) 219 pts randomized 2:1 to Ruxolitinib vs best available therapy (BAT) Primary Endpoint Ruxolitinib 95% CI: 21.3, 36.6 P < % n = 41 BAT 95% CI:., 5. Ruxolitinib BAT Week 48 Median time to response, weeks 44/69 (64%) responders did so at 12 weeks Spleen Volume (MRI or CT) Ruxolitinib BAT Harrison et al. EHA 211 Phase 2 Study of SB1518 in Patients with Myelofibrosis Phase I study identified 4 mg QD as RP2D; 43% responded ( 5% reduction splenomegaly) (Seymour et al EHA 21- #1348) 34 pts with MF (primary or post PV/ET) treated with 4 mg daily Splenomegaly 5 cm BCM No minimum neutrophil or platelet requirement (53% baseline thrombocytopenia) Splenomegaly assessed by PE every 4 weeks, by MRI every 12 weeks Mesa et al. ASCO 211; abstract #6515 7

8 Spleen Response with SB1518 in MF By Physical Exam By MRI % Change in Spleen Size by PE /34 (44%) patients with 25 IWG MRT Response 2 IWG-MRT Response Maximum Change per Subject % Change in Spleen Volume by MRI /34 (41%) 25% reduction (IWG-MRT) 11/34 (32%) 35% reduction Maximum Change per Subject Baseline spleen size (cm BCM) 16; 11-15; 5-1 Baseline spleen volume (mm 3 ) 41; 21-4; 2 Mesa et al. ASCO 211; abstract #6515 Hematologic Effects of SB1518 in MF an ± SEM) Hemoglobin Level, g/l (mea Time on Study No increase in transfusion requirements and no dose reduction due to anemia 1/9 patients transfusion dependent at baseline became transfusion independent 9% thrombocytopenia (3% grade 3) No dose reductions for myelosuppression Mesa et al. ASCO 211; abstract #6515 8

9 Effect of SB1518 in MF-related Symptoms Mean reduction in Symptom Score * Only pts with baseline 4 (MF-SAF) (N) For paired values Abdominal Pain Bone Pain Early Satiety Fatigue (worst) Inactivity Night Sweats Pruritus C4D1 C7D1 C1D1 * = No change in mean symptom score Symptom Mesa et al. ASCO 211; abstract #6515 Phase I/II Study of CYT387 for Patients With Myelofibrosis MF Int-1 with hepato/splenomegaly, or Int-2 or high risk ANC.5 x1 9 /L, platelets 5 x1 9 /L 3 stages: Phase I (n= 21) - dose finding Dose confirmation (n= 39) - 15mg & 3mg QD Dose expansion (n= 95) - Multicenter, 15mg & 3 mg QD, and 15 mg BID Median follow-up 1.1 mo ( mo) Median age 64 y (34 85 y) 88% still on study Pardanani et al. ASCO 211; abstract #6514 9

10 Spleen Response to CYT387 Maximal change from baseline (Dose escalation and confirmation phases) 25% decrease: 92% 5% decrease: 62% 1% decrease: 25% Pardanani et al. ASCO 211; abstract #6514 Hematologic Effects of CYT387 in MF Overall anemia response (IWG-MRT): 5% Transfusion independence rate 12 weeks: 58% Grade 3-4 thrombocytopenia 28%, neutropenia 5%, anemia 2% Pardanani et al. ASCO 211; abstract #6514 1

11 CCC CCC What Does This Mean? JAK2 inhibition: effective strategy in MF What is the ideal endpoint? Remaining i questions? Improvement of hematopoiesis Will natural history of disease change? JAK2 effect vs JAK1 or cytokine effect How specific should an inhibitor be? Late effects of prolonged JAK2 inhibition Role in PV and ET Role in other hematologic malignancies How critical is JAK2 to pathophysiology of MF Overall Survival With Ruxolitinib vs Placebo 1..8 C C C C C C CC C C C C C C C C C CC C CC C CC C CCC CCC CCCCCC CCC CCC CCC C C CC CC C CCC CCC CCC C C C CC C C C C C C CCC C C CC CCC C CCC C C C C C CCC C C C C C C C C C CC CC CCC CC C CC C C CC CC C CCC C CC Probability of Survival Number (%) of Events Hazard Ratio =.67 LogRank P value =.3268 Ruxolitinib Placebo 1 (6.5) 14 (9.1) Number of Patients at Risk Ruxolitinib Number of Patients at Risk Placebo Ruxolitinib C CC Ruxolitinib censored Placebo C C C Placebo censored Weeks Verstovsek et al. ASCO 211; abstract #65 11

12 Results with Imatinib in Early CP CML The IRIS Trial at 8-Years 34 (55%) patients on imatinib on study Projected results at 8 years: CCyR 83% 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP Event-free survival 81% Transformation-free survival 92% If MMR at 12 mo: 1% Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%,.9%,.5%, %, %, &.4% Deininger et al; Blood 29; 114: Abst# 1126 Probability Long-Term Outcome With Imatinib in ECP CML (ITT) Survival PFS CHR EFS Loss of MCyR 63% (88% per IRIS definition) Time From Start of Imatinib Therapy (months) EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or WBC, failure to achieve MCyR, intolerance de Lavallade H et al. J Clin Oncol. 28; 26:

13 Nilotinib vs Imatinib in Newly Dx CML (ENESTnd) N = centers 35 countries R A N D O M I Z E D * Primary endpoint: Key secondary endpoint: Other endpoints: Nilotinib 3 mg BID (n = 282) Nilotinib 4 mg BID (n = 281) Imatinib 4 mg QD (n = 283) Follow-up 5 years MMR at 12 months Durable MMR at 24 months CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up *Stratification by Sokal risk score Larson et al. ASCO 21; abstract #6511 Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML 846 pts randomized to nilotinib 3 mg BID (n=282), nilotinib 4 mg BID (n=281), or imatinib 4 mg QD (n=283) Minimum follow-up 24 mo Outcome Nil 3 Nil 4 IM 4 % CCyR* % MMR* % BCR-ABL.32%* % discontinued treatment New mutation (No.) * by 24 months Larson et al. ASCO 21; abstract #

14 Percentage Number of Patients ENESTnd - Progression to AP/BC Nilotinib 3 mg BID Nilotinib 4 mg BID Imatinib 4 mg QD P =.59 P = P =.3 P =.89.7% 1.1% 4.2%.7% 1.8% 6.% Including Clonal Evolution Progression events after discontinuation of treatment occurred in an additional 7, 2, and 6 patients (excluding clonal evolution) in nilotinib 3 mg BID, nilotinib 4 mg BID, and imatinib arms, respectively; progression within 6 days of discontinuation occurred in 1, 1, and 2 of these patients across respective arms 5 17 Larson et al. ASCO 21; abstract #6511 Dasatinib Versus Imatinib Study In Treatmentnaïve CML (DASISION). Trial Design N= centers 26 countries Dasatinib 1 mg QD (n=259) Randomized* Imatinib 4 mg QD (n=26) *Stratified by Hasford risk score Follow-up 5 years Primary endpoint: Confirmed CCyR by 12 months Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival Kantarjian et al. ASCO 211; abstract #651 14

15 Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML 519 pts randomized to dasatinib 1 mg QD (n=259) or imatinib 4 mg QD (n=26) Median follow-up 28 mo Outcome Das 1 IM 4 % CCyR % MMR % BCR-ABL.32% 17 8 % discontinued therapy New mutations (No.) 1 1 * by 24 months Kantarjian et al. ASCO 211; abstract #651 DASISION: Transformation To AP/BP CML (ITT) 18 6 Dasatinib 1 mg QD 5 Imatinib 4 mg QD 5.8 % n/n 6/259 13/26 9/259 15/26 On study Including follow-up beyond discontinuation Kantarjian et al. ASCO 211; abstract #651 15

16 Bosutinib Efficacy and Safely in Newly Diagnosed CML (BELA): Study Design Phase 3 open-lapel trial in newly diagnosed chronic phase CML N = sites, 31 countries Stratification factors: Geographical region (3 regions), Sokal score, R A N D O M I Z E Bosutinib 5 mg/day n = 25 Imatinib 4 mg/day n = year follow-up 5-year follow-up 1-year analysis Eligibility criteria: Cytogenetic diagnosis of Ph+ CP CML 6 months prior; No prior therapy other than hydroxyurea or anagrelide Primary endpoint: complete cytogenetic response (CCyR) rate at 12 mo Secondary endpoints: Major molecular response (MMR) rate at 12 mo Time to CCyR and MMR Time to and rate of transformation to accelerated phase (AP) or blast phase (BP) CML, survival Safety and tolerability Gambacorti-Passerini et al. ASH 21; abst #28 Bosutinib vs Imatinib in Newly Diagnosed Chronic Phase CML 52 pts randomized to bosutinib 5 mg QD (n=25) or imatinib 4 mg QD (n=252) Minimum follow-up 18 mo Response at 12 mo Bos 5 IM 4 % CCyR % MMR % CMR 18 1 % discontinued therapy * by 18 months Gambacorti-Passerini et al. ASCO 211; abstract #659 16

17 Outcome by Frontline Therapy in CML CP - BELA 12 1 Bosutinib Imatinib Patients (%) Treatment failure Transformation to AP/BP Death due to CML progression Gambacorti-Passerini et al. ASCO 211; abstract #659 Dasatinib in CML Chronic Phase After Imatinib Failure 6 month follow-up of dose optimization study 35% still on treatment: 46% still at 1 mg QD (35% <1 mg QD) Parameter (%) N=167 MCyR (2 yr) 63 CCyR (2 yr) 5 5- yr MMR 44 5-yr PFS 57 5-yr OS 78 Pleural effusion 24 Grade Mutations persisting or developing after dasatinib discontinuation for loss of response: V299L, T315I, and F317L Shah et al. ASCO 211; abstract #

18 Long-Term Outcome with Dasatinib After Imatinib Failure by Response at 12 Months 12-Month 5-Year Outcome Response PFS OS MMR 86 9 CCyR PCyR Other Shah et al. ASCO 211; abstract #6512 What Does This Mean? Frontline therapy: new standard Imatinib is good; 2 nd generation TKI (dasatinib, nilotinib,?bosutinib) are better Sequential therapy? Failure to therapy: New definitions (no CCyR at 6 months) Change quickly if imatinib therapy No need to change if responding to imatinib Good (but not great) 2 nd line therapy Future needs: 3 rd line (Ponatinib 2 nd and 1 st line?) Treatment discontinuation 18

19 Bruton s Tyrosine Kinase (Btk) A Critical B-Cell Signaling Kinase B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation Bruton s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway Mutations in Btk prevent B cell maturation Inhibitors of Btk block BCR signaling and induce apoptosis BTK Inhibitor PCI in CLL Orally bioavaliable In CLL cells promotes apoptosis, inhibits CLL cell migration and adhesion Phase II study with 2 cohorts: Treatment naïve age 65 y (42 mg/d) (n=23) Relapsed/refractory 2 prior therapies (42 mg or 84 mg/d) (n=6) Median follow-up 4.6 to 7.8 months Byrd et al. ASCO 211; abstract #658 19

20 % Response Rate Response to PCI in CLL Treatment-Naïve (42 mg/d) Relapsed/Refractory (42 mg/d) 8% 6% 4% 24% 2% 8% 67% 5% 6% 59% 48% 4% 4% 33% 41% 62% 19% 2% 19% 44% % Cycle 2 (n=21) Best Response (n=21) % CR PR Nodal Response Cycle 2 (n=27) Best Response (n=27) Response in del 17p = 44%, del11q = 63%, IgVH unmutated = 53% Byrd et al. ASCO 211; abstract #658 ITT Respo onse Rate [Exact Binomial 95% CI] % Response to CAL-11 in Patients with Refractory/Relapsed CLL Response Rates 26% Overall Response a CLL (N=54) 8% Lymph Node Response b % Progression-F Free Duration of Tumor Control All medians >11 cycles Cycles (28 days) Duration of Response (N=14) Duration of Nodal Response (N=44) Progression-Free Survival (N=54) a IWCLL response criteria b Decrease by 5% in the nodal SPD Furman RR, et al. Blood. 21; Abstract #55 2

21 Response to CAL-11, a PI3K Inhibitor, in CLL mor Area (%) Change in Tu Pre (49) 1 (49) 2 (42) Lymph Nodes 4 (3) 6 (22) Cycle (N) 8 (18) 1 (13) 12 (1) Lymph node activity: Rapid and sustained lymph node size reduction in all evaluable patients ALC (K/uL) Pre (5) Lymphocyte Counts 1 (5) 2 (49) 4 (37) 6 (29) Cycle (N) 8 (27) 1 (19) 12 (14) Lymphocyte redistribution: Transient asymptomatic increase in circulating lymphocytes in a subset of patients (58%); maximal during the first 2 cycles Furman RR, et al. Blood. 21; Abstract #55 What Does This Mean? Improved CLL therapy Understanding the biology of CLL CAL-11 & PCI effective in CLL Role in CLL? Combination therapy Elderly CLL Frontline Role of new agents in frontline therapy Cure for CLL is here (almost) 21

22 Inotuzumab Ozogamycin in ALL CD22 Mo Ab bound to calicheamycin CD22 expression in 9+% of ALL 36 pts with refractory ALL Rx with IO mg/m 2 IV Q 3wks Ph+ / t (4;11) in 8 Response: CR 9 (25%); marrow CR 11; OR 2/36 = 56%. 66% in Salvage 1, 48% in salvage 2, 4% in salvage 3 12 underwent allo SCT in CR Toxicities: liver 25% (grade %) Jabbour et al. ASCO 211; abstract #657 Decitabine vs SC or LD - ara-c in Elderly AML Enrolled (N=485) Preselect treatment choice with physician s advice Supportive care (n=5) or low-dose cytarabine (n=432)* Stratification and randomization 1:1 ECOG ( 1 vs 2); age (65 69 vs 7+); cytogenetic risk (poor vs intermediate) Decitabine (n=242) 2 mg/m 2 by 1-h IV infusion once daily for 5 days, every 4 wk Treatment Choice (n=243) Supportive care or Treatment CR + CRp (%) Decitabine (n=242) 17.8* Cytarabine (n=215) 8.4 SC (n=28) 3.6 TC (n=243) 7.8* *P value =.1; odds ratio 2.5 (95% CI: 1.4, 4.78) cytarabine 2 mg/m 2 SC injection once daily for 1 days, every 4 wk 22

23 Survival with Decitabine vs. SC or LD ara-c in Elderly AML ) Subjects Alive (%) N Death (%) Median, mo 95% Cl Decitabine (9) 7.7 (6.2, 9.2) Total TC (93) 5. (4.3, 6.3) HR (95% Cl):.82 (.68,.99) 6 Log-rank P value: Time (mo) No. of Subjects at Risk: Decitabine Total TC Thomas XG, et al. ASCO 211; abstract #654 CLASSIC I Ara-C ± Clofarabine in 1 st Relapse AML Age 55 Yrs 326 pts from 57 sites (US, CAN, EU) age 55 yrs and with R/R AML Stra atification REF REL Ra andomize Placebo IV + Ara-C 1g/m 2 iv daily x 5 Clo 4 mg/m 2 iv daily x 5 + Ara-C 1 g/m 2 iv daily x 5 Maximum of 3 cycles of treatment Stratification: tifi ti REF: No response or CR1 <6 mos; REL: CR1 > 6 mos Primary objective: Overall survival Secondary objectives: CR rate, ORR, EFS, DFS, DOR, safety Faderl et al. ASCO 211; abstract #653 23

24 CLASSIC I - EFS and OS ORR: Ara-C + Clof 47%, Ara-C 23% CR: Ara-C + Clof 35%, Ara-C 18% Event-Free Survival Overall Survival Percent P HR =.63 (.49,.8) p=.1 Percent HR = 1. (.78, 1.28) p=.9951 Median: Clo+Ara- C: 6.6 mos Ara-C: 6.4 mos Time (Months) Time (Months) Time (Months) Clo+Ara-C Ara-C Clo+Ara-C Ara-C Faderl et al. ASCO 211; abstract #653 What Does This Mean? Acute leukemias are more difficult than chronic leukemias Hope for ALL CMC future? Combinations? Elderly? Clofarabine, decitabine useful in older AML Optimal schedules? Will they get approval? 24

25 Questions?