Should Intermediate-I risk PMF be transplanted immediately or later? Position: Later

Transcription

1 Should Intermediate-I risk PMF be transplanted immediately or later? Position: Later Vikas Gupta, MD, FRCP, FRCPath Associate Professor Department of Medicine Leukemia/BMT Programs Princess Margaret Cancer Centre Toronto, Canada

2 Disclosures Vikas Gupta, MD, FRCP, FRCPath Research support/p.i. Employee Consultant Major Stockholder Speakers Bureau Scientific Advisory Board Novartis, Incyte None Novartis, Incyte, None Novartis, Incyte Incyte, Novartis

3 Q1. How do we define Intermediate-1 risk Myelofibrosis in 2013?

4 Ever Growing Prognostic scores for MF - What should I use? Lille score International Prognostic Scoring system (IPSS) Dynamic IPSS (DIPSS) DIPSS plus Impact of various mutations

5 Prognostic Factors in IPSS for PMF Risk Factor Frequency HR (95% CI) P Value Age > 65 years 44.6% 1.95 ( ) <.001 Constitutional symptoms 26.4% 1.97 ( ) <.001 Anemia 35.2% 2.89 ( ) <.001 WBC count >25 9.6% 2.40 ( ) <.001 PB blasts 1% 36.2% 1.80 ( ) <.001

6 Survival in Risk Groups of IPSS Risk Group No of factors Proportion of patients Median survival (95% CI) Low ( ) Intermediate (79-114) Intermediate (43-59) High (23-31)

7 Relative Survival of 4 Risk Groups Vs. General Population, Expected survival;, observed survival;, relative survival,, 95% confidence interval. 0 Factors 1 Factor 2 Factors 3-5 Factors Cervantes et al. Blood. 2009;113:

8 DIPSS Risk Group Score Median Survival Low 0 Not reached Intermediate years Intermediate years High years

9 Impact of DIPSS on blast phase occurrence Passamonti F et al. Blood 2010;116:

10 DIPSS PLUS Thrombocytopenia Platelets <100 x 10 9 /L Anemia Hemoglobin <10 g/dl Red blood cell transfusion need* DIPSS-plus Risk Categories in Primary Myelofibrosis Age above 65 years 1.Low (score 0, median survival ~15.4 yrs) 2.Intermediate-1 (score 1, median survival ~6.5 yrs) 3.Intermediate-2 (score 2-3, median survival ~2.9 yrs) 4.High (score 4; median survival ~1.3 yrs) Constitutional Symptoms** Leukocytosis leukocytes > 25x10 9 /L Unfavorable karyotype *** Circulation blasts 1%

11 Mutational Profile 382 (79.1%) of patients presented at least one somatic mutation 154 pts (32.5%) had >2 mutations 31 pts (6.4%) had >3 mutations

12 Mutations Associated with Reduced Overall Survival EZH2 ASXL1 P= P< SRSF2 Hazard Risk (95% CI range) P P< EZH ( ) ASXL ( ) < SRSF ( ) <0.0001

13 Impact of mutations on survival and leukemic transformation

14 Limitations of Risk Stratification Tools Mainly derived from retrospective studies in Primary MF Have not been well validated in Post- PV/Post ET MF

15 Q2. What are the therapeutic Options available to patients with Int-I risk Myelofibrosis in 2013?

16 Therapeutic Options available to Intermediate-1 risk Myelofibrosis in 2013 Transplant options Myeloablative Reduced-intensity Experimental drug therapy 1. Pomalidomide 2. Novel JAK inhibitors 3. Others a. Hypomethylating agents b. HIDAC inhibitors c. mtor inhibitors Non-transplant options Conventional Treatment for anemia Transfusion support Erythropoietin Corticosteriods Androgen + prednisone IMiDs Treatment for splenomegaly Hydroxyurea Splenectomy Low-dose irradiation Novel emerging option Ruxolitinib Abbreviations: HIDAC, histone deacetylase; IMiD, immunomodulatory drug; JAK, Janus kinase; mtor, mammalian target of rapamycin.

17 Potential Impact of BMT on Resolution of Myelofibrosis

18 Allogeneic Transplant in Myelofibrosis (n 20) Study N Med. Age MF Subtype Regimen I/H Risk % TRM at 1 y % OS Guardiola PMF=47 Ablative % at 5 y (age > 45 y) 62% (age < 45y) Daly PMF=19 Ablative % at 2 y Deeg Ditschokowsky PMF=33 Blastic=3 PMF=12 Blastic=3 Ablative % at 3 y Ablative % at 5 y I/H risk 16% Low risk 67% Kerbauy PMF=62 Blastic=7 Ablative % I/H risk 46% Low risk 80% Ballen Ablative n/a 30 33% at 5 y Hertenstein RIC % at 1 y Rondelli RIC % at 2.5 y Kroger PMF=15 RIC % at 3 y Gupta PMF=32 RIC/Ablati ve % at 3 y Kroger PMF=63 RIC % at 5 y

19 Do Intermediate-1 risk patients have better survival after transplant? (Scott et al, Blood, 2012)

20 Do Intermediate-1 risk patients have better survival after transplant? (Gupta et al, CIBMTR data, submitted) Months Int-2/High Low/Int-1 p=0.10

21 Outcomes of MF patients according to DIPSS treated with supportive therapy and HCT Passamonti et al, Blood 2010 Scott et al, Blood, 2012

22 Q3. Can I offer some thing meaningful if I have a Intermediate -1 risk patient with significant symptom burden?

23 Phase III Trials With Ruxolitinib: Study Designs COMFORT-I 1 Patients with MF (N = 309) Double-blind Randomized 1:1 Ruxolitinib 15 mg BID or 20 mg BID N = 155 Placebo BID N = 154 Crossover to Ruxolitinib COMFORT-II 2 Patients with MF (N = 219) Open-label Randomized 2:1 Ruxolitinib 15 mg BID or 20 mg BID N = 146 BAT N = 73 Patients with progressive disease eligible for crossover The primary endpoint: 35% reduction in spleen volume from baseline to week 24 (COMFORT-I) or week 48 (COMFORT-II), as measured by MRI or CT Abbreviations: BAT, best available therapy; BID, twice daily; COMFORT, Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment; CT, computed tomography; MF, myelofibrosis; MRI, magnetic resonance imaging. 1. Verstovsek S, et al. N Engl J Med. 2012;366: ; 2. Harrison CN, et al. N Engl J Med. 2012;366:

24 % Change from Baseline Best % Change from Baseline Within 48 Weeks COMFORT-I and II: Effect on Spleen Volume Reduction COMFORT-I 1 (week 24) COMFORT II 2 (week 48) Ruxolitinib (n=155) Placebo (n=153) Ruxolitinib (n=136) BAT (n=63) % decrease % decrease Ruxolitinib (n = 155) Placebo (n = 153) P value Response a 41.9% 0.7% <.001 Ruxolitinib (n = 144) BAT (n = 72) P Value Response a 28.5% 0% <.001 Abbreviation: BAT, best available therapy; COMFORT, Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment. a Reduction in spleen volume of 35%. 1. Verstovsek S, et al. N Engl J Med. 2012;366: ; 2. Harrison CN, et al. N Engl J Med. 2012;366:

25 Percent of Patients With 50% Decrease in Total Symptom Score at Week 24 (ITT) Ruxolitinib (n = 149) Placebo (n = 152) Total Symptom Score = the sum of scores for night sweats, itching, abdominal discomfort, pain under the ribs on the left, early satiety, muscle or bone pain, and inactivity Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as failures Abbreviation: ITT, intention to treat. Verstovsek S, et al. N Engl J Med. 2012;366:

26 Mantra for timing of HCT in MF NOT TOO EARLY, BUT NOT TOO LATE Advanced disease Worse prognostic score Higher risk of HCT failure Worsening prognostic score Splenomegaly Portal hypertension Iron overload Leukemic transformation Ideal Timing for HCT Decision Analysis Loss of potential life years with each strategy Quality adjusted life years Modeling different strategies early, late, and risk adapted Early disease Better risk score Higher chances of HCT success Likely to be OK with non-hct NRM shortening of life span Quality of life impact

27 Decision Analysis of RIC vs. Non-transplant therapies in MDS

28 HCT in Int-1 MF Early or Later? Patients with Int-1 risk MF have reasonably long median survival with supportive therapy alone. No role of HCT as front line therapy in Int-1 risk MF, & HCT should be deferred until disease progression. Increasing accessibility to modern tools such as NGS and mutational analysis will add precision to risk stratification for MF in near future.