Post-ASH 2015 CML - MPN

Transcription

1 Post-ASH 2015 CML - MPN Fleur Samantha Benghiat, MD, PhD Hôpital Erasme, Brussels

2 1. CML

3 CML 1st line ttt Prognosis Imatinib Nilotinib Response Discontinuation Dasatinib

4 Low RISK PROFILE High 1ST LINE TREATMENT ACCORDING TO RISK PROFILE AND THERAPEUTIC GOAL NILO / DASA NILO / DASA NILO / DASA IMA IMA NILO / DASA IMA IMA NILO / DASA Low TREATMENT FREE REMISSION PRIORITY High Hughes T. White D. ASH 2013

5 CML Prognosis ELTS Score 1st line ttt Response Discontinuation

6 PROGNOSIS OF CHRONIC PHASE - CML EUTOS Long Term Survival Score (ELTS) Pfirrmann M. et al. (Abstract #0595) Sokal Euro/Hasford EUTOS EUTOS Long Term Survival Risk groups (1984) (1998) (2011) ELTS (2015) 1 Chemo IFN-a Imatinib Imatinib CCR 18 mo 8-year probability of CML-related death Age x x 0,0025x(age/10)³ LOW Spleen size x x x + 0,0615 spleen size 2% Blasts % x x + 0,1052 PB blasts INTERMEDIATE Platelet count x + 0,4104x(plt/1000) -0,5 6% Basophils % x x HIGH Eosinophils % x 11% Better id of High risk patients than Sokal Low = Intermediate Low Intermediate Online calculators 1. Pfirrmann M et al. Prognosis of long-term survival considering disease specific death in patients with CML. Leukemia Advance online publication, 3 November 2015; doi: /leu

7 Cumulative incidence probabilities of dying because of CML SOKAL HASFORD N= 2205 patients ELN/EUTOS registry Prospectively enrolled ( ) Imatinib-based ttt Ima 400, 600 or 800 mg Ima + IFNa Ima + Ara-C ELTS Pfirrmann M et al. Prognosis of long-term survival considering disease specific death in patients with CML. Leukemia Advance online publication, 3 November 2015; doi: /leu

8 CML Prognosis ELTS 1st line ttt Ima-Nilo-Dasa Response *Dose optimization Discontinuation *IFN-a

9 How to achieve better response with Imatinib? OPTIM Imatinib trial Rousselot P. et al. Abstract #0133 Personalized imatinib doses by drug monitoring MMR 64%! N=43 N=43 N=133 N=47 Courtesy of P. Rousselot

10 E s tim a te d M M R ra te (% ) OPTIM results by 12 months MMR by 12 months (post randomization) Improved MMR in a magnitude similar to 2 nd gen TKI % 5 0 % p = A d a p te d N o n a d a p te d D a y s s in c e ra n d o m is a tio n to T D M Reason for discontinuation Adapted arm (C1) Non adapted arm (C2) Consent withdrawal 1 1 Adverse event 2 2 Lack of response 1 3 TOTAL % (N) 9% (4) 14% (6) Courtesy of P. Rousselot

11 HOW TO ACHIEVE BETTER RESPONSE? PEG-IFN + Imatinib [SPIRIT, Preudhomme et al. NEJM 2010] High rate of MMR + Nilotinib [NILOPEG, Nicolini FE et al. Lancet Hematology 2015] High rate of deep MR + Dasatinib Roy L. et al. (Abstract #0134) Henrik HH. et al. (Abstract #0477) High early MMR and deep MR 30%) Toxicity profile not negligible but manageable

12 CML Prognosis ETLT 1st line ttt Ima/Nilo/Dasa Response Discontinuation

13 Etienne G. et al. (Abstract #0345 ) (= MR 5.0) 65 months follow up Courtesy of Pr Etienne G.

14 - Sokal = Strong factor associated with recurrence - 2 nd deep MR after TKI resumption No molecular recurrence after 24 months Very rare molecular recurrences after 6 months CONCLUSIONS: Imatinib discontinuation is safe provided that: - A deep sustained molecular response have been achieved before discontinuation - A close molecular monitoring is available after treatment discontinuation Courtesy of Pr Etienne G.

15 TKI WITHDRAWAL SYNDROME (WS) Berger M. et al. (Abstract #0137) Musculoskeletal pain after stopping TKI Study Prevalence Onset TKI Location Duration Euroski and STIM-2 (n= 428) 24% 21 days Imatinib and nilotinib (n=2) Shoulders Spine A few weeks to several months Risk factors R/ Time on TKI Previous history of osteo-articular symptoms NSAIDs, corticosteroids or local infiltration Restart TKIs: WS disappeared in 50% after a median of 3 weeks

16 2. Myelofibrosis

17 DIAGNOSIS PROPOSED REVISED CRITERIA WHO 2015 WHO 2008 WHO 2015 revised MF Diagnosis PMF Barbui T et al. Blood Cancer J. 2015;5:e337 Courtesy of Pr C. Harrison

18 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT MF Prognosis Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

19 MIPSS MOLECULAR - IPSS IPSS 2009 DIPSS 2010 DIPSS MIPSS 2014 Weighted Value Age 1,5 Symptoms 0,5 WBC Hb < 10 g/dl 0,5 PB Blasts > 1% Platelet count 1 RBC transfusion Karyotype Mutational status Triple neg 1,5 JAK2/MPL 0,5 ASXL1 0,5 SRSF2 0,5 Risk Score OS, y Low 0-0,5 26,4 Int-1 1-1,5 9,7 Int-2 2-3,5 6,4 High 4 1,9 Utility of MIPSS: Potential allosct candidates in current Int-1 and Int-2 IPSS risk category Vannucchi AM, et al. Blood (Annual Meeting Abstract). 2014,124, abstract 405

20 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT MF IPSS DIPSS (+) MIPSS Low / Int-1 Symptomatic No Yes *Observation *Conventional treatment (Spleen HU ) Int-2 / High Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

21 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT MF IPSS DIPSS (+) MIPSS Low / Int-1 Symptomatic No Yes *Observation *Conventional treatment (Spleen HU ) Int-2 / High AlloSCT eligible? Yes AlloSCT *Conventional *RIC Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

22 ALLO SCT IN PMF Consensus process by an EBMT/ELN international working group 1. IPSS or DIPSS int-2 or high-risk, age <70y Potential candidates for SCT 2. Int-1-risk and age <60y Potential candidates for SCT if Refractory transfusion-dependent anemia Refractory symptomatic splenomegaly Peripheral blood blast >2% OR adverse cytogenetics (as in DIPSS+) 3. Int-1-risk triple negative and/or ASXL1+ Considered for allo-sct 4. Low-risk No SCT Evaluation for SCT when progression Kröger N, et al. Leukemia epub ahead of print. Courtesy of Pr Vannucchi

23 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT No *Observation Low / Int-1 Symptomatic Yes *Conventional treatment (Spleen HU ) MF IPSS DIPSS (+) MIPSS Platelets > /mm³ Splenomegaly Int-2 / High AlloSCT eligible? No *Ruxolitinib *Drugs for anemia *Clinical trials Yes AlloSCT *Conventional *RIC Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

24 RUXOLITINIB COMFORT 2 5 YEARS FINAL RESULTS Harrison C, et al. #059 Randomized, open-label, multicenter phase 3 study MF with 2 IPSS N=219 Randomize 2:1 Treatment until progressive splenomegaly unless discontinued earlier for splenectomy, toxicity or death BAT: Crossover allowed for patients with progressive splenomegaly Ruxolitinib 15 or 20 mg BID N= 146 Best Available Therapy (BAT) N= 73 Crossover to Ruxolitinib N= 45 Primary results and 3-year follow-up: - Primary endpoint reached: 35% reduction spleen volume at week 48 : Ruxolitinib 28% vs BAT 0% (p<.0001) - Sustained spleen volume reduction at 3-years

25 RESULTS Spleen response Median duration: 3,2 y The K-M estimated probability of maintaining response Ruxolitinib a n = 78 BAT a n = 1 5 years, 0.48 Events Censored 34 (43.6%) 44 (56.4%) 0 1 (100%) JAK2 V617F allele Burden The majority had a reduction over the course of ttt (1/3 with >20% ) BM fibrosis Improved or stabilized in 48% of patients Safety issues VZV Hb levels during the 12 first weeks then and remained > 10g/dl Thrombocytopenia mainly grade 1-2; 19% grade 3-4 at any time

26 Probability HR, hazard ratio; ITT, intent-to-treat; RPSFT, Rank-Preserving Structural Failure Time. OVERAL SURVIVAL Median Overall Survival Ruxolitinib (ITT) = not reached BAT (ITT) = 4.1 years BAT (RPSFT) = 2.7 years Ruxolitinib BAT (ITT) BAT (RPSFT) Median OS was not yet reached in the RUX arm (ie, > 5 years) 33% reduction in risk of death with RUX vs BAT ITT: HR, 0.67 (95% CI, ); P=.06 confounding effect of cross-over RPSFT (OS correcting for cross-over) n = Time, years HR, 0.44 (95% IC, ) in favor of ruxolitinib vs BAT

27 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT No *Observation Low / Int-1 Symptomatic Yes *Conventional treatment (Spleen HU ) MF IPSS DIPSS (+) MIPSS Platelets < /mm³? Int-2 / High AlloSCT eligible? No *Ruxolitinib *Drugs for anemia *Clinical trials Yes AlloSCT *Conventional *RIC Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

28 Vannucchi MA, et al. #2817 Safely administred Plt x10 9 /L : starting dose of up to 15mg BID Plt x10 9 /L : starting dose of up to 10mg BID No new or unexpected AEs Spleen reduction across all groups Consistent with those observed in patients with higher Plt counts Study still ongoing But revised: Starting dose : 10mg BID for Plt x10 9 /L

29 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT No *Observation Low / Int-1 Symptomatic Yes *Conventional treatment (Spleen HU ) MF IPSS DIPSS (+) MIPSS Platelets < /mm³? Int-2 / High AlloSCT eligible? No *Ruxolitinib *Drugs for anemia *Clinical trials Yes AlloSCT *Conventional *RIC Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

30 FDA New drug Application JAK2 INHIBITORS TESTED IN CLINICAL TRIALS Agent JAK family target Non JAK target Hem toxicity Non-heme toxicity Hem Response APPROVED Ruxolitinib JAK1/2 Plt Hb None III Trial phase Momelotinib JAK1/2 JNK1 CDk2 Plt Neuro Anemia III vs Ruxo Pacritinib JAK2 FLT3 Hb GI None III Phase III PERSIST-1 TRIAL (Vannucchi MA, et al. #058) MF Int-1, Int-2, High risk Palpable spleen 5cm No exclusion for baseline Plt and Hb levels No prior ttt with JAK2 inhibitors R (2:1) Pacritinib 400 mg QD (N=220) BAT excluding Ruxolitinib (N=107) Endpoints - Primary : Spleen volume reduction 35% by week 24 Reached : 19.1% vs 4.7% (p=.0003) - Secondary: Total Symptom Score (TSS) reduction 50% by week 24 Reached Outcome across subgroups (age, Hb, plt, ECOG, JAK2 mutation, RBC transf )

31 Changes in PLT levels, Hb and RBC transfusion dependence over time Achievement of SVR >35% and TSS >50% irrespective of baseline characteristics, including baseline Plt count

32 MF: ESMO GUIDELINES FOR DIAGNOSIS AND TREATMENT Low / Int-1 Symptomatic No Yes *Observation *Conventional treatment (HU ) MF IPSS DIPSS (+) MIPSS Infections? Int-2 / High AlloSCT eligible? No *Ruxolitinib *Drugs for anemia *Clinical trials Yes AlloSCT *Conventional *RIC Vannucchi AM, et al. Ann Oncol. 2015; 26:v85-v99 Courtesy of Pr Vannucchi

33 RISK FACTORS FOR INFECTIONS IN MF Polverelli N. et al. (Abstract #1606) Retrospective, 507 MF patients Infection in 22% MF patients grade 3-4: 45% Bacterial (pneumonia) 89% Increased risk of infection Baseline IPSS int-2 and high Splenomegaly > 10cm Ruxolitinib Positive prognostic factor Spleen reduction > 50% Negative prognostic factor Age >65 Corticosteroids

34 3. Essential Thrombocytemia Don t worry, only 30 slides to go

35 DIAGNOSIS PROPOSED REVISED CRITERIA WHO 2015 WHO criteria 2008 A1 Platelets > 450 x 10 9 /L A2 A3 A4 ET BM biopsy: proliferation mainly of the MK lineage with increased numbers of enlarged mature MKs. No significant increase of neutrophil granulopoïesis or erythropoïesis. Not meeting WHO criteria for BCR-ABL CML, PV, PMF, MDS or other myeloid neoplasm V617F-JAK2 or other clonal marker Or in the absence, no evidence for reactive thrombocytosis A1+A2+A3+A4 Barbui T et al. Blood Cancer J. 2015;5:e337 Proposed WHO criteria 2015 A1 Platelets > 450 x 10 9 /L A2 A3 A4 B ET BM biopsy: proliferation mainly of the MK lineage with increased numbers of enlarged mature MKs. No significant increase of neutrophil granulopoïesis or erythropoïesis, & very rarely minor increase in reticulin fibers. Not meeting WHO criteria for BCR-ABL CML, PV, PMF, MDS or other myeloid neoplasm Presence of JAK2, CALR or MPL mutation Presence of a clonal marker Or absence of evidence for reactive thrombocytosis A1+A2+A3+A4 Or A1+A2+A3+B Courtesy of Pr C. Harrison

36 THROMBOSIS-Free SURVIVAL Practice-relevant revision of ipset-thrombosis based on 1019 patients with WHO-defined ET Barbui T. et al. (Abstract #4055) Low risk Age 60 and no history of thrombosis No add RF CV RF + JAK2 + CV + JAK2 + High risk Age > 60 OR history of thrombosis No add RF CV RF + JAK2 + CV + JAK2 + CVRF- AAS 80/160 CVRF+ AAS 160 Very Low = JAK2 neg CVRF- FU CVRF+ AAS 80 Low = JAK2 + Cytoreduction Intermediate = Age > 60 and JAK2 neg Cytoreduction or AAS 160 High = Thrombosis history OR Age > 60 and JAK2 +! To be confirmed by prospective controlled studies

37 4. Polycythemia Vera

38 DIAGNOSIS PROPOSED REVISED CRITERIA WHO 2015 WHO criteria 2008 Proposed WHO criteria 2015 A1 Hb > 18.5 g/dl, 16.5 OR HCT OR Red Cell Mass (RCM) A1 Hb > 16.5 g/dl, 16.0 OR HCT >0.49 or >0.48 OR RCM A2 B1 JAK2 mutation BM with age-adjusted hypercellularity and panmyelosis A2 A3 BM with age-adjusted hypercellularity, panmyelosis with pleiomorphic mature MK JAK2 mutation B2 EPO B3 Endogenous erythroid colony formation B EPO PV A1+A2 and one B OR A1 and two B PV A1 + A2 + A3 OR A1 + A2 and the B Barbui T et al. Blood Cancer J. 2015;5:e337

39 RESPONSE: RUXOLITINIB IN 2 ND LINE PV + SPLENOMEGALY Results after week 32 Kiladjan JJ. Et al. (Abstract #2804)

40 THANK YOU!