Update in Myeloproliferative Neoplasms

Transcription

1 Update in Myeloproliferative Neoplasms 2018 UPDATE IN HEMATOLOGIC MALIGNANCIES January 26, 2018 Daria Babushok, MD PhD

2 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

3 Key Changes in the 2016 WHO Diagnostic Criteria Polycythemia Vera Lower Hgb threshold BM Biopsy requirement

4 Key Changes in the 2016 WHO Diagnostic Criteria Prefibrotic/Early MF Distinguished from ET by: 1) BM morphology 2) Minor criteria Has worse prognosis than ET

5 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

6 Risk Stratification in PV and ET Revised IPSET <60 years + no Hx of thrombosis + NO JAK2 mutation VERY LOW ET <60 years + no Hx of thrombosis + HAS JAK2 mutation > 60 years + no Hx of thrombosis + NO JAK2 mutation LOW INT PV LOW RISK <60 years and no Hx of thrombosis HIGH RISK >60 years AND/OR Hx of thrombosis Barbui T, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 2015;5:e369. Hx of thrombosis OR >60 years WITH JAK2 mutation HIGH

7 Approach to First Line Therapy in PV LOW RISK <60 years and no Hx of thrombosis Aspirin Phlebotomy PV HIGH RISK >60 years AND/OR Hx of thrombosis Aspirin Phlebotomy PLUS Cytoreduction: Hydroxyurea (or Interferon*) Symptomatic requiring therapy?

8 Hydroxyurea versus Interferon Frontline for High-Risk PV? Ropeginterferon Alfa-2b Induces High Rates of Clinical, Hematological and Molecular Responses in Polycythemia Vera: Two-Year Results from the First Prospective Randomized Controlled Trial Gisslinger et al. ASH 2017

9 83 mo follow-up of peginterferon alpha 2a in PV 43 pts with PV Responses: OHR 79%/CHR 77% Time to response: 2 mo Complete molecular response: 20% Time to molecular response: 24 mo Toxicity: 22% discontinued due to toxicity Thromboses: 1.2/patient-years Transformation: Similar rates to matched controls

10 Ropeginterferon Alfa-2b Induces High Rates of Clinical, Hematological and Molecular Responses in Polycythemia Vera: Two-Year Results from the First Prospective Randomized Controlled Trial Gisslinger et al. ASH 2017 Ropeginterferon alfa-2b (Ropeg) administered once every 2 weeks or monthly during maintenance. 2 years treatment data obtained from the follow-up phase III CONTI-PV study. 254 PV patients randomized to Ropeg vs. HU After 12 months, 95 of 106 (89.6%) patients completing Ropeg arm 76 of 111 (68.5%) patients completing HU arm continued 2 nd year. Results: Efficacy: CHR: Ropeg 70.5%, compared to HU/BAT 49.3% (p=0.010) Mutant JAK2 allele burden: PMR at 24 months 69.6% (Ropeg) vs 28.6% (HU/BAT) (p=0.004). Safety: Treatment-related adverse events: 70.1% (Ropeg) and 77.2% (HU). Thyroid disorders and depression <5% in Ropeg arm. No increase in treatment-related malignancies with Ropeg.

11 Bottom Line on Interferon in PV Complete hematologic response rates >70% Minority of patients (~20%) may achieve complete molecular responses No increased leukemogenicity noted Significant treatment toxicity (~22% discontinuation rate), but newer formulations (e.g. Ropeg) may be better tolerated Should be considered in younger patients as potential frontline therapy

12 Approach to First Line Therapy in ET VERY LOW <60 years + no Hx of thrombosis + NO JAK2 mutation Aspirin 81mg daily OR Observation without therapy Symptomatic? <60 years + LOW no Hx of thrombosis + Aspirin 81mg daily ET INT HAS JAK2 mutation > 60 years + no Hx of thrombosis + NO JAK2 mutation Aspirin 81 mg daily AND evaluate for indications for cytoreduction HIGH Hx of thrombosis or >60 years WITH JAK2 mutation Aspirin 81mg daily AND cytoreductive therapy with hydroxyurea (or interferons*)

13 Clinical Scenario 46yo F with thrombocytosis, Plt 820k/ul. Bone marrow biopsy and other criteria consistent with ET. No prior thromboses. JAK2 V617 F mutation is detected. Would she benefit from cytoreduction?

14 Approach to First Line Therapy in ET VERY LOW <60 years + no Hx of thrombosis + NO JAK2 mutation Aspirin 81mg daily OR Observation without therapy Symptomatic? <60 years + LOW no Hx of thrombosis + Aspirin 81mg daily ET INT HAS JAK2 mutation > 60 years + no Hx of thrombosis + NO JAK2 mutation Aspirin 81 mg daily AND evaluate for indications for cytoreduction HIGH Hx of thrombosis or >60 years WITH JAK2 mutation Aspirin 81mg daily AND cytoreductive therapy with hydroxyurea (or interferons*)

15 Is cytoreduction helpful in low-risk ET patients aged years? Hydroxycarbamide Plus Aspirin Vs Aspirin Alone in Intermediate Risk Essential Thrombocythemia: Results of the PT-1 International, Prospective, Randomized Clinical Trial

16 No benefit to adding cytoreduction Thrombosis, hemorrhage or death

17 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

18 Clinical Scenario 46yo F incidentally found to have asymptomatic, isolated thrombocytosis of 1.3M/µl. Clinical and BM features consistent with ET. No prior thromboses or excessive bleeding. CALR mutation detected. How would you manage her?

19 Approach to First Line Therapy in ET VERY LOW <60 years + no Hx ofd thrombosis + NO JAK2 mutation Aspirin 81mg daily OR Observation without therapy <60 years + Symptomatic? LOW no Hx of thrombosis + Aspirin 81mg daily ET INT HAS JAK2 mutation > 60 years + no Hx of thrombosis + NO JAK2 mutation Aspirin 81 mg daily AND evaluate for indications for cytoreduction HIGH >60 years OR Hx of thrombosis WITH JAK2 mutation Aspirin 81mg daily AND cytoreductive therapy with hydroxyurea or interferons

20 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

21 ELN Definition of Resistance or Intolerance to Hydroxyurea in PV Resistance at 3 months of 2g/day of Hydrea Need for phlebotomy to keep Hct <45% Plt >400 AND WBC>10 Failure to reduce splenomegaly >10cm by 50% or relieve splenomegaly-related symptoms Intolerance Prohibitive myelosuppression (ANC<1000 OR Plt<100 OR Hgb<10) Leg ulcers or other nonhematologic toxicities (mucocutaneous, GI, pneumonitis, fever)

22 Ruxolitinib in Hydrea-resistant/intolerant PV

23 RESPONSE Week 32: Hct response 60% rux vs 19% BAT, spleen 40% rux vs 1% BAT Thromboembolic rate/100 patient-years: 1.8 rux vs 8.2 BAT Toxicities: Zoster reactivation: 5.3 (rux) vs. none (BAT) Non-melanoma skin cancer: 4.4 (rux) vs 2.7 (BAT) Probability of sustained response >80% (Hct control AND >35% spleen reduction) RESPONSE-2 (HU-resistant or intolerant patients without splenomegaly)

24 Non-hematologic Toxicities on Ruxolitinib Lipid elevations: Assess lipids 8-12 weeks following initiation of rux. Infections: Increased risk of opportunistic infections. Assess risk for serious bacterial, mycobacterial, fungal and viral infections. Screen for HBV, HCV, HIV, and, if appropriate, latent TB. Consider long-term zoster prophylaxis. Monitor and treat chronic HBV infections. If an infection develops, wherever possible, do not stop ruxolitinib. Non-melanoma skin cancer*: Basal, squamous, Merkel cell carcinoma have occurred. Counsel patients about sun exposure. Periodic skin exam. Ruxolitinib withdrawal syndrome. Avoid abrupt discontinuation of ruxolitinib. If discontinuing, taper and counsel patient re: resurgence of symptoms and splenomegaly. Consider covering with steroids. Adapted from Harrison and McLornan, ASH Education Book 2017

25 Is There a Benefit to Ruxolitinib in ET as 2 nd Line? CHR (46% rux vs 44% BAT) Thrombosis (17% rux vs 6% BAT, p=0.09) Hemorrhage (2% rux vs 9% BAT) Transformation (9 pts rux vs 5 pts BAT, p=0.29) Symptom score

26 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

27 MIPSS70 AND MIPSS70-Plus Updated Risk Stratification Algorithm in Myelofibrosis

28 MIPSS70 Clinical Feature Points Prognostic Median Survival (Yrs, Points Category Italian/Mayo) 5-Year OS Hgb < 10g/dl 1 Low / not reached 96% Fibrosis grade 2 1 Intermediate /6.3 67% Constitutional Symptoms¹ 1 High 5 2.3/3/1 34% Absence of CALR type 1 mutation 1 Circulating blasts 2 1 HMR (mutations in ASXL1, SRSF2, EZH2, IDH1/2) 1 WBC count > 25 x 10⁹/L 2 Platelet <100,000/ul 2 2 HMR Mutations 2 MIPSS70-Plus Prognostic Median Survival (Yrs, 5-Year OS Clinical Feature Points Category Points Mayo/Italian) Hgb < 10g/dl 1 Low / not reached 100% Constitutional Symptoms¹ 1 Intermediate 3 6.3/ % Circulating blasts 2 1 High / % HMR (mutations in ASXL1, SRSF2, 46.5% EZH2, IDH1/2) 1 Very High 7 1.7/3.9 Absence of CALR type 1 mutation 2 2 HMR Mutations 2 Unfavorable Karyotype² 3

29 MIPSS70 MIPSS70-Plus

30 Online Calculator:

31 Approach to Myelofibrosis 2018 Primary MF or Post-PV/ET MF Assess Risk Category (MIPSS70/MIPSS70-Plus DIPSS/DIPSS-Plus) DIPSS: Low + Int-1 MIPSS70: Low + Int DIPSS: Int-2 + High MIPSS70: High + Very High Asymptomatic Symptomatic Allo SCT candidate Non-transplant candidate Close Observation Consider HLA typing?role of Interferon Symptom-oriented therapy, including rux Consider HLA typing?role of Interferon Clinical trial HLA typing and donor search Consider pre-allo SCT optimization (e.g. ruxolitinib)?optimal timing of allo SCT Symptom-directed therapy including Ruxolitinib Clinical trial?role of interferon

32 Interferon in Myelofibrosis

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34 Pegylated Interferon May Provide A Survival Benefit in Intermediate and High-Risk MF Patients Limitations: Non-randomized Comparison to historical controls No follow-up BM biopsies

35 Other Agents in Myelofibrosis Standard Therapies Danazol Erythropoietin-Stimulating Agents Pegylated Interferon-α Hydroxyurea Thalidomide/prednisone Radiotherapy Splenectomy Allo SCT Investigational Agents either alone or in combination with Ruxolitinib Activin receptor antagonists (sotatercept, luspatercept) Antifibrotic agents (PRM-151) CDK4/6 Inhibitor and PIM kinase inhibitor Demethylating agents (azacytidine, decitabine) Other JAK inhibitors (fedratinib, pacritinib, itacitinib) HDAC inhibitors (panobinostat) PI3K/AKT/mTOR inhibitors Immune checkpoint inhibitors (nivolumab) Telomerase inhibitors (imetelstat) Hedgehog (Smoothened) inhibitor

36 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

37 Advances in Systemic Mastocytosis 2017: Midostaurin approved for aggressive systemic mastocytosis Single arm N=116 ORR 60% OS 28.7 mo PFS 14.1 mo

38 Clinical Activity in a Phase 1 Study of Blu-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis (AdvSM) Erica K. Evans et al., Sci Transl Med 2017;9:eaao1690

39 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

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41 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

42 Stopping TKI: Current Data and Controversy Why consider stopping TKI in eligible patients: Quality of life/toxicities? Financial issues? Criteria for discontinuation of TKI now part of NCCN CML guidelines

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44 TKI Withdrawal Syndrome 25-50% of patients in TKI discontinuation studies Musculoskeletal and joint pain Localized to shoulder, hip, extremities (wrists/hands) resembling polymyalgia rheumatica Appears ~1-4 weeks after TKI discontinuation Severity: mild-to-moderate Treatment Required: acetaminophen, NSAIDS, some patients required steroids Duration/Resolution: months to years

45 Treatment-Free Remission in CML: For Whom and How? For Whom: Chronic phase CML, with no history of TKI resistance Long-term treatment with TKI (e.g. 5-7 years) Followed with very sensitive molecular monitoring (i.e. MMR4 or MMR4.5 IS scale, >4-4.5 log detection sensitivity) Stable MMR4 or greater molecular response for 2 years, documented by at least 4 tests, performed at least 3 months apart Reliable follow-up and access to sensitive molecular monitoring How: Counseling on requirements for follow-up, need for TKI resumption with loss of remission, TKI withdrawal syndrome, etc. Molecular monitoring on IS scale with >4.5 log sensitivity: Q month x 6 months then Q2 months x 18 months then Q3 months indefinitely With loss of MMR (MMR3, IS 0.1%): Resume TKI promptly Monthly monitoring x 6 months, then q3 months indefinitely Central reporting of: failure to re-enter MMR at 3 months progression to accelerated or blast phase at any time any significant adverse event due to discontinuation

46 Learning Objectives Philadelphia-chromosome negative MPNs 1. To review key changes in the 2016 WHO Diagnostic Criteria for MPN 2. To review current risk stratification and 1 st line therapy of ET and PV 3. To review approach to extreme thrombocytosis in ET 4. To become familiar with the definition of resistance and intolerance to hydrea in PV and the role of alternative treatment options 5. To review current treatment algorithm in MF 6. To become familiar with treatment advances for systemic mastocytosis 7. To be aware of the new MPN NCCN guidelines (ET, PV, PMF) CML 1. To review advances in treatment-free remission in CML: achievable in whom and how? 2. To become familiar with cardiovascular care of CML patient

47 Cardiovascular Complications of TKI Therapy Nilotinib: QT prolongation Severe PAD: 6.2% Hyperglycemia: any grade 36% nilotinib vs 20% imatinib grade 3+ 6% nilotinib vs 0% imatinib) CV event risk (ischemic heart disease, cerebrovascular disease, PAD): 7.5% with nilotinib 300mg bid, 13.4 % with nilotinib 400mg bid Vs. 2.1% with imatinib 400mg daily Ponatinib: CV event rate 27% Cardiovascular occlusion 12% Cerebrovascular occlusion 6% Peripheral arterial occlusion 8% Heart failure including fatalities 8% Hypertension >26% Mary C. Barber et al. ASH Education Book 2017;2017:

48 Algorithm for Cardiovascular Management of Patients on Long-Term TKI Therapy Mary C. Barber et al. ASH Education Book 2017;2017:

49 Clinical Recommendations for Assessing Cardiovascular Toxicity in CML Patients on TKIs Mary C. Barber et al. ASH Education Book 2017;2017:

50 Thank you!

51 Criteria for TKI Discontinuation in Treatment Free Remission (TFR) Studies in CML Mahon, ASH Education Book, 2017