NeoplasiasMieloproliferativas

Renato Sampaio TavaresProf Assistente de Hematologia da Fac Medicina da UFG

CRM - GO: 6538

Policitemia vera: Algode novo apóshidroxiuréia?

MPN symptoms perception – Physicians vs Patients

MPN treatment objectives – Physicians vs Patients

• 365 patients

• Median follow-up: 30 months

• Plhebotomy with and without Hydrea

• 1:1

• Htc < 45% vs Htc 45% - 50%

High Htc vs Low Htc - Results

PV – LeukemiaNet recommendations

Leukemogenic:ChlorambucilP32Other Alkilant agents

Non-Leukemogenic:InterferonAnagrelide

Polycytemia Vera – Treatmentand Leukemic Transformation

Interferon in Polycytemia Vera

Ongoing Interferon vs Hydrea Phase III studies

• MPD-RC 112 trial 1 (pegylated interferon alpha-2a ) - interim analysisin

No benefit (hematologic control, allele burden reduction, BM changes

Tolerability was inferior

• PROUD study 2 (ropeginterferon alfa-2b) - preliminarily report

Not inferior in hematologic control

Less adverse events

1. Gisslinger H, et al. Blood. 2016; 128(22). Abstract 4752. Mascarenhas J, et al. Blood. 2016;128(22). Abstract 479

Hydroxyurea Leg Ulcers

• RESPONSE TRIAL• 222 patients resistant /

intolerant to Hydrea• Phlebotomy dependence *• Spleen: 450 >= cm3

• Ruxolitinib vs BAT – 1:1• End-point

• Hematocrit control• >35% spleen reduction

* 2 or more within 24 weeks

RESPONSE Trial - Phlebotomies

RESPONSE Trial – Patient Global Impression

RESPONSE Trial – Symptom Assessment

RESPONSE Trial - Itching

RESPONSE Trial – Funtional Scales and Individual Symptoms

RESPONSE – 80-week analysis

RESPONSE – 80-week analysis

RESPONSE – 80-week analysis

• 149 patients resistant / intolerant

to Hydrea without splenomegaly

• Phlebotomy dependent

• Ruxolitinib vs BAT – 1:1

• End-point

• Hematocrit control

Take Home Messages• ASA continuously and hematocrit below 45% should be

offered to all PV patients

• Interferon is a suitable treatment option for young andrelapsed PV patients, but still lacks phase III studies finalresults

• Hydroxyurea-resistance leads to thrombosis, leukemiaprogression and shorter survival

• Ruxolitinib 10 mg bid is an effective and safe option tomanage hydroxyurea-resistant PV patients

Thank you!!!renatosampaiotavares@gmail.com

JAK2 Inhibitors in Myelofibrosis

Myelofibrosis

•About the disease

• It can be insidious

• It kills people

• It’s vicious and unforgiving

• It’s orphan

Cervantes F, et al. Blood, 2009

Primary Myelofibrosis – IPSS

”High-Risk” vs ”Low-Hisk” Mutations Profile

• Spleen reduction

• Can induce / aggravate cytopenias

• Overall response - 40% / Medians duration - 13,2 months

• After first year, 80% will need to chance to another therapy

• Skin and mucosa ulcers not uncommon

Hydroxiurea

Martinez-Trillos A, et al. Ann Hematol 2010Cervantes F, et al. Blood 2014

Erythopoetin in PMF

• Studies are small - no larger prospective study than N=20

• Response Criteria used are not uniform

• Positive factors for response:

• Lack of transfusion dependency

• S-Epolevel < 125 U/L

• rHuEPO dose: 30.000 U/week

Birgegard G. Best Pr Res Cl Hematol, 2014

Danazol in PMF

• Studies are small

• Response Criteria used are not uniform

• Response in 40% or more patients (worse if transfusion dependent)

• Time to response: 3 – 6 months

• Toxixity

• Mild

• Dose dependent

Birgegard G. Best Pr Res Cl Hematol, 2014

Cervantes F. et al Ann Hematol 201550 patientsIWGMRT criteriaResponse: 30%

Thalidomide in PMF

• First studies: High doses – High drop out - intolerance

• Low Doses plus Predinisone

• Response in 40% patients

• Time to response – less than 12 weeks

• Duration of response – varies widely

• However, notable toxicity even with low doses

Birgegard G. Best Pr Res Cl Hematol, 2014

Lenalidomide and Pomalidomide:Lower side-efectsLower response rates

Median follow-up: 58 monthsMedian treatment duration: 39 months (range: 6-107)Forty-five pts (72.6%) discontinued

55.6% due to resistance 44.4% due to intolerance

Ianotto JC, et al. ASH 2017

BMT and MF

• It’s the only curative therapy - 30 to 60%

• Primary graft failure: 10 to 20%

• Secondary graft failure: plus 10%

• 100-day mortality: 10 to 30%

• Non-fatal relapses: 30% to 50%

• Long term overall survival: 30 to 70%

Gergis U, et al. Cl Lymp Myel Leuk, 2016

EBMT/ELN international working group consensus

Pacientes com MF

Primária ou

Secundária

(N=309)

Randomizados

1:1

Ruxolitinibe (oral)

15 mg 2x/dia ou

20 mg 2x/dia

Melhor terapia

disponível

Pacientes com MF

Primária ou

Secundária

(N=219)

Objetivo Primário COMFORT-I: % pacientes ≥ 35% de redução do volume do baço até a semana 24*

Verstovsek et al., NEJM, 2012; 366(9):799-807Harrison et al., NEJM, 2012; 366(9):787-98

*Conforme medido por RNM (ou TC em pacientes aplicáveis)

Placebo (oral)

2x/dia

Randomizados

2:1

Ruxolitinibe (oral)

15 mg 2x/dia ou

20 mg 2x/dia

COMFORT-II (Europa)

Objetivo Primário COMFORT-II: % pacientes ≥ 35% de redução do volume do baço até a semana 48*

Ruxolitinibe em MF - Estudos de Fase IIICOMFORT-I (EUA,Canadá, Austrália)

Pooled analysis – COMFORT I e II

Verstovsek et al. ASH 2016. Session 634. Abstract 3110.

Pooled analysis – COMFORT I e II

Verstovsek et al. ASH 2016. Session 634. Abstract 3110.

Pooled analysis – COMFORT I e II

Verstovsek et al. ASH 2016. Session 634. Abstract 3110.

OVERAL SURVIVAL corrected for crossover with the RPSFT model

OVERALL SURVIVAL CORRECTED BY CENSORING AT CROSSOVER

Pooled analysis – COMFORT I e II

Verstovsek et al. ASH 2016. Session 634. Abstract 3110.

OVERALL SURVIVAL BY IPSS RISK STATUS AMONG PATIENTS TREATED WITH RUXOLITINIB

Pooled analysis – COMFORT I e II

Verstovsek et al. ASH 2016. Session 634. Abstract 3110.

Molecular score and Ruxolitinib response – COMFORT II

Guglielmelli P, et al. Blood, 2014

Ruben A. Mesa et al. Blood 2012;120:1733

Ruben A. Mesa et al. Blood 2012;120:1733

Ruben A. Mesa et al. Blood 2012;120:1733

COMFORT I - 3 Year Update

Mean Platelet Count and Hemoglobin Level Over Time

Platelet Count Hemoglobin

85

90

95

100

105

110

115

0 12 24 36 48 60 72 84 96 108 120 132 144

Weeks

Mean H

em

oglo

bin

(g/L

)

120

170

220

270

320

0 12 24 36 48 60 72 84 96 108 120 132 144

Weeks

Mean

Pla

tele

ts (

x10

9/L

)

128 82PBO

144 136 112 107 100 88RUX

Number of patients

151

155

112 37

143 124 110 104 94 79

132 83

145 136 113 107 100 88

151

155

113 37

143 124 110 104 94 79

Number of patients

370Ruxolitinib Placebo Ruxolitinib Placebo

EHA 2017

Adverse Events – COMFORT II

Harrisson C, et al. Leukemia, 2016. doi: 10.1038/leu.2016.148

Tavares RS et al. ASH 2015 #Abs 2799

Adverse events - JUMP trial

COMFORT I/II trials - Caveats

• Overall survival – secondary objective

• Low number of patients – rare disease

• No Low risk / Intermediate 1 IPSS stage were included

• Crossover was allowed for ethical reasons – compromised overall

survival analysis

• Median overall survival of ruxolitinib arm has not been reached yet

94

Other JAK2 Inhibitors

• Fedratinib – some cases of Wernick’s encephalopaty discontinued 2015

• Pacritinib – some cases with major cardiovascular complications – temporally

hold in 2016. Nowadays new explorations are being conducted

• Momelotinib – not inferior in spleen reduction, better in transfusion-

independence, worst for alleviate symptoms – discontinued 2017

Bose P & Verstovsek S, Blood, 2017

Ruxolitinib is recommended for:

Symptomatic or severe splenomegalyIntermediate-2 / high-risk - strong recommendationIntermediate-1-risk not responsive / intolerant to HU or IFN - weak recommendationIntermediate-1-risk not previously treated - weak recommendation

Disease-related symptoms- strong recommendation(MPN10 score 444 / refractory severe itching (score 46) / weight loss / unexplained fever)

Improving survival - not recommended uniquely for survival benefit - weak recommendation

Thank you!!!renatosampaiotavares@gmail.com