Tratamiento de pacientes 5q - y pacientes con resistencia a EPO - Dra. Silvia Magalhaes

MYELODYSPLASTIC SYNDROME LOW-RISK Silvia Magalhรฃes Universidade Federal do Cearรก - Brazil 2016

Steensma DP Leuk Lymphoma 2016; 57: 17.

Steensma DP Leuk Lymphoma 2016; 57: 17.

4,147 patients from the Duesseldorf MDS registry

the improvement of the prognosis was restricted to high-risk MDS patients diagnosed between 2002 and 2014 in comparison to the patient group diagnosed between 1982 and 2001 (19 vs.

13 months, p < 0.001), whereas the prognosis of low-risk MDS patients did not change significantly.

Neukirchen J et al Leuk Res 2015; 39: 679.

OVERALL SURVIVAL

2004 AZACITIDINE 2005 LENALIDOMIDE 2006 DECITABINE

Gangat N et al. Blood Cancer J 2016; 6: e414.

OS according to bone marrow fibrosis grade

Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis

Ramos F et al Oncotarget. 2016 May 24; 7: 30492

• NEW CONCEPTS • PHISIOPATHOLOGY • TREATMENT Platzbecker U et al Haematologica 2016; 101: 891

LOW-RISK MDS

• Menor probabilidade de evolução para leucemia aguda • Maior sobrevida • Grande heterogeneidade • Anemia citopenia mais frequente • Dependência transfusional • impacto prognóstico • impacto na QOL

MDS with del(5q

Except for patients with low neutrophil counts or low platelet counts. Recommended initial dose is: 10 mg/d for 21 out of 28 days or 28 days monthly for 2 to 4 months to assess response. Alternative option to lenalidomide may include an initial trial of ESAs in patients with serum EPO â&#x2030;¤500 mU/mL v

• curto • longo

• Elevados índices de independência transfusional • Prolongada duração de resposta • Altos índices de resposta citogenética • Melhora da qualidade de vida • Ausência de aumento do risco de transformação leucêmica • Aumento da sobrevida e do tempo para progressão Komrokji RS et al Annals of Oncology, 2016 Jan; 27: 62.

cohort of MDS patients (n = 1248) treated with lenalidomide lenalidomide was not associated with increased risk of subsequent primary malignancies or AML transformation Rollison DE et al Cancer Med 2016 Jul; 5: 1694.

MARCADOR MOLECULAR • A presença de del(5q) isolada ou associada a uma alteração citogenética adicional exceto -7 ou del(7q) • WHO 2016: pesquisa de mutação TP53 • Mutação TP53 define pior resposta à lenalidomida e pior prognóstico

Jadersten M et al. J Clin Oncol . 2011, 29:1971.

Strong p53 expression in ≥1% of bone marrow progenitor cells (35% of patients) was significantly associated with:

• higher acute myeloid leukemia risk (p=0.00) • shorter overall survival (p=0.01) • lower cytogenetic response rate (p=0.00)

p53

This study validates p53 immunohistochemistry as a strong and useful predictive tool in patients with lower-risk del(5q) MDS Saft L et al Haematologica. 2014; 99: 1041.

p53

Strong p53 expression in â&#x2030;Ľ1% of bone marrow progenitor cells Saft L et al Haematologica. 2014; 99: 1041.

p53 cellular TP53 mutation burden (next-generation sequencing) was strongly correlated with strength of p53 expression

McGraw KL et al Haematologica. 2016 Aug;101: e320

p53

McGraw KL et al Haematologica. 2016 Aug;101: e320

high correlation in the mutational data from cells of the peripheral blood and bone marrow: PB is a reliable source for mutation monitoring Belickova M et al Oncotarget 2016 Jun 14; 7: 36266.

Overall survival Mutated 1.296 days wild-type TP53 = not reached p=0,002

Multivariable analysis: Mutated TP53 most powerful factor predicting survival HR 5,044 p=0,008 Mossner M et al Leukemia 2016 Sep; 30: 1956.

PRACTICAL CONSIDERATIONS adverse events occurred primarily during the first two cycles and decreased thereafter and should be managed with treatment interruption or dose reduction when appropriate response should be assessed after 2–4 months of treatment 67% of patients achieved RBC-transfusion independency ≥8 weeks, with a median time to onset of 4.6 weeks (up to four cycles)

PRACTICAL CONSIDERATIONS 73% of patients achieved a CyR, including 45% with a complete CyR (suppressing the del(5q) clone rather than eradicating it) median duration of response was 2.3 years in patients with isolated del(5q) achievement of RBC-TI or CyR with lenalidomide treatment is associated with prolonged survival and time to AML progression

p53

PRACTICAL CONSIDERATIONS

Currently, there are no clear guidelines on how to manage patients with mutated p53. It is not known if their outcomes are improved by treatment with hypomethylating agents or transplant. Keep them under close observation Lenalidomide should not be withdrawn prematurely in patients who achieve transfusion independence, as PCyR patients seem to have a higher relapse rate than CCyR patients Only CCyR patients (treated for at least 6 months beyond CCyR) consistently seem to achieve very prolonged freedom from transfusion.

Perguntas que ainda aguardam respostas:

• Qual a segurança da interrupção do tratamento após resposta hematológica e citogenética? Impacto na sobrevida global?

• Qual a chance de resposta ao re-tratamento com lenalidomida após a recidiva?

• Nos casos em que não se dispõe da citogenética

convencional, FISH é válido para monitoramento de resposta e decisão terapêutica?

• Há benefício na associação de drogas em caso de falha primária ou perda de resposta?

MDS without del

LOW RISK • anemia • dependência transfusional

ERITROPOETINA • resposta: 40-50% • duração: 24-36m

refratariedade recidiva

Resistência primária: LMA em 5 anos: 18.9% SG: 40.1m

Resistência primária/falha precoce (<6m): LMA em 5 anos: 21.6% vs 9% (p=0,02) SG: 36.7m vs 54.3m (p=0,02)

Falha de resposta: LMA em 5 anos: 11.6% SG: 44,9m Kelaidi C et al Leukemia 2013; 27: 1283.

• Higher probability of achieving TI: • shorter time from TD to ESA initiation (early administration) • use of darbepoetin • The probability of achieving TI decreased beyond 8 weeks of treatment and was very low beyond 16 weeks

Duong VH et al Leuk Res 2015; 39: 586.

Lenalidomida (não aprovada pelo FDA ou EMEA ) menor percentual de resposta e duração de resposta

LEN alone resposta: 20 a 25% duração: 12 a 18 m

Toma A et al Leukemia 2016; 30: 897.

Erythroid response after 4 cycles: 23.1% and 39.4% (p= 0.004) RBC-TI: NS Median duration response: NS Toma A et al Leukemia 2016; 30: 897.

Lenalidomide yields sustained RBC-TI in 26.9% of RBC transfusionâ&#x20AC;&#x201C; dependent patients with lower risk non-del(5q) MDS ineligible for or refractory to erythropoiesis-stimulating agents.

Response to lenalidomide was associated with improved HRQoL. Treatment-emergent adverse event data were consistent with the known safety profile of lenalidomide.

Santini V et al J Clin Oncol. 2016 Sep ; 34: 2988.

Santini V et al J Clin Oncol. 2016 Sep ; 34: 2988.

LENALIDOMIDE OR HYPOMETHYLATING AGENT AFTER FAILURE OF TREATMENT WITH ESA? Moffitt Cancer Center Retrospective anaysis of 64 patients The HI-E rate with lenalidomide as first-line therapy was 38% versus only 12% when lenalidomide was used as second-line therapy (P = .04).

No significant differences in overall survival or rates of leukemic progression, Zeidan AM Clin Lymphoma Myeloma Leuk 2015; 15: 705.

Lenalidomida Azacitidina com ou sem EPO (mut TET2)

The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin ThĂŠopot S et al Haeamatologica 2016 Aug; 101: 918.

RBC-TI

Overall response

ThĂŠopot S et al Haeamatologica 2016 Aug; 101: 918.

ThĂŠopot S et al Haeamatologica 2016 Aug; 101: 918.

Lenalidomida Azacitidina com ou sem EPO (mut TET2) resultados insatisfatรณrios Azacitidina oral

Garcia-Manero G et al Leukemia 2016 Apr; 30: 889.

• 300mg once daily for 14 days or 21 days (28-day cycles) • Overall response (IWG 2006) 36% of patients receiving 14-day dosing 41% receiving 21-day dosing

• RBC TI was similar with both dosing schedules (31% and 38%, respectively)

Garcia-Manero G et al Leukemia 2016 Apr; 30: 889.

Garcia-Manero G et al BMC Hematol 2016 May; 16: 12.

Lenalidomida Azacitidina com ou sem EPO (mut TET2) resultados insatisfatórios Azacitidina oral menor incidência de citopenias menor efeito hipometilante nova posologia: 14 ou 21 (fase III QUAZAR) independência transfusional: 38% Inibidores de TGF-β melhor resposta em pacientes com SA / mut SF3B1 • sotatercept (fase II) • luspatercept (fase III)

National Institute of Health Response Model: Younger age Shorter transfusion duration HLA-DR15 genotype positivity

• • •

Moffitt Cancer Center: retrospective anaysis of 66 patients hematologic response (42%) in the range of other therapies no significant effect of age, HLA-DR15, or duration of transfusions trend favored treatment within 2 years from diagnosis (early) first-line ATG or after lenalidomide responded better than after azacitidine or third-line therapy.

• • • • •

Haider M et al Clin Lymphoma Myeloma Leuk 2016 Aug; 16: S44-8.

Publicação no Diário Oficial da União: D.O.U. Nº 244, de 17 de dezembro de 2014, pág.

79

Resposta eritróide variável: 10 a 50%

Hematopoietic Cell Transplantation for Myelodysplastic Syndromes expectant nontransplant management is more appropriate for patients with lower-risk disease

Bhatt VR et al J Oncol Pract 2016 Sept; 12: 786.

heterogeneous genomic background

Malcovati L et al Blood 2014; 124: 1513.

Prebet T et al Clin Lymphoma Myeloma Leuk 2016 Aug 16: 57.

Optimization of frontline therapies Biomarkers of response New strategies to prevent resistence New stategies to restore drug sensitivity New drugs

UNIVERSIDADE FEDERAL DO CEARÁ Hospital Universitário Walter Cantídio Serviço de Hematologia

silviamm@ufc.br