Treatment of high risk MDS Valeria Santini MDS Unit, AOU Careggi, - PowerPoint PPT Presentation

Treatment of high risk MDS Valeria Santini MDS Unit, AOU Careggi, Università di Firenze

Therapeutical options

Azanucleosides, Cytosine Analogues with hypomethylating properties Cytosine 5-methyl- 5-aza- 5-aza-2 � -deoxy- cytosine cytidine cytidine Azacitidine Decitabine Santini et al, Ann Int Med 2001

Hypomethylating agents in higher risk MDS: response AZACITIDINE DECITABINE 60 60 European ADOPT cumulative 50 50 MDACC CALGB 40 40 2007 % Response % Response CALGB 2006 AZA-001 30 30 MDACC EORTC 2006 20 20 10 10 0 0 75mg/m 2 /day 75mg/m 2 /day 75mg/m2/day 15mg/m 2 /T 15mg/m 2 / 20mg/m 2 / 20mg/m 2 / 15mg/m 2 / x 7 sc x 7 sc/iv x 7 sc IDx3 iv TIDx3 iv day x5 sc dayx5iv TIDx3 iv 20mg/m 2 / day x5 iv 10mg/m 2 / day x10iv CR+PR HI CR+PR+HI 1) Wjiermans Ann Hematol 2005;84:9 2) Kantarjian Cancer 2006;106:1794 1) Silverman JCO 2002;20:2429 3) Kantarjian Blood 2007;109:52 4) Steensma JCO 2009;24:3842 2) Silverman JCO 2006;24:3895 3) Fenaux Lancet Oncol 2009;10:223. 5) Luebbert JCO 2011;29:1987

Hypomethylating agents in higher risk MDS: Overall survival AZACITIDINE DECITABINE 30 30 AZA-001 MDACC 25 25 2007 European CALGB cumulative 20 20 OS months OS months MDACC CALGB 2006 ADOPT 2006 15 15 EORTC 10 10 5 5 0 0 75mg/m 2 /day 75mg/m 2 /day 75mg/m 2 /day 15mg/m 2 /T 15mg/m 2 / 20mg/m 2 / 20mg/m 2 / 15mg/m 2 / x 7 sc x 7 sc/iv x 7 sc IDx3 iv TIDx3 iv day x5 sc dayx5iv TIDx3 iv 20mg/m 2 / day x5 iv 10mg/m 2 / day x10iv 1) Wjiermans Ann Hematol 2005;84:9 2) Kantarjian Cancer 2006;106:1794 1) Silverman JCO 2002;20:2429 3) Kantarjian Blood 2007;109:52 4) Steensma JCO 2009;24:3842 2) Silverman JCO 2006;24:3895 3) Fenaux Lancet Oncol 2009;10:223 5) Luebbert JCO 2011;29:1987

Response duration with decitabine or azacitidine therapy ranges from 6 to 26 months

FACTS OF HYPOMETHYLATING AGENTS Beneficial effects of hypomethylating agents are noted generally after 2-4 cycles of therapy Achievement of sole hematological improvement may assure prolonged survival Patients with complex karyotype may achieve response although not durable Interruption of treatment provokes loss of response BUT… Patients resistant or relapsed have an extreme short survival irrespective of further treatment References: JCO 201129: 1987;Lancet Oncol 2009 10:223; JCO 2009 27:3842; Blood 2007 109:52; Cancer 2006 106:1794; JCO 2002; Cancer 2010 116:3830; JCO 2011 29:3322; Leukemia 2011 25:1207)

Overall survival: AZA vs CCR ITT analysis Log-rank p = 0.0001 1.0 HR 0.58, 95% CI 0.43–0.77 0.9 Proportion surviving Deaths: AZA 82, CCR 113 0.8 Difference: 9.4 mos 0.7 50.8% 0.6 24.4 mos 0.5 0.4 15 mos 26.2% AZA 0.3 CCR 0.2 0.1 0 0 5 10 15 20 25 30 35 40 Time from randomization: months CI, confidence interval; ITT, intention-to-treat. Fenaux P, et al. Lancet Oncol. 2009;10:223-32.

MDS: treatment with HMT Advantages: prolonged survival high rate hematologic improvement no need of hospitalization low toxicity feasible in very elderly patients Disadvantages: prolonged treatment retarded effect relapse/resistance no eradication of the clone

AZA vs CCR: OS in Pts with Best Response of HI Log rank p = <0.0001 1.0 HR=0.23 [95% CI: 0.10-0.51] 0.9 Death: AZA = 8, CCR = 27 0.8 AZA - HI 0.7 71.7% Proportion Surviving Median not reached 0.6 0.5 0.4 16.6 months 27.1% 0.3 CCR - 0.2 HI 0.1 0.0 24 0 5 10 15 20 25 30 35 40 Time (months) from Randomization Gore S, et al, Haematologica. 2013 Jul;98(7):1067-72.

Azacitidine (AZA) in Higher Risk MDS Patients (pts) Aged ≥ 80 Years : OS 1.0 < 0.8 Age > 80 years 0.6 OS 0.4 0.2 0.0 5 Time (months) • OS similar in patients aged < 80 and ≥ 80 years ( P = .6) • Median OS 12.1 months; 1- and 2-year OS: 50% and 23.2% Itzykson, R., et al. Blood . 2009;114(22):705. OS, overall survival.

What happens in real life? 370 higher risk MDS pts treated with AZA Median aza cycles 7 Median OS 16 mos

What happens in real life? AZA treatment/Spanish experience Median OS 13,4 vs 12,2 Age, IPSS, LDH adapted Bernal et al, Leukemia (2015) 29, 1875 – 1881

What happens in real life? AZA treatment Dutch experience Dinmohamed et al. Leukemia (2015) 29, 2449 – 2451

What happens in real life? AZA treatment/Dutch experience Dinmohamed et al. Leukemia (2015) 29, 2449 – 2451

Low dose decitabine vs. BSC in elderly patients with intermediate or high risk MDS not eligible for chemotherapy: Randomized Phase 3 Study 100 Overall 90 survival 80 Median (months): 10.1 vs 8.5 70 60 HR = 0.88 , 95% CI (0.66, 1.17) Decitabine 50 Logrank test: p=0.38 40 Supportive care 30 20 10 0 (months) 0 6 12 18 24 30 36 42 O N Number of patients at risk : Supportive care 96 114 71 38 22 10 6 3 Decitabine 99 119 83 53 24 15 4 4

Progression-Free Survival 100 90 80 70 Median (months): 6.6 vs 3 60 Decitabine HR = 0.68 , 95% CI (0.52, 0.88) 50 Logrank test: p=0.004 40 30 20 Supportive care 10 0 (months) 0 6 12 18 24 30 36 O N Number of patients at risk : Supportive care 105 114 33 15 7 3 1 Decitabine 113 119 62 32 11 2 0

Progression-free survival after decitabine is strikingly prolonged in the presence of 2 or more monosomies Lübbert, Suciu et al., 2016

Resistance to HMA: 40-60% of MDS patients fail to achieve a response to HMAs Silverman LR et al JCO 2002;20:2429-40 Silverman LR et al Leukemia 1993;7 Suppl 1:21-9 Itkynson R et al Blood 2011;117:403-11 Kadia tm et al Semin Oncol 2011;38:682-92

Resistance/sensitivity to HMAs: Clinical/individual Disease related cytogenetics somatic mutations drug metabolizing enzyme expression DNA methylation pattern baseline

Survival after decitabine failure in MDS/AML patients Median OS 4.3 mos Jabbour et al, Cancer 116:3830(2008)

Survival after azacitidine failure in MDS/AML patients A 100 JHU AZA001 French program 75 Overall Survival (%) Median survival 50 5.6 mos 25 P = .34 0 365 730 1,095 1,460 Time Since AZA Failure (days) B Prebet et al, JCO 29:3322 (2011)

Survival according to salvage therapy 100 Median OS Type of salvage N ORR (months) Unknown 165 NA 3.6 Overall Survival (%) 75 Best supportive 122 NA 4.1 care Low-dose 32 0/18 7.3 chemotherapy 50 Intensive 35 3/22 8.9* chemotherapy Investigational The difference between IT and HSCT did 13.2* † 44 4/36 therapy Allogeneic not reach significance (P .09). 25 19.5* † 37 13/19 transplantation 0 365 730 1,095 1,460 Time Since AZA Failure (days) Prebet et al, JCO 29:3322 (2011)

Can we predict response to HMAs?

Parameters predictive of HMT response Clinical Positive Negative Doubling of platelets BM blasts > 15% Previous therapy Transfusion dependency Marrow fibrosis grade 3 Molecular Positive Negative Mutated TET2 Mutated p53 ?????? Mutated DNMT3a Abnormal/complex Karyotype Low expression of UCK1 Mutated ASXL1 Overexpression of CXCL7 and CXCL4 Wjiermans et al Ann Haematol 2005; Itkynson et al Leukemia 2011; Kulasekararaj et al Blood 2010; Itkynson et al Leukemia 2011; Itkynson et al Blood 2011; Sanna et al Leuk Res 2011; Sekeres et al Blood 2012, Meldi, et al, JCI 2015

Impact of bone marrow cellularity on efficacy and tolerance of AZA AZA – median OS NR 1.0 1.0 CCR – median OS AZA – median OS 21.1 months Proportion surviving 16.9 months CCR ‒ median OS 15.3 months Log-rank p = 0.001 Log-rank p = 0.012 Time since randomization, months Time since randomization, months § No difference in HI rate (hypocellular 52.5% vs normocellular 48%) § Median cycle duration (hypocellular 35.5 days vs normocellular 33 days) § No difference in grade ≥ 3 haematological AEs Seymour JF, et al Br J Haematol. 2014 Apr;165(1):49-56.. AE, adverse event.

Prognostic factors for response and OS in Int-2/High-risk MDS patients treated with AZA OS prognostic score GFM ATU compassionate use study Variable Score (n = 282) Performance status ≥ 2 1 Circulating blasts 1 AZA response score RBC transfusion 1 dependence ≥ 4 U/8 wks Response rate, Intermediate karyotype 1 Variable p value* yes/no % High-risk karyotype 2 Prior LD ARA- 24/46 0.009 C Low 1.0 Intermediate Cumulative proportion High Normal 0.8 51/39 0.003 p < 0.0001 karyotype surviving 0.6 Marrow blasts Low: 0 35/50 0.004 > 15% Intermediate: 1–3 0.4 High: 4–5 Response duration 0.2 Complex 4.6 vs 10.3 0.0003 0 karyotype months 0 6 12 18 24 36 42 48 54 60 30 Duration, months * Multivariate analysis. Itzykson R, et al. Blood. 2011;117:403-11. ATU, authorization for temporary use.

TET2 mutations predict response to hypomethylating agents Bejar R et al; Blood 2014; 124:2705

Risk stratification in MDS patients treated with hypomethylating agents Response to HMT OS after HMT Traina F et al, Leukemia 2013

Mutational profiles do not correlate with response to DAC Non- Responders Responders p=NS for all mutations Meldi et al; J Clin Invest. 2015 May;125(5):1857-72.