LE SINDROMI MIELODISPLASTICHE : Aspetti biologici e terapia. Pescara, Auditorium Petruzzi - 7 Luglio 2011

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1 LE SINDROMI MIELODISPLASTICHE : Aspetti biologici e terapia Pescara, Auditorium Petruzzi - 7 Luglio 2011

2 Il supporto trasfusionale e la Terapia Ferrochelante

3 Rischio cardiovascolare nei pazienti trasfusione dipendenti I pazienti che sviluppano dipendenza da trasfusione hanno un rischio significativamente più elevato di: morte per cause non leucemica: HR 4.31, p< sviluppare patologie cardiache: HR 4.16, p< morte per cause cardiache: HR 4.88, p< Della Porta, Abstract ASH 2008 Della Porta, Abstract 2453, ASH 2007

4 MDS e Rischio cardiovascolare Da un analisi retrospettiva condotta su 840 pazienti con MDS: 25% dei pazienti è affetto da comorbidità cardiovascolari 63% delle morti NLD è dovuto a insufficienza cardiaca Dall analisi multivariata è emerso che l insorgenza di una qualsiasi comorbidità cardiaca: Aumenta in modo significativo il rischio di morte non leucemica: HR= 3.7 p<0.001 Della Porta, Abstract 2453, ASH 2007 Della Porta, Abstract ASH 2008

5 Conseguenze dell anemia sul sistema cardiovascolare L analisi ecocardiografica di 39 pazienti con MDS ha dimostrato che: 11/12 pazienti trasfusione-dipendenti vs 13/27 pazienti non trasfusione-dipendenti il rimodellamento cardiaco è più frequente nei pazienti trasfusione-dipendenti rispetto a quelli liberi da trasfusione (p=0.017) il rimodellamento cardiaco è associato a bassi livelli di Hb (valore cut-off: Hb <10,7 g/dl) l incremento di 1 g/dl Hb riduce il rischio di rimodellamento cardiaco del 49% Oliva EN, et al. Leukemia Research 2005;29:

6 Anemia e malattie cardiovascolari Riduzione dell emoglobina Ipossia tissutale Aumento del lavoro cardiaco Attivazione neurormonale Ipertrofia ventricolare sinistra Cardiopatia ischemica Peggioramento o precipitazione di: Insufficienza cardiaca congestizia Aritmie Angina pectoris Infarto miocardico Modificata da National Anemia Action Council. Anemia: A Hidden Epidemic. Los Angeles, CA: HealthVizion Communications, Inc., 2002

7 Survival of MDS patients according to transfusion dependency Overall survival (HR = 1.91, p < 0.001) Leukaemia-free survival (HR = 1.84, p = 0.001) Cumulative proportion surviving Transfusion-independent Transfusion-dependent Survival time (months) Cumulative proportion surviving Transfusion-independent Transfusion-dependent Survival time (months) 180 Data from Malcovati L, et al. J Clin Oncol. 2005;23:

8 Survival and risk of leukemic evolution according to WPSS at diagnosis Overall survival (P<.001) Risk of AML evolution (P<.001) J Clin Oncol 2007;25:

9 Linee guida per il supporto trasfusionale Ottimizzazione del supporto trasfusionale

10 GIMEMA MDS0306 Livello Hb Pretransfusionale Mediana 8.2±1 (range 5,1 12 g/dl)

11 Il supporto trasfusionale e la Terapia Ferrochelante

12 Is iron overload associated with reduced survival? Can iron chelation improve survival?

13 Is iron overload associated with reduced survival? Can iron chelation improve survival?

14 Iron overload in malignancies clinical studies patients Units transfused Results Ref 15 (40-71 years) Mean 120 (range ) Glucose intolerance (all) Heart failure (5) Liver iron 7-26 ULN Schafer AI, et al. N Engl J Med 1981;304: MDS patients mean survival: 39.4 mo Mean 79 (range ) 20 cardiac failure (14 died) Hepatomegaly 11 Diabetes mellitus 5 Jaeger M, et al. Beitr Infusion Ther 1992;30: patients with 5q Projected median survival 63 mo NA Myocardial dysfunction = 7 (two died) Elevated LFT = 6 Cirrhosis = 1 Diabetes = 4 Skin changes = 3 Mathew P, et al. Blood 1993;81:

15 Non-leukaemic death in patients with MDS Probability of non-leukaemic death in low-risk MDS patients according to transfusion dependency 1 Non-leukaemic cause of death in patients with MDS N = N = 840 Percentage Cardiac failure Infection Haemorrhage Hepatic cirrhosis 0 Cardiac failure Infection Haemorrhage 1. Malcovati L, et al. J Clin Oncol. 2005;23: Della Porta et al. Blood. 2007;110:[abstract 2453].

16 Survival of MDS patients according to transfusion dependency Overall survival (HR = 1.91, p < 0.001) Leukaemia-free survival (HR = 1.84, p = 0.001) Cumulative proportion surviving Transfusion-independent Transfusion-dependent Survival time (months) Cumulative proportion surviving Transfusion-independent Transfusion-dependent Survival time (months) 180 Data from Malcovati L, et al. J Clin Oncol. 2005;23:

17 Survival of MDS patients according to ferritin level RA/RARS/5q (HR = 1.42, p < 0.001) RCMD/RCMD-RS (HR = 1.33, p = 0.07) Cumulative proportion surviving Serum ferritin (µg/l) 1,000 1,500 2,000 2, Survival time (months) Cumulative proportion surviving Serum ferritin (µg/l) 1,000 1,500 2,000 2, Survival time (months) 180 RA = refractory anaemia; RARS = RA with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia. Based on Malcovati L, et al. Haematologica. 2006;91:

18 Patient characteristics SURVIRON Study n=2994 according to FAB criteria (n=2107 according to WHO 2001 criteria); median age: 74 years n Complete transfusional history available 2241 Transfusion dependent at diagnosis 835 Transfusion dependent during follow-up 526 Non-transfusion dependent 880 SF levels available* 1634 Karyotyping successfully performed (classification by IPSS) 2074 Low 861 Intermediate Intermediate High risk 154 WPSS-defined 1228 Very low 257 (21%) Low 385 (31%) Intermediate 217 (18%) High 271 (22%) Very high 98 (8%) * 3 measurements in 762 patients Update ASH 2008 MDS

19 Multivariate analysis: by RBC transfusion dependency (n=2241) Overall survival y t i l i b a b No RBC transfusion dependency o r P Time without AML SURVIRON Study Simon & Makuch method No RBC transfusion dependency RBC transfusion dependency P< RBC transfusion dependency Years from diagnosis Variable* HR P value RBC TD 7.20 <0.001 Iron overload 2.11 <0.001 IPSS 1.50 < P< Years from diagnosis Variable* HR P value RBC TD 2.90 <0.001 IPSS 1.92 <0.001 Iron overload * Multivariate analyses including all variables except WPSS. Cases with less than 3 ferritin measurements were excluded (n=731)

20 Multivariate analysis: by serum ferritin level SURVIRON Study Overall survival Time without AML Simon & Makuch method Ferritin <1000 ng/ml 0.6 Ferritin <1000 ng/ml 0.6 Ferritin 1000 ng/ml P< n=762 Ferritin 1000 ng/ml Years from diagnosis Variable* HR P value Iron overload 4.34 <0.001 WPSS 1.60 < P< n= Years from diagnosis Variable* HR P value WPSS 2.24 <0.001 Iron overload 2.13 <0.001 * Multivariate analyses including WPSS and development of iron overload (time-dependent). Cases with less than 3 ferritin measurements were excluded (No. = 580)

21 Majo clinic study in RARS Chee CE, Steensma DP, Wu W, Hanson CA, Tefferi A. Am J Hematol Aug;83(8): In a retrospective study of 126 adult patients with refractory anemia with ringed sideroblasts (RARS) red blood cell (RBC) transfusion requirement at diagnosis (P = 0.001), but not the number of RBC units transfused during the disease course (P = 0.17) neither serum ferritin, were independently associated with inferior survival. Median follow up 36 mo There were no correlations between survival and serum ferritin level, This study does not support the contention that transfusional hemosiderosis is an adverse prognostic factor in "good risk" myelodysplastic syndrome.

22 Literature review Transfusion dependency on outcome Serum ferritin on outcome Serum ferritin on Leukemia Pavia Group MDS yes yes no Düsseldorf Registry Japan registry Spanish registry Mayo Experience MDS yes yes NA MDS yes yes NA 2241 MDS yes yes yes 126 RARS yes no no

23 Literature review Transfusion dependency on outcome Serum ferritin on outcome Serum ferritin on Leukemia Pavia Group MDS yes yes no Düsseldorf Registry Japan registry Spanish registry Mayo Experience MDS yes yes NA MDS yes yes NA 2241 MDS yes yes yes 126 RARS yes no no

24 Literature review Transfusion dependency on outcome Serum ferritin on outcome Serum ferritin on Leukemia Pavia Group MDS yes yes no Düsseldorf Registry Japan registry Spanish registry Mayo Experience MDS yes yes NA MDS yes yes NA 2241 MDS yes yes yes 126 RARS yes no no

25 Literature review Transfusion dependency on outcome Serum ferritin on outcome Serum ferritin on Leukemia Pavia Group MDS yes yes no Düsseldorf Registry MDS yes yes NA Japan registry MDS yes yes NA Spanish registry 2241 MDS yes yes yes Mayo Experience 126 RARS yes no no

26 Is iron overload associated with reduced survival? Conclusions Retrospective studies Consensus regarding transfusion dependency impact on survival Large majority consensus regarding transfusion burden and serum ferritin impact on survival Limited clinical data regarding serum ferritin impact on leukemia risk Limitation: all these study refer to patients on supportive care only

27 Is iron overload associated with reduced survival? Can iron chelation improve survival?

28 Improved survival in patients with MDS receiving chelation therapy Retrospective review of 178 patients (36 RA, 42 RARS, 28 RAEB, 16 RAEB-T or AML, 25 CMML, 31 other) 28 Serum ferritin 2000 ng/ml 22 Clinical evidence of iron overload 18 Chelation therapy 10 No ICT Median overall survival for Low or Int-1 IPSS Not reached at 160 mo 40 mo ( ) ICT, iron chelation therapy Leitch HA. Clin Leukemia 2008;2: (P<0.03)

29 Iron chelation therapy improves survival in heavily transfused lower-risk MDS 165 patients with MDS in France, 97 of whom had Low- or Int-1 MDS 53 patients (55%) received chelation therapy for at least 6 months: Rose C et al. Leuk Res 2010;34: overnight sc DFO, 5 deferiprone alone, 4 deferiprone + DFO, 4 deferasirox, 7 bolus DFO, 5 iv DFO Mean serum ferritin levels were 541, 1491 and 2788 ng/ml at diagnosis, onset of chelation and last evaluation, respectively No significant differences between the two groups in total number of comorbidities or the number of patients with iron-related comorbidities WHO classification IPSS, n(%) No iron chelation therapy (n=44) Iron chelation therapy (n=53) Total (n=97) P-value Low 15 (34.1) 30 (56.6) 45 (46.4) Int-1 29 (65.9) 23 (43.4) 52 (53.6) ns

30 Improved survival in patients with MDS receiving chelation therapy: Kaplan-Meier survival Survival distribution function Non-chelated Chelated P< Median overall survival: 53 months in non-chelated patients 124 months in chelated patients Time from diagnosis to death (months) Rose C et al. Leuk Res 2010;34:

31 Improved survival in adequately chelated patients with MDS (b) Survival distribution function Non-chelated Weak chelation Adequate chelation P< Median overall survival: 85 months in patients with weak chelation 124 months in patients with adequate chelation Time from diagnosis to death (months) Rose C et al. Leuk Res 2010;34:

32 Iron chelation therapy improves survival in MDS Matched-pair analysis of 186 MDS patients to evaluate survival after receiving ICT or transfusion therapy 1.0 Overall survival 1.0 AML transformation Cumulative survival Months Chelation No Chelation P= Cumulative risk of AML evolution Chelation No Chelation P= Months Fox F et al. Presented at ASH 2009 [Blood 2009;114(11):abst 1747] Slide used with the permission of Dr Frank Fox, Heinrich-Heine-University, Düsseldorf, Germany

33 Improved survival in patients monitored for iron overload Patients monitored for iron overload (n=55) had significantly longer median survival compared with unmonitored patients (n=44; 16.1 vs 2.3 months, P<0.001) Overall survival rate (%) Log-rank P Months since 10th RBC unit Patients monitored Patients not monitored Ray L et al. Presented at ASH 2010 [Blood 2010;116(21):abst 1503]

34 Literature review Note Chelation on outcome Chelation on leukemia Leitch HA retrospective yes NA Clin Leukemia 2008;2: Ref. Rose C Retrospective prospective. Not randomized yes NA Leuk Res 2010;34: Fox F Case Control yes NO ASH 2009 (Abs 1747) Ray L Case control yes NA ASH 2010 (Abs 1503)

35 Literature review Note Chelation on outcome Chelation on leukemia Leitch HA retrospective yes NA Clin Leukemia 2008;2: Ref. Rose C Retrospective prospective. Not randomized yes NA Leuk Res 2010;34: Fox F Case Control yes NO ASH 2009 (Abs 1747) Ray L Case control yes NA ASH 2010 (Abs 1503)

36 Literature review Note Chelation on outcome Chelation on leukemia Leitch HA retrospective yes NA Clin Leukemia 2008;2: Ref. Rose C Retrospective prospective. Not randomized yes NA Leuk Res 2010;34: Fox F Case Control yes NO ASH 2009 (Abs 1747) Ray L Case control yes NA ASH 2010 (Abs 1503)

37 Can iron chelation improve survival? Conclusions Retrospective prospective non randomized - studies Consensus on chelation therapy impact on survival All these study refer to patients on supportive care only Need for prospective randomized trial

38 The Majo clinic point of view. A Tefferi and R M Stone Iron chelation therapy in myelodysplastic syndrome Cui bono? Leukemia 2009; 23: Increased serum ferritin in transfusion-dependent cancer patients is a fact and not necessarily a problem. Controlled clinical trials, and not a litany of consensus statements, are needed to justify such treatment. Primary outcome measures in such trials must portray meaningful health outcome rather than a banal effect on laboratory surrogates of iron overload.

39 TELESTO TRIAL - A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF DEFERASIROX (EXJADE ) IN PATIENTS WITH LOW/INTERMEDIATE-1 RISK MDS AND TRANSFUSIONAL IRON OVERLOAD. Composite primary endpoint (event-free survival) has been including: death, cardiac and hepatic non-fatal events. echo-cardiographic evidence of worsening cardiac function demonstrated by at least >15% worsening of left ventricular ejection fraction, hospitalization for congestive cardiac failure. increase in transaminases and bilirubin or cirrhosis development. 630 patients in 125 Centers worldwide

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41 Iron chelation therapy is recommended in all patients with low-int1 IPSS risk disease who receive regular red-cell transfusion therapy; Iron chelation therapy should be considered for transfusion-dependent patients with INT2-high IPSS risk disease when they are responding to therapies able to modify their life expectancy or have a HSCT in their therapeutic program (grade D).

42 The therapy should be started after the patients has received 20 packed red blood cell units (i.e. 4 grams of iron) (grade B). Inception of iron chelation therapy should not be decided based uniquely on the level of serum ferritin (grade D).

43 Due to proven efficacy, oral administration and favourable pharmacokinetics, deferasirox is the firstchoice iron chelation therapy in MDS (grade B).

44 In patients timely starting iron chelation, the initial dosage of deferasirox should be low, i.e. 10 mg/kg. Deferasirox dosage should be adjusted according to the transfusional regimen, serum ferritin and iron-induced organ damage up to mg/kg, if tolerated (grade C). Serum ferritin should be used as a routine monitoring measurement (grade D).

45 Iron chelation in MDS future directions Comprehension of impact of iron damage in MDS scenario (stronger and faster) Differences from thalassemia age Co-morbodity Malignant disease Compliance Chelation strategy optimization on MDS clinical scenario

46 Thank you for your attention