Tratamiento de soporte incluido la sobrecarga de hierro - Dra. Silvia Magalhaes

UNIVERSIDADE FEDERAL DO CEARÁ Hospital Universitário Walter Cantídio

MYELODYSPLASTIC SYNDROMES IRON OVERLOAD AND IRON CHELATION Silvia Magalhães Universidade Federal do Ceará - Brazil 2016

A total of four RCTs met the inclusion criteria, however three studies are ongoing, with only one being completed (13 patients).

There is currently a lack of evidence for the recommendation of a particular transfusion strategy for bone marrow failure patients undergoing supportive treatment only.

Gu Y et al Cochrane Database Syst Rev 2015; 5: CD011577 Universidade Federal do Cearรก

IRON OVERLOAD Iron overload is a potentially life-threatening consequence of multiple red-blood-cell transfusions

Individually tailored approach to chelation reduces morbidity and mortality Universidade Federal do Cearรก

IRON OVERLOAD DIAGNOSIS

Adapted from Taher AT, Hemoglobin, 2009

NUMBER OF UNITS TRANSFUSED !

Universidade Federal do Cearรก

MECHANISMS OF TOXICITY

Universidade Federal do Cearรก

MECHANISMS OF TOXICITY NTBI

Porter JB et al Hematol Oncol Clin North Am. 2014 Aug; 28: 683.

Universidade Federal do Cearรก

de Souza GF et al J Clin Pathol. 2013 ; 66: 996.

Universidade Federal do Cearรก

CONDITIONS ASSOCIATED WITH TRANSFUSIONAL IOL

COMORBIDITIES

Porter JB et al Hematol Oncol Clin N Am 2014; 28: 683 Universidade Federal do Cearรก

MDS – IMPACT OF IRON OVERLOAD

• Medicare: increased risk of cardiac events and diabetes mellitus

Goldberg SL J Clin Oncol 2010; 28: 2847

• Deleterious effect on erythropoiesis Hartmann J et al Leuk Res 2013; 37: 327

Universidade Federal do Ceará

• iron overload suppresses the proliferation of erythroid progenitors cells (BFU-E) • myeloid compartment (CFU-GM) not affected • negative impact reversible by sufficient iron chelation therapy.

Hartmann J et al Leuk Res 2013; 37: 327 Universidade Federal do Ceará

MDS – IMPACT OF IRON OVERLOAD

• Medicare: increased risk of cardiac events and diabetes mellitus

Goldberg SL J Clin Oncol 2010; 28: 2847

• Deleterious effect on erythropoiesis • Deleterious effect on bone marrow microenvironment Hartmann J et al Leuk Res 2013; 37: 327

Okabe H et al Eur J Haematol 2014; 93: 118

Universidade Federal do Ceará

• bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution

CONCLUSIONS: findings indicate that excess iron can damage bone marrow stromal cells and other vital organs and impacts the hematopoietic microenvironment negatively presumably by increased oxidative stress Okabe H et al Eur J Haematol 2014; 93: 118 Universidade Federal do Ceará

MDS – IMPACT OF IRON OVERLOAD

• Medicare: increased risk of cardiac events and diabetes mellitus

Goldberg SL J Clin Oncol 2010; 28: 2847

• Deleterious effect on erythropoiesis • Deleterious effect on bone marrow microenvironment Hartmann J et al Leuk Res 2013; 37: 327

Okabe H et al Eur J Haematol 2014; 93: 118

Negative impact on overall survival in lower-risk MDS patients Malcovati L, et al Haematologica 2006; 91: 1588

Universidade Federal do Ceará

MDS – IMPACT OF IRON OVERLOAD 0 U pRBC/4 weeks 1 U pRBC/4 weeks 2 U pRBC/4 weeks 3 U pRBC/4 weeks 4 U pRBC/4 weeks

Cumulative survival

1.0 0.8 0.6 0.4 0.2 0.0 0

20

40

60

80 100 120 140 160 180

Survival time (months)

Malcovati L, et al. Haematologica. 2006;91:1588-90.

Universidade Federal do Ceará

The findings revealed a 59% pooled reduction in mortality among TI patients when compared with TD patients Harnan S et al Acta Haematol 2016; 136:23.

Universidade Federal do Cearรก

ABOUT MECHANISMS OF ONCOGENESIS BY IRON

Universidade Federal do Cearรก

IRON OVERLOAD and GENETIC INSTABILITY

• IOL has the potential to accelerate progression of MDS towards secondary leukemia with a lower survival rate.

• Genetic instability is a common driver of MDS progression • Oxidative stress is considered to be a main factor for IOL related genetic instability

To investigate the influence of IOL (SF) on the stability of the genome of MDS patients

Westhofen G et al, 2015 Universidade Federal do Ceará

IRON OVERLOAD and GENETIC INSTABILITY

31 patients with MDS and ferritin > 275 µg/L were evaluated:

• TP53 mutations • chromosome banding analysis • molecular karyotyping (SNP array analysis) • DNA double-strand breaks • telomere length (PB granulocytes and lymphocytes) Westhofen G et al, 2015 Universidade Federal do Ceará

pts with increased SF levels were found to have significantly bigger total genomic aberrations size

Westhofen G et al, 2015 Universidade Federal do Cearรก

Patients with increased SF levels showed significant more age-adapted telomere shortening in granulocytes

Westhofen G et al, 2015

Universidade Federal do Cearรก

Patients with increased SF levels exhibited higher numbers of DNA double-strand breaks

marrow blasts <10%

Westhofen G et al, 2015

Universidade Federal do Cearรก

CONCLUSIONS

• IOL might be causally related to genetic instability in MDS patients

• SF levels not only above 1,000 µg/L, but also between upper limit of normal value but below 1,000 µg/L adversely affect genetic stability (lower than previously thought)

• Is level of genetic instability by comprehensive genomic analysis beneficial for the therapeutic decision?

Westhofen G et al, 2015

Universidade Federal do Ceará

IRON OVERLOAD and ONCOGENESIS

• Iron overload not only impacts on certain tissues, but may affect the clonal evolution of MDS through generation of reactive oxygen species

• Multivariate analyses have shown that iron overload in MDS has a prognostic impact independent of transfusion dependency Porter JB et al Crit Rev Oncol Hematol 2016; 99: 261 Universidade Federal do Ceará

Pathological mechanisms and consequences of iron overload

NF- B, nuclear factor B; ROS, reactive oxygen species; TGF, transforming growth factor.

Porter JB et al Crit Rev Oncol Hematol 2016; 99: 261 Universidade Federal do Cearรก

IRON OVERLOAD and ONCOGENESIS Iron overload causes DNA damage

• ROS may also have anti-apoptotic effects by activating

nuclear factor- B, which may contribute to MDS progression and to iron-mediated neoplasia, such as hepatoma

• patients

with hereditary hemochromatosis are at increased risk of cancer

Porter JB et al Crit Rev Oncol Hematol 2016; 99: 261 Universidade Federal do Ceará

IRON OVERLOAD and ONCOGENESIS administration of iron chelators have shed light on the role of iron overload in oncogenesis

• reduces

levels of intra- and extra-cellular free iron species and down-regulates oxidative stress parameters (in vitro and in vivo )

• antiproliferative effect due to an additional mode of action, independent from cell iron deprivation by chelation

• the activity of NF- κB is dramatically decreased after incubation with deferasirox, independent deprivation by chelation

from cell iron

Porter JB et al Crit Rev Oncol Hematol 2016; 99: 261 Universidade Federal do Ceará

IRON OVERLOAD and ONCOGENESIS

CONCLUSIONS

• These results provide further support for the hypothesis whereby iron overload-related genomic damage contributes to leukemic transformation of the MDS clone.

• It may be concluded that deferasirox might provide a

clinical benefit not only in terms of iron chelation, but also as an antiproliferative agent in some myeloid neoplasias

Porter JB et al Crit Rev Oncol Hematol 2016; 99: 261 Universidade Federal do Ceará

CHELATION THERAPY Chelation therapy must be individualized considering:

• trends in serum ferritin • ongoing transfusional iron intake • toxicities • degree of cardiac and hepatic iron loading.

Universidade Federal do Ceará

CHELATORS IN CLINICAL USE

Sheth S Curr Opin Hematology 2014 May; 21: 179 Universidade Federal do Cearรก

MECHANISM OF ACTION OF IRON CHELATORS

Temrza S et al Crit Rev Oncol Hematol 2014 Jul; 91:64 Universidade Federal do Cearรก

The recommended daily dose varies between 10-40 mg/Kg/d and is must be individually adjusted Shenoy N et al Blood 2014 Aug;124: 873.

Universidade Federal do Cearรก

Therapeutic algorithm of deferasirox High transfusional need: 30 mg/kg/day Increased transfusional need: 25 mg/kg/day Begin therapy when serum ferritin > 1,000 µg/L

Increase after dose reduction or therapy interruption

Standard dose: 20 mg/kg/day

Treatment goal serum ferritin < 1,000 µg/L

Second week: 15 mg/kg/day First week: 10 mg/kg/day

Universidade Federal do Ceará

UPDATED RECOMMENDATIONS flat dose of 500mg once daily increased weekly to achieve therapeutic goals

Nolte F et al Leuk Res 2015; 39: 1028 Universidade Federal do Cearรก

IRON CHELATION

• Multidisciplinary approach • Information and direction before initiating therapy • Regular monitoring • Early detection of adverse events and supportive care • The challenge of adherence Universidade Federal do Ceará

information is needed: ACCEPTABILITY

• risks of iron overload: the condition and its treatment • effectiveness not perceived • gradual dose titration to achieve therapeutic goals • AEs are common: discuss potential AEs before initiating therapy

• most AEs are mild to moderate in severity: tolerability

• AEs are easily and effectively managed Universidade Federal do Ceará

clear direction is needed: TOLERABILITY

• direction of use • once-daily formulation • gradual titration • need for close and regular monitoring: blood samples once a week in first month and then every four weeks

• early report of adverse events Universidade Federal do Ceará

ABOUT ADHERENCE

Universidade Federal do Cearรก

ADHERENCE

• Oral route offers important advantages over the subcutaneous or intravenous infusion

• Average adherence among patients with chronic diseases in developed countries is only ̴ 50%

WHO recognizes lack of adherence to oral medication to be the most important modifiable factor that compromises clinical response (http://whqlibdoc.who.int/publications/2003/9241545992.pdf) 2015

Universidade Federal do Ceará

EPIC Discontinuation of treatment MEAN AGE

%

GENERAL POPULATION

30,6

20,4

THALASSEMIA

18,2

9,4

SICKLE-CELL DISEASE

23,9

21,3

MDS

67,9

48,7 Gattermann N et al. Leuk Res 2010; 34: 1143.

Universidade Federal do Cearรก

What is the impact of adherence on the effectiveness of deferasirox for treatment of iron overload in myelodysplastic syndrome

Escudero-Vilaplana V et al J Clin Pharm Ther 2016 Feb; 41: 59.

Universidade Federal do Cearรก

Considering the advanced age and the high number of associated comorbidities in patients with MDS (not elegible for randomized trials)...

And more... polipharmacy, lack of confidence in the benefits of chelation, drugâ&#x20AC;&#x2122;s taste, adverse events, dose changes, complicated posology,etc What would be the real-world data?

Escudero-Vilaplana V et al J Clin Pharm Ther 2016 Feb; 41: 59.

Universidade Federal do CearĂĄ

EVOLUTION OF SERUM FERRITIN, DEFERASIROX DOSAGE AND TREATMENT ADHERENCE OVER TIME A statistically significant negative correlation between adherence and serum ferritin during treatment was observed (r= -0.288, p- 0.004)

Escudero-Vilaplana V et al J Clin Pharm Ther. 2016 Feb; 41: 59.

Universidade Federal do Cearรก

Only 54,8% of the patients maintained an adherence rate ≥90% during the whole treatment!!!!

CONCLUSIONS

• Importance of systematically evaluating adherence • Investigating causes for therapeutic non-compliance • Carry out interventions to improve therapy outcomes: multidisciplinary approach

• Education healthcare programs Universidade Federal do Ceará

Clinical case presentation

• A 59-year-old male patient presented with pancitopenia (Hb 5.4 g/dL)

• Bone marrow analysis: MDS – RCMD • Bone marrow cytogenetics: 46 XY [20] • IPSS: intermediate -I • Transfusion dependence 4 units/ m • Serum ferritin: 3,407 ng/mL (28.0–365.0) Universidade Federal do Ceará

Clinical case presentation • Treatment with ESA was started • Commencement of iron chelation with deferasirox • Significant social problems and cognitive deficit seriously compromised clinical response

INFORMATION IS CRUCIAL • how much, how often, and HOW

Universidade Federal do Ceará

Clinical case presentation MULTIDISCIPLINARY TEAM IS IMPORTANT key players needed to support adherence: doctor nurse pharmacist psychologist social service caregivers Universidade Federal do Cearรก

PRACTICAL RECOMMENDATIONS

Universidade Federal do Cearรก

BENEFIT OF CHELATION

Universidade Federal do Cearรก

BENEFIT FROM CHELATION

• prevent toxicity and reduce risks of complications • improve hematopoietic function • improve outcome of allogeneic SCT • improve overall survival

Universidade Federal do Ceará

HEMATOLOGIC IMPROVEMENT

• Direct effect on a neoplastic clone or on bone marrow environment

• Reduction in oxidative species • Inhibition of NK-κB (nuclear factor kappa-light-chainenhancer of activated B cells), abnormally activated in leukemic and MDS blast cells

• Increasing endogenous hepcidin levels Gattermann N, et al. Haematologica. 2012; 97: 1364.

Angelucci E et al Eur J Haematol 2014 Jun; 92: 527 Universidade Federal do Ceará

HEMATOLOGIC IMPROVEMENT

760 MDS patients with IOL receiving deferasirox were included in six different studies

• increase in hemoglobin level from 6 to 44.5 % • increase in platelet count from 13 to 61 % • Increase in neutrophil count from 3 to 76 %. hematologic improvements were not related to serum ferritin Breccia M et al Acta Hematol 2015; 94: 771.

Universidade Federal do Ceará

OVERALL SURVIVAL Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes

Lyons RM Leuk Res 2014 Feb; 38: 149 Universidade Federal do Cearรก

THE IMPACT OF CHELATION THERAPY ON SURVIVAL A METAANALYSIS OF MDS

Pooled differences in median overall survival. Squares represent individual studies; the size of the square represents the weight given to each study in the meta-analysis. Horizontal lines indicate 95% confidence intervals. The diamond represents the pooled results. ICT, iron chelation therapy; 95% confidence interval.

Mainous AG et al Br J Haematol 2014; 167: 720.

Universidade Federal do Cearรก

CONCLUSIONS

• Iron overload has a deleterious impact in MDS lower-risk patients

• Discontinuation rates of chelator are high.

• Information, clear direction and regular monitoring are necessary

• Adherence still a challenge • Benefit from chelation includes preventing toxicity and reducing risks of complications, improving hematopoietic function, improving outcome of allogeneic SCT and overall survival Universidade Federal do Ceará

UNIVERSIDADE FEDERAL DO CEARÁ Hospital Universitário Walter Cantídio Serviço de Hematologia

silviamm@ufc.br

Universidade Federal do Ceará