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Myelodysplastic Syndromes, Red Cell Transfusion

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Myelodysplastic Syndromes, Red Cell Transfusion Presentation by Pr. David Bowen, St James’s Institute of Oncology, Leeds Teaching Hospitals, UK

Myelodysplastic Syndromes, Red Cell Transfusion Presentation by Pr. David Bowen, St James’s Institute of Oncology, Leeds Teaching Hospitals, UK

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    Myelodysplastic Syndromes, Red Cell Transfusion Myelodysplastic Syndromes, Red Cell Transfusion Presentation Transcript

    • Myelodysplastic Syndromes red cell transfusion Pr. David Bowen St James’s Institute of Oncology Leeds Teaching Hospitals UK
    • MDS - age at diagnosis 74 (72.5-75) ELN MDS Registry 75 HMRN Yorkshire Mid-late 70s ≥ 80y – 38% ≥ 70y – 33% SEER 77 (77-78) SW Thames 66 MD Anderson 65-71 Pavia 69-73 Dusseldorf Median age at diagnosis (years) Registry
    • European LeukemiaNet (ELN) low-risk MDS registry
      • Prospective registry for newly diagnosed IPSS Low/INT-1
      • Recruiting from 11 countries, 107 sites
      • Data collection at baseline and 6-monthly
        • Haematological, MDS therapy (incl. transfusions), concomitant medication, co-morbidity, QoL (EQ-5D), serum and urine samples.
    • ELN registry: Sorror Score of Co-morbidity Mean Score 2.4, range (0 to 11)
    • ELN registry patients at diagnosis: Past Medical History & Treatment
      • Cardiac Disease 28%
      • Pulmonary Disease 13%
      • Diabetes Mellitus 16%
      • Thyroid Disease 12%
      • Anti –Hypertensive Drugs 37%
      • Anti-Platelet 16%
      • Cholesterol Lowering 14%
    • French MDS Group practice survey one week cross sectional study (n= 907 patients)
      • Median age = 74 years
      • Throughout the one week observational period:
        • ~5% patient episodes were in-patient admission for transfusion
        • 31% all episodes were for red cell transfusion
        • 61% patients required red cell transfusion
      Kelaidi et al, Haematologica 2010, 95, 892
    • French MDS Group practice survey one week cross sectional study (n= 907 patients) Kelaidi et al, Haematologica 2010, 95, 892
    • Transfusion frequency Service evaluation of chronically transfused patients at Leeds General Infirmary, 2006-2007
    • Transfusion burden
    • Red cell transfusion as a negative prognostic factor : WHO- based prognostic scoring system Cazzola & Malcovati Hematol/Oncol Clin North Am 2010, 24, 459
    • Complications of red cell transfusion in MDS Fluit et al, Transfusion 1990, 30, 532
    • Questions
      • Optimal transfusion strategy to maximise quality of life?
      • Optimal trigger for transfusion for individual patients?
      • If, who, when to offer iron chelation?
    • Quality of life in transfused MDS patients
    •  
    • ELN Registry: QoL - EQ-5D Health Score baseline Median Score 70 , range (4 to 100)
    • Health related quality of life by transfusion dependence / independence (EQ-5D)
    • Iron chelation – if, who, when?
    • Ferritin concentration influences overall survival A. WHO RA, RARS, 5q- B. WHO RCMD/RS
    • Transfusion burden influences survival Malcovati, Haematologica 2006
    • Elevated serum ferritin as adverse factor for transplant outcome Armand, P. et al. Blood 2007;109:4586-4588
    • French MDS group transfusion / chelation survey
      • 18 GFM centres surveyed for transfusion data in 2005
        • Patients surveyed again in 2007
      • 53/97 patients with IPSS Low/INT-1 received iron chelation therapy (ICT) for at least 6 months (median duration = 36 mo, and median interval from diagnosis to chelation = 23 mo)
      • Overall survival from diagnosis
        • 124 months for chelated patients
        • 53 months non-chelated
      • No information re. triggers or barriers for iron chelation (co-morbidity)
      • Arms are balanced for
        • median ferritin concentration
        • causes of death
      • Arms are imbalanced for age, IPSS.
      Rose et al, Leuk Res 2010 Feb 1 online BUT
    • Prevalence of comorbid conditions among transfused and nontransfused patients with myelodysplastic syndromes (MDS). Goldberg S L et al. JCO 2010;28:2847-2852 ©2010 by American Society of Clinical Oncology
    • Morbidity and mortality associated with iron overload in MDS patients?
      • Cardiac failure
        • Malcovati et al, 2005
          • Cause of death in up to 50% low-risk patients
          • Cardiac failure more common cause of death in transfused patients
        • Oliva et al, 2005
          • Cardiac remodelling (left ventricular hypertrophy)
            • more frequent in transfusion-dependent patients
            • Correlated with haemoglobin concentration
    • Cardiac pathology
      • Cardiac failure is associated with anaemia in MDS?
        • High cardiac output state
          • particularly at haemoglobin concentration < 8g/dl
        • Stiff vascular bed
        • ?right heart strain ??pulmonary hypertension
        • Renal impairment (cardio-renal-anemia syndrome)
      • Transfusion practice across Europe varies but many countries transfuse only when Hb.<9 g/dl (or lower triggers)
    • 20
      • EPIC trial (  -thal major)
      • 12 months Deferasirox
      • T2* increase from 11.2 ms to 12.9 ms
      • No change in LVEF
      Pennell et al, Eur H J, 2001, 22, 2171
      • Mamtani & Kulkarni BJH 2008, 141, 882
      • Systematic review and meta-analysis
      • Iron chelators reduce myocardial iron content
      • No influence on LVEF
      Iron chelation therapy and T2* values in thal major
    • MRI T2* studies in MDS suggest infrequent cardiac iron loading:
      • Ferte et al, ASH 2006
        • 21 MDS patients
        • 3/8 patients with > 100 units transfused had reduced T2* ( but 5/8 did not!! )
        • 2/3 had clinical cardiac failure
        • No correlation between T2* and serum ferritin
    • Deferasirox reduces serum ferritin in MDS
      • EPIC study
      • 341 low/INT-1 MDS pts
      • 12 months DFX: median 19 mg/kg/d
      • Serum ferritin reduced by median of 253 mcg/l (for patients completing 12 months)
      • 49% withdrawal (13% drug related)
      Gattermann et al, Leuk Res 2010 34, 1143
    • Deferasirox reduces serum ferritin and labile plasma iron in MDS: US03 study List et al, ASH 2008 & 2009 42% (~15% drug related) 45% (10% drug related) Withdrawal rate 3002 to 2069 mcg/l in 2 years (n=50 pts) 3397 to 2501 mcg/l (all) Serum ferritin reduction 20 mg/kg/day 20 mg/kg/day Median deferasirox dose 83 176 Number of patients Year 2 Year 1
    • Argument for chelation:
      • Iron mediated organ toxicity is caused by toxic free iron
        • No direct evidence in MDS patients
        • Yes , there is evidence for oxidative stress in MDS cells but ?bystander or driver
    • We need to iron out some misconceptions
    • Influence of iron chelation therapy in MDS patients
      • Only biochemical improvements convincingly demonstrated to date
      • No clinical benefit yet proven in MDS patients (survival, AML transformation)
    • Practical approach
      • My practice now:
        • chelate younger / fitter patients with RARS, 5q-, RA
      • Use Desferrioxamine (Deferiprone) and rarely Deferasirox
    • Trial opportunity
      • TELESTO 2302 study
        • Randomise deferasirox: placebo (2:1)
        • 3-5 year treatment period
        • Several UK centres
        • Open in UK
    • Thank you for your attention Questions?