Diagnosis, monitoring and treatment of adult Gaucher patients

Transcription

1 Diagnosis, monitoring and treatment of adult Gaucher patients Stephan vom Dahl, M.D., Professor of Medicine St. Franziskus Hospital, Köln, Germany Podčetrtek, Slovenia, April 22, 2006 Strokovni Sestanek

2 Topics What is Gaucher disease? What are the manifestations? How is it treated? What is the outcome of treatment? How is a controlled treatment managed? How can I improve my patient s treatment?

3 Glucocerebroside metabolism glucose substrate reduction therapy, SRT miglustat ceramide glucocerebroside synthase glucocerebroside enzyme replacement therapy, ERT imiglucerase glucocerebrosidase glucose ceramide

4 Pathophysiology of Gaucher disease Enzyme deficiency Bone marrow macrophages spleen bone lungs liver results in activation of osteoclasts

5 Typical complaints Loss of power Abdominal discomfort Bone pain Frequent infections Bleeding

6 Findings Anemia, low platelets Hepatosplenomegaly Typical bone lesions in MRT Increased ACE, ferritin, tartrate-resistent acid phosphatase Massively increased chitotriosidase

7 Bone complications Bone crises Pathological fractures Osteonecroses New osteolytic lesions Bone tumours.. are a major determinant of the clinical prognosis in type I GD patients

8 Initial assessment Blood tests Primary tests Additional tests Visceral Skeletal Pulmonary Haemoglobin; platelet count; biochemical markers (e.g. chitotriosidase); glucocerebrosidase activity; mutation analysis; antibody sample White blood cell count; AST, ALT (SGOT, SGPT); alkaline phosphatase; total and direct bilirubin; hepatitis profile; albumin; total protein; serum immunoelectrophoresis; calcium; phosphorus; iron; ironbinding capacity; ferritin; vitamin B12; PT; PTT Spleen and liver volume (volumetric MRI or CT) X-ray; AP view of femora and lateral view of spine; MRI (coronal) of femora, hips and lumbar vertebrae (QCSI); DEXA of lumbar spine and femoral neck ECG; chest X-ray and Doppler echocardiogram for patients > 18 years

9 Enzyme replacement therapy

10 Effects of ERT Decrease of organ volumes Normalization of hemoglobin and platelets Partial reversal of bone lesions Improved QOL and decreased bone pain No further bone complications Partial improvement of atypical complications

11 Cessation of therapy on therapy off therapy ,8 7, ,6 12,2 chitotriosidase ferritin platelets ACE hemoglobin acid phosphatase Jahr vom Dahl et al., Br. J. Haematol (2001)

12 Therapeutic goals Normalise growth/intellectual development of children Restore spirit and mobility, get rid of mobility aids Prevent a progress to invalidity Prevent bone complications Improve atypical manifestations (eye, cardiac, pulmonary, Gaucherom) Generate freedom or relief of pain Normalize organ volumes Prevent bleeding Normalize leucocytes, hemoglobin and platelets Reach optimal time point for prosthetic orthopedic surgery Prevent cancer? Prolong life?

13 Life expectancy is decreased Type of Population Average Life Expectancy (years) Difference (years) (90 deaths in 2201 patients, diagnosed after 1991) Normal U.S Type 1 GD (method 1) Type 1 GD (method 2) Weinreb, Kacena, Yee, Mistry, Pastores, vom Dahl Abstracts ASHG 2005, ESHG 2006, from the ICGG registry

14 Recommended initial dosage Start high, level off, when stable No bone symptoms, no to mild involvement: 20 IU/kg/2 wks. Mild to moderate involvement, symptoms: 40 IU/kg/2 wks. Bone complications: 60 IU/kg/2 wks. Interruptions may be deleterious and must only be done under close control

15 University Hospital, Duesseldorf Stephan vom Dahl Nicole Brill Sarah Brett Ludger W. Poll Dieter Häussinger Academic Medical Center (AMC ) Amsterdam Maaike de Fost Maaike Wiersma Hans Aerts Ans Groener Mario Maas Carla Hollak

16 Patient characteristics Amsterdam Duesseldorf P number of patients age in NS gender (% male) NS splenectomies (N/%) NS Hb (g/dl) P=0.03 platelets (x 10 9 /l) NS spleen volume (ml) NS chitotriosidase P=0.06 severity score (SSI) 8 7 NS BMB NS initial dosing (I.U./kg/2 wks) P<0.0001

17 Goals in the DD-AMC study Normalization of Hb (>12 g/dl) Normalization of platelets (>100 x 10 9 /l) Reach a 20 % decrease of liver volume Reach a 40 % decrease of spleen volume Reach a chitotriosidase of <5000 nmol/(ml x h) Reach a change of BMB by 2 points De Fost, Hollak,... and vom Dahl, Blood (2006), in press

18 Time to normalisation of hemoglobin and platelets 1.0 hemoglobin 1.0 platelets Share of patients AMC HHU Share of patients AMC HHU months on ERT months on ERT Median time ± SEM AMC HHU Log rank 12 ± 3 10 ± 1 P=0,6 Median time ± SEM AMC HHU Log rank 16 ± 3 16 ± 1 P=0,5 De Fost, Hollak,... and vom Dahl, Blood (2006), in press

19 Time to spleen size 60 % baseline level Share of patients AMC HHU months on ERT AMC HHU Log rank Median time ± SEM 18 ± 5 19 ± 2 P=0,7 De Fost, Hollak,... and vom Dahl, Blood (2006), in press

20 Time to chitotriosidase < 5000 nmol/(ml h) Share of patients AMC HHU months on ERT AMC HHU Log rank Median time to <5000 ± SEM 48 ± ± 8 0,015 De Fost, Hollak,... and vom Dahl, Blood (2006), in press

21 Time to improvement of bone marrow burden in MRT ( BMB = 2) Share of patients AMC HHU Share of patients AMC HHU months on ERT months on ERT Baseline BMB 2-8 Baseline BMB 6 De Fost, Hollak,... and vom Dahl, Blood (2006), in press

22 Dosing strategy Initiation Adaptation Stabilization Tapering? Maintenance? 3-6 months 6 months months 48 months rest of life

23 Maintenance dosage? There is evidence that the lowest effective dose is U/kg. There are not enough data at the moment to determine the right time point to start tapering the dose and when to finally reach maintenance dosage. It is also not known why some patients show a flare-up of the disease when reducing an initially higher dose.

24 Stability criteria No new bone complications No or significantly improved bone pain Surrogate parameters normal or stable ACE, ferritin, TRAP normal or change < 10 % within 6 months Chitotriosidase changes of < 15 % upon 2 consecutive measurements within 1 year Blood parameters normal or significantly improved, visceromegaly significantly responding

25 Monitoring recommendations

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27 Growth Patient Enrollment in ICGG Gaucher Registry * Number of Patients Enrolled Year * As of Oct 05

28 Data collection Hematologic Visceral organ Skeletal Quality of life Other clinical assessments Neurological subregistry

29 Jones_1234 JDY 30 F Intact Type I N370S/L444P Y

30 In and Out of the Registry Data Gaucher registry Patient case records Data requests Annual report Region report Country report Posters Papers Recommendations Guidelines Evidence-based medicine Regulatory role

31 Documentation of your patient

32 Definition of therapeutic goals

33 Disease Management Consistent data collection from sites Patient Case Reports reviewed by Gaucher Disease Advisory Committee

34 Summary Systemic disease Effective treatment forms available Ways of controlled diagnosis and treatment Individualization of enzyme replacement therapy Monitoring guidelines There are structures that support the individual physician in improving his patients treatment