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GAUCHER DISEASE THE ICCG REGISTRY

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GAUCHER DISEASE THE ICCG REGISTRY Powered By Docstoc
					Prevalence of Skeletal Disease
      Neal J. Weinreb, M.D.
   Impact of Skeletal Manifestations

• Discomfort, pain, and disability occur in a
  majority of patients.

• Impact QOL more than hematological and
  organ abnormalities.

• Bone disease is common even with normal
  hematology.
Patient Demographics - Type 1 Patients
   Mean                         On                           Not
   Ages                         ERT                         On ERT

    Age                      (n=1601)                       (n=518)
  Mean (SD)                 37.1 (19.5)                    39.3 (20.6)
   Range                       1, 92                          0, 93

  Diagnosis                  (n=1406)                       (n=488)
  Mean (SD)                 17.9 (17.4)                    25.7 (19.4)
   Range                       0, 82                          0, 91

 First Infusion              (n=1600)
  Mean (SD)                 30.6 (19.2)                         N/A
     Range                     0, 84

                  2000 Gaucher Registry Aggregate Data Report
  History of Bone Symptoms at
    Baseline Type 1 Patients

Symptom            On ERT                      Not on
                                                ERT

Bone Pain            66%                        49%
                  (811/1232)                  (147/299)

Bone Crisis          29%                         5%
                  (336/1162)                   (15/280)


        2000 Gaucher Registry Aggregate Data Report
  History of Bone Disease at Baseline –
              Type 1 Patients
                           On ERT                 Not on ERT
  Radiological          94% (1201/1278)            76% (275/360)
  Bone Disease
    Avascular           34% (406/1201)              12% (32/275)
    Necrosis
Erlenmeyer Flask        61% (733/1201)             56% (153/275)
   Deformity
   Infarction           35% (424/1201)              16% (45/275)
Joint Replacement       14% (171/1201)               6% (16/275)
  Lytic Lesions         18% (214/1201)              10% (28/275)
    Marrow              59% (708/1201)             53% (147/275)
   Infiltration
 New Fractures          26% (310/1201)              10% (28/275)
   Osteopenia           50% (595/1201)              34% (94/275)

            2000 Gaucher Registry Aggregate Data Report
  55
            49
                     45

                               34




N = 449   N = 196   N = 159   N = 61
                        Gaucher Registry: Mean Age at 1st Infusion
                   35


                   30
                          29.3         29.4
Mean Age (Years)




                                                           28.3
                   25

                                                                   23.4
                   20


                   15


                   10


                   5


                   0
                         1992-94      1995-96          1997-98    1999-00
                          N = 810     N = 311          N = 237     N = 73
                                    Year of 1st Infusion
                       History of Bone Pain at Baseline - Type 1 Patients
                                       By Age Category
                      90


                      80                                                                                             Yes No
                                                 76.5

                                       69.1
                      70
Percent of Patients




                                                                                          62.3
                                                                                                           60.3
                                                           58.9                                                         58.3
                      60
                               51.9                                                              50.8
                            48.1                                                                    49.2
                      50
                                                              41.1                                                   41.7
                                                                                   38.8                       39.7
                      40
                                          30.9
                      30
                                                    23.5

                      20


                      10


                       0
                           0-18 Y 19-40 Y 41-60 Y 61+ Y                          0-18 Y 19-40 Y 41-60 Y 61+ Y
                           N=335        N=362 N=247          N=90                   N=80          N=122    N=73       N=36
                                                           Gaucher Registry: April 2001
                                      Patients on ERT                                            Patients Not on ERT
                                       History of Bone Crises at Baseline
                                       Type 1 Patients By Age Category
                  100.0                                                                             97.0     97.1
                                                                                           94.5
                                                                                92.6
                                                                     Yes No
                      90.0
                                                              80.0
                                78.3
                      80.0
Percent of Patients




                                                    70.4
                      70.0
                                          61.9
                      60.0

                      50.0

                      40.0             38.1

                             31.6
                                                 29.6
                      30.0
                                                           20.0
                      20.0

                      10.0                                                    7.4
                                                                                         5.5
                                                                                                  3.0      2.9

                       0.0
                             0-18 Y 19-40 Y 41-60 Y 61+ Y                     0-18 Y 19-40 Y 41-60 Y 61+ Y
                             N=304 N=312         N=216     N=81               N=81       N=110    N=67     N=34
                                    Patients on ERT                                    Patients Not on ERT
                                           History of Bone Disease at Baseline
                                            Type 1 Patients By Age Category
                      100.0                96.7     98.1     97.5
                              93.2
                                                                        Yes     No                                 87.2
                       90.0
                                                                                     82.5
                       80.0                                                                              76.4
                                                                                               73.7
Percent of Patients




                       70.0

                       60.0

                       50.0

                       40.0

                       30.0                                                                       26.3
                                                                                                            23.6

                       20.0                                                             17.5
                                                                                                                      12.8
                       10.0          6.8
                                              3.3      1.9       2.5
                        0.0
                              0-18 Y 19-40 Y 41-60 Y 61+ Y                           0-18 Y 19-40 Y 41-60 Y 61+ Y
                              N=339 N=360 N=266               N=81                   N=80       N=118     N=72     N=39
                                                             Gaucher Registry: April 2001
                                       Patients on ERT                                         Patients Not on ERT
 Patient Genotypes - Type 1 Patients
       Genotype                  On ERT                   Not On ERT
        N370S/?                  190 (19%)                    48 (16%)
     N370S/N370S                 275 (28%)                   169 (56%)
     N370S/L444P                 164 (17%)                    31 (10%)
     N370S/84GG                  144 (15%)                        12 (4%)
     L444P/L444P                   26 (3%)                        1 (<1%)
        L444P/?                    28 (3%)                        3 (1%)
    N370S/IVS2+1                   28 (3%)                        4 (1%)
           ?/?                     13 (1%)                        4 (1%)
       All Others                118 (12%)                    29 (10%)

Sixty percent (1287/2129) of all Type 1 patients enrolled reported genotype.

                    2000 Gaucher Registry Aggregate Data Report
                                          History of Bone Pain at Baseline
                                           Type 1 Patients By Genotype
                      70
                            63.2              63.6
                                                                                  Yes        No
                      60

                                                                 52.3          52.2
Percent of Patients




                      50                                                47.7          47.8



                      40           36.8              36.4


                      30



                      20



                      10



                       0
                           N370S/N370S        All Others        N370S/N370S    All Others
                             N=209             N=472              N=130          N=92
                              Patients on ERT                     Patients Not on ERT
                                       History of Bone Crises at Baseline
                                         Type 1 Patients By Genotype
                                                                              99.2
                      100.0
                                                                                             89.7
                       90.0                                 Yes No

                       80.0            77.0
Percent of Patients




                       70.0                          66.5


                       60.0

                       50.0

                       40.0
                                              33.5

                       30.0
                                23.0

                       20.0
                                                                                      10.3
                       10.0
                                                                        0.8
                        0.0
                              N370S/N370S     All Others             N370S/N370S     All Others
                                N=196          N=454                    N=129           N=87
                                  Patients on ERT                     Patients Not on ERT
                                   History of Bone Disease at Baseline
                                       Type 1 Patients By Genotype
                      100.0
                                              95.2
                                 98.5
                       90.0                                Yes No
                                                                                     79.8
                       80.0
                                                                       73.6
Percent of Patients




                       70.0

                       60.0

                       50.0

                       40.0

                       30.0                                                   26.4
                                                                                            20.2
                       20.0

                       10.0
                                                     4.8
                                        1.5
                        0.0
                              N370S/N370S     All Others            N370S/N370S      All Others
                                 N=194         N=501                     N=125        N=99
                                 Patients on ERT                       Patients Not on ERT
                      Mobility History at Baseline –
                        Type 1 Patients on ERT
                     Orthopedic
                     Aid: 7.1%        Wheelchair: 1.2%
Walks with
Difficulty : 12.0%
                                                    Bedridden: 0.5%




             N=602
                                                                 Unrestricted: 79.2%

                                  Gaucher Registry: March 2001
              Skeletal Manifestations in
              Elderly Gaucher Patients
        Dx     Onset
 Pt     Age    Age      Presenting Sx   Subsequent Sx________

• PL*    24    26       AVN hip         THR (59)
                                        Fx distal femur (64)

• JW* 20        61      Multiple Fx’s   None on ERT; less pain

• MA     75     75      AVN; THR        Prosthesis failed (80)
                                        Wheelchair bound (82)

• RS     71    77       R hip pain      R hip Fx (79)
                                        L hip Fx (84)
        * Splenectomy
Age at Diagnosis and Severity
   Score Index (Weinreb)
Skeletal Response to ERT
    Neal J. Weinreb, M.D.
 Problems in Assessing Skeletal
Symptoms and Response to ERT
• Multiple etiologies
  – Degenerative vertebral disk disease
  – Concurrent “senile” osteoporosis
  – Degenerative and other arthritis
  – Increased incidence of myeloma
• Uncertain correlation between clinical and
  MRI status
Concurrent Illnesses in Patients > 65 Years Old

                                                     N = 159
Percent of Patients




                      Gaucher Registry: March 2001
Osteoarthritis: Association of Knee
 Pain With Bone Marrow Lesions
    Clinical Course of Gaucher Disease
       (Zimran et al, Medicine 1992)

•   Evaluation: 20 years after initial diagnosis
•   Mean age at evaluation: 33 years
•   Splenectomy: 43%
•   Chronic symptoms mainly skeletal
•   N370S homozygotes: milder clinical course
•   Progression: childhood to early adulthood
•   Stable in adulthood, especially N370S/ N370S
 The Clinical Course of Treated
 and Untreated Gaucher Disease
• 45 patients examined at least 3 times
• Observation period greater than one year
• Little progression in adults (Beutler E et. al.
  Blood Cells Mol Dis 1995; 21(2):86-108)
  – Few changes in blood counts
  – No increase in liver and spleen sizes
  – Changes in bone lesions largely in
    preexistent site
Clinical Course of Gaucher Disease:
        Non-Jewish Patients
• Neiderau: 51 German patients, ages 5-74
  – Observed average 16 years from diagnosis
  – Progressive complications until ERT started
     • Bleeding and/or anemia splenectomy
     • Increasing bone disease including fracture
• Giraldo: 48 Spanish patients: progression 81%
• Goldblatt: 10 Afrikaner patients: rapid
  progression
• Hollak: 20 Dutch patients: progressive in most
  children and adults
  Response to ERT (Literature)
• Decreases in bone pain during first year
   – Both frequency and intensity
• Radiological improvement rare
• Painful crises may persist more than 3
  years
• New AVN and fractures may occur
History of Bone Pain     12 Months*            24 Months**           Overall at 24 Months

                                             N-64/76(84.2%)
                       N-129/292(44.2%)
                                             Y-12/76(15.8%)
                                                                         N-89/172(51.7%)
  Y (n=620)
                                                                         Y-83/172(48.3%)
                                             N-25/96(26.0%)
                       Y-163/292(55.8%)
                                             Y-71/96(74.0%)


                                             N-106/111(95.5%)
                       N-166/177(93.8%)
                                             Y-5/111(4.5%)
                                                                         N-108/116(93.1%)
  N (n=349)
                                                                         Y-8/116(6.9%)
                                             N-2/5(40.0%)
                       Y-11/177(6.2%)
                                             Y-3/5(60.0%)



 Y = yes or present      * Last report of Bone Pain through 12 months.
 N = no or absent        ** Last report of Bone Pain between 12 and 24 months among those
                         with data at 12 months.
History of Bone Crisis         12 Months*              24 Months**          Overall at 24 Months

                                                    N-50/52(96.2%)
                             N-87/107(81.3%)
                                                    Y-2/52(3.8%)
                                                                                N-57/61(93.4%)
    Y (n=283)
                                                                                Y-4/61(6.6%)
                                                    N-7/9(77.8%)
                             Y-20/107(18.7%)
                                                    Y-2/9(22.2%)


                                                    N-186/187(99.5%)
                             N-297/300(99.0%)
                                                    Y-1/187(0.5%)
                                                                                N-187/188(99.5%)
    N (n=597)
                                                                                Y-1/188(0.5%)
                                                    N-1/1(100.0%)
                             Y-3/300(1.0%)
                                                    Y-0/1(0.0%)



                                            * Last report of Bone Crisis through 12 months.
        Y = yes or present
        N = no or absent                    ** Last report of Bone Crisis between 12 and 24 months
                                            among those with data at 12 months.
                                 Overall Bone Assessment: Response to ERT
                                         Type 1 Patients <18 Years Old

                      80.0                                               73.7                Improved
                                                                                             Stable
                      70.0                           64.7
                                                                                             Worse

                      60.0                                                                   55.0
Percent of Patients




                      50.0
                               41.3                                                   40.0

                      40.0
                                              32.3                26.3

                      30.0
                                      17.4

                      20.0


                      10.0                                  2.9                                     5.0
                                                                                0.0

                       0.0
                             12 Months          24 Months     36 Months                48 Months
                                N=46               N=34          N=19                     N=20
                                             Time (Months) Post 1st Infusion
 Natural History of Gaucher Disease in
Untreated Patients: Growth in Childhood
• Zevin et al, 1993 (Shaare Zedek) N=34
  – Growth retardation (height and weight) prominent (30%)
  – Most marked ages 2-5
• Kaplan et al, 1996 (Gaucher Registry) N=99
  – Abnormal growth pattern relative to general population
    and family in 50% at all ages to 15 years
  – Associated with degree of hepatomegaly
• Kauli et al, 2000 (Petah Tiqva) N=52
  – Growth retardation and delay in puberty are common
  – More frequent with severe disease
  – Spontaneous catch-up even in untreated patients
                                    Overall Bone Assessment: Response to ERT
                                           Type 1 Patients > 18 Years Old

                      80.0
                                                                                                  76.0
                                    68.5                 71.7

                      70.0
                                                                             56.8
Percent of Patients




                      60.0


                      50.0


                      40.0                                            32.4

                      30.0   22.5                 23.9
                                                                                           20.0

                      20.0
                                           9.0                                      10.8

                                                                4.4                                      4.0
                      10.0


                       0.0
                              12 Months             24 Months           36 Months           48 Months
                                N=111                  N=46                N=37                N=25
                                                 Time (Months) Post 1st Infusion
                                                                                                                  Unrestricted
                    Mobility: Response to ERT - Type 1 Patients                                                   Walks with Difficulty
                  12 Months Post 1st Infusion (N=188/602) (31.2%)                                                 Orthopedic Aid
                                                                                                                  Wheelchair
                                                                                                                  Bedridden



                      90
                                   99.3
                      80
Percent of Patients




                      70

                      60
                                                        50             50
                      50
                                          47.6          47.6
                      40                                                          46.1
                                                 30.7




                      30                                                                                              Baseline
                                                                23.0




                                                                                                                       Status
                      20
                                                                                                                  Bedridden     (N=0)
                       10                                                                                       Wheelchair      (N=2)
                                                                                                            Orthopedic Aid      (N=13)
                           0                                                4.8                         Walks with Difficulty   (N=21)
                               Unrestricted Walks with                                               Unrestricted
                                             Difficulty Orthopedic Wheelchair
                                                           Aid                           Bedridden    (N=152)
                                                             12 Months
  Gaucher Registry Results
• Bone pain resolves in 50% of
  symptomatic patients within 1-2 years of
  starting ERT.
• New onset of bone pain in asymptomatic
  patients occurred in 4% on ERT for 2
  years.
• 80-90% with prior bone crises had no
  recurrences during first 2 years of ERT.
• Incidence of de novo crises during first 2
  years of ERT is less than 1%.
 Gaucher Registry Results
• After 2-4 years of ERT, physician
  assessment of overall bone involvement
  (clinical and radiological) suggests:
  –   Improvement in 30-40% in pediatric patients
  –   Progression in <5% in pediatric patients
  –   Improvement in 20-30% of adult patients
  –   Progression in 5-10% of adult patients
 Gaucher Registry Results
• After 12 months of ERT, mobility status is
  often improved:
  – 54% of patients requiring orthopedic aid at
    baseline able to ambulate without assistance.
  – 48% of patients who walked only with
    difficulty at baseline have unrestricted mobility.
  – Only 5% of patients who walked with difficulty
    at baseline progressed to use an orthopedic aid.
  – Worsening mobility occurred in <5% of
    patients who were unrestricted at baseline.
 Gaucher Registry Results
• After 2 years of ERT, patients with
  residual bone pain are significantly
  older than those whose pain resolved
   – Long-standing skeletal damage may
     be irreversible.
   – ERT usually prevents symptomatic
     progression and may forestall
     irreversible complications
   – Early treatment for symptomatic or
     high risk patients is advisable.
  Natural History of Gaucher Disease in
Untreated Patients: Gaucher Registry Goals

 • Obtain missing data and retrieve
   retrospective data on current patients
 • Accrual of appropriate new patients
 • Obtain data on untreated patients for
   the existent sub-Registries:
    – Quality of Life          Pregnancy
    – Bone Density (DEXA) Pulmonary

				
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