Transcript No Slide Title

Results of the Cord Blood Transplantation Study (COBLT): Clinical Outcomes of Unrelated Donor
Umbilical Cord Blood Transplantation in Pediatric Patients with Inborn Errors of Metabolism
Paul L. Martin, M.D., Ph.D.1, Shelly L Carter, Sc.D.2, Nancy A Kernan, M.D.3, Indira Sahdev, M.D.4, Donna
Wall, M.D.5, Daniel Pietryga, M.D.6, John E Wagner, M.D.7 and Joanne Kurtzberg, M.D.1 on behalf of the
COBLT Steering Committee
1
Duke University Medical Center, Durham, North Carolina, United States; 2 The EMMES Corporation,
Rockville, Maryland, United States; 3 Memorial Sloan-Kettering Cancer Center, New York, New York,
United States; 4 Schneider Children’s Hospital, New Hyde Park, New York, United States; 5 Texas
Transplant Institute, San Antonio, Texas, United States; 6 DeVos Children’s Hospital, Grand Rapids,
Michigan, United States; and 7 University of Minnesota, Minneapolis, Minnesota, United States.
Abstract
The Cord Blood Transplantation Study (COBLT), sponsored by the National Heart, Lung,
and Blood Institute, evaluated the outcomes of unrelated donor umbilical cord blood
transplantation (UCBT) in 69 patients (64% males, 77% Caucasian) with inborn errors of
metabolism. A common protocol was used for the preparative regimen (busulfan,
cyclophosphamide, ATG) and GvHD prophylaxis (cyclosporine and steroids). Patients
with MPS I-V (n=36; 20 reported NEJM2004:350:1960-9), globoid cell leukodystrophy
(n=16), adrenoleukodystrophy (ALD, n=8), metachromatic leukodystrophy (n=6) and Tay
Sachs Syndrome (n=3) with a median age of 1.8 years were transplanted with an HLA 6/6
(n=5), 5/6 (n=29), 4/6 (n=33) or 3/6 (n=2) matched unit with a median of 8.7x107 nucleated
cells/kg selected from COBLT banks (83%) or other banks (17%). CBUs were screened
for enzyme activity to prevent use of a carrier donor. The cumulative incidence of
neutrophil engraftment and Grade II-IV acute GvHD were 78% in a median of 26 days and
46%, respectively. The probability of survival at 180 days and 1 year was 80% and 72%,
respectively. Twenty patients died after transplant (5 aGvHD, 4 autologous recovery, 4
graft failure, 2 infection-polyorganism, 1 infection-bacterial, 2 progressive disease,1
pulmonary organ failure and 1 hemolytic anemia). The surviving patients with MPS
syndromes and Tay Sachs Disease all stabilized and/or gained skills post transplant.
Three of 8 patients with ALD experienced disease progression, while all others stabilized
and continue to gain developmental skills. Levels of HLA disparity between recipient and
donor determined by retrospective high resolution DNA typing did not influence
engraftment, GvHD or overall survival. The COBLT study represents the first prospective
multi-center trial in children with inborn errors of metabolism undergoing UCBT. UCBT
provides rapid access to donors and favorably alters the natural history of the disease
and should be considered for patients with metabolic diseases who are eligible for
transplantation therapy.
Introduction
•Inherited metabolic storage diseases are a group of heterogeneous diseases characterized
by a selective enzyme deficiency. Sequelae of these diseases include accumulation of toxic
metabolites in various tissues with life threatening damage to brain, heart, liver and other
organs.
•Stem cell transplantation can prevent progression of many of the symptoms of storage
diseases by providing a source of normal enzyme from the donor stem cells and
leukocytes.
•The majority of children with metabolic storage diseases lack an appropriately matched
allogeneic donor. Partially HLA mismatched, UCB can provide rapidly available donor stem
cells for children with who lack suitable bone marrow donors.
•This poster reports the results of the COBLT study experience using unrelated donor
umbilical cord blood as the source of hematopoietic stem cells for transplantation in 69
children with various inherited metabolic storage diseases.
Preparative Regimen
•Days -9 to -6: Busulfan 40mg/m2/dose PO Q6h x 16 doses
•Days -5 to -2: Cyclophosphamide 50mg/kg/dose IV/day
•Days -3 to -1: ATG 30mg/kg/dose IV/d x 3 days
GvHD Prophylaxis and Supportive Care
•GvHD Prophylaxis: Cyclosporine x 9 months; Solumedrol x 2-3 months
•Supportive Care: Antifungals, Antivirals, PCP prophylaxis, IVIG, G-CSF, LD heparin for VOD
prophylaxis
Patient Characteristics (n=69)
•Patient age (years): 1.8 (Range 0.1 – 11.7)
•Patient weight (kg): 12.3 (Range 3.9 – 42.3)
•Total viable nucleated cell dose (x 107/ kg): 8.7 (Range 2.8 – 38.8)
•CD34+ cell dose (x 105/ kg): 2.4 (Range 0.4 – 13.3)
Patient Characteristics
•64% Male Recipients
Primary disease
•77% Caucasian Recipients
•36% Lansky Performance Status 100
•48% 4/6 HLA Match
(low resolution HLA-A, -B
high resolution –DRB1)
•57% Caucasians had 5/6 or 6/6 HLA match
N
36
16
(%)
(51)
(23)
Adrenoleukodystrophy 8
6
Metachromatic
leukodystrophy
(12)
(9)
MPS I - V
Globoid cell
leukodystrophy
Tay Sachs Syndrome
•25% Non-Caucasians had 5/6 or 6/6 HLA match
•23% Positive Pre-transplant CMV Status
3
(4)
Neutrophil Engraftment (ANC500/mm3)
1.0
Probability
0.8
0.6
Median time to recovery = 26 days
(Range 13 to 51 days)
0.4
CINC at Day 42 = 78%
(95% CI = 69%, 88%)
0.2
0.0
0
2
4
6
8
10
12
Weeks Post-Transplant
14
By Day 42, 15/69 patients (22%) had not engrafted. However, 4 patients
engrafted on Days 47, 48, 50 and 51; 1 died due to transplant related
mortality prior to Day 42.
Platelet Engraftment (>50K/mm3)
1.0
Median time to recovery = 95 days
(Range 30 to 236 days)
Probability
0.8
0.6
0.4
CINC at Day 180 = 60%
(95% CI = 49%, 71%)
0.2
0.0
0
1
2
3 4 5 6 7 8 9 10 11 12
Months Post-Transplant
Acute GVHD Grades II - IV
1.0
Probability
0.8
CINC at Day 100 = 46%
(95% CI = 34%, 58%)
0.6
0.4
0.2
0.0
0
1
2
3
4
5
Months Post-Transplant
6
Maximum grade by Day 150 and graded based on symptoms. Grades
calculated from conventionally reported weekly GVHD organ stages
down-scored 1 stage for a clinically recognized differential diagnosis in
either Gut or Liver.
Chronic GVHD
Probability
1.0
0.8
CINC at 1 Year = 18%
(95% CI = 8%, 27%)
0.6
0.4
0.2
0.0
0
6
12
18
24
30
Months Post-Transplant
36
Chronic GVHD occurred in 13 patients (11 limited, 2 extensive) who
survived more than 100 days (n=56), with 69 patients evaluable.
Maximum Regimen-Related Toxicity1
GI
Maximum
Grade
Organ System
Stomatitis
CNS
Hepatic
0
1
2
3
4
Pulmonary
Renal
Bladder
Cardiac
0%
1
20%
40%
60%
% of Patients
80%
100%
Toxicity data collected on Day 28 and Day 42 post-transplant.
Using the Bearman toxicity grading scale by Day 42, the maximum toxicity
experienced in any organ system was 1 (1%) Grade 0, 5 (7%) Grade I, 47
(68%) Grade II, 13 (19%) Grade III, and 3 (4%) Grade IV.
Causes of Death
Primary COD
Acute GVHD
Contributing
Infection No Infection
N
N
4
1
Total
N
(%)
5
(25)
Autologous Recovery
Graft Failure
4
2
0
2
4
4
(20)
(20)
Other 1
Infection - Polyorganism
Infection - Bacterial
Organ Failure
- - Pulmonary
Total
10
3
3
2
1
1
20
(15)
(10)
(5)
(5)
(100)
1
Progressive Disease (N=2) and Refractory Hemolytic Anemia (N=1)
Overall Survival
1.0
I
I
Probability
I
II I
0.8
I
I
I II
IIIIIIII
II
I
I
I
0.6
II
I
I
I
I II
I
I
I
I
I
I
Median follow-up time = 24.5 months
(Range 1.9 to 58.5 months)
0.4
0.2
0.0
II I I II I III I
Survival at Day 180 = 80%
(95% CI = 71%, 90%)
0
6
12
18 24 30 36 42 48
Months Post-Transplant
54
60
Overall Survival – Recipient Ethnicity
Probability
1.0
Survival at Day 180 = 86%
(95% CI = 76%, 96%)
I
I II I
I
0.8
I
I I III II II
I I
I II I I I I III I II
I
I
I II
I
I
I
I
0.6
+
p <0.01
++
0.4
+
+ +
Survival at Day 180 = 63%
(95% CI = 39%, 86%)
0.2
0.0
+
0
6
12
18
24
30
36
42
48
54
Months Post-Transplant
Recipient Ethnicity
Caucasian (N = 53)
Other (N = 16)
60
Conclusions
•Hematopoietic stem cell transplantation with partially HLA matched unrelated donor
umbilical cord blood is a viable approach to stem cell transplantation of pediatric patients
with metabolic storage diseases not amenable to other therapies.
•The probability of neutrophil engraftment by Day 42 was 78% (CI 69% to 88%).
•In univariate analyses increased CD3+ cell dose was associated with an increase in
probability of neutrophil engraftment (Log-Rank p <0.01).
•The overall survival at 1 year was 72% (CI 61% to 83%).
•Non-white ethnicity had a negative impact on survival (Log-Rank P <0.01)
•While long-term follow-up is needed to determine the full impact of umbilical cord blood
transplantation on the natural history of these syndromes, it is clear that many patients will
derive significant benefit from this therapy and that it should be considered for all young
patients with severe storage disease syndromes lacking a matched related, non-carrier
bone marrow donor.