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Cellular, Tissue, and Gene Therapies Advisory Committee
CliniMACS® CD34 Reagent System APPLICANT: Miltenyi Biotec
HDE BH110018
September 23, 2011
2
CliniMACS® CD34 Reagent System
Proposed Indication
• For processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-A) from a related donor to obtain a CD34+ cell enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-vs-host disease (GVHD) prophylaxis in patients with acute myeloid leukemia (AML) in first or second morphologic complete remission.”
3
FDA Presenters• Deborah Hursh, PhD – Device Performance
Division of Cellular and Gene TherapiesOffice of Cellular, Tissue and Gene Therapies
• Peter Bross, MD - Clinical Safety and Probable BenefitDivision of Clinical Evaluation and Pharmacology/ToxicologyOffice of Cellular, Tissue and Gene Therapies
• Mary Lin, PhD - StatisticsDivision of BiostatisticsOffice of Biostatistics and Epidemiology
4
CliniMACS® CD34 Reagent System Review Team
• Clinical– Donna Przepiorka, MD
PhD, CBER• Statistics
– Mary Lin, PhD, CBER• Pharmacology/
Toxicology– Shamsul Hoque, PhD,
CBER• Project Management
– Candace Jarvis, CBER– Ramani Sista, PhD,
CBER
• Labeling– Dana Martin, CBER– Lisa Stockbridge, CBER
• Bioresearch Monitoring– Bhanu Kannan, CBER
• Manufacturing and Product Quality– Gang Wang, PhD, CBER– Deborah Trout, CBER– John Diehl, CDRH– Damaris Lopez-Rosario,
CBER
5
CliniMACS® CD34 Reagent System Review Team
– CliniMACS® Instrument • Howard Bassen, CDRH:
Magnetic Field • Sandy Weininger,
CDRH: Electrical Safety• Donald Witters, CDRH:
Electromagnetic compatibility
• Joseph Jorgens, CDRH: Software
• Nikhil Thakur, CDRH: Bench testing, Valve and Pump performance, Human Factors
– CliniMACS® CD34 Reagent System Performance
• Deborah Hursh, PhD CBER
– CliniMACS® CD34 Reagent• Marjorie Shapiro, PhD
CDER• Laurie Graham, PhD
CDER• Mark Lee, PhD CBER
– CliniMACS® Buffer• Rabia Ballica PhD CBER• Donald Fink PhD CBER
– CliniMACS® Tubing• Nikhil Thakur, CDRH• Ingrid Markovic, PhD
CDER• Kurt Brorson, PhD
CDER
6
What is the CliniMACS® CD34 Reagent System?
• Components of the system– Instrument with magnet– Proprietary PBS/EDTA buffer– Tubing set with selection column– CD34 Reagent (CD34 monoclonal antibody bound
to paramagnetic beads)
• Principle of operation– CD34 expressing cells are labeled with CD34
reagent and separated from other cells using magnet in instrument
7
Why use cell selection?
• Actively enriches for CD34+ cell population intended for hematopoietic reconstitution
• Passively depletes donor lymphocytes– May obviate need for immunosuppressive
drugs to prevent GVHD– May reduce T cells that mediate anti-
leukemia and anti-infection effects
8
Cells from Apheresis
Antibody Linked to Paramagnetic Nanobead
9
Antibody Binds to Cells Expressing CD34 Antigen
10
Schematic Depiction of Device
Image from Miltenyi User Manual, US Edition
11
Antibody labeled cells are bound by magnet
12
CD34 enriched cells are released from magnet and used for transplantation
13
Graft Quality and Device Performance
• Clinical utility depends on device cellular output quality.– Clinical recommendations focus on dose
•Total CD34 and CD3 cell numbers– Device performance focuses on
•CD34 yield and purity, CD3 reduction•No acceptance criteria specified
14
What does Miltenyi provide to ensure appropriate device function?
• Training and Tech Support
• Instructions
• Historical data
15
Training and Technical Support
• Training of end users by certified Miltenyi employees
• Technical support Hotline
16
Instructions (User Manual)• User manual instructs user to test the cells before
and after use of the device • User must measure
– Total number of leukocytes– Percentage of CD34 positive cells– Total number of CD34 positive cells– Viability
• User Manual does not provide expectations for CD34 yield, purity, or log reduction of CD3 cells
• Instructions from Miltenyi necessitate individual institutional standard operating instructions – Considerable variety exists among SOPs
17
Historical Data Supporting Performance
• Retrospective Process Validation of the CliniMACS® plus Instrument manufacturing and performance evaluation in field (BMT CTN trial 0303) – 84 selections from 44 patients at 8 sites,
2005-2008
18
Cell Output Parameters• Cell Dose-determined by BMT/CTN 0303 trial
prospectively – > 5 X 106 CD34+/kg recipient body weight, with a
minimum of >2 X 106 CD34+/kg recipient body weight
– < 1.0 X 105 CD3+ T cells/kg recipient body weight
• Device Performance-not prespecified – Yield of CD34+ cells– Purity of CD34+ cells
– Depletion of CD3+ cells, measured in log10
19
Performance data from BMT CTN 0303 Study*
Table 4: Overall Cell Processing Data Abbreviated Summary (n=84)
Attributes Measured Mean Std Dev %CV
Starting TNC x 1010 7.46 3.26 43.67
Initial Viability (%) 97.60 2.74 2.81
CD34+ Cells x 107Starting Count 59.71 41.09 68.81
Final Count 36.90 25.05 67.90
Final CD34+ Yield (%) 66.06 20.25 30.66
Final CD34+ Purity (%) 93.03 8.31 8.93
CD3+ T-Cells x 108Starting Count 179.50 69.80 38.87
Final Count 0.0065 0.0103 159.39
Log10 CD3+ T-Cell Depletion 4.78 0.55 11.55
Final Viability (%) 96.57 3.84 3.97
Total CD34+ Cells Infused/Kg x 106 8.81 5.21 59.17
Total CD3+ Cells Infused/Kg x 106 0.015 0.020 132.9
* The investigators have submitted the clinical outcome results and cell processing data from these studies for publication. The former are currently under review for publication. The latter are pending publication in Biology of Blood and Marrow Transplantation (in press).
20
FDA asks the committee to discuss the following question
regarding device performance: • Miltenyi proposes to supply device users with the instructions
for use outlined in the CliniMACS® user manual, provide training by certified Miltenyi employees, and maintain a technical support hotline as resources pertaining to correct operation of the device.
• The table shown on the previous slide provides a summary of the data contained in Appendix B of the FDA Briefing Document that depicts the attributes of CD34+-enriched hematopoietic progenitor cells obtained after processing donor apheresis with the CliniMACS® CD34 Reagent System at clinical sites participating in the BMT CTN 0303 clinical study.
• Please discuss the adequacy of the user instructions and device performance data provided to demonstrate end users will be able to use the CliniMACS® CD34 Reagent System, if approved, for processing HPC-A collected from an HLA-matched related donor for recipient hematopoietic reconstitution.
• Please discuss any recommendations for establishing device performance criteria.
Clinical/Statistical Review CliniMACS® CD34 Reagent
System BH110018
Peter Bross, MD, FDA/CBER/OCTGT/CEB Clinical
Mary Lin, PhD, FDA/CBER/OBE/DB/TEB Statistical
September 23, 2011
22
Agenda• Regulatory
History• Clinical studies• Probable benefit• Safety• Summary
23
Regulatory History • May 2004: Pre-IDE meeting; requirements
for an HDE application were discussed.
• Oct 2004: IDE 11965 for investigational use of CliniMACS device in treatment of leukemia
• June 2005: HUD designation granted
• Dec 2009: Pre-HDE meeting, FDA suggested sponsor perform a comparison to matched historical or concurrent control to support HDE application
• April 2011: HDE submitted
24
BMT CTN Study 0303• Single-arm, open-label, Phase 2,
multicenter study of T-cell depleted peripheral blood stem cells isolated by the CliniMACS® System
• Population: Patients with AML in first or second morphologic complete remission undergoing myeloablative allogeneic SCT from an HLA-matched sibling donor
• Endpoints: 6-month DFS, hematopoietic recovery, acute and chronic GVHD, transplant-related mortality (TRM), Disease-free Survival (DFS), overall survival (OS), and achievement of targeted cell doses
25
Historical Controls• BMT CTN Study 0101: Randomized, double-
blind, multicenter trial comparing two drugs for the prevention of invasive fungal infections in allogeneic blood and marrow transplant patients
• Population: Patients with hematologic malignancies undergoing allogeneic SCT
• Endpoints: fungal-free survival through Day-180, frequency of and time to invasive fungal infection, OS, duration of antifungal treatment, time to acute and chronic GVHD, and safety
Comparison of Key Design ElementsStudy 0303 Study 0101
Design Phase 2 single-arm Phase 3 randomized
Eligibility Age 18-65 yrs >2 yrs
Diagnosis
Acute myelogenous leukemia in 1st or 2nd remission
Leukemia, myelodysplastic syndrome, malignant lymphoma
Donor HLA-identical Related or unrelated, HLA-matched or mismatched
Preparative Regimen
Myeloablative100% received ATG
Myeloablative8% received ATG
Stem Cells HPC-A HPC-A, M or C
Cell Processing CD34-Reagent (CliniMACS)
4% had T cell depleted grafts
Minimum Follow-up Two years One year
Target Accrual 45 600
27
Selection of Control Cohort
Controls from 0101 were selected by the key eligibility criteria used in 0303:
• Diagnosis of AML • 1st or 2nd complete remission (CR)• Age 18-65 years • HLA-matched related donor • Peripheral blood stem cell allograft
28
Selection of Control Cohort
Criterion Resulting
Sample Size
Excluded
All enrolled subjects 600 0
Subjects transplanted 599 1
HPC-A from related donor
236 363
HLA-matched donor 233 3
Subjects age 18-65 years
231 2
Subjects with AML 96 135
First or second remission
85 11
Allograft not T cell depleted
84 1
29
Demographics of Subjects Used in the Analyses
All Subjects First CR Second CR
0303 0101 p 0303 0101 p 0303 0101 p
NumberNumber 4444 8484 3737 6565 77 1919
Gender Female
63.6% 44.0% 0.04 62.2% 44.6% 0.09 42.1% 42.1% 0.38
Male 36.4% 56.0% 37.8% 55.4% 57.9% 57.9%
Median Age (Range)
49 yrs(21-60)
45 yrs(20-63)
0.14 48 yrs (21-60)
43 yrs(20-63)
0.09 49 yrs (26-58)
48 yrs (25-63)
0.89
Age Group
<50 yrs 56.8% 67.9% 0.22 56.8% 69.2% 0.21 57.1% 63.2% 1.00
>50 yrs 43.2% 32.1% 43.2% 30.8% 42.9% 36.8%
* The investigators have submitted the clinical outcome results and cell processing data from these studies for publication. The former are currently under review for publication. The latter are pending publication in Biology of Blood and Marrow Transplantation (in press).
30
Demographics (continued)
All Subjects First CR Second CR
0303
0101
p 0303
0101
p 0303
0101
p
Number 44 84 37 65 7 19
Race White 95.5% 85.7% 0.51 94.6% 90.8% 0.44 100% 68.3% 0.58
Asian 2.3% 2.4% 2.7% 1.5% 0.0% 5.5%
Black 0.0% 2.4% 0.0% 1.5% 0.0% 5.5%
Other 2.3% 3.6% 2.7% 3.1% 0.0% 5.3%
Unknown 0.0% 6.0% 0.0% 3.1% 0.0% 15.9%
Performance Status
90- 100 77.3% 91.0% 0.62 78.3% 80.0% 0.85 71.4% 84.3% 0.46
70-80 22.7% 19.2% 21.6% 20.0% 28.6% 15.8%
Cytogenetics Risk Group
Favorable 4.5% 10.7% 0.34 0.0% 6.2% 0.18 28.6% 26.3% 0.53
Intermediate
63.6% 65.5% 67.6% 66.2% 42.9% 63.2%
Unfavorable 25.0% 14.3% 27.0% 16.9% 14.3% 5.3%
Unknown 6.8% 9.5% 5.4% 10.8% 14.3% 5.3%
31
Study 0303Patient Disposition
Number (%)
Enrolled 47 (100%)
Off study prior to transplantation (n=3)
Relapse 2 (4.3%)
Ineligible 1 (2.1%)
Transplanted(n=44)
Died 17 (36.2%)
Completed
19 (40.4%)
Ongoing 8 (17.0%)
32
Study 0303 CD34 Cell Doses Administered
NCD34
(x 106/kg)CD3
(x 105/kg)
All 44 7.9 (2.4-30.4) 0.07 (0.01-0.83)
CR1 37 7.4 (2.4-30.4) 0.07 (0.01-0.63)
CR2 7 8.0 (7.4-22.8) 0.07 (0.03-0.83)
33
Probable Benefit and Safety
• Probable benefit: GVHD-related endpoints – Device excludes T cells that may cause GVHD – Allows for transplantation to proceed without
the need for immunosuppressive drugs
• Safety: Endpoints related to hematopoietic recovery, infection, treatment-related mortality, relapse, and survival– Potential damage of hematopoietic stem cells
during processing– Reduction in T cells that mediate anti-leukemia
and anti-infection effects
34
Statistical Analyses
35
FDA’s Analysis Methods• Acute GVHD and chronic GVDH - Competing risk analyses with relapse
and death as the competing risks • Relapse and engraftment - Competing risk analyses with death
as the competing risk • Comparison of cumulative incidence
functions - Gray’s method• Cumulative incidence rates and 95%
CIs - R function CumIncidence
36
FDA’s Analysis Methods (cont’d)
• Disease-free survival, overall survival - Hazard ratios were estimated by the Cox proportional hazard model
- Covariates included age group (<=50 and >50)
and CR stage (cytogenetics data insufficient)
- Stratified log-rank test was used to compare
survival curves
37
Limitations of the Analyses
• Retrospective comparison • Nonrandomized cohorts• Heterogeneous populations• Number of subjects is small• P-values must be interpreted with
caution • ATG was given to enhance engraftment
in 100% of patients in 0303 and only 8% of patients in 0101 (ATG is known to reduce GVHD)
38
FDA Analyses of Probable Benefit
• Acute GVHD • GVHD-free survival• Chronic GVHD
39
Cumulative Incidence Function (CIF) of Acute GVHD
0 100 200 300 400
0.0
0.2
0.4
0.6
0.8
1.0
Gr2-4aGVHD Estimated CIF: Study 0303 vs. 0101
Days after Transplantation
Pro
ba
bili
ty o
f aG
VH
D
0101 (n=84)0303 (n=44)
0 100 200 300 400
0.0
0.2
0.4
0.6
0.8
1.0
Gr3-4aGVHD Estimated CIF: Study 0303 vs. 0101
Days after Transplantation
Pro
ba
bili
ty o
f aG
VH
D
0101 (n=84)0303 (n=44)
40
Comparison of Acute GVHD
Gr 2-4 GVHD Gr 3-4 GVHDSubgroup
andStudy N
Incidence rate at Day
100 (95%CI)
p-value*
Incidence rate at
Day 100 (95%CI)
p-value*
All
0101 84 38.1% (27.7-48.4)
22.7% (11.6-36.0)
0.05
9.5% (4.4-17.0)
4.5% (0.8-13.7)0.240303 44
CR1
0101 65 35.4% (23.9-47.0)
24.3% (11.9-39.1)
0.15
9.2% (3.7-17.8)
2.7% (0.2-12.3)0.15
0303 37
CR2
0101 19 47.4% (23.6-67.9)
14.3% (0.5-49.1)
0.14
10.5% (1.7-29.0)
14.3% (0.5-49.1)
0.820303 7
* Gray’s test
41
Comparison of Acute GVHD-Free Survival
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Grade3-4 GVHD-free survival: Study 0303 vs. 0101
days after transplantation
Pro
ba
bili
ty
0303 (n=44)0101 (n=84)
0 200 400 600
0.0
0.2
0.4
0.6
0.8
1.0
Grade2-4 GVHD-free survival: Study 0303 vs. 0101
days after transplantation
Pro
ba
bili
ty
0303 (n=44)0101 (n=84)
42
Summary of Acute GVHD-Free SurvivalGrades 2-4 GVHD-Free
Survival
Grades 3-4 GVHD-Free
Survival
Subgroupand
Study NHR1 (95%C
I)p-value2
HR1
(95%CI) p-value2
All
0101 840.617 3
(0.356, 1.069)
0.0933
0.7783 (0.390,
1.552)0.55730303 44
CR1
0101 650.631
(0.338, 1.177)
0.1420.682
(0.299, 1.558)
0.3600303 37
CR2
0101 190.634 (0.202,
1.988)0.414
1.261(0.374,
4.252)0.7020303 7
1. hazard ratio (0303 vs. 0101) 2. log-rank test 3.stratified by CR stage
43
Cumulative Incidence function (CIF) of Chronic GVHD
0 100 200 300 400
0.0
0.2
0.4
0.6
0.8
1.0
cGVHD Estimated CIF: Study 0303 vs. 0101
Days after Transplantation
Pro
ba
bili
ty o
f cG
VH
D
0101 (n=84)0303 (n=44)
Comparison of Chronic GVHD
Group Study NIncidence rate at 1 year (95%CI) p-value*
All0101 84 44.9% (33.4-55.8)
15.9% (6.9-28.3) 0.0020303 44
CR10101 65 46.9% (33.5-59.2)
18.9% (8.2-33.0) 0.0100303 37
CR20101 19 36.8% (15.4-58.7)
0 0.0870303 7
* Gray’s test
45
Overview: Probable Benefit• Outcomes using the CliniMACS® Reagent
System and no standard GVHD prophylaxis– Day-100 Grades 2-4 acute GVHD is 22.7% and
Grades 3-4 acute GVHD is 4.5%– Day-180 acute GVHD-free survival is 68.2%– 1-Year chronic GVHD rate is 15.9%
• All subjects also received ATG in the preparative regimen.
• Not all subjects have completed 2-year follow-up
• No pediatric subjects
46
FDA Analyses of Safety
• Engraftment• Infection• Treatment-related
mortality• Relapse• DFS• OS
47
Cumulative Incidence Function (CIF) of Engraftment
0 10 20 30 40
0.0
0.2
0.4
0.6
0.8
1.0
Neutrophil Engraftment CIF
Days after Transplantation
Pro
ba
bili
ty
0101 (n=84)0303 (n=44)
0 10 20 30 40
0.0
0.2
0.4
0.6
0.8
1.0
Platelet Engraftment CIF
Days after Transplantation
Pro
ba
bili
ty
0101 (n=84)0303 (n=44)
48
Comparison of EngraftmentSubgroupAnd Study N
ANC >500% at Day 30
(95%CI)p-
value*
Platelets >20,000
% at Day 30 (95%CI)
p-value*
All
010184
96.4% (88.3-99.0)
100.0%
0.002
83.3% (73.2-89.9)
93.2% (78.6-98.0)
0.230303
44
CR1
010165
95.4% (85.1-98.6)
100% 0.004
83.1% (71.2-90.4)
91.9% (75.0-97.6)
0.260303
37
CR20101
19
100%
100%0.57
84.2% (55.1-95.2)
100% 0.51
0303 7
* Gray’s test
49
Infections Within One Year
After Transplantation0101
(n=84)0303(n=44
)p
Subjects with any infection
57 (68%)32
(73%)0.69
Maximum Severity: None
28 (33%)12
(27%)0.57
Moderate
30 (36%)15
(34%)
Severe
23 (27%)13
(30%)
Life Threatening/Fatal
3 (4%) 4 (9%)
Subjects with : No infection
28 (33%)12
(27%)0.60
1-4 infections
49 (58%)26
(59%)
>5 infections
8 (10%) 6 (14%)
50
Infections Within One Year
After Transplantation (cont’d)0101
(n=84)0303
(n=44)p
Subjects with infection due to: Bacteria
48 (57%) 25 (57%) 1.00
Virus 30 (36%) 24 (55%) 0.06
Fungus 9 (11%) 5 (11%) 1.00
Protozoa 0 1 (2%) 0.34
Other 3 (4%) 0 0.55
Number of Infections due to: Bacteria
103 (64%) 62 (55%)
Virus 46 (28%) 41 (37%)
Fungus 9 (6%) 8 (7%)
Protozoa 0 1 (1%)
Other 4 (2%) 0
51
Comparison of Treatment-Related Mortality
Group Protocol
NIncidence rate at 1 year (95%CI)
p-value*
All
0101 84 15.7% (8.79-24.33)
13.6% (5.46-25.54)
0.520303 44
CR1
0101 65 15.6% (7.97- 25.61)
13.5% (4.85-26.61)
0.760303 37
CR2
0101 19 15.8% (3.68-35.64)
14.3% (0.45- 49.6)
0.680303 7
* Gray’s test
52
Cumulative Incidence Function (CIF) of Relapse
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Leukemia Relapse Estimated CIF: by Study
Days since Transplantation
Pro
ba
bili
ty o
f Re
lap
se
0101 (n=84)0303 (n=44)
53
CIF of Relapse by CR Number
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Leukemia Relapse Estimated CIF: CR2
Days since Transplantation
Pro
ba
bili
ty o
f Re
lap
se
0101 CR2 (n=19)0303 CR2 (n=7)
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Leukemia Relapse Estimated CIF: CR1
Days since Transplantation
Pro
ba
bili
ty o
f Re
lap
se
0101 CR1 (n=65)0303 CR1 (n=37)
Comparison of Relapse
Group Protocol
NIncidence rate at 1 year (95%CI) p-
value*
All
0101 84 20.5% (12.58-29.87)
20.6% (10.06-33.77)
0.880303 44
CR1
0101 65 17.3% (9.13-27.54)
13.7% (4.90-27.03)
0.540303 37
CR2
0101 19 31.6% (12.33-53.00)
57.1% (12.07-86.23)
0.330303 7
*Gray’s test
55
Comparison of Disease-Free Survival
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Disease-free survival: Study 0303 vs. 0101
days after transplantation
Pro
ba
bili
ty
0303 (n=44)0101 (n=84)
56
Disease-Free Survival by CR Number
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Disease-free survival: Study 0303 vs. 0101 CR1
days after transplantation
Pro
ba
bili
ty
0303 CR1 (n=37)0101 CR1(n=65)
0 100 200 300 400 500 600 700
0.0
0.2
0.4
0.6
0.8
1.0
Disease-free survival: Study 0303 vs. 0101 CR2
days after transplantation
Pro
ba
bili
ty
0303 CR2 (n=7)0101 CR2 (n=19)
57
Summary of Disease-Free Survival
Group Protocol
NHR1
(95%CI) p-value 2
All0101 84 0.836 (0.445-
1.569)*0.710*
0303 44
CR10101 65 0.687 (0.321-
1.472)0.383
0303 37
CR20101 19 1.415 (0.478-
4.191)0.482
0303 7
1. hazard ratio (0303 vs. 0101) 2. stratified log-rank test
58
Comparison of Overall Survival
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Overall survival: Study 0303 vs. 0101
days after transplantation
Pro
ba
bili
ty
0303 (n=44)0101 (n=84)
59
Overall Survival by CR Number
0 200 400 600 800
0.0
0.2
0.4
0.6
0.8
1.0
Overall survival:CR1
days after transplantation
Pro
ba
bili
ty
0303 CR1 (n=37)0101 CR1 (n=65)
0 100 200 300 400 500 600 700
0.0
0.2
0.4
0.6
0.8
1.0
Overall survival: CR2
days after transplantation
Pro
ba
bili
ty
0303 CR2 (n=7)0101 CR2 (n=19)
60
Summary of Overall Survival
Group
Protocol
NHR1
(95%CI) p-value 2
All0101 84 0.843 (0.403-
1.765)*0.716*
0303 44
CR10101 65 0.715 (0.289-
1.765)0.441
0303 37
CR20101 19 1.352 (0.391-
4.680)0.609
0303 7
1. hazard ratio (0303 vs. 0101) 2. stratified log-rank test
61
Overview: Safety• Outcomes using the CliniMACS® Reagent
System and no standard GVHD prophylaxis– 100% Neutrophil recovery by Day 30– Viral infection in 55% (EBV infection in 18%)– 1-Year treatment-related mortality is 13.6%– 1-Year relapse rate is 20.6%
• The incidence of viral infection is higher than for the standard transplant controls
• The relapse rate for CR2 patients is higher than for the standard transplant controls
• Follow-up is incomplete
62
Issues for Discussion• Safety: With respect to graft failure,
infections, relapse and treatment-related mortality at 1 year
• Probable Benefit: For processing allogeneic HLA-matched HPC-A to obtain a CD34+ cell enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen without additional immunosppression in patients with acute myeloid leukemia (AML)
• Indication: CR 1 vs. CR 2
• Pediatric studies
63
Reference
• Gray R J. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Annals of Statistics. 1988; 16:1141:54
• Scrucca L et al. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplantation. 2007; 40: 381-7