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