Umbilical Cord Blood Transplantation in Pediatric Patients with Malignant Diseases

J Kurtzberg, SL Carter, JE Wagner, LA Baxter-Lowe, D Wall, N Kapoor, E Guinan, S Feig, E Wagner, NA Kernan on behalf of the

COBLT Steering Committee

Results of a Prospective, Multi-Institutional NHLBI Sponsored Trial

Overview of the COBLT Study• Prospective, multi-institutional study

sponsored by the NHLBI.– 3 banks:

• Duke J Kurtzberg• UCLA J Fraser• CHOC/GT M Cairo

• Created inventory of approx 8,000 units• 71 % of transplants used COBLT units• Transplantation study: Strata for adults,

peds ID, metabolic ds & peds malignancies.

The Transplantation Study

• Common protocol for preparative regimen, GvHD prophylaxis and supportive care.

• Common criteria for evaluation of risk status at study entry, donor selection, engraftment, GvHD, infection and causes of death.

Study End Points

Primary Endpoint• 180 day survival

Secondary Endpoints• Disease-free survival• Incidence of neutrophil engraftment• Incidence of platelet engraftment• Incidence of acute and chronic GVHD• Incidence of relapse

Analysis of high resolution HLA typing and effect on outcomes.

Definitions

• Original HLA Matching– Low resolution DNA based typing for Class I, A and

B, High resolution DNA typing for Class II, DRB1

• Retrospective (final) HLA Matching– High resolution DNA typing for A, B, DRB1

• Engraftment– ANC 500/uL with >90% donor chimerism by day 42

Patient Eligibility

• Pediatric Patients between 1-18 years • Hematological malignancies

– Exclude CML blast crisis– Exclude ALL relapse

• No related donor• UCB donor delivering >10e7 cells/kg, matching

at 4/6 HLA loci by low resolution typing at Class I, or 3/6 with high resolution matching, 1 allele at A, B, DRB1.

Treatment• Preparative Regimen

– TBI 1350– Cyclophosphamide 120– Horse ATG 90

• GvHD Prophylaxis– Cyclosporine– Methyprednisolone

• Supportive Care– Anti viral, fungal and PCP prophylaxis– Antigen/DNA monitoring for CMV– G-CSF from day 0– IVIG prophylaxis

191 subjects transplanted between 2000-2003

Median Age: 7.7 (0.9 – 17.9) yearsMedian Weight: 25.9 (7.5-118.4) kg 61% Males58% White/38% Other/5% Unknown51% CMV+77% High RiskMedian pre cryo cell dose:5.2x10e7/kgMedian CD34 cell dose: 1.52x10e5/kg

Demographics

Primary Disease N (%)

ALL 109 (57)

AML 57 (30)

MDS 15 (8)

CML 7 (4)

Bi-Phenotypic 2 (1)

JMML 1 (1)

HLA Matching at HLA A, B & DRB1

Original HLA

Match

Final HLA Match Total # Patients Enrolled

Total # Patients with

HR HLA Typing

2 of 6 3 of 6 4 of 6 5 of 6 6 of 6

N (%) 1 N (%) 1 N (%) 1 N (%) 1 N (%) 1 N N (%) 2

3 of 6 2 (40) 2 (40) 1 (20) 0 (0) 0 (0) 5 5 (100)

4 of 6 8 (8) 30 (29) 65 (63) 0 (0) 0 (0) 110 103 (94)

5 of 6 1 (2) 3 (5) 11 (20) 37 (67) 3 (5) 59 55 (93)

6 of 6 0 (0) 1 (6) 0 (0) 3 (19) 12 (75) 17 16 (94)

Total 11 (6) 36 (20) 77 (43) 40 (22) 15 (8) 191 179 (94)1 Percent based on number of patients that have been retrospectively typed.

2 Percent based on number enrolled.

EngraftmentCumulative Incidence (CINC) and 1-Kaplan-Meier (1-KM)

Neutrophil Engraftment Platelet Engraftment (>50K/mm3)

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Days Post-Transplant

0 20 40 60 80 100

CINC1-KM

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 2 4 6 8 10 12

CINC1-KM

153/189 at d42

CI 75.1 (95%CI 69.3-81-5)

107/189 at d180

CI 50.5 (95% CI 42.5-58.7)

Multivariate AnalysisNeutrophil Engraftment

1 Original HLA Match 5/6 versus 4/6

Characteristic HR 95% CI P-value Favorable Characteristics

Pre-Cryopreserved TNC (x107/kg)

2.04 (1.00-4.19) 0.05 Larger TNC (>=2.5)

Gestational Age 1.37 (0.97-1.92) 0.07 Younger Gestational Age (<38 weeks)

HLA Match1 0.99 (0.69-1.43) 0.97 Not Signficant

Graft Versus Host DiseaseCumulative Incidence (CINC) and 1-Kaplan-Meier (1-KM)

Acute GVHD Grades III/IV Chronic GVHDP

roba

bilit

y

0.0

0.2

0.4

0.6

0.8

1.0

Days Post-Transplant0 20 40 60 80 100 120 140 160

CINC1-KM

CINC1-KM

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 6 12 18 24

CI at d100 18.6%

(95% CI 12.2-23.8)

CI at 1 yr 20.4%

(95% CI 14.6-26.4)

70% Limited

Multivariate AnalysisAcute GVHD Grades III/IV

Characteristic HR 95% CI P-value Favorable Characteristics

HLA Match1 0.35 (0.16-0.75) 0.007 5/6 or 6/6 HLA Match

1 Original HLA Match 5/6 or 6/6 versus 3/6 or 4/6

RelapseCumulative Incidence (CINC) and 1-Kaplan-Meier (1-KM)

Pro

ba

bili

ty

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 6 12 18 24 30 36 42

CINC1-KM

CI at 1 year 19.1

(95% CI 13.8-24.8)

Causes of Death

Primary COD

Contributing

Infection No Infection Total

N N N (%)

Recurrence/Relapse - - 39 (41)

Rejection 1 0 1 (1)

Graft Failure 13 5 18 (19)

Acute GVHD 12 10 22 (23)

Chronic GVHD 6 1 7 (7)

Infection-Bacterial - - 1 (1)

Infection-Fungal - - 1 (1)

Infection-Viral - - 2 (2)

EBV 0 1 1 (1)

Organ Failure-Cardiac 0 2 2 (2)

Hemorrhage 0 1 1 (1)

Total 32 20 95 (100)

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Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 6 12 18 24 30 36 42

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N=191

Overall Survival

180 days 67.4 (95% CI 60-7-74.1)

1 yr 57.3 (95%CI 50.2-64.3)

Median 24 months

Overall Survival Recipient Gender Donor Gender Donor/Recipient Gender

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1.0

Pro

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0.6

0.8

Months Post-Transplant0 6 12 18 24 30 36 42

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Male, N=116Female, N=75

P<0.01

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Male, N=102Female, N=85

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Months Post-Transplant0 6 12 18 24 30 36 42

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P=0.65

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Pro

babi

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0.0

0.2

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Months Post-Transplant0 6 12 18 24 30 36 42

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M/M or F/F, N=96M/F or F/M, N=91

P=0.30

Overall Survival Recipient Cytomegalovirus Serostatus

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Pro

ba

bili

ty

0.0

0.2

0.4

0.6

0.8

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Months Post-Transplant0 6 12 18 24 30 36 42

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Positive, N=98Negative, N=92

P<0.01

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Pro

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bili

ty

0.0

0.2

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Months Post-Transplant0 6 12 18 24 30 36 42

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<2.5, N=172.5-5.0, N=735.0-7.5, N=54>7.5, N=47

P=0.03

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Pro

ba

bili

ty

0.0

0.2

0.4

0.6

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Months Post-Transplant0 6 12 18 24 30 36 42

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P=0.73

<1.51, N=69>=1.51, N=91

Overall Survival Pre-Cryopreserved TNC (x107/kg) Pre-Cryopreserved CD34+ (x105/kg)

Overall Survival Original HLA Match Retrospective HLA Match

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5/6, N=594/6, N=110

P=0.92

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5/6, N=404/6, N=77

Pro

ba

bili

ty

0.0

0.2

0.4

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Months Post-Transplant0 6 12 18 24 30 36 42

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P=0.37

Multivariate AnalysisFor Survival

Characteristic HR 95% CI P-value Favorable Characteristics

ANC Engraftment1 3.03 (1.87-4.91) <0.001 Early Engrafter

Recipient Cytomegalovirus Serostatus

0.50 (0.33-0.77) 0.002 Negative

Recipient Gender 1.64 (1.09-2.48) 0.01 Male

1 Time Dependent Covariate

Summary

• The COBLT Study represents the first prospective, multi-institutional study of cord blood transplantation

– Standard treatment protocol– Standard supportive care– Standard outcome definitions and assessments–Analysis of retrospective high resolution HLA

typing on outcomes (with 34% of patients having greater disparity than original typing)

Conclusions• Incidence of engraftment is 75% which correlated with

nucleated cell dose and donor gestational age.• Incidence of acute grade III/IV acute GVHD was 19%;

chronic GVHD was 20% (70% limited) and GVHD was cause of death in 30% of fatalities.

• Incidence of relapse was 25% (77% of pts were high risk).

Conclusions• Overall survival was 55% with early

engraftment, recipient CMV seronegative status and male gender being favorable risk factors.

• Notably, level of HLA match (original or high resolution) and risk status at diagnoses did not impact survival .

Acknowledgements• Cardinal Glennon Children's Hospital - Dr. Michael Kelly• Case Western Reserve University Hospital - Dr. Mary Laughlin

• Children's Hospital – Los Angeles - Dr. Neena Kapoor• Children's Hospital – New Orleans - Dr. Lolie Yu• Children's Hospital – Orange County - Dr. Steven Neudorf• Children's Hospital – Philadelphia - Dr. Nancy Bunin• Children's Hospital – Pittsburgh - Dr. Rakesh Goyal• Children's Medical Center of Dallas - Drs. Victor Aquino & Donna Wall

• Children's Mercy Hospital - Dr. Andrew Gilman• Children's National Medical Center - Dr. Naynesh Kamani• City of Hope National Medical Center - Dr. Joseph Rosenthal• Dana Farber Cancer Institute - Drs. Eva Guinan & Leslie Lehmann

• DeVos Children's Hospital - Dr. Daniel Pietryga• Fred Hutchinson Cancer Research Center - Dr. Colleen Delaney

• Hackensack University Medical Center - Drs. Joel Brochstein & Stuart Goldberg

• Indiana University Cancer Center - Dr. Paul Haut• North Texas Hospital for Children - Dr. Joel Weinthal• Roswell Park Cancer Institute - Drs. Philip McCarthy & Barbara Bambach

• Schneider Children's Hospital - Dr. Indira Sahdev• Texas Transplant Institute - Drs. Carlos Bachier & Donna Wall

• University of California, Los Angeles - Dr. Stephen Feig• University of California, San Francisco - Drs. Morton Cowan & Biljana Horn

• University of Florida - Dr. Steven Hunger• University of Minnesota - Dr. John Wagner• University of Rochester - Drs. John Horan & Jane Liesveld• Vanderbilt University - Dr. Haydar Frangoul• The EMMES Corporation – Dr. Shelly Carter & Mr. Adam Mendizabal

• National Heart, Lung and Blood Institute – Dr. Luiz Barbosa, Ms. Liz Wagner & Dr. LeeAnn Jensen

•Dr. Nancy A. Kernan,•Steering Committee Chair