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Umbilical Cord Blood Transplantation in Pediatric Patients with Malignant Diseases. Results of a Prospective, Multi-Institutional NHLBI Sponsored Trial.
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Umbilical Cord Blood Transplantation in Pediatric Patients with Malignant Diseases Results of a Prospective, Multi-Institutional NHLBI Sponsored Trial 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
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
Demographics 191 subjects transplanted between 2000-2003 Median Age: 7.7 (0.9 – 17.9) years Median Weight: 25.9 (7.5-118.4) kg 61% Males 58% White/38% Other/5% Unknown 51% CMV+ 77% High Risk Median pre cryo cell dose:5.2x10e7/kg Median CD34 cell dose: 1.52x10e5/kg
HLA Matching at HLA A, B & DRB1 1 Percent based on number of patients that have been retrospectively typed. 2 Percent based on number enrolled.
1.0 1.0 0.8 0.8 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 CINC CINC 0.0 0.0 1-KM 1-KM 0 20 40 60 80 100 0 2 4 6 8 10 12 Days Post-Transplant Months Post-Transplant Engraftment Cumulative Incidence (CINC) and 1-Kaplan-Meier (1-KM) Neutrophil Engraftment Platelet Engraftment (>50K/mm3) 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 Analysis Neutrophil Engraftment 1 Original HLA Match 5/6 versus 4/6
1.0 1.0 0.8 0.8 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 0.0 0.0 CINC CINC 0 6 12 18 24 0 20 40 60 80 100 120 140 160 1-KM 1-KM Months Post-Transplant Days Post-Transplant Graft Versus Host Disease Cumulative Incidence (CINC) and 1-Kaplan-Meier (1-KM) Acute GVHD Grades III/IV Chronic GVHD 70% Limited CI at d100 18.6% (95% CI 12.2-23.8) CI at 1 yr 20.4% (95% CI 14.6-26.4)
Multivariate Analysis Acute GVHD Grades III/IV 1 Original HLA Match 5/6 or 6/6 versus 3/6 or 4/6
1.0 0.8 0.6 Probability 0.4 0.2 CINC 0.0 1-KM 0 6 12 18 24 30 36 42 Months Post-Transplant Relapse Cumulative Incidence (CINC) and 1-Kaplan-Meier (1-KM) CI at 1 year 19.1 (95% CI 13.8-24.8)
Overall Survival 1.0 | 0.8 | 0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | Probability | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.4 180 days 67.4 (95% CI 60-7-74.1) 1 yr 57.3 (95%CI 50.2-64.3) Median 24 months 0.2 0.0 0 6 12 18 24 30 36 42 Months Post-Transplant N=191
1.0 1.0 1.0 | | | 0.8 0.8 0.8 | | | | | | | | | | | | | 0.6 0.6 0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Probability Probability Probability | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.4 0.4 0.4 | | | | | | | | | | | | | 0.2 0.2 0.2 P<0.01 P=0.65 P=0.30 0.0 0.0 0.0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Months Post-Transplant Months Post-Transplant Months Post-Transplant Male, N=116 Male, N=102 M/M or F/F, N=96 Female, N=75 M/F or F/M, N=91 Female, N=85 Overall Survival Recipient Gender Donor Gender Donor/Recipient Gender | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
1.0 0.8 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.6 Probability | | | | | | | | 0.4 | | | | | | | | | | | | | | | | | | | 0.2 P<0.01 0.0 Positive, N=98 0 6 12 18 24 30 36 42 Negative, N=92 Months Post-Transplant Overall Survival Recipient Cytomegalovirus Serostatus | | | | | | | | | |
1.0 1.0 | 0.8 0.8 | | | | | | | | | 0.6 | | | | | | | | | | | | | | | | | 0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Probability | Probability | | | | | | | | | | | | | | | | | | | | | | | | | 0.4 0.4 | 0.2 0.2 P=0.03 P=0.73 0.0 0.0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 <2.5, N=17 <1.51, N=69 Months Post-Transplant >=1.51, N=91 2.5-5.0, N=73 Months Post-Transplant 5.0-7.5, N=54 >7.5, N=47 Overall Survival Pre-Cryopreserved TNC (x107/kg) Pre-Cryopreserved CD34+ (x105/kg) | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
1.0 1.0 0.8 0.8 | | 0.6 0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | | | Probability Probability | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.4 0.4 0.2 0.2 P=0.92 P=0.37 0.0 0.0 5/6, N=59 5/6, N=40 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 4/6, N=110 4/6, N=77 Months Post-Transplant Months Post-Transplant Overall Survival Original HLA Match Retrospective HLA Match | | | | | | | | | | | | | | | |
Multivariate Analysis For Survival 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