immune recovery in children after bone marrow transplant rollo hoare supervisors: robin callard...

Immune Recovery in Children after Bone Marrow Transplant

Rollo Hoare

Supervisors:

Robin Callard & Joseph Standing

Bone Marrow Transplant (BMT)

• BMT done post leukemia or other immune system failure

• Before BMT patients undergo conditioning during which all lymphocytes in the body may be killed

• We are looking at the recovery of the immune system after BMT

• In particular the concentration of CD4 in the blood

The aim of the project

1. Build a model for the CD4 cell count recovery

2. Fit the model to the data (CD4 count time series)

3. Add parameters related to covariates

4. Analyse results of included covariates

The aim of the project

1. Build a model for the CD4 cell count recovery

2. Fit the model to the data (CD4 count time series)

3. Add parameters related to covariates

4. Analyse results of included covariates

1. The Model

• Start with an exponential model:

asy

int

Parametersasy = asymptoteint = interceptc = rate of change

The aim of the project

1. Build a model for the CD4 cell count recovery

2. Fit the model to the data (CD4 count time series)

3. Add parameters related to covariates

4. Analyse results of included covariates

2. Fit model to dataa) Age adjustment• CD4 count drops non-linearly with age in healthy

children

2. Fit model to dataNLME Modelling•

The aim of the project

1. Build a model for the CD4 cell count recovery

2. Fit the model to the data (CD4 count time series)

3. Add parameters related to covariates

4. Analyse results of included covariates

3. Add covariates • Multivariate analysis: we add covariate

parameters into the model for:- BMT Age- Sex - BMT Number- Donor type- Donor cells type- Leukaemia- HCMV- EBV- Alem/anti-CD45/ATG

- Total body irradiation- Cyclosporine- Methotrexate- Mycophenolate- Prednisone- Muromonab- No conditioning- Reduced conditioning- Chimerism

3. Diagnostic Plots

3. Diagnostic Plots

The aim of the project

1. Build a model for the CD4 cell count recovery

2. Fit the model to the data (CD4 count time series)

3. Add parameters related to covariates

4. Analyse results of included covariates

4. Results• After SCM, we included the following covariates:

• Int:- Alemtuzumab/Anti-CD45/Anti-thymocyte Globulin- Leukaemia- Donor type

• Asy:- HCMV- No conditioning

• c:- Mycophenolate

4. Results• Int: Alem/anti-CD45/ATG

4. Results• Int: Leukaemia

4. Results• Int: Donor type

4. Results• Asy: HCMV

4. Results• Asy: Conditioning

4. Results• C: Mycophenolate

Next Steps• Include age adjustment in the model rather than pre-

adjustment- Linear- Free exponential- Fixed exponential- Fixed exponential with ratio

• Or use another form of age adjustment- Square root ratio- Fourth root ratio

• Add in further covariates for conditioning drugs and diagnoses

• Look at dosage information

Next StepsInclude age in model: Linear

• ASY = THETA(1) + THETA(2) * (3650-AGE)

Next StepsInclude age in model: Linear

• ASY = THETA(1) + THETA(2) * (3650-AGE)

Next StepsInclude age in model: Free exponential

• ASY = THETA(1) +THETA(2) * EXP(-THETA(3)*AGE)

Next StepsInclude age in model: Free exponential

• ASY = THETA(1) +THETA(2) * EXP(-THETA(3)*AGE)

Next StepsInclude age in model: Fixed exponential

• ASY = 924.2 + 23545.* EXP(-0.00101*AGE)

Next StepsInclude age in model: Fixed exponential

• ASY = 924.2 + 23545.* EXP(-0.00101*AGE)

Next StepsInclude age in model: Fixed exponential with ratio

• ASY = THETA(1) * (924.2 + 2355* EXP(-0.00101*AGE))

Next StepsInclude age in model: Fixed exponential with ratio

• ASY = THETA(1) * (924.2 + 2355* EXP(-0.00101*AGE))

Next StepsAge adjustment: Fourth root ratio

Next StepsAdditional Covariates to be tested

- BMT Failure- Alemtuzumab- Anti CD-45- Anti-thymocyte globulin- Busulphan- Cyclosporine

(Conditioning)- Melphalan

- Fludarabine- Treosulphan- Diagnosis- Edited EBV- Edited HCMV- Edited donor cells- Edited donor type

Conclusion• We have modelled the CD4 count recovery of children

post BMT using the logratio• We have found the following covariates affect recovery:

- Int: Alem/anti-CD45/ATG, Leukaemia, donor type

- Asy: Conditioning, HCMV

- c: mycophenolate• More work needs to be done to ascertain the reliability

of these results.

Questions??