1. DR. YETUNDE T. ISRAEL-AINA PAEDIATRICIAN, UNIVERSITY OF BENIN TEACHING HOSPITAL, BENIN CITY BENIN BLOOD AND MARROW TRANSPLANT WORKSHOP, UNIVERSITY OF BENIN TEACHING HOSPITAL, BENIN CITY. JULY 15 – 27, 2013. HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR LEUKAEMIA IN CHILDREN

2. Overview The spectrum and biological characteristics of haematological malignancies are significantly different between children and adults. Questioning the applicability of transplant for any diagnosis is appropriate, especially in the field of paediatric leukaemia. Improvements in survival of children with leukaemia: over 80% for standard risk ALL and 50-70% for AML

3. Introduction HSCT is reserved for high-risk leukaemia patients in first and subsequent remission who are unlikely to be cured by chemotherapy. Identify high risk children with the knowledge of current outcome with chemotherapy, leukaemia biology and likely transplant outcomes

4. How HSCT works in leukaemia Transplant allows use of high doses of chemotherapeutic drugs to kill leukaemic cells. Graft versus leukaemia effect (GvL): Alloreactive T- cells in the graft attack leukaemic cells in the recipient. Effect of GvL is seen more in CML than in AML and ALL. Role of donor lymphocyte infusion (DLI)- survival at 2yrs greater in children who had DLI.

5. ALL Curable by first-line treatment in 80% of cases EFS at 8 years is 75% for ALL patients

6. Indications for transplant in ALL CR1 In high-risk children with ALL in CR1 CR could not be achieved after initial induction therapy. Over 10-2 minimal residual disease (MRD) remains after induction therapy, Ph+ chromosome or the Bcr-AbL fusion gene is positive. In infants aged less than one year with t (4:11) and the MLL/AF4 fusion gene, WBC>100X109/L ≥CR2 Intermediate and standard-risk ALL in ≥CR2 who relapsed less than 36 months after diagnosis.

7. AML With intensive chemotherapy, 80-90% achieve CR 30-70% are cured with post induction chemotherapy 45-64% long term survival in children with high risk AML in CR1 – using MRD transplant Over 60% of children do not have MRD Individual case assessment needed for transplant in children with AML

8. Indications for transplant in AML AML-High-risk acute myelogenous leukaemia (AML) includes M4, M5, M6, M7 subtypes in FAB classification In CR1, Ph' chromosome (+) AML in CR1, 5q, 7q deletion in CR1, and Flt3-ITD mutation in CR1. CR could not be achieved after one or two courses of standardized induction therapy. The WBC count is over 100×109/L initially in CR1. CR2 AML or secondary AML due to MDS transformation Relapsed AML with a suitable donor CR1 in treatment-related AML (t-AML). Chronic myelogenous leukaemia in chronic phase,

9. MDS Acct for < 5% of haematologic malignancies Variants important for transplant - RAEB and RAEB-t - Juvenile myelomonocytic leukaemia JMML JMML – median age at diagnosis is 2years - M: F= 2:1 - Allo-HSCT is the only cure, with long term survival - age >4yrs and female sex predicted poor outcome in transplanted children.

10. Myeloablative conditioning High-dose regimens are particularly useful in conditioning patients with aggressive malignancies. Cyclophosphamide plus total body irradiation (TBI) or busulfan and cyclophosphamide are typical combinations for full myeloablative regimens.

11. Reduced intensity conditioning - RIC Reduced-intensity or non-myeloablative regimens use lower doses of pre-transplant chemotherapy drugs and/or radiation These regimens do not completely eliminate malignant cells, but rely on graft-versus-malignancy effect mediated by donor-origin lymphoid cells, mostly T cells. Reduced-intensity regimens use combinations of chemotherapy drugs such as fludarabine, busulfan, and melphalan, with or without low-dose radiation.

12. Conditioning for malignant diseases For ALL 1. fTBI (fractionated total body irradiatin) VP 16 (Etoposide) or Cyclophosphamide 2. Busulfan Cyclophosphamide 3. Clofarabin Busulfan 4. Busulfan Fludarabin Thiotepa For AML/MDS/RAEB Busulfan Cyclophosphamide Melphalan

13. Type of transplant Autologous - Used as consolidation in high risk AML in CR1 or 2 without MRD. - Auto-HSCT (with in- vitro purging) is not a valid alternative to multi- drug chemotherapy or to allo-HSCT Allogeneic - Best option - Early allo-HSCT led to better overall results than auto-HSCT

14. Donor selection and stem cell source MSD – still the gold standard. Available in only 25% of cases. MUD – acceptable Unmanipulated bone marrow – standard for MSD. PBSC – risk of GVHD T- cell depletion performed only in mismatched donor. UCBT – acceptable outcome if sufficient dose is infused Haploidentical transplant

15. Outcome Transplants for acute leukaemias, ALL and AML, in remission at the time of transplant have survival rates of 55-68% if the donor is related and 26-50% if the donor is unrelated.

16. Summary HSCT with bone marrow source is the first choice. Then, MRD with cord blood with sufficient dose, if lower UCB, supplement with BM from the sibling. If above two are not available, MUD is indicated.

17. References Davies SM, Parinda M. Pediatric acute lymphoblastic leukaemia: is there still a role for transplant? American Society of Haematology Education Program. (asheducationbook.hem) EBMT Handbook. Haematopoietic Stem Cell Transplantation. 6 th ed. 2012.

18. THANKS!!!