What about stem cell transplantation

1. What about stem cell transplantation? Dr Catherine Flynn Consultant Haematologist St James’s Hospital 17/06/2011

2. What is Myelodysplasia? Stem cell disorder with a variable clinical course Treatment strategy with the highest curative potential is an allogeneic stem cell transplant

3. Incidence

4. MDS transplant Activity Increase in the number of reduced intensity transplants Increase in the number of unrelated donor transplants Increase in patients >50 years

5. Current transplant activity in MDS EBMT 2008: 1147 allografts for MDS ~ 10% of total 1998-2006 1333 MDS patients > 50yrs allografted

6. Types of transplant Autograft Allogeneic Syngeneic Myeloablative/traditional Mini-transplant/reduced intensity

7. MA Allogeneic 2009:Disease Indication

8. RIC Allogeneic Transplants 2009:Disease Indication

9. 25 years of BMT in Ireland

10. Decision to Transplant Patient Factors Disease Factors Patient Wishes + Support Stage Age and Performance MRD Co-Morbidities Previous Treatment Transfusions/Iron Status Indolent/Proliferative Infection Extramedullary Disease

11. Curative Potential

12. Outcomes (Kroger MDS ESH meeting) Survival without relapse 29-40% Mortality without relapse 37-50% Relapse 23-48%

13. Early Consideration of Transplant Potential candidates should have a donor search and be referred for discussion

14. Timing Is important…… Delaying SCT can result in maximising overall survival for low and intermediate risk MDS (Cutler et al) Optimal Timing Time of a new cytogenetic abnormality Appearance of a clinically significant cytopenia Increase in the percentage of bone marrow blasts

15. Net benefit or loss overall discounted life expectancy for the 4 IPSS risk groups are shown above and below the x-axis.

16. Co-Morbidities Lung problems Liver problems Joint/Bone problems Psychiatric disorders Previous other cancer Stomach Ulcer Brain/stroke illness

17. Performance Score

18. Biological Age Chronological Age Physical Function Organ co-morbidities Ability to withstand the harshness of chemo-radiotherapy To process different medications and large volumes of fluid To tolerate serious infections and harmful effects of GVHD

19. Disease Stage Low Risk MDS High Risk MDS

20. Chromosomes Count…..

21. International prognostic Scoring System

22. WHO Prognostic Scoring System

23. Number of transfusions and iron overload

24. High Ferritin pre transplant is associated with a poor survival

25. To make a treatment decision or a risk assessment in any patient…. Patient factors medical co-morbidity Disease Factors Cytogenetics, Transfusion/Iron, WHO subtype

26. Impact not yet known…… Timing of Transplant Chemotherapy before HCT or not ?

27. Miss A 24 year old girl referred in 2008 with anaemia Hb=9.7g/DL, normal WCC and platelet count Karyotype normal Bone marrow Refractory Cytopenia and multi-lineage dysplasia April 2011 Hb= 8.8g/DL ? Consider Transplant

28. What to do?? IPSS score = 0, WPSS =1 Low risk MDS No sibling donor Defer transplant at present

29. Mrs B 56 year old lady seen in September 2010 Hb 9.1, platelets 41, WCC 1.2 Normal karyotype Bone marrow refractory cytopenia and ring sideroblasts Not requiring Transfusions HLA matched sibling

30. What to do? IPSS= 0.5, WPSS =1 Low risk MDS Defer transplant at present

31. Update January 2011 Increasing transfusion requirment Bone marrow and karyotype unchanged March 2011 reduced intensity sibling transplant Currently 80 days post transplant with skin and liver GVHD

32. Mrs C 46 year old woman Presented June 2008 Hb 7, WCC 3, Plats = 53 Bone marrow 7% blasts Complex karyotype No sibling donor

33. What did we do? IPSS Int-2 Unrelated donor search started 2 courses of chemotherapy Unrelated transplant May 2009 Some minor liver GVHD

34. Unfortunately…. Died May 2011 with pneumonia Delayed immune recovery

35. Myeloablative Vs Reduced Intensity High TRM Low relapse Low TRM Higher relapse

36. Transplant Complications

37. Immune Recovery Approximate immune cell counts (expressed as percentage of normal counts) before and after myeloablative hematopoietic cell transplantation. Nadirs are higher and occur later after nonmyeloablative than myeloablative transplantation, as recipient cells persist after nonmyeloablative transplant for several weeks to months (in the presence of GVHD) or longer (in the absence of GVHD). The orange line represents innate immune cells (for example, neutrophils, monocytes and natural killer (NK) cells), the recovery of which is influenced by graft type (fastest with filgrastim-mobilized blood stem cells, intermediate with marrow and slowest with umbilical cord blood). The green line represents the recovery of CD8+ T cells and B cells, the counts of which may transiently become supranormal. B-cell recovery is influenced by graft type (fastest after cord blood transplant) and is delayed by GVHD and/or its treatment. The blue line represents the recovery of relatively radiotherapy/chemotherapy-resistant cells such as plasma cells, tissue DCs (for example, Langerhans cells) and, perhaps, tissue macrophages/microglia. The nadir of these cells may be lower in patients with acute GVHD because of graft vs host plasma cell/langerhans cell effect. The red line represents CD4+ T cells, the recovery of which is influenced primarily by the T-cell content of the graft and patient age (faster in children than adults). From Storek J: Immunological reconstitution after hematopoietic cell transplantation—its relation to the contents of the graft. Expert Opinion on Biological Therapy (Informa) 8(5): 583–597, 2008.Approximate immune cell counts (expressed as percentage of normal counts) before and after myeloablative hematopoietic cell transplantation. Nadirs are higher and occur later after nonmyeloablative than myeloablative transplantation, as recipient cells persist after nonmyeloablative transplant for several weeks to months (in the presence of GVHD) or longer (in the absence of GVHD). The orange line represents innate immune cells (for example, neutrophils, monocytes and natural killer (NK) cells), the recovery of which is influenced by graft type (fastest with filgrastim-mobilized blood stem cells, intermediate with marrow and slowest with umbilical cord blood). The green line represents the recovery of CD8+ T cells and B cells, the counts of which may transiently become supranormal. B-cell recovery is influenced by graft type (fastest after cord blood transplant) and is delayed by GVHD and/or its treatment. The blue line represents the recovery of relatively radiotherapy/chemotherapy-resistant cells such as plasma cells, tissue DCs (for example, Langerhans cells) and, perhaps, tissue macrophages/microglia. The nadir of these cells may be lower in patients with acute GVHD because of graft vs host plasma cell/langerhans cell effect. The red line represents CD4+ T cells, the recovery of which is influenced primarily by the T-cell content of the graft and patient age (faster in children than adults). From Storek J: Immunological reconstitution after hematopoietic cell transplantation—its relation to the contents of the graft. Expert Opinion on Biological Therapy (Informa) 8(5): 583–597, 2008.

38. Questions……