Hematopoietic Stem Cell Transplantation: When Blood is Not an Option

1. Hematopoietic Stem Cell Transplantation: When Blood is Not an Option Michael Lill, MB,BS, FRACP, FRCPA Director, BMT Program Samuel Oschin Comprehensive Cancer Institute

2. History of Hematopoietic Stem Cell Transplantation Appelbaum F. N Engl J Med 2007;357:1472-1475

3. Dose Intense Rationale for Transplantation Other organ toxicity Dose intensity Marrow toxicity % cured

4. Relapse rate after myeloablative allogeneic transplant (from Horowitz et al, Blood 1990) Risk of Relapse secondary to immunologic disparity Probability of relapse 0.6 0.4 0.2

5. Erythrocyte LHSC CLP Lympho-Hematopoietic differentiation from bone marrow stem cells MEP Megakaryocyte CMEP GMP Granulocyte ? ? Monocyte ? Natural Killer T Lymphocyte B Lymphocyte

6. Hematopoietic stem cells are responsible for all the circulating elements of blood, and all the elements of the cellular immune system Common sources include Umbilical cord blood Bone marrow Mobilized peripheral blood stem cells Stem cell donors Autologous (from yourself) Allogeneic (from someone else) Related Matched unrelated Hematopoietic Stem Cell Transplantation; What, How and Why?

7. Mobilized peripheral blood stem cells are bone marrow cells that have been induced to move temporarily from the marrow into the blood by the use of Chemotherapy Hematopoietic growth factors Chemokine receptor blockade Mobilized peripheral blood stem cells have several advantages More rapid neutrophil engraftment More rapid platelet engraftment Ability to increase dose administered Hematopoietic Stem Cell Transplantation; What, How and Why?

8. Transplant Activity in the U.S. 1980-2011 Transplants Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2012. Available at: www.cibmtr.org

9. Indications for Hematopoietic Stem Cell Transplants in the United States, 2009 Number of Transplants Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2012. Available at: www.cibmtr.org

10. Trends in Transplants by Transplant Type and Recipient Age* 1989-2009 Transplants, % Allogeneic Transplants Autologous Transplants * Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2012. Available at: www.cibmtr.org

11. Reduction in Transplant-Related Mortality

12. Timing Matters Patients transplanted earlier in their disease have better outcomes than patients with advanced disease, regardless of the degree of match

13. Improved Survival inUnrelated Transplant Unadjusted one-year overall survival of NMDP transplant recipients after first allogeneic transplantation at U.S. transplant centers.

14. Summary • Patient selection is expanding – as outcomes improve and donor and cord blood registries grow, more patients have access to transplant • Timing matters – research shows that patients transplanted earlier in their disease have better outcomes than patients with advanced disease • Survival is improving – outcomes have improved due to a number of factors including changes in clinical practice and a better understanding of HLA typing and matching

15. Timely Referral Affects Survival Because disease stage at the time of transplant is the only factor under direct control of a physician, an early referral is perhaps the single most important step that can affect survival. Lee SJ, et al. Blood; 2007

16. Need for Transplantation without Transfusion • 1,200,000 Jehovah’s Witnesses in the USA • 240,000 Jehovah’s Witnesses in California • Strongly held religious beliefs that forbid blood transfusion • RBC • Platelets • Plasma • Use of some blood fractions is a matter for personal belief and interpretation • Not opposed to use of medical technology

17. Genesis 9:3 Every moving animal that is alive may serve as food for YOU.+ As in the case of green vegetation, I do give it all to YOU.+ 4 Only flesh with its soul*+—its blood+—YOU must not eat. Biblical Justification for Refusal of Blood Transfusion

18. Leviticus 17:10“‘As for any man of the house of Israel or some alien resident who is residing as an alien in yourmidst who eats any sort of blood,+ I shall certainly set my face against the soul+ that is eating the blood, and I shall indeed cut him* off from among his* people.11 For the soul of the flesh is in the blood,+ and I myself have put it upon the altar for YOU to make atonement+ for YOUR souls, because it is the blood+ that makes atonement+ by the soul [in it].* 12 That is why I have said to the sons of Israel: “No soul of YOU must eat blood and no alien resident who is residing as an alien in YOUR midst+ should eat blood.”+ Biblical Justification for Refusal of Blood Transfusion

19. Acts 15:20:  “. . . but to write them to abstain from things polluted by idols and from fornication and from what is strangled and from blood.” Acts 15:28, 29:“The holy spirit and we ourselves [the governing body of the Christian congregation] have favored adding no further burden to you, except these necessary things, to keep abstaining from things sacrificed to idols and from blood and from things strangled [or, killed without draining their blood] and from fornication. Scriptural basis for avoidance of blood products

20. Chemotherapy induced organ dysfunction Pancytopenia induced infection Bacterial Fungal Viral Immunesuppression Mucositis/colitis Graft versus host disease Acute and chronic Immunesuppressive drug complications Risks of Hematopoietic Stem Cell Transplantation

21. Anemia Insufficient O2 transportation Patients die with Hgb < 2gm/dl Experience from many patients with AML/MDS Thrombocytopenia bleeding Risks specific to lack of transfusion support for HSCT

22. O2 consumption in resting human is 200-250 ml/min Trained athletes can decrease O2 saturation of venous blood to 15% ie can remove almost, but not all, the O2 bound to Hgb Most of us can’t extract that much O2 from our blood Cardiac output can be increased approx 5 fold ie 5 L/min to 25 L/min But cardiac O2 consumption also increases with increased cardiac output Fever, rigors and shivering all increase O2 consumption significantly Each 1 degree rise may increase O2 consumption by 50 ml/min Oxygen Supply and Demand

23. Oxygen Carrying Capacity of Blood

24. Risk of bleeding was recognized by Gaydos et al in early 60s Pediatric patients with ALL Not good chemotherapy or antibiotics Common use of aspirin as antipyretic Platelet transfusions introduced at this time Concept of threshold and prophylactic use derived from Gaydos study Prophylactic threshold set to keep platelet count >20k Randomized studies in late 80s showed that threshold of 10k was as effective as 20k in preventing severe bleeding. Recent studies have addressed issue of prophylactic v therapeutic platelet transfusions Risk of Bleeding While Thrombocytopenic

25. Randomized study of prophylactic v therapeutic platelet transfusion 600 randomized No deaths due to bleeding 7/600 patients had grade III/IV bleeding 6/7 patients were in therapeutic group 5/7 patients with grade III/IV bleeding had platelets > 10k Stanworth et al, NEJM 2013 Risk of Grade III/IV Bleeding with severe thrombocytopenia

26. 396 patients with AML or having an autologous PBSCT randomized to prophylactic v therapeutic platelet transfusion 7/194 prophylactic v 21/197 therapeutic patients bled 7/7 prophylactic and 20/21 therapeutic bleeding patients had AML Autologous transplants had 0 v 1 bleed Wandt et al, Lancet, 2012 Risk of grade III/IV bleeding with severe thrombocytopenia

27. Risk is increased, but acceptable Somewhere around 1% risk of severe bleeding in autologous transplant setting Randomized studies are not completely generalizable Patients transfused when bleeding Patients often received prophylactic transfusions even when randomized to therapeutic Nevertheless, despite a slightly increased risk of potentially fatal bleeding, the 800 lb gorilla is always the disease for which a patient is receiving therapy Risk of thrombocytopenic bleeding without transfusions

28. Minimize blood loss Daily CBC not required (no intervention would happen) No blood draws from central lines (no flushing and disposal of first 10 cc) Use of “pediatric” microtainers and culture bottles Maximize O2 supply 100% high flow O2 when Hgb < 4 gm/dl Note that O2 saturation is irrelevant, dissolved plasma O2 becomes increasingly important Decrease O2 consumption Bed rest when Hgb < 6 gm/dl Prophylactic antibiotics Management of severe anemia in Jehovah’s Witnesses

29. Bed rest Antifibrinolytic therapy (amicar) No evidence for this, but this is our current practice Maximize CD34 stem cell dose Associated with increased chance of early engraftment Control symptoms eg nausea, vomiting, straining at stool, coughing, picking nose etc ? Start with higher platelet count Use of thrombopoietic agents? Management of severe thrombocytopenia in Jehovah’s Witnesses

30. Median Transfusions; Autologous Transplants 2011/12

31. Median Transfusions; Allogeneic Transplants 2011/12

32. Mean Transfusions; Allogeneic Transplants 2011/12

33. Start with normal Hgb level Anticipate a drop of 4-6 gm/dl Anticipate a fairly short time with platelets < 10k Antifibrinolytic therapy while platelets < 10k High dose ESA and IV Fe and folate pre and post transplant Federal regulations have now made it very difficult to administer ESA in the pretransplant setting Management of HSCT patients without transfusion support

34. Jehovah’s Witnesses with a standard indication for transplantation Initially on IRB approved protocols, most now transplanted as standard of care Informed consent process very detailed and explicit Use of Reduced Intensity Conditioning for allogeneic transplantation Avoidance of methotrexate for GVHD prophylaxis Causes delayed engraftment and mucositis Preferred use of PBPC for allogeneic transplantation Increased risk of chronic GVHD, but earlier engraftment Management of HSCT patients without transfusion support

35. Diagnosis Overview in Jehovah’s Witness Patients Autologous Transplant N = 42 Allogeneic Transplant N = 8 Total Patient Count: 50

36. Indication for Transplant in Jehovah’s Witness Patients

37. Average Count of CD34 x 10⁶ cells/kg Infused

38. Engraftment Definition Neutrophil engraftment ANC recovery is defined as an absolute neutrophil count (ANC) of ≥ 0.5 x 109/L (500/mm3) for three consecutive laboratory values obtained on different days. Date of ANC recovery is the date of the first of three consecutive laboratory values where the ANC is ≥ 0.5 x 109/L. Platelet engraftment The date reflects no platelet transfusions administered for seven consecutive days post HSCT. The date is the first of three consecutive laboratory values ≥ 20 x 109 L obtained on different days. Note; some patients never dropped below 20k. Time to engraftment was counted as 0 days. http://www.cibmtr.org/DataManagement/TrainingReference/Manuals/DataManagement/Documents/post-ted-instruction.pdf

39. Median Neutrophil Engraftment – Jehovah’s Witness v Non-Jehovah’s Witness Patients Mean and Median: in Days

40. Median PlateletEngraftment – Jehovah’s Witness v Non-Jehovah’s Witness Patients Mean and Median: in Days

41. Median Length of Stay – Jehovah’s Witnesses v Non Jehovah’s Witnesses Average Length of Stay: in Days

42. Survival – Jehovah’s Witness Patients

43. Outcomes of allogeneic transplantation without transfusion support

44. Outcomes no different than patients with transfusion support Average Length of Stay Mortality Potentially curative for otherwise fatal illnesses Allogeneic transplantation more difficult Induction chemotherapy for ALL feasible Induction chemotherapy for AML very difficult with almost universal death Patients should be referred early to a center with experience in management of these patients NCCN, ASBMT and NMDP all recommend early referral to transplant centers for many hematologic cancers HSCT transplantation without transfusion support

45. Possible addition of thrombopoietic agents Romiplostim etc Bridging therapies for patients with AML to decrease O2 consumption Intubation and ventilation? Decreasing body temperature? Barbiturate coma? Future steps

46. Nursing staff on 4SW Many guidelines developed by 4SW CNS, Sandra Rome Nursing staff in the Samuel Oschin Comprehensive Cancer Center Nursing and laboratory staff in transfusion medicine who collect and process hematopoietic stem cells Transplant coordinators who have educated and cared for all these patients Colleagues within the transplant program and transfusion medicine program Lorraine Alonzo, data manager Bloodless Transplant Program; Thanks to